bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon-Induced Ifit Proteins: Their Role in Viral Pathogenesis
Authors: Fensterl Volker , Sen Ganes C. 
Published: November 2014

ABSTRACT

A major component of the protective antiviral host defense is contributed by the intracellular actions of the proteins encoded by interferon-stimulated genes (ISGs); among these are the
i
nter
f
eron-
i
nduced proteins with
t
etratricopeptide repeats (IFITs), consisting of four members in human and three in mouse. IFIT proteins do not have any known enzyme activity. Instead, they inhibit virus replication by binding and regulating the functions of cellular and viral proteins and RNAs. Although all IFITs are comprised of multiple copies of the degenerate tetratricopeptide repeats, their distinct tertiary structures enable them to bind different partners and affect host-virus interactions differently. The recent use of
Ifit
knockout mouse models has revealed novel antiviral functions of these proteins and new insights into the specificities of ISG actions. This article focuses on human and murine IFIT1 and IFIT2 by reviewing their mechanisms of action, their critical roles in protecting mice from viral pathogenesis, and viral strategies to evade IFIT action.
Human Noroviruses' Fondness for Histo-Blood Group Antigens
Authors: Singh Bishal K. , Leuthold Mila M. , Hansman Grant S. 
Published: November 2014

ABSTRACT
Human noroviruses are the dominant cause of outbreaks of gastroenteritis around the world. Human noroviruses interact with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. Indeed, synthetic HBGAs or HBGA-expressing enteric bacteria were shown to enhance norovirus infection in B cells. A number of studies have found a possible relationship between HBGA type and norovirus susceptibility. The genogroup II, genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Here we show high-resolution X-ray crystal structures of the capsid protruding (P) domains from epidemic GII.4 variants from 2004, 2006, and 2012, cocrystallized with a panel of HBGA types (H type 2, Lewis Y, Lewis B, Lewis A, Lewis X, A type, and B type). Many of the HBGA binding interactions were found to be complex, involving capsid loop movements, alternative HBGA conformations, and HBGA rotations. We showed that a loop (residues 391 to 395) was elegantly repositioned to allow for Lewis Y binding. This loop was also slightly shifted to provide direct hydrogen- and water-mediated bonds with Lewis B. We considered that the flexible loop modulated Lewis HBGA binding. The GII.4 noroviruses have dominated outbreaks over the past decade, which may be explained by their exquisite HBGA binding mechanisms, their fondness for Lewis HBGAs, and their temporal amino acid modifications.

IMPORTANCE
Our data provide a comprehensive picture of GII.4 P domain and HBGA binding interactions. The exceptionally high resolutions of our X-ray crystal structures allowed us to accurately recognize novel GII.4 P domain interactions with numerous HBGA types. We showed that the GII.4 P domain-HBGA interactions involved complex binding mechanisms that were not previously observed in norovirus structural studies. Many of the GII.4 P domain-HBGA interactions we identified were negative in earlier enzyme-linked immunosorbent assay (ELISA)-based studies. Altogether, our data show that the GII.4 norovirus P domains can accommodate numerous HBGA types.
Characterization of a Proteolytically Stable D-Peptide That Suppresses Herpes Simplex Virus 1 Infection: Implications for the Development of Entry-Based Antiviral Therapy
Authors: Jaishankar Dinesh , Yakoub Abraam M. , Bogdanov Anita , Valyi-Nagy Tibor , Shukla Deepak 
Published: November 2014

ABSTRACT

Uncontrolled herpes simplex virus 1 (HSV-1) infection can advance to serious conditions, including corneal blindness or fatal encephalitis. Here, we describe a highly potent anti-HSV-1 peptide (DG2) that inhibits HSV-1 entry into host cells and blocks all aspects of infection. Importantly, DG2 is highly resistant to proteases and shows minimal toxicity, paving the way for prophylactic or therapeutic application of the peptide
in vivo
.
The Enterovirus 71 Procapsid Binds Neutralizing Antibodies and Rescues Virus Infection
In Vitro
Authors: Shingler Kristin L. , Cifuente Javier O. , Ashley Robert E. , Makhov Alexander M. , Conway James F. , Hafenstein Susan 
Published: November 2014

ABSTRACT

Enterovirus 71 (EV71) is responsible for seasonal outbreaks of hand, foot, and mouth disease in the Asia-Pacific region. The virus has the capability to cause severe disease and death, especially in young children. Although several vaccines are currently in clinical trials, no vaccines or therapeutics have been approved for use. Previous structural studies have revealed that two antigenically distinct capsid forms are produced in EV71-infected cells: an expanded empty capsid, sometimes called a procapsid, and the infectious virus. Specifically, an immunodominant epitope of EV71 that maps to the virus canyon is structurally different in the procapsid and virus. This structure-function study shows that the procapsid can sequester antibodies, thus enhancing EV71 infection
in vitro
. The results presented here suggest that, due to conformational differences between the EV71 procapsid and virus, the presence of the procapsid in natural virus infections should be considered in the future design of vaccines or therapeutics.

IMPORTANCE
In a picornavirus infection, both an infectious and a noninfectious empty capsid, sometimes referred to as a procapsid, are produced. It was novel to discover that the procapsid form of EV71 was expanded and antigenically distinct from the infectious virus. Previously, it had been supposed that this empty capsid was an off-pathway dead end or at best served for storage of pentameric subunits, which was later shown to be unlikely. It remains unexplained why picornaviruses evolutionarily conserve the wasteful production of so much noninfectious capsid. Here, we demonstrate that the EV71 procapsid has different antigenic properties than the infectious virus. Thus, the procapsid has the capacity to sequester neutralizing antibody and protect the virus, promoting or restoring a successful infection
in vitro
. This important observation should be considered in the future design and development of vaccines and therapeutics.
Influenza A Virus Uses Intercellular Connections To Spread to Neighboring Cells
Authors: Roberts Kari L. , Manicassamy Balaji , Lamb Robert A. 
Published: November 2014

ABSTRACT
In the extracellular environment, cell-free virions seek out naive host cells over long distances and between organisms. This is the primary mechanism of spread for most viruses. Here we provide evidence for an alternative pathway previously undescribed for orthomyxoviruses, whereby the spread of influenza A virus (IAV) infectious cores to neighboring cells can occur within intercellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection. Connected cells have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. A live-cell movie of green fluorescent protein (GFP)-tagged NS1 of IAV shows viral protein moving from one cell to another through an intercellular connection. The movement of tagged protein was saltatory but overall traveled only in one direction. Infectious virus cores can move from one cell to another without budding and release of cell-free virions, as evidenced by the finding that whereas a neuraminidase inhibitor alone did not inhibit the development of IAV microplaques, the presence of a neuraminidase inhibitor together with drugs inhibiting actin dynamics or the microtubule stabilizer paclitaxel (originally named taxol) precluded microplaque formation. Similar results were also observed with parainfluenza virus 5 (PIV5), a paramyxovirus, when neutralizing antibody was used to block spread by cell-free virions. Intercellular spread of infectious core particles was unaffected or enhanced in the presence of nocodazole for IAV but inhibited for PIV5. The intercellular connections have a core of filamentous actin, which hints toward transport of virus particles through the use of a myosin motor.

IMPORTANCE
Here we describe a new method by which influenza A virus (IAV) spreads from cell to cell: IAV uses intracellular connections. The formation of these connections requires actin dynamics and is enhanced by viral infection and the absence of microtubules. Connected cells appeared to have contiguous membranes, and the core infectious viral machinery (RNP and polymerase) was present inside the intercellular connections. Infectious virus cores can move from one cell to another without budding and release of cell-free virions. Similar results were also observed with parainfluenza virus 5 (PIV5).
Identification of a Role for Nucleolin in Rabies Virus Infection
Authors: Oksayan S. , Nikolic J. , David C. T. , Blondel D. , Jans D. A. , Moseley G. W. 
Published: November 2014

ABSTRACT
Rabies virus replicates in the cytoplasm of host cells, but rabies virus phosphoprotein (P-protein) undergoes active nucleocytoplasmic trafficking. Here we show that the largely nuclear P-protein isoform P3 can localize to nucleoli and forms specific interactions with nucleolin. Importantly, depletion of nucleolin expression inhibits viral protein expression and infectious virus production by infected cells. This provides the first evidence that lyssaviruses interact with nucleolin and that nucleolin is important to lyssavirus infection.
Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis
Authors: Cheelo M , Lodge C J , Dharmage S C , Simpson J A , Matheson M , Heinrich J , Lowe A J 
Published: November 2014

Background and objectiveWhile paracetamol exposure in pregnancy and early infancy has been associated with asthma, it remains unclear whether this is confounded by respiratory tract infections, which have been suggested as an alternative explanation. We undertook a systematic review and meta-analysis of longitudinal studies that reported the association between paracetamol exposure during pregnancy or infancy and the subsequent development of childhood asthma (≥5 years).MethodsTwo independent researchers searched the databases EMBASE and PUBMED on 12 August 2013 for relevant articles using predefined inclusion and exclusion criteria. Study quality was assessed and results were pooled using fixed effect models or random effect models when moderate between-study heterogeneity was observed. We explicitly assessed whether the observed associations are due to confounding by respiratory tract infections.ResultsEleven observational cohort studies met the inclusion criteria. Any paracetamol use during the first trimester was related to increased risk of childhood asthma (5 studies, pooled OR=1.39, 95% CI 1.01 to 1.91) but there was marked between-study heterogeneity (I2=63%) and only one of these studies adjusted for maternal respiratory tract infections. Increasing frequency of use of paracetamol during infancy was associated with increased odds of childhood asthma (3 studies, pooled OR=1.15, 95% CI 1.00 to 1.31 per doubling of days exposure), but in these same three studies adjusting for respiratory tract infections reduced this association (OR=1.06, 95% CI 0.92 to 1.22).DiscussionThe association during early pregnancy exposure was highly variable between studies and exposure during infancy appears to be moderately confounded by respiratory tract infections. There is insufficient evidence to warrant changing guidelines on early life paracetamol exposure at this time.
Longitudinal follow-up of employment status in patients with chronic fatigue syndrome after mononucleosis
Authors: Nyland Morten , Naess Halvor , Birkeland Jon Steinar , Nyland Harald 
Published: November 2014

ObjectiveTo examine the effect of early clinical and demographic factors on occupational outcome, return to work or awarded permanent disability pension in young patients with chronic fatigue syndrome (CFS).DesignLongitudinal cohort study.InterventionA written self-management programme including a description of active coping strategies for daily life was provided.Setting, participantsPatients with CFS after mononucleosis were evaluated at Department of Neurology, Haukeland University Hospital during 1996–2006 (contact 1). In 2009 self-report questionnaires were sent to all patients (contact 2).Primary and secondary outcome measuresPrimary measure was employment status at contact 2.Secondary measures included clinical symptoms, and Fatigue Severity Scale (FSS) scores on both contacts, and Work and Social Adjustment Scale (WSAS) at contact 2.ResultsOf 111 patients at contact 1, 92 (83%) patients returned the questionnaire at contact 2. Mean disease duration at contact 1 was 4.7 years and at contact 2 11.4 years. At contact 1, 9 (10%) were part-time or full-time employed. At contact 2, 49 (55%) were part-time or full-time employed. Logical regression analysis showed that FSS≥5 at contact 2 was associated with depression, arthralgia and long disease duration (all at contact 1).ConclusionsAbout half of younger patients with CFS with long-term incapacity for work experienced marked improvement including full-time or part-time employment showing better outcomes than expected. Risk factors for transition to permanent disability were depression, arthralgia and disease duration.
The population-based Occupational and Environmental Health Prospective Cohort Study (AMIGO) in the Netherlands
Authors: Slottje Pauline , Yzermans C Joris , Korevaar Joke C , Hooiveld Mariëtte , Vermeulen Roel C H 
Published: November 2014

PurposeOccupational and environmental exposures remain important modifiable risk factors of public health. Existing cohort studies are often limited by the level of detail of data collected on these factors and health. It is also often assumed that the more healthy group is over-represented in cohort studies, which is of concern for their external validity. In this cohort profile, we describe how we set up the population-based Occupational and Environmental Health Cohort Study (AMIGO) to longitudinally study occupational and environmental determinants of diseases and well-being from a multidisciplinary and life course point of view. Reviewed by the Medical Ethics Research Committee of the University Medical Center Utrecht (protocol 10-268/C). All cohort members participate voluntarily and gave informed consent prior to their inclusion.Participants14 829 adult cohort members (16% of those invited) consented and filled in the online baseline questionnaire. Determinants include chemical, biological, physical (eg, electromagnetic fields), and psychosocial factors. Priority health outcomes include cancer, neurological, cardiovascular and respiratory diseases and non-specific symptoms. Owing to the recruitment strategy via general practitioners of an established network, we also collect longitudinal data registered in their electronic medical records including symptoms, diagnosis and treatments. Besides the advantage of health outcomes that cannot be easily captured longitudinally by other means, this created a unique opportunity to assess health-related participation bias by comparing general practitioner-registered prevalence rates in the cohort and its source population.Findings to dateWe found no indications of such a systematic bias. The major assets of the AMIGO approach are its detailed occupational and environmental determinants in combination with the longitudinal health data registered in general practice besides linkage to cancer and mortality registries and self-reported health.Future plansWe are now in the phase of prospective follow-up, with the aim of continuing this for as long as possible (20+ years), pending future funding. Findings will be disseminated through scientific conferences and peer-reviewed journals, and through newsletters and the project website to participants, stakeholders and the wider public.
Emerging role of traditional birth attendants in mountainous terrain: a qualitative exploratory study from Chitral District, Pakistan
Authors: Shaikh Babar Tasneem , Khan Sharifullah , Maab Ayesha , Amjad Sohail 
Published: November 2014

ObjectivesThis research endeavours to identify the role of traditional birth attendants (TBAs) in supporting the maternal, newborn and child health (MNCH) care, partnership mechanism with a formal health system and also explored livelihood options for TBAs in the health system of Pakistan.SettingThe study was conducted in district Chitral, Khyber Pakhtunkhwa province, covering the areas where the Chitral Child Survival programme was implemented.ParticipantsA qualitative exploratory study was conducted, comprising seven key informant interviews with health managers, and four focus group discussions with community midwives (CMWs), TBAs, members of Community Based Saving Groups (CBSGs) and members of village health committees (VHCs).ResultsThe study identified that in the new scenario, after the introduction of CMWs in the health system, TBAs still have a pivotal role in health promotion activities such as breastfeeding promotion and vaccination. TBAs can assist CMWs in normal deliveries, and refer high-risk cases to the formal health system. Generally, TBAs are positive about CMWs’ introduction and welcome this addition. Yet their livelihood has suffered after CMWs’ deployment. Monetary incentives to them in recognition of referrals to CMWs could be one solution. The VHC is an active forum for strengthening co-ordination between the two service providers and to ensure an alternate and permanent livelihood support system for the TBAs.ConclusionsTBAs have assured their continued support in provision of continuum of care for pregnant women, lactating mothers and children under the age of 5 years. The district health authorities must figure out ways to foster a healthy interface vis-à-vis roles and responsibilities of TBAs and CMWs. In time it would be worthwhile to do further research to look into the CMWs’ integration in the system, as well as TBAs’ continued role for provision of MNCH care.
Evaluating the efficacy of thoracoscopy and talc poudrage versus pleurodesis using talc slurry (TAPPS trial): protocol of an open-label randomised controlled trial
Authors: Bhatnagar Rahul , Laskawiec-Szkonter Magda , Piotrowska Hania E G , Kahan Brennan C , Hooper Clare E , Davies Helen E , Harvey John E , Miller Robert F , Rahman Najib M , Maskell Nick A 
Published: November 2014

IntroductionThe management of recurrent malignant pleural effusions (MPE) can be challenging. Various options are available, with the most efficacious and widely used being talc pleurodesis. Talc can either be applied via a chest drain in the form of slurry, or at medical thoracoscopy using poudrage. Current evidence regarding which method is most effective is conflicting and often methodologically flawed. The TAPPS trial is a suitably powered, multicentre, open-label, randomised controlled trial designed to compare the pleurodesis success rate of medical thoracoscopy and talc poudrage with chest drain insertion and talc slurry.Methods and analysis330 patients with a confirmed MPE requiring intervention will be recruited from UK hospitals. Patients will be randomised (1:1) to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g). The allocated procedure will be performed as an inpatient within 3 days of randomisation taking place. Following discharge, patients will be followed up at regular intervals for 6 months. The primary outcome measure is pleurodesis failure rates at 3 months. Pleurodesis failure is defined as the need for further pleural intervention for fluid management on the side of the trial intervention.Ethics and disseminationThe trial has received ethical approval from the National Research Ethics Service Committee North West—Preston (12/NW/0467). There is a trial steering committee which includes independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences, as well as being disseminated via local and national charities and patient groups. All participants who wish to know the study results will also be contacted directly on their publication.Trial registration numberISRCTN47845793.
Internet use, social engagement and health literacy decline during ageing in a longitudinal cohort of older English adults
Authors: Kobayashi Lindsay C , Wardle Jane , von Wagner Christian 
Published: November 2014

BackgroundHealth literacy skills tend to decline during ageing, which is often attributed to age-related cognitive decline. Whether health literacy skills may be influenced by technological and social factors during ageing is unknown.MethodsWe investigated whether internet use and social engagement protect against health literacy decline during ageing, independent of cognitive decline. We used prospective data from 4368 men and women aged ≥52 years in the English Longitudinal Study of Ageing from 2004 to 2011. Health literacy was measured at baseline (2004–2005) and at follow-up (2010–2011) using a reading comprehension test of a fictitious medicine label. The influences of consistent internet use and engagement in each of the civic, leisure and cultural activities on health literacy decline over the follow-up were estimated.ResultsAfter adjusting for cognitive decline and other covariates, consistent internet use (1379/4368; 32%) was protectively associated with health literacy decline (OR=0.77; 95% CI 0.60 to 0.99), as was consistent engagement in cultural activities (1715/4368; 39%; OR=0.73; 95% CI 0.56 to 0.93). As the number of activities engaged in increased, the likelihood of health literacy decline steadily decreased (ptrend<0.0001), with OR=0.51 (95% CI 0.33 to 0.79) for engaging in all four of the internet use and civic, leisure and cultural activities versus none.ConclusionsInternet use and social engagement, particularly in cultural activities (eg, attending the cinema, art galleries, museums and the theatre), may help older adults to maintain health literacy during ageing. Support for older adults to maintain socially engaged lives and to access the internet should help promote the maintenance of functional literacy skills during ageing.