bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Single Dose of an Avian H3N8 Influenza Virus Vaccine Is Highly Immunogenic and Efficacious against a Recently Emerged Seal Influenza Virus in Mice and Ferrets
Authors: Baz Mariana , Paskel Myeisha , Matsuoka Yumiko , Zengel James R. , Cheng Xing , Treanor John J. , Jin Hong , Subbarao Kanta 
Published: April 2015

ABSTRACTH3N8 influenza viruses are a commonly found subtype in wild birds, usually causing mild or no disease in infected birds. However, they have crossed the species barrier and have been associated with outbreaks in dogs, pigs, donkeys, and seals and therefore pose a threat to humans. A live attenuated, cold-adapted (ca) H3N8 vaccine virus was generated by reverse genetics using the wild-type (wt) hemagglutinin (HA) and neuraminidase (NA) genes from the A/blue-winged teal/Texas/Sg-00079/2007 (H3N8) (tl/TX/079/07) wt virus and the six internal protein gene segments from thecainfluenza A virus vaccine donor strain, A/Ann Arbor/6/60ca(H2N2), the backbone of the licensed seasonal live attenuated influenza vaccine. One dose of the tl/TX/079/07cavaccine induced a robust neutralizing antibody response against the homologous (tl/TX/079/07) and two heterologous influenza viruses, including the recently emerged A/harbor seal/New Hampshire/179629/2011 (H3N8) and A/northern pintail/Alaska/44228-129/2006 (H3N8) viruses, and conferred robust protection against the homologous and heterologous influenza viruses. We also analyzed human sera against the tl/TX/079/07 H3N8 avian influenza virus and observed low but detectable antibody reactivity in elderly subjects, suggesting that older H3N2 influenza viruses confer some cross-reactive antibody. The latter observation was confirmed in a ferret study. The safety, immunogenicity, and efficacy of the tl/TX/079/07cavaccine in mice and ferrets support further evaluation of this vaccine in humans for use in the event of transmission of an H3N8 avian influenza virus to humans. The human and ferret serology data suggest that a single dose of the vaccine may be sufficient in older subjects.IMPORTANCEAlthough natural infection of humans with an avian H3N8 influenza virus has not yet been reported, this influenza virus subtype has already crossed the species barrier and productively infected mammals. Pandemic preparedness is an important public health priority. Therefore, we generated a live attenuated avian H3N8 vaccine candidate and demonstrated that a single dose of the vaccine was highly immunogenic and protected mice and ferrets against homologous and heterologous H3N8 avian viruses.
Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells
Authors: Li Xiao-Jun , Liu Xi-Juan , Yang Bo , Fu Ya-Ru , Zhao Fei , Shen Zhang-Zhou , Miao Ling-Feng , Rayner Simon , Chavanas Stéphane , Zhu Hua , Britt William J. , Tang Qiyi , McVoy Michael A. , Luo Min-Hua 
Published: April 2015

ABSTRACTHuman cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell developmentin vitro. Similar eventsin vivomay be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain.IMPORTANCECongenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.
Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein
Authors: McGinnes Cullen Lori , Schmidt Madelyn R. , Kenward Sarah A. , Woodland Robert T. , Morrison Trudy G. 
Published: April 2015

ABSTRACT
Virus-like particles (VLPs) built on the Newcastle disease virus (NDV) core proteins, NP and M, and containing two chimeric proteins, F/F and H/G, composed of respiratory syncytial virus (RSV) fusion protein (F) and glycoprotein (G) ectodomains fused to the transmembrane and cytoplasmic domains of the NDV F and HN proteins, respectively, stimulate durable, protective RSV neutralizing antibodies in mice. Here, we report the properties of VLPs constructed to contain mutant RSV F protein ectodomains stabilized in prefusion (pre-F/F) or postfusion (post-F/F) configurations. The structures of the chimeric proteins assembled into VLPs were verified immunologically by their reactivities with a conformationally restricted anti-F protein monoclonal antibody. Following immunization of mice, without adjuvant, pre-F/F-containing VLPs induced significantly higher neutralizing antibody titers than the post-F/F-containing VLPs or the wild-type F/F-containing VLPs after a single immunization but not after prime and boost immunization. The specificities of anti-F IgG induced by the two mutant VLPs were assessed by enzyme-linked immunosorbent assay (ELISA) using soluble forms of the prefusion and postfusion forms of the F protein as targets. While both types of VLPs stimulated similar levels of IgG specific for the soluble postfusion F protein, titers of IgG specific for prefusion F induced by the pre-F/F-containing VLPs were higher than those induced by post-F/F-containing VLPs. Thus, VLPs containing a stabilized prefusion form of the RSV F protein represent a promising RSV vaccine candidate.

IMPORTANCE
The development of vaccines for respiratory syncytial virus has been hampered by a lack of understanding of the requirements for eliciting high titers of neutralizing antibodies. The results of this study suggest that particle-associated RSV F protein containing mutations that stabilize the structure in a prefusion conformation may stimulate higher titers of protective antibodies than particles containing F protein in a wild-type or postfusion conformation. These findings indicate that the prefusion F protein assembled into VLPs has the potential to produce a successful RSV vaccine candidate.
Studies on the Contribution of Human Cytomegalovirus UL21a and UL97 to Viral Growth and Inactivation of the Anaphase-Promoting Complex/Cyclosome (APC/C) E3 Ubiquitin Ligase Reveal a Unique Cellular Mechanism for Downmodulation of the APC/C Subunits APC1, APC4, and APC5
Authors: Clark Elizabeth , Spector Deborah H. 
Published: April 2015

ABSTRACT

Human cytomegalovirus (HCMV) deregulates the cell cycle by several means, including inactivation of the
a
naphase-
p
romoting
c
omplex/
c
yclosome (APC/C) E3 ubiquitin ligase. Viral proteins UL97 and UL21a, respectively, affect the APC/C by phosphorylation of APC/C coactivator Cdh1 and by inducing the degradation of subunits APC4 and APC5, which along with APC1 form the APC/C platform subcomplex. The aim of this study was to further characterize the mechanism of APC/C inactivation and define the relative contributions of UL21a and UL97 to APC/C substrate accumulation and to viral growth. We show that in uninfected cells, UL21a but not UL97 can disrupt APC/C function, leading to the accumulation of substrates. We find that UL21a is necessary and sufficient to induce the degradation of APC1, in addition to the previously reported APC4 and APC5. We also demonstrate that there is a previously unreported cellular mechanism for a specific decrease in the levels of all three platform subunits, APC1, APC4, and APC5, upon the depletion of any one of these subunits or of subunit APC8. Finally, we show that at a low multiplicity of infection, either UL97 or UL21a can partially complement a growth-defective mutant virus lacking both UL21a and UL97, with significantly greater benefit afforded by the expression of both proteins. This double mutant also can be partially rescued by inactivation of the APC/C using small interfering RNAs against specific subunits. These results further our understanding of HCMV's interaction with the cell cycle machinery and reveal a new cellular pattern of APC/C subunit downmodulation.

IMPORTANCE
HCMV lytic infection subverts the host cell cycle machinery in multiple ways. A major effect is inactivation of the APC/C, which plays a central role in the control of cell cycle progression. This study provides further insight into the mechanism of inactivation. We discovered that the APC1 subunit, which along with APC4 and APC5 form the platform subcomplex of the APC/C, is an additional target of the degradation induced by HCMV protein UL21a. This study also shows for the first time that there is a unique cellular process in uninfected cells whereby depletion of APC1, APC4, APC5, or APC8 recapitulates the pattern of HCMV-mediated APC/C subunit degradation.
Identification of Cholesterol 25-Hydroxylase as a Novel Host Restriction Factor and a Part of the Primary Innate Immune Responses against Hepatitis C Virus Infection
Authors: Xiang Yu , Tang Jing-Jie , Tao Wanyin , Cao Xuezhi , Song Bao-Liang , Zhong Jin 
Published: April 2015

ABSTRACT

Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the
Flaviviridae
family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I·C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics.

IMPORTANCE
Recent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that
ch25h
is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy.
Accumulation of Cytotoxic CD16+NK Cells in Simian Immunodeficiency Virus-Infected Lymph Nodes Associated withIn SituDifferentiation and Functional Anergy
Authors: Schafer Jamie L. , Li Haiying , Evans Tristan I. , Estes Jacob D. , Reeves R. Keith 
Published: April 2015

ABSTRACTRecent evidence suggests that even in treated infections, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication may continue in lymph nodes (LN), serving as a potential virus reservoir. Here we investigated the effects of lentivirus infection on natural killer (NK) cell frequencies, phenotypes, and functions in naive and acutely or chronically SIVmac239-infected rhesus macaques. Compared to that in naive animals, we observed a 3-fold-greater frequency of cytotoxic CD16+CD56−NK cells in LN of chronically infected macaques. However, NK cells did not appear to be trafficking to LN, as homing markers CD62L and CCR7 did not increase on circulating NK cells during infection. LN NK cells demonstrated enhanced cytotoxicity in acute infection, with 2-fold increases in perforin expression and 3-fold increases in CD107a expression following mitogen stimulation. Lysis of K562 cells by LN NK cells from acutely infected animals was greater than lysis by preinfection samples from the same animals. LN NK cells from chronically infected animals lysed K562 cells more efficiently than LN NK cells from uninfected animals, but importantly, surrogate markers of cytotoxicity in infected macaques were disproportionately greater thanex vivokilling. Furthermore, Tim-3, an indicator of activation and/or exhaustion, was upregulated 3-fold on LN NK cells in chronically infected animals. Collectively, these data suggest that LN NK cells are skewed toward a cytotoxic phenotype during SIV infection but may become dysfunctional and exhausted in chronic disease.IMPORTANCEThe accumulation of CD16+CD56−NK cells in the SIV-infected lymph node without changes in NK homing to the LN could suggest that these cells are differentiatingin situ. Surprisingly, this increase in frequency of the cytotoxic subset of NK cells is not accompanied by an increase of similar magnitude in the cytolytic function of LN lymphocytes. This functional modulation, together with the higher Tim-3 expression observed on LN NK cells isolated from chronically infected animals than on those from naive macaques, is indicative of an exhausted phenotype. This exhaustion could contribute to the robust replication of HIV and SIV in the LN during acute and chronic stages of infection, allowing the survival of infected cells and maintenance of a viral reservoir.
Improving the care of children with urinary tract infection: use of a clinical decision proforma
Authors: Leach Daniel 
Published: April 2015

AbstractUrinary tract infection (UTI) is a common and important clinical problem in children. Follow up imaging is indicated in some cases to reduce the risk of long-term harm from UTI and sometimes to help guide acute management. Overuse of imaging may be harmful due to radiation exposure, as well as increasing demand on services and budgets. On the other hand under-use of imaging may leave children vulnerable to renal damage and long-term morbidity. Accepted standards propose an imaging strategy specific to age and type of UTI. The complexity of the guideline makes compliance with the standards challenging.The aim of this project was to assess current practice for imaging of children with UTI managed at The Royal Oldham Hospital and to improve compliance with accepted standards through the use of a proforma to aid clinical decision making, supported by an education programme. A retrospective audit was performed over a 6 month period both prior to and after the intervention. The baseline audit found 57.7% of children treated for UTI (n=26) had imaging compliant with the accepted standards, which improved to 75.9% (n=29) on post-measurement. The percentage of inappropriate investigations reduced from 52.4% to 10.5%. The percentage of missed investigations reduced from 35.0% to 32.0%. The proforma was used and filed in 40% of cases where practice was in line with accepted standards. It was not used in any of the cases where practice deviated.In conclusion, a clear clinical decision aid, supported by an education programme, can significantly improve compliance with accepted standards for imaging of children with UTI. This may also be transferable to other scenarios where guidelines exist but have reduced efficacy due to complexity and/or lack of understanding.
Enhanced recovery clinical education programme improves quality of post-operative care
Authors: McDonald Ruth 
Published: April 2015

AbstractQuality is the driving principle of Enhanced Recovery (ER). It improves the patient experience by getting patients better sooner and changes clinical practice to make care safer and more efficient. As a consequence of ER patients spend less time in hospital.A successful ER programme began to fail after organisational restructuring and staff changes. Patients did not meet their ER goals and length of stay (LOS) increased. An ER nurse was appointed to get the programme back on track.This involved a multidisciplinary approach to an ER clinical education programme. The programme aimed to develop knowledge of the physiology of post-operative recovery and the evidence underpinning the interventions required. This was considered crucial to secure longer term staff engagement while avoiding unthinking protocol driven compliance. Success of the education programme was measured by improved outcomes in patient LOS and readmission statistics.During the four months of the clinical education programme there were no significant changes in monthly LOS. At six months post implementation of the programme there was a reduction in LOS of 0.6 days compared to the previous six months. At 12 months there was a reduction in 1.1 days compared with previous 12 months. There was a mean reduction of 28 day readmissions for all elective gynaecology surgery of 1.1 patients per month in the 12 months post programme implementation compared to the 12 months before. Delivering a multidisciplinary participatory education programme improved overall understanding of ER, and achieved sustained improvement in ER for patient benefit.
The impact of job strain on smoking cessation and relapse in the Canadian population: a cohort study
Authors: Rowe Daniel J , Dunn James R , Muntaner Carles 
Published: April 2015

BackgroundThe aim of this study is to investigate the impact of job strain, as measured by the Karasek demand/control model (DCM), on smoking cessation and relapse in a representative general population sample.MethodsA secondary analysis of data from the Canadian National Population Health Survey (NPHS) was undertaken. Daily smokers and former daily smokers (n=1287 and 1184, respectively) at cycle 1 (1994/1995) of the NPHS were followed up at cycle 2 (1996/1997). Measures of job strain (the independent variables) were based on data from cycle 1, predicting smoking status at cycle 2. Logistic regression analysis was employed in two ways. Individuals were stratified into job strain quartiles while continuous measures were also employed in separate analyses for job strain and its component dimensions.ResultsIn the quartile analysis, no effect of job strain was observed on the likelihood of cessation, while a non-linear effect was observed on the likelihood of relapse, although this relationship lost significance (p>0.05 and <0.10) after controlling for personal characteristics. No effect was observed using the continuous measure of job strain or the continuous measure of job demand on either cessation or relapse. For job control, no effect was observed on the likelihood of cessation, but increased control was found to decrease the likelihood of relapse in the unadjusted model only.ConclusionsPsychosocial work environments may be too diverse for uniform trends in the relationship between job stress and smoking behaviour to emerge in a population sample. Future research should avoid use of the scaled-down DCM instrument where possible.
Integrating reproductive health services into HIV care: strategies for successful implementation in a low-resource HIV clinic in Lilongwe, Malawi
Authors: Phiri Sam , Feldacker Caryl , Chaweza Thomas , Mlundira Linly , Tweya Hannock , Speight Colin , Samala Bernadette , Kachale Fannie , Umpierrez Denise , Haddad Lisa 
Published: April 2015

BackgroundLighthouse Trust operates two public HIV testing, treatment and care clinics in Lilongwe, Malawi, caring for over 26 000 people living with HIV, 23 000 of whom are on antiretroviral treatment (ART). In August 2010, Lighthouse Trust piloted a step-wise integration of sexual and reproductive health (SRH) services into routine HIV care at its Lighthouse clinic site. The objectives were to increase uptake of family planning (FP), promote long-term reversible contraceptive methods, and increase access, screening and treatment for cervical cancer using visual inspection with acetic acid.Methods and resultsPatients found integrated SRH/ART services acceptable; service availability appeared to increase uptake. Between August 2010 and May 2014, over 6000 women at Lighthouse received FP education messages. Of 859 women who initiated FP, 55% chose depot medroxyprogesterone acetate, 19% chose an intrauterine contraceptive device, 14% chose oral contraceptive pills, and 12% chose an implant. By May 2014, 21% of eligible female patients received cervical cancer screening: 11% (166 women) had abnormal cervical findings during screening for cervical cancer and underwent further treatment.ConclusionsSeveral lessons were learned in overcoming initial concerns about integration. First, our integrated services required minimal additional resources over those needed for provision of HIV care alone. Second, patient flow improved during implementation, reducing a barrier for clients seeking multiple services. Lastly, analysis of routine data showed that the proportion of women using some form of modern contraception was 45% higher at Lighthouse than at Lighthouse's sister clinic where services were not integrated (42% vs 29%), providing further evidence for promotion of SRH/ART integration.