bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the Glycoprotein Stable Signal Peptide in Mediating Pichinde Virus Replication and Virulence
Authors: Shao Junjie , Liu Xiaoying , Ly Hinh , Liang Yuying
Published: September 2016

Arenaviruses can cause lethal hemorrhagic fevers in humans with few preventative and therapeutic measures. The arenaviral glycoprotein stable signal peptide (SSP) is unique among signal peptides in that it is an integral component of the mature glycoprotein complex (GPC) and plays important roles not only in GPC expression and processing but also in the membrane fusion process during viral entry. Using the Pichinde virus (PICV) reverse genetics system, we analyzed the effects of alanine substitutions at many conserved residues within the SSP on viral replication in cell culture and in a guinea pig infection model. Our data showed that the K33A, F49A, and C57A mutations abolished GPC-mediated cell entry and therefore could not allow for the generation of viable recombinant viruses, demonstrating that these residues are essential for the PICV life cycle. The G2A mutation caused a marked reduction of cell entry at the membrane fusion step, and while this mutant virus was viable, it was significantly attenuated
in vitro
and
in vivo
. The N20A mutation also reduced membrane fusion activity and viral virulence in guinea pigs, but it did not significantly affect cell entry or viral growth in cell culture. Two other mutations (N37A and R55A) did not affect membrane fusion or viral growth
in vitro
but significantly reduced viral virulence
in vivo
. Taken together, our data suggest that the GPC SSP plays an essential role in mediating viral entry and also contributes to viral virulence
in vivo
.

IMPORTANCE
Several arenaviruses, such as Lassa fever virus, can cause severe and lethal hemorrhagic fever diseases with high mortality and morbidity, and no FDA-approved vaccines or therapies are currently available. Viral entry into cells is mediated by arenavirus GPC that consists of an SSP, the receptor-binding GP1, and transmembrane GP2 protein subunits. Using a reverse genetics system of a prototypic arenavirus, Pichinde virus (PICV), we have shown for the first time in the context of virus infections of cell culture and of guinea pigs that the SSP plays an essential role in mediating the membrane fusion step as well as in other yet-to-be-determined processes during viral infection. Our study provides important insights into the biological roles of GPC SSP and implicates it as a good target for the development of antivirals against deadly human arenavirus pathogens.
Herpes Simplex Virus 1 UL37 Protein Tyrosine Residues Conserved among All Alphaherpesviruses Are Required for Interactions with Glycoprotein K, Cytoplasmic Virion Envelopment, and Infectious Virus Production
Authors: Chouljenko Dmitry V. , Jambunathan Nithya , Chouljenko Vladimir N. , Naderi Misagh , Brylinski Michal , Caskey John R. , Kousoulas Konstantin G.
Published: September 2016

The herpes simplex virus 1 (HSV-1) UL37 protein functions in virion envelopment at
trans
-Golgi membranes, as well as in retrograde and anterograde transport of virion capsids. Recently, we reported that UL37 interacts with glycoprotein K (gK) and its interacting partner protein UL20 (N. Jambunathan, D. Chouljenko, P. Desai, A. S. Charles, R. Subramanian, V. N. Chouljenko, and K. G. Kousoulas, J Virol 88:5927–5935, 2014,
http://dx.doi.org/10.1128/JVI.00278-14
), facilitating cytoplasmic virion envelopment. Alignment of UL37 homologs encoded by alphaherpesviruses revealed the presence of highly conserved residues in the central portion of the UL37 protein. A cadre of nine UL37 site-specific mutations were produced and tested for their ability to inhibit virion envelopment and infectious virus production. Complementation analysis revealed that replacement of tyrosines 474 and 480 with alanine failed to complement the UL37-null virus, while all other mutated UL37 genes complemented the virus efficiently. The recombinant virus DC474-480 constructed with tyrosines 474, 476, 477, and 480 mutated to alanine residues produced a gK-null-like phenotype characterized by the production of very small plaques and accumulation of capsids in the cytoplasm of infected cells. Recombinant viruses having either tyrosine 476 or 477 replaced with alanine produced a wild-type phenotype. Immunoprecipitation assays revealed that replacement of all four tyrosines with alanines substantially reduced the ability of gK to interact with UL37. Alignment of HSV UL37 with the human cytomegalovirus and Epstein-Barr virus UL37 homologs revealed that Y480 was conserved only for alphaherpesviruses. Collectively, these results suggest that the UL37 conserved tyrosine 480 residue plays a crucial role in interactions with gK to facilitate cytoplasmic virion envelopment and infectious virus production.

IMPORTANCE
The HSV-1 UL37 protein is conserved among all herpesviruses, functions in both retrograde and anterograde transport of virion capsids, and plays critical roles in cytoplasmic virion envelopment by interacting with gK. We show here that UL37 tyrosine residues conserved among all alphaherpesviruses serve critical roles in cytoplasmic virion envelopment and interactions with gK.
Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001
Authors: Costa Matthew R. , Pollara Justin , Edwards Regina Whitney , Seaman Michael S. , Gorny Miroslaw K. , Montefiori David C. , Liao Hua-Xin , Ferrari Guido , Lu Shan , Wang Shixia
Published: September 2016

HIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design.

IMPORTANCE
The roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used.
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

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

HIV 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

We 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

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

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.
Paired suicide in a young refugee couple on the Thai-Myanmar border
Authors: Fellmeth Gracia , Oo May May , Lay Billion , McGready Rose
Published: September 2016

A young refugee woman attended antenatal clinic on the Thai-Myanmar border at 9 weeks' gestation. As part of an ongoing study of perinatal mental health, she underwent a structured psychiatric interview during which she described occasional depressed mood, anhedonia and passive suicidal ideation. Her husband was a young refugee known to use alcohol and drugs. 2 days later, the couple committed suicide together by herbicide ingestion. Refugee populations are at risk of developing mental disorders as a result of their marginalised status, socioeconomic disadvantage and exposures to trauma. Pregnancy may have exacerbated feelings of hopelessness in this couple. The prevalence of mental disorders such as depression is increased in the perinatal period and suicide is the second leading cause of death in young women globally. Prevention programmes and early recognition of mental disorders may improve detection and lead to better support for vulnerable individuals.
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

Objectives

The 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.

Methods

Data 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.

Results

Younger 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.

Conclusions

If 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

Introduction

Self-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.

Methods

This 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 dissemination

Ethical 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 number

ISRCTN76914248; 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

Background

Secondary 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.

Objectives

To conduct a systematic review of barriers and facilitators to adherence/persistence to secondary CVD prevention medications at health system level.

Methods

Included 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.

Results

Of 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.

Conclusions

High-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.
A new simplified method and its verification for calculation of consolidation settlement of a clayey soil with creep
Authors: Yin Jian-Hua , Feng Wei-Qiang
Published: September 2016

The calculation of the consolidation settlement of clayey soils with creep behaviour has been a challenging issue with a long history. After a brief review the assumptions made in the two methods based on Hypothesis A and Hypothesis B, the authors present a new simplified hypothesis B method for calculation of consolidation settlement of a clayey soil with creep. Equations of this method are derived based on the “equivalent time” concept for different stress–strain states. This simplified Hypothesis B method is then used to calculate the consolidation settlement of a number of typical consolidation problems. The approximation and verification of this simplified method are examined by comparing the calculated settlements with settlements computed using two fully coupled finite element (FE) consolidation analysis programs using elastic viscoplastic (EVP) constitutive models (Hypothesis B) and the Hypothesis A method. It is found that the curves calculated using the new Hypothesis B simplified method with a factor α = 0.8 are close to curves from two FE model simulations with relative errors in the range 0.37%∼8.42% only for three layers of Hong Kong marine clay (HKMC). In overall, the settlements calculated using Hypothesis A method are smaller than those from the two FE simulations with relative error in the range 6.52%∼46.17% for the three layers of HKMC. In addition, this new simplified Hypothesis B method is used to calculate the average strain of consolidation tests done by Berre and Iversen in 1972. The calculated results are compared with the test data, and values from a fully coupled finite difference (FD) consolidation analysis using Yin and Graham’s EVP constitutive model (Hypothesis B), and Hypothesis A method. It is found that, again, the results from the new simplified Hypothesis B method are very close to the measured data. In conclusion, the new simplified Hypothesis B method is a suitable simple method, by spread-sheet calculation of the consolidation settlement of a single layer of a clayey soil with creep.
Availability of holding habitat in lakes and rivers affects the incidence of spring (premature) upriver migration by Atlantic salmon
Authors: Reed Thomas E. , de Eyto Elvira , O’Higgins Kealan , Gargan Paddy , Roche William , White Jonathan , O’Maoileidigh Niall , Quinn Thomas P. , McGinnity Phil
Published: September 2016

Premature migration is a key component of the biocomplexity of anadromous fishes, yet remains poorly understood. Many Atlantic salmon (Salmo salar) populations leave the ocean in spring, months prior to spawning, though this curtails feeding in productive marine environments. We hypothesized that habitat features encourage the evolution of this trait by providing fish with physical and thermal refuge during their long freshwater holding period. We document substantial variation in Atlantic salmon return-migration timing across 70 Irish rivers using 8 years of angling data, validated with electronic-counter data from 23 of the rivers. A higher frequency of spring migrating salmon was observed in rivers with accessible lakes and larger rivers in general. Spring migration may have evolved in rivers with suitable holding habitat as a strategy to minimize cumulative marine mortality, which is traded off against additional marine feeding. More research on this neglected topic is needed, given the value of large spring migrating Atlantic salmon to anglers, ongoing declines in their abundance in Ireland and elsewhere, and the widespread occurrence of premature migration in salmonids generally.
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.
Magnolia officinalis L. Fortified Gum Improves Resistance of Oral Epithelial Cells Against Inflammation
Authors: Walker Jessica , Imboeck Julia Maria , Walker Joel Michael , Maitra Amarnath , Haririan Hady , Rausch-Fan Xiaohui , Dodds Michael , Inui Taichi , Somoza Veronika
Published: September 2016

Inflammatory diseases of the periodontal tissues are known health problems worldwide. Therefore, anti-inflammatory active compounds are used in oral care products to reduce long-term inflammation. In addition to inducing inflammation, pathogen attack leads to an increased production of reactive oxygen species (ROS), which may lead to oxidative damage of macromolecules. Magnolia officinalis L. bark extract (MBE) has been shown to possess antioxidant and anti-inflammatory potential in vitro. In the present study, the influence of MBE-fortified chewing gum on the resistance against lipopolysaccharide (LPS)-induced inflammation and oxidative stress of oral epithelial cells was investigated in a four-armed parallel designed human intervention trial with 40 healthy volunteers. Ex vivo stimulation of oral epithelial cells with LPS from Porphyromonas gingivalis for 6[Formula: see text]h increased the mRNA expression and release of the pro-inflammatory cytokines IL-1[Formula: see text], IL-[Formula: see text], IL-8, MIP-1[Formula: see text], and TNF[Formula: see text]. Chewing MBE-fortified gum for 10[Formula: see text]min reduced the ex vivo LPS-induced increase of IL-8 release by 43.8 [Formula: see text] 17.1% at the beginning of the intervention. In addition, after the two-week intervention with MBE-fortified chewing gum, LPS-stimulated TNF[Formula: see text] release was attenuated by 73.4 [Formula: see text] 12.0% compared to chewing regular control gum. This increased resistance against LPS-induced inflammation suggests that MBE possesses anti-inflammatory activity in vivo when added to chewing gum. In contrast, the conditions used to stimulate an immune response of oral epithelial cells failed to induce oxidative stress, measured by catalase activity, or oxidative DNA damage.
Low-frequency and tuning characteristic of band gap in a symmetrical double-sided locally resonant phononic crystal plate with slit structure
Authors: Wang X. P. , Jiang P. , Song A. L.
Published: September 2016

In this paper, the low-frequency and tuning characteristic of band gap in a two-dimensional phononic crystal structure, consisting of a square array of aluminum cylindrical stubs deposited on both sides of a thin rubber plate with slit structure, are investigated. Using the finite element method, the dispersion relationships and power transmission spectra of this structure are calculated. In contrast to a typical phononic crystal without slit structure, the proposed slit structure shows band gaps at lower frequencies. The vibration modes of the band gap edges are analyzed to clarify the mechanism of the lowest band gaps. Additionally, the influence of the slit parameters and stub parameters on the band gaps in slit structure are investigated. The geometrical parameters of the slits and stubs were found to influence the band gaps; this is critical to understand for practical applications. These results will help in fabricating phononic crystal structures whose band frequency can be modulated at lower frequencies.
Performance of turbulence models for transonic flows in a diffuser
Authors: Liu Yangwei , Wu Jianuo , Lu Lipeng
Published: September 2016

Eight turbulence models frequently used in aerodynamics have been employed in the detailed numerical investigations for transonic flows in the Sajben diffuser, to assess the predictive capabilities of the turbulence models for shock wave/turbulent boundary layer interactions (SWTBLI) in internal flows. The eight turbulence models include: the Spalart–Allmaras model, the standard [Formula: see text] model, the RNG [Formula: see text] model, the realizable [Formula: see text] model, the standard [Formula: see text] model, the SST [Formula: see text] model, the [Formula: see text] model and the Reynolds stress model. The performance of the different turbulence models adopted has been systematically assessed by comparing the numerical results with the available experimental data. The comparisons show that the predictive performance becomes worse as the shock wave becomes stronger. The [Formula: see text] model and the SST [Formula: see text] model perform much better than other models, and the SST [Formula: see text] model predicts a little better than the [Formula: see text] model for pressure on walls and velocity profile, whereas the [Formula: see text] model predicts a little better than the SST [Formula: see text] model for separation location, reattachment location and separation length for strong shock case.
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.
New mechanism of acceleration of particles by stellar black holes
Authors: Osmanov Zaza
Published: September 2016

In this paper, we study the efficiency of particle acceleration in the magnetospheres of stellar mass black holes. For this purpose, we consider the linearized set of the Euler equation, continuity equation and Poisson equation, respectively. After introducing the varying relativistic centrifugal force, we show that the charge separation undergoes the parametric instability, leading to generation of centrifugally-excited Langmuir waves. It is shown that these waves, via the Langmuir collapse damp by means of the Landau damping, as a result, energy transfers to particles accelerating them to energies of the order of [Formula: see text] eV.
UNCERTAINTIES OF IMPACT CONFIGURATION FOR NUMERICAL REPLICATIONS OF REAL-WORLD TRAUMA: A FE ANALYSIS
Authors: BODO MICHÈLE , ROTH SÉBASTIEN
Published: September 2016

This study deals with free fall accident analysis involving adults, and their numerical replications using a finite element model of the human thorax. The main purpose is to determine the role of body position at impact in the thorax injury risk appearance. For this study, cases of real-world free-fall provided by an emergency department were selected and investigated. These cases involved both male and female with an age range of 20 to 63 years, who sustained accidental free-fall with both injured and uninjured cases. The examination of the patients' medical record provided helpful information to accurately perform numerical replications with the finite element model HUByx (Hermaphrodite Universal Biomechanical yx model) which was already validated for various experimental tests in the field of automobile, ballistic impacts and blast. The results of simulations at different impact location allowed highlighting the crucial influence of the body orientation in the risk of thoracic injury occurrence.
SM22α inhibits lamellipodium formation and migration via Ras-Arp2/3 signaling in synthetic VSMCs
Authors: Lv Pin , Zhang Fan , Yin Ya-Juan , Wang Yu-Can , Gao Min , Xie Xiao-Li , Zhao Li-Li , Dong Li-Hua , Lin Yan-Ling , Shu Ya-Nan , Zhang Dan-Dan , Liu Gui-Xia , Han Mei
Published: September 2016

We previously demonstrated that smooth muscle (SM) 22α promotes the migration activity in contractile vascular smooth muscle cells (VSMCs). Based on the varied functions exhibited by SM22α in different VSMC phenotypes, we investigated the effect of SM22α on VSMC migration under pathological conditions. The results demonstrated that SM22α overexpression in synthetic VSMCs inhibited platelet-derived growth factor (PDGF)-BB-induced cell lamellipodium formation and migration, which was different from its action in contractile cells. The results indicated two distinct mechanisms underlying inhibition of lamellipodium formation by SM22α, increased actin dynamic stability and decreased Ras activity via interference with interactions between Ras and guanine nucleotide exchange factor. The former inhibited actin cytoskeleton rearrangement in the cell cortex, while the latter significantly disrupted actin nucleation activation of the Arp2/3 complex. Baicalin, a herb-derived flavonoid compound, inhibited VSMC migration via upregulation of SM22α expression in vitro and in vivo. These data suggest that SM22α regulates lamellipodium formation and cell migration in a phenotype-dependent manner in VSMCs, which may be a new therapeutic target for vascular lesion formation.
Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat
Authors: Johnson Miranda D. , Bouret Sebastien G. , Dunn-Meynell Ambrose A. , Boyle Christina N. , Lutz Thomas A. , Levin Barry E.
Published: September 2016

Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0–6 and from P0–16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0–16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development.