bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host DNA Damage Response Factors Localize to Merkel Cell Polyomavirus DNA Replication Sites To Support Efficient Viral DNA Replication
Authors: Tsang Sabrina H. , Wang Xin , Li Jing , Buck Christopher B. , You Jianxin 
Published: January 2014

ABSTRACT

Accumulating evidence indicates a role for Merkel cell polyomavirus (MCPyV) in the development of Merkel cell carcinoma (MCC), making MCPyV the first polyomavirus to be clearly associated with human cancer. With the high prevalence of MCPyV infection and the increasing amount of MCC diagnosis, there is a need to better understand the virus and its oncogenic potential. In this study, we examined the relationship between the host DNA damage response (DDR) and MCPyV replication. We found that components of the ATM- and ATR-mediated DDR pathways accumulate in MCPyV large T antigen (LT)-positive nuclear foci in cells infected with native MCPyV virions. To further study MCPyV replication, we employed our previously established system, in which recombinant MCPyV episomal DNA is autonomously replicated in cultured cells. Similar to native MCPyV infection, where both MCPyV origin and LT are present, the host DDR machinery colocalized with LT in distinct nuclear foci. Immunofluorescence
in situ
hybridization and bromodeoxyuridine (BrdU) incorporation analysis showed that these DDR proteins and MCPyV LT in fact colocalized at the actively replicating MCPyV replication complexes, which were absent when a replication-defective LT mutant or an MCPyV-origin mutant was introduced in place of wild-type LT or wild-type viral origin. Inhibition of DDR kinases using chemical inhibitors and ATR/ATM small interfering RNA (siRNA) knockdown reduced MCPyV DNA replication without significantly affecting LT expression or the host cell cycle. This study demonstrates that these host DDR factors are important for MCPyV DNA replication, providing new insight into the host machinery involved in the MCPyV life cycle.

IMPORTANCE
MCPyV is the first polyomavirus to be clearly associated with human cancer. However, the MCPyV life cycle and its oncogenic mechanism remain poorly understood. In this report, we show that, in cells infected with native MCPyV virions, components of the ATM- and ATR-mediated DDR pathways accumulate in MCPyV LT-positive nuclear foci. Such a phenotype was recapitulated using our previously established system for visualizing MCPyV replication complexes in cells. By combining immunofluorescent staining, fluorescence
in situ
hybridization, and BrdU incorporation analysis, we demonstrate that DDR proteins are important for maintaining robust MCPyV DNA replication. This study not only provides the first look into the microscopic details of DDR factor/LT replication complexes at the MCPyV origin but also provides a platform for further studying the mechanistic role of host DDR factors in the MCPyV life cycle and virus-associated oncogenesis.
A Double-Mimetic Peptide Efficiently Neutralizes HIV-1 by Bridging the CD4- and Coreceptor-Binding Sites of gp120
Authors: Quinlan Brian D. , Joshi Vinita R. , Gardner Matthew R. , Ebrahimi Kourosh H. , Farzan Michael 
Published: January 2014

ABSTRACT
The HIV-1 envelope glycoprotein binds cooperatively to its cellular receptor CD4 and a coreceptor, principally CXCR4 or CCR5. We have previously improved a natural amino-acid form of a scorpion toxin-derived CD4-mimetic peptide and in parallel generated sulfopeptide mimetics of the CCR5 amino terminus. Here we show that some fusions of these CCR5- and CD4-mimetic peptides, expressed as immunoadhesins, neutralize HIV-1 more efficiently than CD4-Fc or equimolar mixtures of immunoadhesin forms of each peptide. Specifically, double-mimetic peptides with linkers of 11 amino acids or greater, and with the CCR5-mimetic component preceding the CD4-mimetic component, were more efficient than constructs with shorter linkers or in a reverse orientation. The potency of these constructs derives from (i) their ability to simultaneously and cooperatively bind the CD4- and CCR5-binding sites of a single gp120 monomer of the HIV-1 envelope glycoprotein trimer and (ii) the ability of the CCR5-mimetic component to prevent the CD4-mimetic peptide from promoting infection when cellular CD4 is limiting. Thus, there is a significant advantage to simultaneously targeting both conserved regions of the HIV-1 envelope glycoprotein.

IMPORTANCE
This report describes a novel class of peptides that potently inhibit HIV-1 entry. These peptides simultaneously target the receptor- and coreceptor-binding sites of the HIV-1 envelope glycoprotein gp120. Peptides of this class overcome key limitations of inhibitors that target only one gp120 binding region and illustrate the utility of binding the sulfotyrosine-binding pockets of gp120.
Core Binding Factor Beta Plays a Critical Role by Facilitating the Assembly of the Vif-Cullin 5 E3 Ubiquitin Ligase
Authors: Fribourgh Jennifer L. , Nguyen Henry C. , Wolfe Leslie S. , DeWitt David C. , Zhang Wenyan , Yu Xiao-Fang , Rhoades Elizabeth , Xiong Yong 
Published: January 2014

ABSTRACT
The HIV-1 virion infectivity factor (Vif) targets the cellular cytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) for degradation via the host ubiquitin-proteasome pathway. Vif recruits a cellular E3 ubiquitin ligase to polyubiquitinate A3G/F. The activity of Vif critically depends on the cellular core binding factor beta (CBFβ). In this study, we investigated the Vif-CBFβ interaction and the role of CBFβ in the E3 ligase assembly. Vif-CBFβ interaction requires an extensive region of Vif spanning most of its amino terminus and zinc finger region, and cullin 5 (Cul5) binding enhances the stability of the Vif-CBFβ interaction. Our results further demonstrate that CBFβ plays a critical role in facilitating Cul5 binding to the Vif/elongin B/elongin C complex. Vif, with or without bound substrate, is unable to bind Cul5 in the absence of CBFβ. These studies support the notion that CBFβ serves as a molecular chaperone to facilitate Vif-E3 ligase assembly.

IMPORTANCE
The host antiviral restriction factors A3G/F inhibit viral replication. The HIV-1 protein Vif targets A3G/F for degradation. This immune evasion activity of Vif is dependent on the cellular factor CBFβ. Multiple regions of Vif are known to be important for Vif function, but the mechanisms are unclear. The studies described here provide important information about the Vif-CBFβ interaction interface and the function of CBFβ in E3 ligase assembly. In particular, our comprehensive Vif-CBFβ interface mapping results help to delineate the role of various Vif regions, determining if they are important for binding CBFβ or A3G/F. Furthermore, our studies reveal an important potential mechanism of CBFβ that has not been shown before. Our results suggest that CBFβ may serve as a molecular chaperone to enable Vif to adopt an appropriate conformation for interaction with the Cul5-based E3 ligase. This study advances our understanding of how CBFβ facilitates the Vif-mediated degradation of APOBEC3 proteins.
Evolutionarily Conserved Requirement for Core Binding Factor Beta in the Assembly of the Human Immunodeficiency Virus/Simian Immunodeficiency Virus Vif-Cullin 5-RING E3 Ubiquitin Ligase
Authors: Han Xue , Liang Weizi , Hua Deping , Zhou Xiaohong , Du Juan , Evans Sean L. , Gao Qimeng , Wang Hong , Viqueira Rachel , Wei Wei , Zhang Wenyan , Yu Xiao-Fang 
Published: January 2014

ABSTRACT

The human immunodeficiency virus type 1 (HIV-1)-encoded virion infectivity factor (Vif) is required to inactivate the host restriction factor APOBEC3 by engaging Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function; as yet, its mechanism of regulation remains unclear. In the present study, we demonstrate that CBF-β promotion of Vif-CRL5 assembly is independent of its influence on Vif stability and is also a conserved feature of primate lentiviral Vif proteins. Furthermore, CBF-β is critical for the formation of the Vif-ElonginB/ElonginC-Cul5 core E3 ubiquitin ligase complex
in vitro
. CBF-β from diverse vertebrate species supported HIV-1 Vif function, indicating the conserved nature of Vif–CBF-β interfaces. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.

IMPORTANCE
HIV-1 encodes virion infectivity factor (Vif) to inactivate its host's antiviral APOBEC3 proteins. Vif triggers APOBEC3 degradation by forming Vif-Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function whose mechanism of regulation remains poorly defined. In the present study, we demonstrate that the promotion of Vif-CRL5 assembly by CBF-β can be separated from its influence on Vif stability. The promotion of Vif-CRL5 assembly, but not the influence on Vif stability, is conserved among primate lentiviral Vif proteins: we found that CBF-β from diverse vertebrate species supported HIV-1 Vif function. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function and HIV-1 replication, disrupting this interaction is an attractive strategy against HIV-1.
What explains worse patient experience in London? Evidence from secondary analysis of the Cancer Patient Experience Survey
Authors: Saunders Catherine L , Abel Gary A , Lyratzopoulos Georgios 
Published: January 2014

ObjectiveTo explore why patients with cancer treated by London hospitals report worse experiences of care compared with those treated in other English regions.DesignSecondary analysis of the 2011/2012 National Cancer Patient Experience Survey (n=69 086).Setting and participantsPatients with cancer treated by the English National Health Service (NHS) hospitals.Main outcome measures64 patient experience measures covering all aspects of cancer care (pre-diagnosis to discharge).MethodsUsing mixed effects logistic regression, we explored whether poorer scores in London hospitals could be explained by patient case-mix (age, gender, ethnicity and cancer type). Because patients referred to tertiary centres and/or with complex medical problems may report more critical experiences, we also explored whether the experiences reported in London may reflect higher concentration of teaching hospitals in the capital. Finally, using the data from the (general) Adult Inpatients Survey, we explored whether the extent of poorer experience reported by London patients was similar for respondents to either survey.ResultsFor 52/64 questions, there was evidence of poorer experience in London, with the percentage of patients reporting a positive experience being lower compared with the rest of England by a median of 3.7% (IQR 2.5–5.4%). After case-mix adjustment there was still evidence for worse experience in London for 44/64 questions. In addition, adjusting for teaching hospital status made trivial difference to the case-mix-adjusted findings. There was evidence that London versus rest-of-England differences were greater for patients with cancer compared with (general) hospital inpatients for 10 of 16 questions in both the Cancer Patient Experience and the Adult Inpatients Surveys.ConclusionsPatients with cancer treated by London hospitals report worse care experiences and by and large these differences are not explained by patient case-mix or teaching hospital status. Efforts to improve care in London should aim to meet patient expectations and improve care quality.
Temporal summation of pain and ultrasound Doppler activity as predictors of treatment response in patients with rheumatoid arthritis: protocol for the Frederiksberg hospitals Rheumatoid Arthritis, pain assessment and Medical Evaluation (FRAME-cohort) study
Authors: Christensen Anton Wulf , Rifbjerg-Madsen Signe , Christensen Robin , Amris Kirstine , Taylor Peter C , Locht Henning , Ellegaard Karen , Torp-Pedersen Søren , Jespersen Anders , Bartels Else Marie , Danneskiold-Samsøe Bente , Bliddal Henning 
Published: January 2014

IntroductionChronic pain is common in rheumatoid arthritis (RA) and may still persist despite regression of objective signs of inflammation. This has led researchers to hypothesise that central pain sensitisation may play a role in the generation of chronic pain in RA. Application of the disease activity score DAS28 can classify some patients with active RA solely based on a high tender joint count and poor patient global health score. In such cases, intensified treatment with anti-inflammatory drugs would be expected to yield poorer results than in cases with DAS28 elevation due to a high score for swollen joints and C reactive protein (CRP). Evaluation of central pain sensitisation in patients with few inflammatory indices may be a predictive tool regarding the effect of anti-inflammatory treatment. Computerised pneumatic cuff pressure algometry (CPA) is a method for assessing temporal summation (ie, degree of central sensitisation). The main objective of this study was to examine the prognostic values of pressure pain-induced temporal summation, ultrasound Doppler activity and the interaction between them in relation to treatment response (DAS28-CRP change) in patients with RA initiating any anti-inflammatory therapy.Method and analysis120 participants ≥18 years of age will be recruited. Furthermore, they must be either (1) diagnosed with RA, untreated with disease-modifying antirheumatic drugs for at least 6 months and about to initiate disease-modifying antirheumatic drug treatment or (2) about to begin or switch treatment with any biological drug for their RA. Data (clinical, imaging, blood samples, patient reported outcomes and CPA measurements) will be collected from each participant at baseline and after 4 months of anti-inflammatory treatment.Ethics and disseminationThis study has been approved by the ethics committee for the Copenhagen region (H-4-2013-007). Dissemination will occur through presentations and publication in international peer-reviewed journals.
Improving the use of phlebotomy services in a paediatric inpatient setting
Authors: Pitchforth Jacqueline , Lemer Claire 
Published: January 2014

AbstractThe aim of this project was to improve the use of the current Paediatric Phlebotomy service. The main problem identified was the lack of a system to notify medical teams of unsuccessful blood requests. A phlebotomy process map was constructed to help analyse reasons why failure to notify occurred. Pre and post intervention audits were conducted using the number of unsuccessful blood requests notified as a baseline measurement. The initial intervention was modified based on feedback during the process. A 44% improvement in the number of unsuccessful blood requests notified and a potential cost savings of £6240 was demonstrated in the post-intervention audit. Further work is required as to whether these improvements can be increased, sustained and be cost effective.
Managing human factors in the assembly of the paediatric bronchoscope
Authors: Saxby Clair , Williams Richard 
Published: January 2014

AbstractForeign body aspiration in children is a life threatening event and prompt bronchoscopy and extraction is essential for their survival. During a recent paediatric airway emergency at Torbay hospital, Devon, the theatre staff were unable to assemble the paediatric bronchoscope. We therefore investigated methods to improve the efficiency and timeliness of the assembly of the paediatric bronchoscope.To assess the current problem we asked ten theatre staff at random to assemble the paediatric bronchoscope. 70% of the staff were not able to assemble the paediatric bronchoscope. A prompt poster was developed as a visual aid to help demonstrate how to assemble the paediatric bronchoscope. Another ten theatre staff were asked to assemble the paediatric bronchoscope. Now all of the staff were able to assemble the paediatric bronchoscope.The prompt poster enabled all the theatre staff tested to correctly assemble the paediatric bronchoscope and the average time taken was reduced. To further develop the service mandatory training sessions have been arranged to help theatre staff remain confident and continue to develop their skills and knowledge.
Improving weekend handover between junior doctors on medical and surgical wards
Authors: Bethune Rob , Campbell Kate , Rose Alex , Wassall Richard , Price Catherine , Siese Thomas , Finn Roisin , Whitaker Sean 
Published: January 2014

AbstractPoor weekend handover has been implicated as one of the causes of observed higher mortality rates at weekends in UK hospitals. In a large teaching hospital we, a group of junior doctors, set about improving the quality and effectiveness of weekend handover. We used the Model for Improvement to implement a weekend handover sticker through an iterative process using multiple Plan/Do/Study/Act (PDSA) cycles. Over the 16 week study period the number of completed weekend tasks increased by 30% and the number of patients with a documented weekend handover increased by nearly 50%.Junior doctors are well positioned to notice the quality and safety shortcomings within hospitals, and by using effective improvement methods they can improve these systems at little or no cost.
Fascia iliaca block for pain relief from proximal femoral fracture in the emergency department: a review of the literature
Authors: Chesters Adam , Atkinson Paul 
Published: January 2014

Objectivesto determine the efficacy of the fascia iliaca block in providing analgesia to patients with a proximal femoral fracture in the emergency department.MethodsEMBASE, PubMed, CINAHL and Google Scholar were searched. Free text keywords for population, intervention and outcome were identified to create a search string. The reference lists from articles identified in the primary electronic search were hand searched. Potentially eligible studies were identified based on review of the title and abstract. If eligibility was unclear from the title and abstract, the full text was examined. Randomised controlled trials comparing the fascia iliaca block with standard analgesia were included. A standardised appraisal of the methodological quality of the studies was performed.Results39 articles were identified, of which 13 were duplicates. Of the remaining 26, 15 were relevant to the question and suitable for further sorting. There was one conference poster presenting data, which were later published as an audit, and so was considered to be a duplicate. Of the 14 remaining papers, 2 were randomised controlled trials, 6 were cohort studies and 3 were reports of audit of practice. There were 3 abstracts of conference poster or paper submissions, which were descriptions of reviews or service development projects rather than primary studies. The two randomised controlled trials showed statistically significant superior or equal pain relief between the fascia iliaca block and other forms of acute pain relief.Conclusionsthe fascia iliaca block could have an important role in first-line pain control for patients presenting to the emergency department with a proximal femoral fracture. There is potential to reform the acute management of this common group of patients.
A prediction algorithm for first onset of major depression in the general population: development and validation
Authors: Wang JianLi , Sareen Jitender , Patten Scott , Bolton James , Schmitz Norbert , Birney Arden 
Published: January 2014

ObjectivePrediction algorithms are useful for making clinical decisions and for population health planning. However, such prediction algorithms for first onset of major depression do not exist. The objective of this study was to develop and validate a prediction algorithm for first onset of major depression in the general population.MethodsLongitudinal study design with approximate 3-year follow-up. The study was based on data from a nationally representative sample of the US general population. A total of 28 059 individuals who participated in Waves 1 and 2 of the US National Epidemiologic Survey on Alcohol and Related Conditions and who had not had major depression at Wave 1 were included. The prediction algorithm was developed using logistic regression modelling in 21 813 participants from three census regions. The algorithm was validated in participants from the 4th census region (n=6246). Major depression occurred since Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions, assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule–diagnostic and statistical manual for mental disorders IV.ResultsA prediction algorithm containing 17 unique risk factors was developed. The algorithm had good discriminative power (C statistics=0.7538, 95% CI 0.7378 to 0.7699) and excellent calibration (F-adjusted test=1.00, p=0.448) with the weighted data. In the validation sample, the algorithm had a C statistic of 0.7259 and excellent calibration (Hosmer-Lemeshow χ2=3.41, p=0.906).ConclusionsThe developed prediction algorithm has good discrimination and calibration capacity. It can be used by clinicians, mental health policy-makers and service planners and the general public to predict future risk of having major depression. The application of the algorithm may lead to increased personalisation of treatment, better clinical decisions and more optimal mental health service planning.
Postwar environment and long-term mental health problems in former child soldiers in Northern Uganda: the WAYS study
Authors: Amone-P'Olak Kennedy , Stochl Jan , Ovuga Emilio , Abbott Rosemary , Meiser-Stedman Richard , Croudace Tim J , Jones Peter B 
Published: January 2014

BackgroundWar experiences (WE) and postwar environments (PWE) are associated with mental ill-health. The present study aims to investigate the pathways from WE and PWE to mental ill-health and to define opportunities for intervention through analysis of the war-affected youths study (WAYS) cohort study.MethodWAYS is an ongoing study of a large cohort of former child soldiers being conducted in Uganda. Mental health problems, subjective WE and PWE contexts were assessed by local adaptations of internationally developed measures for use with former child soldiers at least 6 years after the end of the war. Structural equation modeling was used to test two mediation hypotheses: (1) the ‘trauma model’ in which WE directly influence long-term mental health and (2) the ‘psychosocial path’ in which WE influence long-term mental health through PWE stressors.ResultsWE were linked to depression/anxiety (β=0.15 (95% CI 0.01 to 0.30)) through PWE (accounting for 44% of the variance in the relationship between these variables) and to conduct problems (β=0.23 (95% CI 0.03 to 0.43); (accounting for 89% of the variance, ie, near complete mediation)). The direct relation between WE and depression/anxiety attenuated but remained statistically significant. For conduct problems, the direct relationship was no longer significant after accounting for PWE.ConclusionsPWE are a key determinant of continued mental health problems in former child soldiers. Interventions to reduce long-term mental problems should address both PWE stressors (psychosocial model) and specialised mental healthcare (trauma model) and consider both models of intervention as complementary.