bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Interferon-Stimulated Gene
Ifi27l2a
Restricts West Nile Virus Infection and Pathogenesis in a Cell-Type- and Region-Specific Manner
Authors: Lucas Tiffany M. , Richner Justin M. , Diamond Michael S. 
Published: December 2015

ABSTRACT

The mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (ISGs). While the functional significance of many ISGs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. Using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified
Ifi27l2a
as a candidate antiviral ISG within neuronal subsets of the central nervous system (CNS) that restricts infection by West Nile virus (WNV), an encephalitic flavivirus of global concern. To investigate the physiological relevance of Ifi27l2a in the context of viral infection, we generated
Ifi27l2a
−/−
mice. Although adult mice lacking
Ifi27l2a
were more vulnerable to lethal WNV infection, the viral burden was greater only within the CNS, particularly in the brain stem, cerebellum, and spinal cord. Within neurons of the cerebellum and brain stem, in the context of WNV infection, a deficiency of Ifi27l2a was associated with less cell death, which likely contributed to sustained viral replication and higher titers in these regions. Infection studies in a primary cell culture revealed that
Ifi27l2a
−/−
cerebellar granule cell neurons and macrophages but not cerebral cortical neurons, embryonic fibroblasts, or dendritic cells sustained higher levels of WNV infection than wild-type cells and that this difference was greater under conditions of beta interferon (IFN-β) pretreatment. Collectively, these findings suggest that Ifi27l2a has an antiviral phenotype in subsets of cells and that at least some ISGs have specific inhibitory functions in restricted tissues.

IMPORTANCE
The interferon-stimulated
Ifi27l2a
gene is expressed differentially within the central nervous system upon interferon stimulation or viral infection. Prior studies in cell culture suggested an antiviral role for Ifi27l2a during infection by West Nile virus (WNV). To characterize its antiviral activity
in vivo
, we generated mice with a targeted gene deletion of
Ifi27l2a
. Based on extensive virological analyses, we determined that Ifi27l2a protects mice from WNV-induced mortality by contributing to the control of infection of the hindbrain and spinal cord, possibly by regulating cell death of neurons. This antiviral activity was validated in granule cell neurons derived from the cerebellum and in macrophages but was not observed in other cell types. Collectively, these data suggest that Ifi27l2a contributes to innate immune restriction of WNV in a cell-type- and tissue-specific manner.
Generation of Recombinant Oropouche Viruses Lacking the Nonstructural Protein NSm or NSs
Authors: Tilston-Lunel Natasha L. , Acrani Gustavo Olszanski , Randall Richard E. , Elliott Richard M. 
Published: December 2015

ABSTRACT

Oropouche virus (OROV) is a midge-borne human pathogen with a geographic distribution in South America. OROV was first isolated in 1955, and since then, it has been known to cause recurring outbreaks of a dengue-like illness in the Amazonian regions of Brazil. OROV, however, remains one of the most poorly understood emerging viral zoonoses. Here we describe the successful recovery of infectious OROV entirely from cDNA copies of its genome and generation of OROV mutant viruses lacking either the NSm or the NSs coding region. Characterization of the recombinant viruses carried out
in vitro
demonstrated that the NSs protein of OROV is an interferon (IFN) antagonist as in other NSs-encoding bunyaviruses. Additionally, we demonstrate the importance of the nine C-terminal amino acids of OROV NSs in IFN antagonistic activity. OROV was also found to be sensitive to IFN-α when cells were pretreated; however, the virus was still capable of replicating at doses as high as 10,000 U/ml of IFN-α, in contrast to the family prototype BUNV. We found that OROV lacking the NSm protein displayed characteristics similar to those of the wild-type virus, suggesting that the NSm protein is dispensable for virus replication in the mammalian and mosquito cell lines that were tested.

IMPORTANCE
Oropouche virus (OROV) is a public health threat in Central and South America, where it causes periodic outbreaks of dengue-like illness. In Brazil, OROV is the second most frequent cause of arboviral febrile illness after dengue virus, and with the current rates of urban expansion, more cases of this emerging viral zoonosis could occur. To better understand the molecular biology of OROV, we have successfully rescued the virus along with mutants. We have established that the C terminus of the NSs protein is important in interferon antagonism and that the NSm protein is dispensable for virus replication in cell culture. The tools described in this paper are important in terms of understanding this important yet neglected human pathogen.
Antigenic and Cryo-Electron Microscopy Structure Analysis of a Chimeric Sapovirus Capsid
Authors: Miyazaki Naoyuki , Taylor David W. , Hansman Grant S. , Murata Kazuyoshi 
Published: December 2015

ABSTRACT
The capsid protein (VP1) of all caliciviruses forms an icosahedral particle with two principal domains, shell (S) and protruding (P) domains, which are connected via a flexible hinge region. The S domain forms a scaffold surrounding the nucleic acid, while the P domains form a homodimer that interacts with receptors. The P domain is further subdivided into two subdomains, termed P1 and P2. The P2 subdomain is likely an insertion in the P1 subdomain; consequently, the P domain is divided into the P1-1, P2, and P1-2 subdomains. In order to investigate capsid antigenicity, N-terminal (N-term)/S/P1-1 and P2/P1-2 were switched between two sapovirus genotypes GI.1 and GI.5. The chimeric VP1 constructs were expressed in insect cells and were shown to self-assemble into virus-like particles (VLPs) morphologically similar to the parental VLPs. Interestingly, the chimeric VLPs had higher levels of cross-reactivities to heterogeneous antisera than the parental VLPs. In order to better understand the antigenicity from a structural perspective, we determined an intermediate-resolution (8.5-Å) cryo-electron microscopy (cryo-EM) structure of a chimeric VLP and developed a VP1 homology model. The cryo-EM structure revealed that the P domain dimers were raised slightly (∼5 Å) above the S domain. The VP1 homology model allowed us predict the S domain (67–229) and P1-1 (229–280), P2 (281–447), and P1-2 (448–567) subdomains. Our results suggested that the raised P dimers might expose immunoreactive S/P1-1 subdomain epitopes. Consequently, the higher levels of cross-reactivities with the chimeric VLPs resulted from a combination of GI.1 and GI.5 epitopes.

IMPORTANCE
We developed sapovirus chimeric VP1 constructs and produced the chimeric VLPs in insect cells. We found that both chimeric VLPs had a higher level of cross-reactivity against heterogeneous VLP antisera than the parental VLPs. The cryo-EM structure of one chimeric VLP (Yokote/Mc114) was solved to 8.5-Å resolution. A homology model of the VP1 indicated for the first time the putative S and P (P1-1, P2, and P1-2) domains. The overall structure of Yokote/Mc114 contained features common among other caliciviruses. We showed that the P2 subdomain was mainly involved in the homodimeric interface, whereas a large gap between the P1 subdomains had fewer interactions.
Lipid Membranes Facilitate Conformational Changes Required for Reovirus Cell Entry
Authors: Snyder Anthony J. , Danthi Pranav 
Published: December 2015

ABSTRACT

Cellular entry of nonenveloped and enveloped viruses is often accompanied by dramatic conformational changes within viral structural proteins. These rearrangements are triggered by a variety of mechanisms, such as low pH, virus-receptor interactions, and virus-host chaperone interactions. Reoviruses, a model system for entry of nonenveloped viruses, undergo a series of disassembly steps within the host endosome. One of these steps, infectious subviral particle (ISVP)-to-ISVP* conversion, is necessary for delivering the genome-containing viral core into host cells, but the physiological trigger that mediates ISVP-to-ISVP* conversion during cell entry is unknown. Structural studies of the reovirus membrane penetration protein, μ1, predict that interactions between μ1 and negatively charged lipid head groups may promote ISVP* formation; however, experimental evidence for this idea is lacking. Here, we show that the presence of polyanions (SO
4
2−
and HPO
4
2−
) or lipids in the form of liposomes facilitates ISVP-to-ISVP* conversion. The requirement for charged lipids appears to be selective, since phosphatidylcholine and phosphatidylethanolamine promoted ISVP* formation, whereas other lipids, such as sphingomyelin and sulfatide, either did not affect ISVP* formation or prevented ISVP* formation. Thus, our work provides evidence that interactions with membranes can function as a trigger for a nonenveloped virus to gain entry into host cells.

IMPORTANCE
Cell entry, a critical stage in the virus life cycle, concludes with the delivery of the viral genetic material across host membranes. Regulated structural transitions within nonenveloped and enveloped viruses are necessary for accomplishing this step; these conformational changes are predominantly triggered by low pH and/or interactions with host proteins. In this work, we describe a previously unknown trigger, interactions with lipid membranes, which can induce the structural rearrangements required for cell entry. This mechanism operates during entry of mammalian orthoreoviruses. We show that interactions between reovirus entry intermediates and lipid membranes devoid of host proteins promote conformational changes within the viral outer capsid that lead to membrane penetration. Thus, this work illustrates a novel strategy that nonenveloped viruses can use to gain access into cells and how viruses usurp disparate host factors to initiate infection.
European Academies Advise on Gain-of-Function Studies in Influenza Virus Research
Authors: Fears Robin , ter Meulen Volker 
Published: December 2015

ABSTRACT
Gain-of-function (GoF) studies to understand factors affecting transmissibility of potentially pandemic pathogens are controversial. The European Academies Science Advisory Council (EASAC) recently published consensus recommendations relating to GoF research review and management on self-regulation and harmonization; bioethical considerations; benefit-risk assessment; biosafety, and biosecurity advisory options; and publication of sensitive information. A layered approach to integration of responsibilities must include conforming to the stringent rules and guidance already existing. Further commitment is essential to extend the debate on issues worldwide.
Child Health General Practice Hubs: a service evaluation
Authors: Montgomery-Taylor Sarah , Watson Mando , Klaber Robert 
Published: December 2015

ObjectiveTo evaluate the impact of an integrated child health system.DesignMixed methods service evaluation.Setting and patientsChildren, young people and their families registered in Child Health General Practitioner (GP) Hubs where groups of GP practices come together to form ‘hubs’.InterventionsHospital paediatricians and GPs participating in joint clinics and multidisciplinary team (MDT) meetings in GP practices, a component of an ‘Inside-Out’ change known as ‘Connecting Care For Children (CC4C)’.Main outcome measuresCases seen in clinic or discussed at MDT meetings and their follow-up needs. Hospital Episode data: outpatient and inpatient activity and A&E attendance. Patient-reported experience measures and professionals’ feedback.ResultsIn one hub, 39% of new patient hospital appointments were avoided altogether and a further 42% of appointments were shifted from hospital to GP practice. In addition, there was a 19% decrease in sub-specialty referrals, a 17% reduction in admissions and a 22% decrease in A&E attenders. Smaller hubs running at lower capacity in early stages of implementation had less impact on hospital activity. Patients preferred appointments at the GP practice, gained increased confidence in taking their child to the GP and all respondents said they would recommend the service to family and friends. Professionals valued the improvement in knowledge and learning and, most significantly, the development of trust and collaboration.ConclusionsChild Health GP Hubs increase the connections between secondary and primary care, reduce secondary care usage and receive high patient satisfaction ratings while providing learning for professionals.
Exercise-based management versus surgery for multidirectional instability of the glenohumeral joint: a systematic review
Authors: Warby Sarah A , Pizzari Tania , Ford Jon J , Hahne Andrew J , Watson Lyn 
Published: December 2015

BackgroundThe most commonly recommended treatment for multidirectional instability (MDI) is exercise-based management, followed by surgery if exercise management fails. We aimed to evaluate the effectiveness of exercise-based management compared with surgery in patients with MDI. Secondary aims were to identify effective protocols and any adverse effects associated with exercise or surgery.MethodThe Cochrane database of systematic reviews, MEDLINE, EMBASE, CINAHL, PEDro, Current Contents, AMED, AMI, Ausport and Clinical Trials Registers were searched for published and unpublished studies from inception date to August 2014, using the key words multidirectional instability, and glenohumeral and exercise and surgery. Selection criteria included all study designs (except case reports and case series) and participants with MDI where both exercise-based management and surgery were compared in the same study. Inclusion criteria were not limited by outcomes. Risk of bias was assessed using Cochrane criteria. The GRADE approach was used to synthesise the evidence.Results4 non-randomised studies met the inclusion criteria. Risk of bias was high in all 4 studies. GRADE assessment revealed very low-quality evidence that surgery was superior to exercise therapy for impairment outcome measures, and exercise was favoured over surgery for patient-reported outcome measures.SummaryThe effect of exercise-based management compared with surgery for MDI is difficult to determine due to participant heterogeneity and a high level of bias across included studies.
Central pain processing is altered in people with Achilles tendinopathy
Authors: Tompra Nefeli , van Dieën Jaap H , Coppieters Michel W 
Published: December 2015

BackgroundTendinopathy is often a chronic condition. The mechanisms behind persistent tendon pain are not yet fully understood. It is unknown whether, similar to other persistent pain states, central pain mechanisms contribute to ongoing tendon pain.AimWe investigated the presence of altered central pain processing in Achilles tendinopathy by assessing the conditioned pain modulation (CPM) effect in people with and without Achilles tendinopathy.Methods20 people with Achilles tendinopathy and 23 healthy volunteers participated in this cross-sectional study. CPM was assessed by the cold pressor test. The pressure pain threshold (PPT) was recorded over the Achilles tendon before and during immersion of the participant's hand into cold water. The CPM effect was quantified as the absolute difference in PPT before and during the cold pressor test.ResultsAn increase in PPT was observed in the Achilles tendinopathy and control group during the cold pressor test (p<0.001). However, the CPM effect was stronger in the control group (mean difference=160.5 kPa, SD=84.9 kPa) compared to the Achilles tendinopathy group (mean difference=36.4 kPa, SD=68.1 kPa; p<0.001).SummaryWe report a reduced conditioned pain modulation effect in people with Achilles tendinopathy compared to people without Achilles tendinopathy. A reduced conditioned pain modulation effect reflects altered central pain processing which is believed to contribute to the persistence of pain in other conditions. Altered central pain processing may also be an important factor in persistent tendon pain that has traditionally been regarded to be dominated by peripheral mechanisms.
RISUS study: Rugby Injury Surveillance in Ulster Schools
Authors: Archbold H A P , Rankin A T , Webb M , Nicholas R , Eames N W A , Wilson R K , Henderson L A , Heyes G J , Bleakley C M 
Published: December 2015

ObjectiveTo examine injury patterns in adolescent rugby players and determine factors associated with injury risk.DesignProspective injury surveillance study.SettingN=28 Grammar Schools in Ulster, Ireland (2014–2015 playing season).Participants825 adolescent rugby players, across in 28 school first XV rugby squads; mean age 16.9 years.Main outcome measuresInjuries were classified by body part and diagnosis, and injury incidence using injuries per 1000 match hours of exposure. HRs for injury were calculated through Cox proportional hazard regression after correction for influential covariates.ResultsA total of n=426 injuries were reported across the playing season. Over 50% of injuries occurred in the tackle situation or during collisions (270/426), with few reported during set plays. The 3 most common injury sites were head/face (n=102, 23.9%), clavicle/shoulder (n=65, 15.3%) and the knee (n=56, 13.1%). Sprain (n=133, 31.2%), concussion (n=81, 19%) and muscle injury (n=65, 15.3%) were the most common diagnoses. Injury incidence is calculated at 29.06 injuries per 1000 match hours. There were no catastrophic injuries. A large percentage of injuries (208/424) resulted in absence from play for more than 28 days. Concussion carried the most significant time out from play (n=33; 15.9%), followed by dislocations of the shoulder (n=22; 10.6%), knee sprains (n=19, 9.1%), ankle sprains (n=14, 6.7%), hand/finger/thumb (n=11; 5.3%). 36.8% of participants in the study (304/825) suffered at least one injury during the playing season. Multivariate models found higher risk of injury (adjusted HR (AHR); 95% CI) with: higher age (AHR 1.45; 1.14 to 1.83), heavier weight (AHR 1.32; 1.04 to 1.69), playing representative rugby (AHR 1.42; 1.06 to 1.90) and undertaking regular strength training (AHR 1.65; 1.11 to 2.46). Playing for a lower ranked team (AHR 0.67; 0.49 to 0.90) and wearing a mouthguard (AHR 0.70; 0.54 to 0.92) were associated with lower risk of injury.ConclusionsThere was a high incidence of severe injuries, with concussion, ankle and knee ligament injuries and upper limb fractures/dislocations causing greatest time loss. Players were compliant with current graduated return-to-play regulations following concussion. Physical stature and levels of competition were important risk factors and there was limited evidence for protective equipment.
Death by homicide in National Collegiate Athletic Association athletes between 2003 and 2013
Authors: Rao Ashwin L , Poon Steven , Drezner Jonathan A , Zigman Monica , Asif Irfan M , Harmon Kimberly G 
Published: December 2015

BackgroundThe incidence of homicide-related death among individuals of college age in the United States population is estimated at 15.5/100 000. The incidence of homicide among National Collegiate Athletic Association (NCAA) athletes is unknown.AimTo investigate the rate of homicide-related death in NCAA athletes and to identify associated risk factors.MethodsThe NCAA Resolutions list, NCAA catastrophic insurance claims, media reports, and published NCAA demographic data were used to identify student athlete deaths and total participant seasons from 2003–04 through 2012–13. Homicide-related deaths were analysed by sex, race, division, sport, method, location, and circumstance. Internet searches were used to gather case details.ResultsForty-two cases of homicide-related death were identified from 4 242 519 individual participant seasons during the ten-year study period. The incidence of homicide-related death in NCAA athletes was 1.0/100 000. The incidence in males was 1.45/100 000 and in females was 0.4/100 000 (relative risk (RR) 2.9, p=0.01). The incidence in black athletes was 4.2/100 000 and in white athletes was 0.4/100 000 (RR 7.0, p<0.001). The highest sport-specific homicide-related death rate was in American football (3.7/100 000), with a RR of 4.4 (p=0.002) compared to all other sports. 88% of cases occurred off-campus. 38% of cases occurred at a social gathering, and 38% of cases occurred in a place of residence. 74% involved a fatal shooting.ConclusionsHomicide-related deaths in NCAA athletes occur most commonly in males, black athletes, and American football players. Understanding the incidence, risk factors, and circumstances of homicide-related deaths in college athletes may assist NCAA institutions in developing preventative measures.Trial registration numberUniversity of Washington Human Subjects Application, HSD No. 42077.
Qualitative study of telemonitoring of blood glucose and blood pressure in type 2 diabetes
Authors: Hanley Janet , Fairbrother Peter , McCloughan Lucy , Pagliari Claudia , Paterson Mary , Pinnock Hilary , Sheikh Aziz , Wild Sarah , McKinstry Brian 
Published: December 2015

ObjectivesTo explore the experiences of patients and professionals taking part in a randomised controlled trial (RCT) of blood glucose, blood pressure (BP) and weight telemonitoring in type 2 diabetes supported by primary care, and identify factors facilitating or hindering the effectiveness of the intervention and those likely to influence its potential translation to routine practice.DesignQualitative study adopting an interpretive descriptive approach.Participants23 patients, 6 nurses and 4 doctors who were participating in a RCT of blood glucose and BP telemonitoring. A maximum variation sample of patients from within the trial based on age, sex and deprivation status of the practice was sought.Setting12 primary care practices in Scotland and England.MethodData were collected via recorded semistructured interviews. Analysis was inductive with themes presented within an overarching thematic framework. Multiple strategies were employed to ensure that the analysis was credible and trustworthy.ResultsTelemonitoring of blood glucose, BP and weight by people with type 2 diabetes was feasible. The data generated by telemonitoring supported self-care decisions and medical treatment decisions. Motivation to self-manage diet was increased by telemonitoring of blood glucose, and the ‘benign policing’ aspect of telemonitoring was considered by patients to be important. The convenience of home monitoring was very acceptable to patients although professionals had some concerns about telemonitoring increasing workload and costs.ConclusionsTelemonitoring of blood glucose, BP and weight in primary care is a promising way of improving diabetes management which would be highly acceptable to the type of patients who volunteered for this study.Trial registration numberISRCTN71674628; Pre-results.