bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Immunogenicity of a Parenterally Administered, Structure-Based Rationally Modified Recombinant Staphylococcal Enterotoxin B Protein Vaccine, STEBVax
Authors: Chen Wilbur H. , Pasetti Marcela F. , Adhikari Rajan P. , Baughman Holly , Douglas Robin , El-Khorazaty Jill , Greenberg Nancy , Holtsberg Frederick W. , Liao Grant C. , Reymann Mardi K. , Wang Xiaolin , Warfield Kelly L. , Aman M. Javad 
Published: October 2016

ABSTRACT

Staphylococcus aureus
produces several enterotoxins and superantigens, exposure to which can elicit profound toxic shock. A recombinant staphylococcal enterotoxin B (rSEB) containing 3 distinct mutations in the major histocompatibility complex class II binding site was combined with an alum adjuvant (Alhydrogel) and used as a potential parenteral vaccine named STEBVax. Consenting healthy adult volunteers (age range, 23 to 38 years) participated in a first-in-human open-label dose escalation study of parenteral doses of STEBVax ranging from 0.01 μg up to 20 μg. Safety was assessed by determination of the frequency of adverse events and reactogenicity. Immune responses to the vaccination were determined by measurement of anti-staphylococcal enterotoxin B (anti-SEB) IgG by enzyme-linked immunosorbent assay and a toxin neutralization assay (TNA). Twenty-eight participants were enrolled in 7 dosing cohorts. All doses were well tolerated. The participants exhibited heterogeneous baseline antibody titers. More seroconversions and a faster onset of serum anti-SEB IgG toxin-neutralizing antibodies were observed by TNA with increasing doses of STEBVax. There was a trend for a plateau in antibody responses with doses of STEBVax of between 2.5 and 20 μg. Among the participants vaccinated with 2.5 μg to 20 μg of STEBVax, ∼93% seroconverted for SEB toxin-neutralizing antibody. A strong correlation between individual SEB-specific serum IgG antibody titers and the neutralization of gamma interferon production was found
in vitro
. STEBvax appeared to be safe and immunogenic, inducing functional toxin-neutralizing antibodies. These data support its continued clinical development. (This study has been registered at ClinicalTrials.gov under registration no. NCT00974935.)
The Intracellular Cholesterol Transport Inhibitor U18666A Inhibits the Exosome-Dependent Release of Mature Hepatitis C Virus
Authors: Elgner Fabian , Ren Huimei , Medvedev Regina , Ploen Daniela , Himmelsbach Kiyoshi , Boller Klaus , Hildt Eberhard 
Published: October 2016

ABSTRACT

Hepatitis C virus (HCV) particles are described as lipoviroparticles which are released similarly to very-low-density lipoproteins (VLDLs). However, the release mechanism is still poorly understood; the canonical endoplasmic reticulum-Golgi intermediate compartment (ERGIC) pathway as well as endosome-dependent release has been proposed. Recently, the role of exosomes in the transmission of HCV has been reported. Only a minor fraction of the
de novo
-synthesized lipoviroparticles is released by the infected cell. To investigate the relevance of multivesicular bodies (MVBs) for viral morphogenesis and release, the MVB inhibitor U18666A was used. Intracellular trafficking was analyzed by confocal microscopy and electron microscopy. Moreover, an mCherry-tagged HCV variant was used. Conditions were established that enable U18666A-dependent inhibition of MVBs without affecting viral replication. Under these conditions, significant inhibition of the HCV release was observed. The assembly of viral particles is not affected. In U18666A-treated cells, intact infectious viral particles accumulate in CD63-positive exosomal structures and large dysfunctional lysosomal structures (multilamellar bodies). These retained particles possess a lower density, reflecting a misloading with lipids. Our data indicate that at least a fraction of HCV particles leaves the cell via the endosomal pathway. Endosomes facilitate the sorting of HCV particles for release or degradation.

IMPORTANCE
There are still a variety of open questions regarding morphogenesis and release of hepatitis C virus. The HCV-infected cell produces significant more viral particles that are released, raising the question about the fate of the nonreleased particles. Moreover, the relevance of the endosomal pathway for the release of HCV is under debate. Use of the MVB (multivesicular body) inhibitor U18666A enabled a detailed analysis of the impact of MVBs for viral morphogenesis and release. It was revealed that infectious, fully assembled HCV particles are either MVB-dependently released or intracellularly degraded by the lysosome. Our data indicate that at least a fraction of HCV particles leaves the cell via the endosomal pathway independent from the constitutive secretory pathway. Our study describes a so-far-unprecedented cross talk between two pathways regulating on the one hand the release of infectious viral particles and on the other hand the intracellular degradation of nonreleased particles.
Repression of the Chromatin-Tethering Domain of Murine Leukemia Virus p12
Authors: Brzezinski Jonathon D. , Modi Apexa , Liu Mengdan , Roth Monica J. 
Published: October 2016

ABSTRACT

Murine leukemia virus (MLV) p12, encoded within Gag, binds the viral preintegration complex (PIC) to the mitotic chromatin. This acts to anchor the viral PIC in the nucleus as the nuclear envelope re-forms postmitosis. Mutations within the p12 C terminus (p12 PM13 to PM15) block early stages in viral replication. Within the p12 PM13 region (p12
60
PSPMA
65
), our studies indicated that chromatin tethering was not detected when the wild-type (WT) p12 protein (M63) was expressed as a green fluorescent protein (GFP) fusion; however, constructs bearing p12-I63 were tethered. N-terminal truncations of the activated p12-I63-GFP indicated that tethering increased further upon deletion of p12
25
DLLTEDPPPY
34
, which includes the late domain required for viral assembly. The p12 PM15 sequence (p12
70
RREPP
74
) is critical for wild-type viral viability; however, virions bearing the PM15 mutation (p12
70
AAAAA
74
) with a second M63I mutant were viable, with a titer 18-fold lower than that of the WT. The p12 M63I mutation amplified chromatin tethering and compensated for the loss of chromatin binding of p12 PM15. Rescue of the p12-M63-PM15 nonviable mutant with prototype foamy virus (PFV) and Kaposi's sarcoma herpesvirus (KSHV) tethering sequences confirmed the function of p12
70–74
in chromatin binding. Minimally, full-strength tethering was seen with only p12
61
SPIASRLRGRR
71
fused to GFP. These results indicate that the p12 C terminus alone is sufficient for chromatin binding and that the presence of the p12
25
DLLTEDPPPY
34
motif in the N terminus suppresses the ability to tether.

IMPORTANCE
This study defines a regulatory mechanism controlling the differential roles of the MLV p12 protein in early and late replication. During viral assembly and egress, the late domain within the p12 N terminus functions to bind host vesicle release factors. During viral entry, the C terminus of p12 is required for tethering to host mitotic chromosomes. Our studies indicate that the p12 domain including the PPPY late sequence temporally represses the p12 chromatin tethering motif. Maximal p12 tethering was identified with only an 11-amino-acid minimal chromatin tethering motif encoded at p12
61–71
. Within this region, the p12-M63I substitution switches p12 into a tethering-competent state, partially rescuing the p12-PM15 tethering mutant. A model for how this conformational change regulates early versus late functions is presented.
Protective Capacity of the Human Anamnestic Antibody Response during Acute Dengue Virus Infection
Authors: Xu Meihui , Züst Roland , Toh Ying Xiu , Pfaff Jennifer M. , Kahle Kristen M. , Davidson Edgar , Doranz Benjamin J. , Velumani Sumathy , Tukijan Farhana , Wang Cheng-I , Fink Katja 
Published: October 2016

ABSTRACT

Half of the world's population is exposed to the risk of dengue virus infection. Although a vaccine for dengue virus is now available in a few countries, its reported overall efficacy of about 60% is not ideal. Protective immune correlates following natural dengue virus infection remain undefined, which makes it difficult to predict the efficacy of new vaccines. In this study, we address the protective capacity of dengue virus-specific antibodies that are produced by plasmablasts a few days after natural secondary infection. Among a panel of 18 dengue virus-reactive human monoclonal antibodies, four groups of antibodies were identified based on their binding properties. While antibodies targeting the fusion loop of the glycoprotein of dengue virus dominated the antibody response, two smaller groups of antibodies bound to previously undescribed epitopes in domain II of the E protein. The latter, largely serotype-cross-reactive antibodies, demonstrated increased stability of binding at pH 5. These antibodies possessed weak to moderate neutralization capacity
in vitro
but were the most efficacious in promoting the survival of infected mice. Our data suggest that the cross-reactive anamnestic antibody response has a protective capacity despite moderate neutralization
in vitro
and a moderate decrease of viremia
in vivo
.

IMPORTANCE
Antibodies can protect from symptomatic dengue virus infection. However, it is not easy to assess which classes of antibodies provide protection because
in vitro
assays are not always predictive of
in vivo
protection. During a repeat infection, dengue virus-specific immune memory cells are reactivated and large amounts of antibodies are produced. By studying antibodies cloned from patients with heterologous secondary infection, we tested the protective value of the serotype-cross-reactive “recall” or “anamnestic” response. We found that results from
in vitro
neutralization assays did not always correlate with the ability of the antibodies to reduce viremia in a mouse model. In addition, a decrease of viremia in mice did not necessarily improve survival. The most protective antibodies were stable at pH 5, suggesting that antibody binding in the endosomes, after the antibody-virus complex is internalized, might be important to block virus spread in the organism.
Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus
Authors: Okubo Yu , Uchida Hiroaki , Wakata Aika , Suzuki Takuma , Shibata Tomoko , Ikeda Hitomi , Yamaguchi Miki , Cohen Justus B. , Glorioso Joseph C. , Tagaya Mitsuo , Hamada Hirofumi , Tahara Hideaki 
Published: October 2016

ABSTRACT
Membrane fusion, which is the key process for both initial cell entry and subsequent lateral spread of herpes simplex virus (HSV), requires the four envelope glycoproteins gB, gD, gH, and gL. Syncytial mutations, predominantly mapped to the gB and gK genes, confer hyperfusogenicity on HSV and cause multinucleated giant cells, termed syncytia. Here we asked whether interaction of gD with a cognate entry receptor remains indispensable for initiating membrane fusion of syncytial strains. To address this question, we took advantage of mutant viruses whose viral entry into cells relies on the uniquely specific interaction of an engineered gD with epidermal growth factor receptor (EGFR). We introduced selected syncytial mutations into gB and/or gK of the EGFR-retargeted HSV and found that these mutations, especially when combined, enabled formation of extensive syncytia by human cancer cell lines that express the target receptor; these syncytia were substantially larger than the plaques formed by the parental retargeted HSV strain. We assessed the EGFR dependence of entry and spread separately by using direct entry and infectious center assays, respectively, and we found that the syncytial mutations did not override the receptor specificity of the retargeted viruses at either stage. We discuss the implications of these results for the development of more effective targeted oncolytic HSV vectors.

IMPORTANCE
Herpes simplex virus (HSV) is investigated not only as a human pathogen but also as a promising agent for oncolytic virotherapy. We previously showed that both the initial entry and subsequent lateral spread of HSV can be retargeted to cells expressing tumor-associated antigens by single-chain antibodies fused to a receptor-binding-deficient envelope glycoprotein D (gD). Here we introduced syncytial mutations into the gB and/or gK gene of gD-retargeted HSVs to determine whether viral tropism remained dependent on the interaction of gD with the target receptor. Entry and spread profiles of the recombinant viruses indicated that gD retargeting does not abolish the hyperfusogenic activity of syncytial mutations and that these mutations do not eliminate the dependence of HSV entry and spread on a specific gD-receptor interaction. These observations suggest that syncytial mutations may be valuable for increasing the tumor-specific spreading of retargeted oncolytic HSV vectors.
Physical activity and exercise for erectile dysfunction: systematic review and meta-analysis
Authors: Silva André B , Sousa Nelson , Azevedo Luís F , Martins Carlos 
Published: October 2016

BackgroundA growing body of evidence suggests that physical activity and exercise may improve erectile function.ObjectiveTo conduct a systematic review and meta-analysis evaluating the effects of physical activity modalities and exercise on erectile function in erectile dysfunction trials.MethodsA systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement. We searched 6 electronic databases between January 1990 and July 2016 and hand-searched reference lists for randomised controlled trials. Only patients with a diagnosis of erectile dysfunction were included. The mean differences between intervention and control groups were calculated for meta-analysis.Results7 studies were eligible, including 478 participants allocated to aerobic, pelvic or combined exercise interventions. Follow-up ranged from 8 weeks to 2 years. The risk of bias in the trials was deemed moderate to high mainly due to impossible blinding of patients and personnel, as well as questionable blinding of outcome assessors. Random-effects meta-analyses were performed. Pooled data showed a statistically significant improvement in erectile function score (mean difference 3.85, 95% CI 2.33 to 5.37). A benefit was still demonstrable after a sensitivity analysis because the mean difference in International Index of Erectile Function (IIEF) score ranged from 3.39 (95% CI 1.92 to 4.87) to 4.28 (95% CI 2.54 to 6.02). A benefit was also detected in short-term and long-term interventions as well as in trials evaluating physical activity and exercise alone or in addition to usual care.ConclusionsThe present study suggests that physical activity and exercise interventions improve patient-reported erectile dysfunction, particularly aerobic exercise with moderate-to-vigorous intensity.
Toxoplasma gondiiseroprevalence in the Portuguese population: comparison of three cross-sectional studies spanning three decades
Authors: Gargaté Maria João , Ferreira Idalina , Vilares Anabela , Martins Susana , Cardoso Carlos , Silva Susana , Nunes Baltazar , Gomes João Paulo 
Published: October 2016

BackgroundToxoplasma gondiiis an obligate intracellular protozoan infecting up to one-third of the world's population, constituting a life threat if transmitted from mother to child during pregnancy. In Portugal, there is a lack of knowledge of the current epidemiological situation, as the unique toxoplasmosis National Serological Survey was performed in 1979/1980.MethodsWe studied the seroprevalence trends in the Portuguese general population over the past 3 decades, by assessing chronological spread cross-sectional studies, with special focus on women of childbearing age, by age group, region and gender.ResultsTheT. gondiioverall seroprevalence decreased from 47% in 1979/1980 to 22% (95% CI 20% to 24%) in 2013. Generally, we observed that the prevalence ofT. gondiiIgG increased significantly with age and it decreased over time, both in the general population and in the childbearing women (18% prevalence in 2013).ConclusionsThe scenario observed for the latter indicates that more than 80% of childbearing women are susceptible to primary infection yielding a risk of congenital toxoplasmosis and respective sequelae. Since there is no vaccine to prevent human toxoplasmosis, the improvement of primary prevention constitutes a major tool to avoid infection in such susceptible groups.
IMproved exercise tolerance in patients with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation rationale and design of the IMPRESS-AF randomised controlled trial
Authors: Shantsila Eduard , Haynes Ronnie , Calvert Melanie , Fisher James , Kirchhof Paulus , Gill Paramjit S , Lip Gregory Y H 
Published: October 2016

IntroductionPatients with atrial fibrillation frequently suffer from heart failure with preserved ejection fraction. At present there is no proven therapy to improve physical capacity and quality of life in participants with permanent atrial fibrillation with preserved left ventricular contractility.ObjectiveThe single-centre IMproved exercise tolerance In heart failure With PReserved Ejection fraction by Spironolactone On myocardial fibrosiS In Atrial Fibrillation (IMPRESS-AF) trial aims to establish whether treatment with spironolactone as compared with placebo improves exercise tolerance (cardiopulmonary exercise testing), quality of life and diastolic function in patients with permanent atrial fibrillation.Methods and analysisA total of 250 patients have been randomised in this double-blinded trial for 2-year treatment with 25 mg daily dose of spironolactone or matched placebo. Included participants are 50 years old or older, have permanent atrial fibrillation and ejection fraction >55%. Exclusion criteria include contraindications to spironolactone, poorly controlled hypertension and presence of severe comorbidities with life expectancy <2 years. The primary outcome is improvement in exercise tolerance at 2 years and key secondary outcomes include quality of life (assessed using the EuroQol EQ-5D-5L (EQ-5D) and Minnesota Living with Heart Failure (MLWHF) questionnaires), diastolic function and all-cause hospitalisation.Ethics and disseminationThe study has been approved by the National Research and Ethics Committee West Midlands—Coventry and Warwickshire (REC reference number 14/WM/1211). The results of the trial will be published in an international peer-reviewed journal.Trial registration numbersEudraCT2014-003702-33;NCT02673463; Pre-results.
Readmissions and mortality in delirious versus non-delirious octogenarian patients after aortic valve therapy: a prospective cohort study
Authors: Eide Leslie S P , Ranhoff Anette H , Fridlund Bengt , Haaverstad Rune , Hufthammer Karl Ove , Kuiper Karel K J , Nordrehaug Jan Erik , Norekvål Tone M 
Published: October 2016

ObjectivesTo determine whether postoperative delirium predicts first-time readmissions and mortality in octogenarian patients within 180 days after aortic valve therapy with surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI), and to determine the most common diagnoses at readmission.DesignProspective cohort study of patients undergoing elective SAVR or TAVI.SettingTertiary university hospital that performs all SAVRs and TAVIs in Western Norway.ParticipantsPatients 80+ years scheduled for SAVR or TAVI and willing to participate in the study were eligible. Those unable to speak Norwegian were excluded. Overall, 143 patients were included, and data from 136 are presented.Primary and secondary outcome measuresThe primary outcome was a composite variable of time from discharge to first all-cause readmission or death. Secondary outcomes were all-cause first readmission alone and mortality within 180 days after discharge, and the primary diagnosis at discharge from first-time readmission. Delirium was assessed with the confusion assessment method. First-time readmissions, diagnoses and mortality were identified in hospital information registries.ResultsDelirium was identified in 56% of patients. The effect of delirium on readmissions and mortality was greatest during the first 2 months after discharge (adjusted HR 2.9 (95% CI 1.5 to 5.7)). Of 30 first-time readmissions occurring within 30 days, 24 (80%) were patients who experienced delirium. 1 patient (non-delirium group) died within 30 days after therapy. Delirious patients comprised 35 (64%) of 55 first-time readmissions occurring within 180 days. Circulatory system diseases and injuries were common causes of first-time readmissions within 180 days in delirious patients. 8 patients died 180 days after the procedure; 6 (75%) of them experienced delirium.ConclusionsDelirium in octogenarians after aortic valve therapy might be a serious risk factor for postoperative morbidity and mortality. Cardiovascular disorders and injuries were associated with first-time readmissions in these patients.
Integration of palliative and supportive care in the management of advanced liver disease: development and evaluation of a prognostic screening tool and supportive care intervention
Authors: Hudson Benjamin E , Ameneshoa Kelly , Gopfert Anya , Goddard Rachael , Forbes Karen , Verne Julia , Collins Peter , Gordon Fiona , Portal Andrew J , Reid Colette , McCune C Anne 
Published: October 2016

Background and objectivesPatients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life-limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention.DesignClinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. ‘Plan-Do-Study-Act’ (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention.Results73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poor-prognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with decompensated cirrhosis, with the supportive care intervention (developed simultaneously) instigated for appropriate patients.ConclusionsWe describe a model of care which identifies inpatients with cirrhosis at significant risk of dying over the coming year, and describe development of a supportive care intervention, which can be offered to suitable patients in parallel to ongoing active management.