bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphorylation of Herpes Simplex Virus 1 dUTPase Upregulated Viral dUTPase Activity To Compensate for Low Cellular dUTPase Activity for Efficient Viral Replication
Authors: Kato Akihisa , Hirohata Yoshitaka , Arii Jun , Kawaguchi Yasushi 
Published: April 2014

ABSTRACT
We recently reported that herpes simplex virus 1 (HSV-1) protein kinase Us3 phosphorylated viral dUTPase (vdUTPase) at serine 187 (Ser-187) to upregulate its enzymatic activity, which promoted HSV-1 replication in human neuroblastoma SK-N-SH cells but not in human carcinoma HEp-2 cells. In the present study, we showed that endogenous cellular dUTPase activity in SK-N-SH cells was significantly lower than that in HEp-2 cells and that overexpression of cellular dUTPase in SK-N-SH cells increased the replication of an HSV-1 mutant with an alanine substitution for Ser-187 (S187A) in vdUTPase to the wild-type level. In addition, we showed that knockdown of cellular dUTPase in HEp-2 cells significantly reduced replication of the mutant vdUTPase (S187A) virus but not that of wild-type HSV-1. Furthermore, the replacement of Ser-187 in vdUTPase with aspartic acid, which mimics constitutive phosphorylation, and overexpression of cellular dUTPase restored viral replication to the wild-type level in cellular dUTPase knockdown HEp-2 cells. These results indicated that sufficient dUTPase activity was required for efficient HSV-1 replication and supported the hypothesis that Us3 phosphorylation of vdUTPase Ser-187 upregulated vdUTPase activity in host cells with low cellular dUTPase activity to produce efficient viral replication.virus.

IMPORTANCE
It has long been assumed that dUTPase activity is important for replication of viruses encoding a dUTPase and that the viral dUTPase (vdUTPase) activity was needed if host cell dUTPase activity was not sufficient for efficient viral replication. In the present study, we showed that the S187A mutation in HSV-1 vdUTPase, which impaired its enzymatic activity, reduced viral replication in SK-N-SH cells, which have low endogenous cellular dUTPase activity, and that overexpression of cellular dUTPase restored viral replication to the wild-type level. We also showed that knockdown of cellular dUTPase in HEp-2 cells, which have higher dUTPase activity than do SK-N-SH cells, reduced replication of HSV-1 with the vdUTPase mutation but had no effect on wild-type virus replication. This is the first report, to our knowledge, directly showing that dUTPase activity is critical for efficient viral replication and that vdUTPase compensates for low host cell dUTPase activity to produce efficient viral replication.
IRF7-Dependent Type I Interferon Production Induces Lethal Immune-Mediated Disease in STAT1 Knockout Mice Infected with Lymphocytic Choriomeningitis Virus
Authors: Li Wen , Hofer Markus J. , Jung So Ri , Lim Sue-Ling , Campbell Iain L. 
Published: April 2014

ABSTRACTFollowing systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 knockout (KO) mice but not wild-type, STAT2 KO, IRF9 KO, or IFNAR KO mice develop lethal disease perpetrated by CD4+T cells. IRF7 is a key transcriptional activator of type I IFN (IFN-I) during LCMV infection. Here, the role of IRF7 in the lethal host response to LCMV infection in STAT1 KO mice was examined. In contrast to STAT1 KO mice, STAT1/IRF7 double KO (DKO) mice survived LCMV infection with a reduced immune pathology in key organs, such as the liver and spleen. However, similar to STAT1 KO mice, STAT1/IRF7 DKO mice failed to control LCMV replication and spread. LCMV infection in STAT1 KO mice was associated with a significant elevation in the levels of a number of cytokines in serum, including IFN-Is, but this was largely absent in STAT1/IRF7 DKO mice, which had a modest increase in the levels of gamma interferon and CCL2 only. Since IRF7 is known to be a key transcriptional regulator of IFN-I gene expression, the possible role of IFN-I in lethal disease was examined further. STAT1/IFNAR DKO mice, in contrast to STAT1 KO mice, all survived infection with LCMV and exhibited little tissue immune pathology. Additionally, STAT1 KO mice that were deficient for either of the two IFN-I signaling molecules, STAT2 or IRF9, also survived LCMV infection. We conclude that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is (i) dependent on IRF7-induced IFN-I production and (ii) driven by noncanonical IFN-I signaling via STAT2 and IRF9.IMPORTANCEHere we report on the basis for the novel, fatal immune-mediated disease of STAT1 KO mice infected with LCMV. Our findings show that, surprisingly, the pathogenesis of this disease is dependent on IRF7-mediated type I interferon production. Moreover, our study identifies noncanonical type I interferon signaling via STAT2 and IRF9 to be essential for the type I IFN-driven fatal disease in LCMV-infected STAT1 KO mice. These results further highlight the significance of noncanonical type I IFN signaling in the pathogenesis of host-mediated injury following viral infection.
Statistical Linkage Analysis of Substitutions in Patient-Derived Sequences of Genotype 1a Hepatitis C Virus Nonstructural Protein 3 Exposes Targets for Immunogen Design
Authors: Quadeer Ahmed A. , Louie Raymond H. Y. , Shekhar Karthik , Chakraborty Arup K. , Hsing I-Ming , McKay Matthew R. 
Published: April 2014

ABSTRACT

Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4
+
and cytotoxic CD8
+
T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41.

IMPORTANCE
Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the diverse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious.
Aversive tension of adolescents with anorexia nervosa in daily course: a case-controlled and smartphone-based ambulatory monitoring trial
Authors: Kolar David Raphael , Bürger Arne , Hammerle Florian , Jenetzky Ekkehart 
Published: April 2014

IntroductionMonitoring and reduction of aversive tension is a core issue in dialectical behaviour therapy of patients. It has been shown that aversive tension is increased in adult borderline personality disorder and is linked to low emotion labelling ability. However, until now there is no documented evidence that patients with anorexia nervosa suffer from aversive tension as well. Furthermore the usability of a smartphone application for ambulatory monitoring purposes has not been sufficiently explored.Methods and analysisWe compare the mean and maximum self-reported aversive tension in 20 female adolescents (12–19 years) with anorexia nervosa in outpatient treatment with 20 healthy controls. They are required to answer hourly, over a 2-day period, that is, about 30 times, four short questions on their smartphone, which ensures prompt documentation without any recall bias. At the close out, the participants give a structured usability feedback on the application and the procedure.Ethics and disseminationThe achieved result of this trial has direct relevance for efficient therapy strategies and is a prerequisite for trials regarding dialectical behaviour therapy in anorexia nervosa. The results will be disseminated through peer-review publications. The ethics committee of the regional medical association in Mainz, Germany approved the study protocol under the reference number 837.177.13.Trial Registration numberThe trial is registered at the German clinical trials registration under the reference number DRKS00005228.
Correlation of measured and calculated serum osmolality during mannitol or hypertonic saline infusion in patients after craniotomy: a study protocol and statistical analysis plan for a randomised controlled trial
Authors: Li Qian , Xu Ming , Zhou Jian-Xin 
Published: April 2014

IntroductionBrain oedema is a major complication after craniotomy. Hyperosmolar agents have been used as the medical treatment for this condition. Measurement and estimation of serum osmolality during hyperosmolar agent infusion is of clinical importance to evaluate clinical efficacy, adjust dosage and avoid side effects. However, several studies have shown that calculated serum osmolality may lead to a systematic bias compared with direct measurement. In the present study, mannitol or hypertonic saline (HS) will be used in patients after elective craniotomy. We aim to determine the accuracy of serum osmolality estimation during the application of hyperosmolar agent.Methods and analysisThe study is a prospective, randomised, double-blinded, controlled, parallel-group design. Adult patients requiring the use of hyperosmolar agents for the prevention or treatment of postoperative brain oedema are enrolled and assigned randomly to one of the two treatment study groups, labelled as ‘M group’ and ‘HS group’. Patients in the M and HS groups receive intravenous infusion of 125 mL of either 20% mannitol or 3.1% sodium chloride solution, respectively. Data will be collected immediately before the infusion of study agents, 15, 30, 60, 120, 240 and 360 min after the start of infusion of experimental agents, which includes serum osmolality, concentration of serum sodium, potassium, urea and glucose. Serum osmolality will be measured by means of freezing point depression. Estimated serum osmolality will also be calculated by using four formulas published previously. Osmole gap is calculated as the difference between the measured and the estimated values. The primary endpoint is the correlation of measured and estimated serum osmolality during hyperosmolar agent infusion.Ethics and disseminationThe study was approved by the International Review Board (IRB) of Beijing Tiantan Hospital, Capital Medical University. Study findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberClinicalTrials.gov identifier:NCT02037815.
Smoker, ex-smoker or non-smoker? The validity of routinely recorded smoking status in UK primary care: a cross-sectional study
Authors: Marston Louise , Carpenter James R , Walters Kate R , Morris Richard W , Nazareth Irwin , White Ian R , Petersen Irene 
Published: April 2014

ObjectiveTo investigate how smoking status is recorded in UK primary care; to evaluate whether appropriate multiple imputation (MI) of smoking status yields results consistent with health surveys.SettingUK primary care and a population survey conducted in the community.ParticipantsWe identified 354 204 patients aged 16 or over in The Health Improvement Network (THIN) primary care database registered with their general practice 2008–2009 and 15 102 individuals aged 16 or over in the Health Survey for England (HSE).Outcome measuresAge-standardised and age-specific proportions of smokers, ex-smokers and non-smokers in THIN and the HSE before and after MI. Using information on time since quitting in the HSE, we estimated when ex-smokers are typically recorded as non-smokers in primary care records.ResultsIn THIN, smoking status was recorded for 84% of patients within 1 year of registration. Of these, 28% were smokers (21% in the HSE). After MI of missing smoking data, the proportion of smokers was 25% (missing at random) and 20% (missing not at random). With increasing age, more were identified as ex-smokers in the HSE than THIN. It appears that those who quit before age 30 were less likely to be recorded as an ex-smoker in primary care than people who quit later.ConclusionsSmoking status was relatively well recorded in primary care. Misclassification of ex-smokers as non-smokers is likely to occur in those quitting smoking at an early age and/or a long time ago. Those with no smoking status information are more likely to be ex-smokers or non-smokers than smokers.
A group-based HIV and sexually transmitted infections prevention intervention for lesbian, bisexual, queer and other women who have sex with women in Calgary and Toronto, Canada: study protocol for a non-randomised cohort pilot study
Authors: Logie Carmen H , Navia Daniela , Rwigema Marie-Jolie , Tharao Wangari , Este David , Loutfy Mona R 
Published: April 2014

IntroductionThe limited research that exists suggests that lesbian, bisexual queer (LBQ) and other women who have sex with women are at similar risk for sexually transmitted infections (STI) as heterosexual women. However, scant research has evaluated HIV and STI prevention strategies for LBQ women. The authors present the rationale and study protocol for developing and pilot testing a psychoeducational group-based HIV and STI prevention intervention with LBQ women in Calgary and Toronto, Canada.Methods and analysisThis is a multicentre non-randomised cohort pilot study. The target population is LBQ women in Calgary and Toronto, Canada. The authors aim to recruit 40 participants using purposive peer-driven recruitment methods. Participants will conduct a pretest followed by a 2-day group programme of six 2 h sessions addressing stigma, STI and HIV prevention, healthy relationships, safer sex self-efficacy, self-worth, social support and LBQ community engagement. Participants will conduct a post-test directly following the intervention and 6 weeks after the intervention. The primary outcome is safer sex practices; our prespecified index of clinically significant change is an effect size of 0.50. Secondary outcomes include: safer sex self-efficacy, STI testing frequency, STI knowledge, resilient coping, social support, sexual stigma, access to care, depression and self-esteem. We will conduct mixed-effects regression to calculate mean outcome pre–post test score change.Ethics and disseminationResearch ethics approval was attained from the Office of Research Ethics (REB: 29291), University of Toronto, Toronto, Ontario, Canada. Trial results will be published according to the Transparent Reporting of Evaluations with Non-randomised Designs (TREND) statement, regardless of the outcomes.Trial registration numberThis study is registered athttp://clinicaltrials.gov, registration numberNCT02067845.
Validating childhood asthma in an epidemiological study using linked electronic patient records
Authors: Cornish Rosaleen P , Henderson John , Boyd Andrew W , Granell Raquel , Van Staa Tjeerd , Macleod John 
Published: April 2014

ObjectiveTo investigate the performance of parent-reported data in identifying physician-confirmed asthma.Design and settingValidation study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic patient records held within the General Practice Research Database (GPRD).ParticipantsParticipants were those eligible to participate in ALSPAC who also had a record in the GPRD; this included 765 individuals, just under 4% of ALSPAC-eligible participants. The analysis was based on 141 participants with complete parent-reported asthma data.Primary and secondary outcome measuresThe main GPRD outcome measure was whether a child had a diagnosis of asthma before they were nine. Parent-reported measures were doctor diagnosis of asthma (before mean age 7.5 years), various outcomes based on wheezing and breathlessness recorded longitudinally between 6 months and 8.5 years. Secondary outcomes were bronchial hyper-responsiveness (BHR), forced expiratory volume in 1 s/forced vital capacity ratio and skin prick test responses.ResultsAmong the 141 participants with complete parent-reported data, 26 (18%) had an asthma diagnosis before age nine. Using general practitioner (GP)-recorded asthma as the gold standard, the question ‘Has a doctor ever diagnosed your child with asthma?’ was both sensitive (88.5%) and specific (95.7%). ‘Ever wheezed’ had the highest sensitivity (100%) but low specificity (60%). More specific definitions were obtained by restricting to those who had wheezed on more than one occasion, experienced frequent wheeze and/or wheezed after the age of 3, but these measures had low sensitivities. BHR only identified 50% of those with a GP-recorded diagnosis.ConclusionsParental reports of a doctor's diagnosis agree well with a GP-recorded diagnosis. High specificity for asthma can be achieved by using detailed wheezing questions, although these definitions are likely to exclude mild cases of asthma. Our study shows that linkage between observational studies and electronic patient records has the potential to enhance epidemiological research.
Social and economic conditions in childhood and the progression of functional health problems from midlife into old age
Authors: Agahi Neda , Shaw Benjamin A , Fors Stefan 
Published: April 2014

BackgroundChildhood living conditions have been found to predict health and mortality in midlife and in old age. This study examines the associations between social and economic childhood conditions and the onset and progression of functional health problems from midlife into old age, and the extent to which potential associations are mediated by educational attainment and smoking.MethodsData from the Level of Living Survey and the Swedish Panel Study of Living Conditions of the Oldest Old were merged to create a longitudinal data set with five repeated measures from 1968 to 2004 (n=1765, aged 30–50 years and free from functional health problems at baseline). Multilevel regression models were used to analyse retrospective reports of social and economic conditions in childhood (eg, conflicts or economic problems in the family) in relation to the progression of functional health problems over the 36-year period.ResultsResults showed that social and economic disadvantages in childhood were associated with an earlier onset and a faster progression of functional health problems from midlife into old age. Subsequent models showed that differences in educational attainment, but not smoking, explained much of the association between childhood disadvantages and trajectories of functional health problems.ConclusionsAccording to these results, adverse social and economic conditions in childhood affect the development of functional health problems from midlife into old age indirectly through less favourable life careers, including lower education. Creating equal opportunities for educational attainment may help reduce the long-term effects of disadvantaged childhood conditions and postpone functional health problems.
Intervention Completion Rates among African Americans in a Randomized Effectiveness Trial for Diet and Physical Activity Changes
Authors: Halbert Chanita Hughes , Bellamy Scarlett , Briggs Vanessa , Bowman Marjorie , Delmoor Ernestine , Johnson Jerry C. , Kumanyika Shiriki , Melvin Cathy , Purnell Joseph , Rogers Rodney , Weathers Benita 
Published: April 2014

Abstract
Background: The intervention completion rate is an important metric in behavioral and intervention research; trials with limited intervention completion rates may have reduced internal validity. We examined intervention completion rates among 530 African Americans who had been randomized to an integrated (INT) or disease-specific (DSE) risk education protocol as part of a comparative effectiveness trial from September 2009 to August 2012.
Methods: The interventions were developed by an academic-community partnership using community-based participatory research. Intervention completion rates were determined based on attendance at all four intervention sessions. Intervention completers were participants who completed all four sessions and noncompleters were those who did not complete any session or only completed one to three sessions following randomization.
Results: Seventy-three percent of participants were intervention completers and 27% were noncompleters. There were no differences in intervention completion based on randomization to INT (72%) or DSE (75%), sociodemographic factors, or body mass index (BMI) in the total sample. Different factors were associated significantly with intervention completion within study groups. Among participants randomized to INT, the odds of intervention completion were greater with higher levels of intrinsic motivation, less exposure to information about diet and cardiovascular disease, and greater BMI. Among participants randomized to DSE, the odds of completing the intervention were associated significantly with older age and greater dietary self-efficacy.
Conclusions: Many African Americans are likely to complete risk education interventions.
Impact: Psychologic characteristics should be considered when determining intervention completion rates following randomization in behavioral and intervention trials. Cancer Epidemiol Biomarkers Prev; 23(7); 1306–13. ©2014 AACR.