bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal Structure of the Measles Virus Nucleoprotein Core in Complex with an N-Terminal Region of Phosphoprotein
Authors: Guryanov Sergey G. , Liljeroos Lassi , Kasaragod Prasad , Kajander Tommi , Butcher Sarah J. 
Published: December 2015

ABSTRACT

The enveloped negative-stranded RNA virus measles virus (MeV) is an important human pathogen. The nucleoprotein (N
0
) assembles with the viral RNA into helical ribonucleocapsids (NC) which are, in turn, coated by a helical layer of the matrix protein. The viral polymerase complex uses the NC as its template. The N
0
assembly onto the NC and the activity of the polymerase are regulated by the viral phosphoprotein (P). In this study, we pulled down an N
0
1-408
fragment lacking most of its C-terminal tail domain by several affinity-tagged, N-terminal P fragments to map the N
0
-binding region of P to the first 48 amino acids. We showed biochemically and using P mutants the importance of the hydrophobic interactions for the binding. We fused an N
0
binding peptide, P
1-48
, to the C terminus of an N
0
21-408
fragment lacking both the N-terminal peptide and the C-terminal tail of N protein to reconstitute and crystallize the N
0
-P complex. We solved the X-ray structure of the resulting N
0
-P chimeric protein at a resolution of 2.7 Å. The structure reveals the molecular details of the conserved N
0
-P interface and explains how P chaperones N
0
, preventing both self-assembly of N
0
and its binding to RNA. Finally, we propose a model for a preinitiation complex for RNA polymerization.

IMPORTANCE
Measles virus is an important, highly contagious human pathogen. The nucleoprotein N binds only to viral genomic RNA and forms the helical ribonucleocapsid that serves as a template for viral replication. We address how N is regulated by another protein, the phosphoprotein (P), to prevent newly synthesized N from binding to cellular RNA. We describe the atomic model of an N-P complex and compare it to helical ribonucleocapsid. We thus provide insight into how P chaperones N and helps to start viral RNA synthesis. Our results provide a new insight into mechanisms of paramyxovirus replication. New data on the mechanisms of phosphoprotein chaperone action allows better understanding of virus genome replication and nucleocapsid assembly. We describe a conserved structural interface for the N-P interaction which could be a target for drug development to treat not only measles but also potentially other paramyxovirus diseases.
Regulation of Norovirus Virulence by the VP1 Protruding Domain Correlates with B Cell Infection Efficiency
Authors: Zhu Shu , Watanabe Makiko , Kirkpatrick Ericka , Murray Akilah B. , Sok Ryneth , Karst Stephanie M. 
Published: December 2015

ABSTRACT
Human noroviruses are a leading cause of gastroenteritis across the globe, but the pathogenic mechanisms responsible for disease are not well established. The availability of a murine norovirus model system provides the opportunity to elucidate viral and host determinants of virulence in a natural host. For example, previous studies have revealed that the protruding domain of the murine norovirus capsid protein VP1, specifically residue 296 of VP1, regulates virulent infection. We identified a panel of nonsynonymous mutations in the open reading frame 2 (ORF2) gene encoding VP1 that arose in persistently infected mice and tested whether these mutations conferred phenotypic changes to viral replication and virulence. Consistent with previous studies, we demonstrate that a glutamic acid at position 296 results in attenuation. For the first time, we also demonstrate that a lysine at this position is sufficient to confer virulence on an otherwise attenuated murine norovirus strain. Moreover, our studies reveal a direct correlation between the efficiency of viral replication in B cells and virulence. These data are especially striking because mutations causing reduced B cell replication and attenuation had minimal effects on the ability of the virus to replicate in macrophages. Thus, norovirus infection of B cells may directly contribute to disease outcome.

IMPORTANCE
Human noroviruses are a major global cause of disease, yet we know very little about their pathogenic mechanisms. The availability of a murine norovirus model system facilitates investigation of noroviruses in a natural host organism and the identification of viral and host determinants of pathogenesis. We have identified a panel of mutations arising in the viral capsid protein VP1 during persistent infection of mice. Our data reveal that the protruding domain of VP1 regulates the ability of the virus to replicate in B cells, and this directly correlates with virulence. Importantly, mutations impairing B cell infection had minimal effects on macrophage infection, revealing a potentially critical role for B cell infection in norovirus pathogenesis.
New Mechanism of Hepatic Fibrogenesis: Hepatitis C Virus Infection Induces Transforming Growth Factor β1 Production through Glucose-Regulated Protein 94
Authors: Jee Min Hyeok , Hong Ka Young , Park Ji Hoon , Lee Jae Seung , Kim Hee Sun , Lee Song Hee , Jang Sung Key 
Published: December 2015

ABSTRACTHepatitis C virus (HCV) is one of the leading causes of chronic liver inflammatory disease (hepatitis), which often leads to more severe diseases, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis, in particular, is a major pathogenic consequence of HCV infection, and transforming growth factor β1 (TGF-β1) plays a key role in its pathogenesis. Several HCV proteins have been suggested to either augment or suppress the expression of TGF-β1 by HCV-infected cells. Here, we report that TGF-β1 levels are elevated in HCV-infected hepatocytes culturedin vitroand in liver tissue of HCV patients. Notably, the level of TGF-β1 in media fromin vitro-cultured HCV-infected hepatocytes was high enough to activate primary hepatic stellate cells isolated from rats. This indicates that TGF-β1 secreted by HCV-infected hepatocytes is likely to play a key role in the liver fibrosis observed in HCV patients. Moreover, we showed that HCV E2 protein triggers the production of TGF-β1 by HCV-infected cells through overproduction of glucose-regulated protein 94 (GRP94).IMPORTANCEHepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-β1. Here, we provide the first examination of TGF-β1 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-β1 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-β1 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-β1 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-β1 secretion via GRP94 mediated NF-κB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.
Analysis of Assembly and Budding of Lujo Virus
Authors: Urata Shuzo , Weyer Jacqueline , Storm Nadia , Miyazaki Yukiko , van Vuren Petrus Jansen , Paweska Janusz Tadeusz , Yasuda Jiro 
Published: December 2015

ABSTRACT
The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.
Coeliac screening in a Scottish cohort of children with type 1 diabetes mellitus: is DQ typing the way forward?
Authors: Mitchell R T , Sun A , Mayo A , Forgan M , Comrie A , Gillett P M 
Published: December 2015

BackgroundChildren with type 1 diabetes mellitus (T1DM) are at increased risk of coeliac disease (CD). Recent guidelines indicate coeliac screening should include HLA typing for CD predisposing (DQ2/DQ8) alleles and those negative for these alleles require no further coeliac screening.MethodsChildren (n=176) with T1DM attending clinics across two Scottish regions were screened for HLA DQ2/DQ8 as part of routine screening. Data collected included the frequency of DQ2/DQ8 genotypes and the additional cost of HLA screening.ResultsOverall, DQ2/DQ8 alleles were identified in 94% of patients. The additional cost of HLA typing was £3699.52 (£21.02 per patient). All patients with known CD (11/176) were positive for DQ2/DQ8 and all were diagnosed with CD within 5 years of T1DM diagnosis.ConclusionsThe vast majority of children with T1DM have CD-predisposing HLA genotypes limiting the number of patients that can be excluded from further screening. We conclude that HLA genotyping is not currently indicated for CD screening in this population.
Exercise prescription for patients with type 2 diabetes—a synthesis of international recommendations: narrative review
Authors: Mendes Romeu , Sousa Nelson , Almeida António , Subtil Paulo , Guedes-Marques Fernando , Reis Victor Machado , Themudo-Barata José Luís 
Published: December 2015

BackgroundPhysical activity is a cornerstone of type 2 diabetes treatment and control.AimWe analysed and synthesised the guidelines and recommendations issued by scientific organisations, regarding exercise prescription for patients with type 2 diabetes.MethodA systematic bibliographic search in Pubmed, Web of Science and Scopus databases was conducted. Clinical guidelines from major international scientific organisations in the field of diabetology, endocrinology, cardiology, public health and sports medicine were also considered. 11 publications were selected.ResultsPublished guidelines recommend a weekly accumulation of a minimum of 150 min of aerobic exercise at moderate-to-vigorous intensity spread over a minimum of 3 days per week. Resistance exercise for muscle strengthening is also recommended at least 2 days a week. Flexibility exercises may complement other types of exercise. Combining aerobic and resistance exercise within the same exercise session is recommended by most guidelines.ConclusionsExercise prescription for individuals with type 2 diabetes should include specific information on the type, mode, duration, intensity and weekly frequency. The exercise strategies must be adapted for each individual, based on comorbidities, contraindications and realistic personal goals.
Reporting missing participant data in randomised trials: systematic survey of the methodological literature and a proposed guide
Authors: Akl Elie A , Shawwa Khaled , Kahale Lara A , Agoritsas Thomas , Brignardello-Petersen Romina , Busse Jason W , Carrasco–Labra Alonso , Ebrahim Shanil , Johnston Bradley C , Neumann Ignacio , Sola Ivan , Sun Xin , Vandvik Per , Zhang Yuqing , Alonso-Coello Pablo , Guyatt Gordon H 
Published: December 2015

ObjectivesWe conducted a systematic survey of the methodological literature to identify recommended approaches for how and what randomised clinical trial (RCT) authors should report on missing participant data and, on the basis of these approaches, to propose guidance for RCT authors.MethodsWe defined missing participant data (MPD) as missing outcome data for trial participants. We considered both categorical and continuous outcome data. We searched MEDLINE and the Cochrane Methodology Register for articles in which authors proposed approaches to reporting MPD from RCTs. We selected eligible articles independently and in duplicate and extracted data in duplicate. Using an iterative process of discussion and revisions, we used the findings to develop guidance.ResultsOf 10 501 unique citations identified, 13 articles reporting on 10 approaches proved eligible. The identified approaches recommend reporting the following aspects (from most to least frequently recommended): number of participants with MPD (n=10), reasons for MPD (n=7), methods used to handle MPD in the analysis (n=4), flow of participants (n=3), pattern of missingness (eg, whether at random) (n=3), differences in rates of MPD between trial arms (n=2), differences between participants with and without MPD (n=2), results of any sensitivity analyses (n=2), implication of MPD on interpreting the results (n=2) and methods used to prevent missing data (n=1). We propose a guide with nine items related to reporting the number, reasons, patterns, analytical methods and interpretation of MPD.ConclusionsMost identified approaches invite trial authors to report the extent of MPD and the underlying reasons. Fewer approaches focus on reporting missingness patterns, methods for handling MPD and implications of MPD on results. Our proposed guidance could help RCT authors to better report, and readers to better identify participants with missing data.
Monitoring adverse events in Norwegian hospitals from 2010 to 2013
Authors: Deilkås Ellen Tveter , Bukholm Geir , Lindstrøm Jonas Christoffer , Haugen Marion 
Published: December 2015

ObjectivesTo describe how adverse event (AE) rates were monitored and estimated nationally across all Norwegian hospitals from 2010 to 2013, and how they developed during the monitoring period. Monitoring was based on medical record review with Global Trigger Tool (GTT).SettingAll publicly and privately owned hospitals were mandated to review randomly selected medical records to monitor AE rates. The initiative was part of the Norwegian patient safety campaign, launched by the Norwegian Ministry of Health and Care Services. It started in January 2011 and lasted until December 2013. 2010 was the baseline for the review. One of the main aims of the campaign was to reduce patient harm.MethodTo standardise the medical record reviews in all hospitals, GTT was chosen as a standard method. GTT teams from all hospitals reviewed 40 851 medical records randomly selected from 2 249 957 discharges from 2010 to 2013. Data were plotted in time series for local measurement and national AE rates were estimated, plotted and monitored.ResultsAE rates were estimated and published nationally from 2010 to 2013. Estimated AE rates in severity categories E-I decreased significantly from 16.1% in 2011 to 13.0% in 2013 (−3.1% (95% CI −5.2% to −1.1%)).ConclusionsMonitoring estimated AE rates emerges as a potential element in national systems for patient safety. Estimated AE rates in the category of least severity decreased significantly during the first 2 years of the monitoring.
Does a research article's country of origin affect perception of its quality and relevance? A national trial of US public health researchers
Authors: Harris M , Macinko J , Jimenez G , Mahfoud M , Anderson C 
Published: December 2015

ObjectivesThe source of research may influence one's interpretation of it in either negative or positive ways, however, there are no robust experiments to determine how source impacts on one's judgment of the research article. We determine the impact of source on respondents’ assessment of the quality and relevance of selected research abstracts.DesignWeb-based survey design using four healthcare research abstracts previously published and included in Cochrane Reviews.SettingAll Council on the Education of Public Health-accredited Schools and Programmes of Public Health in the USA.Participants899 core faculty members (full, associate and assistant professors)InterventionEach of the four abstracts appeared with a high-income source half of the time, and low-income source half of the time. Participants each reviewed the same four abstracts, but were randomly allocated to receive two abstracts with high-income source, and two abstracts with low-income source, allowing for within-abstract comparison of quality and relevancePrimary outcome measuresWithin-abstract comparison of participants’ rating scores on two measures—strength of the evidence, and likelihood of referral to a peer (1–10 rating scale). OR was calculated using a generalised ordered logit model adjusting for sociodemographic covariates.ResultsParticipants who received high income country source abstracts were equal in all known characteristics to the participants who received the abstracts with low income country sources. For one of the four abstracts (a randomised, controlled trial of a pharmaceutical intervention), likelihood of referral to a peer was greater if the source was a high income country (OR 1.28, 1.02 to 1.62, p<0.05).ConclusionsAll things being equal, in one of the four abstracts, the respondents were influenced by a high-income source in their rating of research abstracts. More research may be needed to explore how the origin of a research article may lead to stereotype activation and application in research evaluation.
A cluster-randomised controlled trial integrating a community-based water, sanitation and hygiene programme, with mass distribution of albendazole to reduce intestinal parasites in Timor-Leste: the WASH for WORMS research protocol
Authors: Nery Susana Vaz , McCarthy James S , Traub Rebecca , Andrews Ross M , Black Jim , Gray Darren , Weking Edmund , Atkinson Jo-An , Campbell Suzy , Francis Naomi , Vallely Andrew , Williams Gail , Clements Archie 
Published: December 2015

IntroductionThere is limited evidence demonstrating the benefits of community-based water, sanitation and hygiene (WASH) programmes on infections with soil-transmitted helminths (STH) and intestinal protozoa. Our study aims to contribute to that evidence base by investigating the effectiveness of combining two complementary approaches for control of STH: periodic mass administration of albendazole, and delivery of a community-based WASH programme.Methods and analysisWASH for WORMS is a cluster-randomised controlled trial to test the hypothesis that a community-based WASH intervention integrated with periodic mass distribution of albendazole will be more effective in reducing infections with STH and protozoa than mass deworming alone. All 18 participating rural communities in Timor-Leste receive mass chemotherapy every 6 months. Half the communities also receive the community-based WASH programme. Primary outcomes are the cumulative incidence of infection with STH. Secondary outcomes include the prevalence of protozoa; intensity of infection with STH; as well as morbidity indicators (anaemia, stunting and wasting). Each of the trial outcomes will be compared between control and intervention communities. End points will be measured 2 years after the first albendazole distribution; and midpoints are measured at 6 months intervals (12 months for haemoglobin and anthropometric indexes). Mixed-methods research will also be conducted in order to identify barriers and enablers associated with the acceptability and uptake of the WASH programme.Ethics and disseminationEthics approval was obtained from the human ethics committees at the University of Queensland, Australian National University, Timorese Ministry of Health, and University of Melbourne. The results of the trial will be published in peer-reviewed journals presented at national and international conferences, and disseminated to relevant stakeholders in health and WASH programmes. This study is funded by a Partnership for Better Health—Project grant from the National Health and Research Council (NHMRC), Australia.Trial registration numberACTRN12614000680662; Pre-results
Compliance with the proper use of an individual radiation dosimeter among children and the effects of improper use on the measured dose: a retrospective study 18–20 months following Japan's 2011 Fukushima nuclear incident
Authors: Nomura Shuhei , Tsubokura Masaharu , Hayano Ryugo , Yoneoka Daisuke , Ozaki Akihiko , Shimada Yuki , Furutani Tomoyuki , Kanazawa Yukio , Oikawa Tomoyoshi 
Published: December 2015

ObjectivesTo identify profiles of children who did not properly use individual radiation dosimeters following Japan's 2011 Fukushima nuclear incident, and to assess how much error is generated by improper dosimeter use.ParticipantsThe participants in this study comprised 1637 school children who participated in the external radiation exposure screening programme administrated by Minamisoma City (located 20–30 km from the Fukushima nuclear plant) between 18 and 20 months after the Fukushima incident.MethodsWe assessed the factors associated with improper use (non-use) of the dosimeters at specific time periods during the day (school commuting hours, at school, at home, outdoors and at bedtime) using logistic regression analyses. Ratios of the measured dose to regression estimates of the ‘expected’ dose (referred to as an error due to non-use) were also examined.ResultsOnly 119 children (7.3%) used the dosimeters properly in all time periods. This low rate was attributed primarily to non-use when children were in the home and outdoors, rather than at school. School level, air dose rate at home, gender, membership in outdoor sports clubs and time spent outdoors on weekends, were significantly associated with improper use, after adjustment for covariates. Data from children who did not wear the dosimeters to school and outdoors had statistically significant (but clinically insignificant) errors (ratio: 1.13, p<0.01; and 0.97, p<0.05, respectively), whereas improper use of the dosimeters at school, at home and at bedtime did not generate significant errors.ConclusionsWell-targeted rigorous instructions on the use of the dosimeter are required, with particular focus on time periods other than school hours. However, given the small dose error due to the improper use of the dosimeters, even if the dosimeters are improperly used, solid evaluation of the radiation exposure may be possible with some accuracy.
Balance ability in 7- and 10-year-old children: associations with prenatal lead and cadmium exposure and with blood lead levels in childhood in a prospective birth cohort study
Authors: Taylor Caroline M , Humphriss Rachel , Hall Amanda , Golding Jean , Emond Alan M 
Published: December 2015

ObjectivesMost studies reporting evidence of adverse effects of lead and cadmium on the ability to balance have been conducted in high-exposure groups or have included adults. The effects of prenatal exposure have not been well studied, nor have the effects in children been directly studied. The aim of the study was to identify the associations of lead (in utero and in childhood) and cadmium (in utero) exposure with the ability to balance in children aged 7 and 10 years.DesignProspective birth cohort study.ParticipantsMaternal blood lead (n=4285) and cadmium (n=4286) levels were measured by inductively coupled plasma mass spectrometry in women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) during pregnancy. Child lead levels were measured in a subsample of 582 of ALSPAC children at age 30 months.Main outcome measuresChildren completed a heel-to-toe walking test at 7 years. At 10 years, the children underwent clinical tests of static and dynamic balance. Statistical analysis using SPSS V.19 included logistic regression modelling, comparing categories of ≥5 vs <5 µg/dL for lead, and ≥1 vs <1 µg/L for cadmium.ResultsBalance at age 7 years was not associated with elevated in utero lead or cadmium exposure (adjusted OR for balance dysfunction: Pb 1.01 (95% CI 0.95 to 1.01), n=1732; Cd 0.95 (0.77 to 1.20), n=1734), or with elevated child blood lead level at age 30 months (adjusted OR 0.98 (0.92 to 1.05), n=354). Similarly, neither measures of static nor dynamic balance at age 10 years were associated with in utero lead or cadmium exposure, or child lead level.ConclusionsThese findings do not provide any evidence of an association of prenatal exposure to lead or cadmium, or lead levels in childhood, on balance ability in children. Confirmation in other cohorts is needed.