bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Molecular Sensor To Characterize Arenavirus Envelope Glycoprotein Cleavage by Subtilisin Kexin Isozyme 1/Site 1 Protease
Authors: Oppliger Joel , da Palma Joel Ramos , Burri Dominique J. , Bergeron Eric , Khatib Abdel-Majid , Spiropoulou Christina F. , Pasquato Antonella , Kunz Stefan 
Published: October 2015

ABSTRACT
Arenaviruses are emerging viruses including several causative agents of severe hemorrhagic fevers in humans. The advent of next-generation sequencing technology has greatly accelerated the discovery of novel arenavirus species. However, for many of these viruses, only genetic information is available, and their zoonotic disease potential remains unknown. During the arenavirus life cycle, processing of the viral envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P) is crucial for productive infection. The ability of newly emerging arenaviruses to hijack human SKI-1/S1P appears, therefore, to be a requirement for efficient zoonotic transmission and human disease potential. Here we implement a newly developed cell-based molecular sensor for SKI-1/S1P to characterize the processing of arenavirus GPC-derived target sequences by human SKI-1/S1P in a quantitative manner. We show that only nine amino acids flanking the putative cleavage site are necessary and sufficient to accurately recapitulate the efficiency and subcellular location of arenavirus GPC processing. In a proof of concept, our sensor correctly predicts efficient processing of the GPC of the newly emergent pathogenic Lujo virus by human SKI-1/S1P and defines the exact cleavage site. Lastly, we employed our sensor to show efficient GPC processing of a panel of pathogenic and nonpathogenic New World arenaviruses, suggesting that GPC cleavage represents no barrier for zoonotic transmission of these pathogens. Our SKI-1/S1P sensor thus represents a rapid and robust test system for assessment of the processing of putative cleavage sites derived from the GPCs of newly discovered arenavirus by the SKI-1/S1P of humans or any other species, based solely on sequence information.

IMPORTANCE
Arenaviruses are important emerging human pathogens that can cause severe hemorrhagic fevers with high mortality in humans. A crucial step in productive arenavirus infection of human cells is the processing of the viral envelope glycoprotein by the cellular subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P). In order to break the species barrier during zoonotic transmission and cause severe disease in humans, newly emerging arenaviruses must be able to hijack human SKI-1/S1P efficiently. Here we implement a newly developed cell-based molecular sensor for human SKI-1/S1P to characterize the processing of arenavirus glycoproteins in a quantitative manner. We further use our sensor to correctly predict efficient processing of the glycoprotein of the newly emergent pathogenic Lujo virus by human SKI-1/S1P. Our sensor thus represents a rapid and robust test system with which to assess whether the glycoprotein of any newly emerging arenavirus can be efficiently processed by human SKI-1/S1P, based solely on sequence information.
Modulation of Mitochondrial Antiviral Signaling by Human Herpesvirus 8 Interferon Regulatory Factor 1
Authors: Hwang Keun Young , Choi Young Bong 
Published: October 2015

ABSTRACTMitochondrial lipid raft-like microdomains, experimentally also termed mitochondrial detergent-resistant membrane fractions (mDRM), play a role as platforms for recruiting signaling molecules involved in antiviral responses such as apoptosis and innate immunity. Viruses can modulate mitochondrial functions for their own survival and replication. However, viral regulation of the antiviral responses via mDRM remains incompletely understood. Here, we report that human herpesvirus 8 (HHV-8) gene product viral interferon regulatory factor 1 (vIRF-1) is targeted to mDRM during virus replication and negatively regulates the mitochondrial antiviral signaling protein (MAVS)-mediated antiviral responses. The N-terminal region of vIRF-1 interacts directly with membrane lipids, including cardiolipin. In addition, a GxRP motif within the N terminus of vIRF-1, conserved in the mDRM-targeting region of mitochondrial proteins, including PTEN-induced putative kinase 1 (PINK1) and MAVS, was found to be important for vIRF-1 association with mitochondria. Furthermore, MAVS, which has the potential to promote vIRF-1 targeting to mDRM possibly by inducing cardiolipin exposure on the outer membrane of mitochondria, interacts with vIRF-1, which, in turn, inhibits MAVS-mediated antiviral signaling. Consistent with these results, vIRF-1 targeting to mDRM contributes to promotion of HHV-8 productive replication and inhibition of associated apoptosis. Combined, our results suggest novel molecular mechanisms for negative-feedback regulation of MAVS by vIRF-1 during virus replication.IMPORTANCESuccessful virus replication is in large part achieved by the ability of viruses to counteract apoptosis and innate immune responses elicited by infection of host cells. Recently, mitochondria have emerged to play a central role in antiviral signaling. In particular, mitochondrial lipid raft-like microdomains appear to function as platforms in cell apoptosis signaling. However, viral regulation of antiviral signaling through the mitochondrial microdomains remains incompletely understood. The present study demonstrates that HHV-8-encoded vIRF-1 targets to the mitochondrial detergent-resistant microdomains via direct interaction with cardiolipin and inhibits MAVS protein-mediated apoptosis and type I interferon gene expression in a negative-feedback manner, thus promoting HHV-8 productive replication. These results suggest that vIRF-1 is the first example of a viral protein to inhibit mitochondrial antiviral signaling through lipid raft-like microdomains.
Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice
Authors: Wohlbold Teddy John , Chromikova Veronika , Tan Gene S. , Meade Philip , Amanat Fatima , Comella Phillip , Hirsh Ariana , Krammer Florian 
Published: October 2015

ABSTRACT

Between November 2013 and February 2014, China reported three human cases of H10N8 influenza virus infection in the Jiangxi province, two of which were fatal. Using hybridoma technology, we isolated a panel of H10- and N8-directed monoclonal antibodies (MAbs) and further characterized the binding reactivity of these antibodies (via enzyme-linked immunosorbent assay) to a range of purified virus and recombinant protein substrates. The H10-directed MAbs displayed functional hemagglutination inhibition (HI) and neutralization activity, and the N8-directed antibodies displayed functional neuraminidase inhibition (NI) activity against H10N8. Surprisingly, the HI-reactive H10 antibodies, as well as a previously generated, group 2 hemagglutinin (HA) stalk-reactive antibody, demonstrated NI activity against H10N8 and an H10N7 strain; this phenomenon was absent when virus was treated with detergent, suggesting the anti-HA antibodies inhibited neuraminidase enzymatic activity through steric hindrance. We tested the prophylactic efficacy of one representative H10-reactive, N8-reactive, and group 2 HA stalk-reactive antibody
in vivo
using a BALB/c challenge model. All three antibodies were protective at a high dose (5 mg/kg). At a low dose (0.5 mg/kg), only the anti-N8 antibody prevented weight loss. Together, these data suggest that antibody targets other than the globular head domain of the HA may be efficacious in preventing influenza virus-induced morbidity and mortality.

IMPORTANCE
Avian H10N8 and H10N7 viruses have recently crossed the species barrier, causing morbidity and mortality in humans and other mammals. Although these reports are likely isolated incidents, it is possible that more cases may emerge in future winter seasons, similar to H7N9. Furthermore, regular transmission of avian influenza viruses to humans increases the risk of adaptive mutations and reassortment events, which may result in a novel virus with pandemic potential. Currently, no specific therapeutics or vaccines are available against the H10N8 influenza virus subtype. We generated a panel of H10- and N8-reactive MAbs. Although these antibodies may practically be developed into therapeutic agents, characterizing the protective potential of MAbs that have targets other than the HA globular head domain will provide insight into novel antibody-mediated mechanisms of protection and help to better understand correlates of protection for influenza A virus infection.
Prion Type-Dependent Deposition of
PRNP
Allelic Products in Heterozygous Sheep
Authors: Langeveld J. P. M. , Jacobs J. G. , Hunter N. , van Keulen L. J. M. , Lantier F. , van Zijderveld F. G. , Bossers A. 
Published: October 2015

ABSTRACT

Susceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrP
res
) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrP
res
material from BSE-infected ARR/VRQ sheep. PrP
res
in BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ-PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrP
res
accumulation process in prion formation as well as the disease-associated phenotypic expressions in the host.

IMPORTANCE
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R-PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation.
Single Mutations in the VP2 300 Loop Region of the Three-Fold Spike of the Carnivore Parvovirus Capsid Can Determine Host Range
Authors: Allison Andrew B. , Organtini Lindsey J. , Zhang Sheng , Hafenstein Susan L. , Holmes Edward C. , Parrish Colin R. 
Published: October 2015

ABSTRACT
Sylvatic carnivores, such as raccoons, have recently been recognized as important hosts in the evolution of canine parvovirus (CPV), a pandemic pathogen of domestic dogs. Although viruses from raccoons do not efficiently bind the dog transferrin receptor (TfR) or infect dog cells, a single mutation changing an aspartic acid to a glycine at capsid (VP2) position 300 in the prototype raccoon CPV allows dog cell infection. Because VP2 position 300 exhibits extensive amino acid variation among the carnivore parvoviruses, we further investigated its role in determining host range by analyzing its diversity and evolution in nature and by creating a comprehensive set of VP2 position 300 mutants in infectious clones. Notably, some position 300 residues rendered CPV noninfectious for dog, but not cat or fox, cells. Changes of adjacent residues (residues 299 and 301) were also observed often after cell culture passage in different hosts, and some of the mutations mimicked changes seen in viruses recovered from natural infections of alternative hosts, suggesting that compensatory mutations were selected to accommodate the new residue at position 300. Analysis of the TfRs of carnivore hosts used in the experimental evolution studies demonstrated that their glycosylation patterns varied, including a glycan present only on the domestic dog TfR that dictates susceptibility to parvoviruses. Overall, there were significant differences in the abilities of viruses with alternative position 300 residues to bind TfRs and infect different carnivore hosts, demonstrating that the process of infection is highly host dependent and that VP2 position 300 is a key determinant of host range.

IMPORTANCE
Although the emergence and pandemic spread of canine parvovirus (CPV) are well documented, the carnivore hosts and evolutionary pathways involved in its emergence remain enigmatic. We recently demonstrated that a region in the capsid structure of CPV, centered around VP2 position 300, varies after transfer to alternative carnivore hosts and may allow infection of previously nonsusceptible hosts
in vitro
. Here we show that VP2 position 300 is the most variable residue in the parvovirus capsid in nature, suggesting that it is a critical determinant in the cross-species transfer of viruses between different carnivores due to its interactions with the transferrin receptor to mediate infection. To this end, we demonstrated that there are substantial differences in receptor binding and infectivity of various VP2 position 300 mutants for different carnivore species and that single mutations in this region can influence whether a host is susceptible or refractory to virus infection.
Does physiotherapy diagnosis of shoulder pathology compare to arthroscopic findings?
Authors: Magarey Mary Elizabeth , Jones Mark Alan , Cook Chad E , Hayes Michael George 
Published: October 2015

AimsTo explore the ability of a physiotherapist, using a standardised musculoskeletal physiotherapy assessment protocol, to accurately identify the structures potentially responsible for shoulder symptoms against a standardised arthroscopic shoulder diagnostic assessment, and to determine the physiotherapists’ ability to influence post-test diagnostic accuracy.Study designConsecutive case-based cohort study.Subject selectionAll participants were selected by two orthopaedic surgeons for arthroscopic investigation during a 6-month period.SettingPrivate orthopaedic clinic.MethodAll consenting participants selected for arthroscopic investigation were examined by the physiotherapist prior to arthroscopy. Presence and priority of impairments/diagnoses were recorded on a standardised form. Inter and intra-rater reliability and diagnostic accuracy were tabulated.Statistical analysisProportional agreement on diagnostic incidence (broad) and priority (strict) using 2×2 contingency tables for sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios were calculated. Post-test probabilities were analysed to determine the influence of a positive or a negative finding.Results211 participants, aged 14–79 years were included. Overall prevalence of subacromial pathology was (77%) and, disorders of the passive restraints (29%). For both negative and positive findings, post-test probabilities were not notably altered; although positive findings yielded greater value in the decision-making modelling. The physiotherapist's ability to identify individual pathology (eg, tendon rupture vs tendinopathy, capsular vs labral) was lower than recognition of pathology within the broader diagnostic category.ConclusionsThe physiotherapist's ability to diagnose individual pathologies was inconsistent. Indirectly, this raises the issue of whether signs and symptoms identified under arthroscopic surgery are reflective of a lesion/pathology reflective of a specific tissue.
The acute:chronic workload ratio predicts injury: high chronic workload may decrease injury risk in elite rugby league players
Authors: Hulin Billy T , Gabbett Tim J , Lawson Daniel W , Caputi Peter , Sampson John A 
Published: October 2015

AimInvestigate whether acute workload (1 week total distance) and chronic workload (4-week average acute workload) predict injury in elite rugby league players.MethodsData were collected from 53 elite players over two rugby league seasons. The ‘acute:chronic workload ratio’ was calculated by dividing acute workload by chronic workload. A value of greater than 1 represented an acute workload greater than chronic workload. All workload data were classified into discrete ranges by z-scores.ResultsCompared with all other ratios, a very-high acute:chronic workload ratio (≥2.11) demonstrated the greatest risk of injury in the current week (16.7% injury risk) and subsequent week (11.8% injury risk). High chronic workload (>16 095 m) combined with a very-high 2-week average acute:chronic workload ratio (≥1.54) was associated with the greatest risk of injury (28.6% injury risk). High chronic workload combined with a moderate workload ratio (1.02–1.18) had a smaller risk of injury than low chronic workload combined with several workload ratios (relative risk range from 0.3 to 0.7×/÷1.4 to 4.4; likelihood range=88–94%, likely). Considering acute and chronic workloads in isolation (ie, not as ratios) did not consistently predict injury risk.ConclusionsHigher workloads can have either positive or negative influences on injury risk in elite rugby league players. Specifically, compared with players who have a low chronic workload, players with a high chronic workload aremore resistant to injurywith moderate-low through moderate-high (0.85–1.35) acute:chronic workload ratios andless resistant to injurywhen subjected to ‘spikes’ in acute workload, that is, very-high acute:chronic workload ratios ∼1.5.
Dentofacial trauma and players’ attitude towards mouthguard use in field hockey: a systematic review and meta-analysis
Authors: Vucic Strahinja , Drost Rosalin W , Ongkosuwito Edwin M , Wolvius Eppo B 
Published: October 2015

BackgroundDentofacial injuries are a risk while playing field hockey. Wearing mouthguards is recommended.ObjectiveTo synthesise findings on the prevalence and characteristics of dentofacial injuries sustained by field hockey players. We also investigated the prevalence of regular mouthguard use and players’ attitude towards use of mouthguard.Material and methodsA literature search was performed using PubMed, EMBASE, OvidSP, Web of Science, Cochrane and Cinahl databases. Eligible studies were identified based on the title, abstract and full text of articles. If applicable, a random effects model was used to calculate the overall effect size; otherwise, pooled prevalence was reported.Results11 studies were eligible for the analysis. The average proportion of field hockey players who had sustained at least one dentofacial injury varied from 12.7% (95% CI 8.5% to 17.0%) among junior and senior players to 45.2% (95% CI 39.3% to 51.0%) among elite players. We did not observe any significant differences with respect to gender. In the 2000s, a significantly higher proportion of players regularly wore a mouthguard, 84.5% (95% CI 69.3% to 99.7%) as compared with players 20 years ago, 31.4% (95% CI 22.7% to 40.1%). The most common complaints about the mouthguard were that it was unnecessary and uncomfortable.ConclusionDentofacial injuries pose a serious problem in field hockey and a substantial number of players do not regularly wear a mouthguard. Greater use of mouthguards would be expected to reduce dentofacial injuries in field hockey.
Engaging South Asian women with type 2 diabetes in a culturally relevant exercise intervention: a randomized controlled trial
Authors: Natesan Alamelu , Nimbal Vani C , Ivey Susan L , Wang Elsie J , Madsen Kristine A , Palaniappan Latha P 
Published: October 2015

BackgroundWe examined the efficacy of a culturally relevant exercise program in improving glycated hemoglobin (HbA1c) among South Asian women with type 2 diabetes, compared with usual care.MethodsThis was a randomized controlled 8-week pilot study of Bollywood dance among South Asian women with type 2 diabetes. The intervention consisted of 1 h Bollywood dance classes offered twice per week. The primary outcome was change in HbA1c. The effect of attendance on this outcome was also examined.ResultsThe intervention group demonstrated a decrease in HbA1c from baseline (−0.18% (0.2%); p=0.018) compared with a non-significant increase in the usual care group (+0.03% (0.2%)); p value for difference between groups was 0.032. Participants attending at least 10 of 16 sessions had a statistically significant reduction in weight (−0.69 kg (0.76 kg)) compared with those attending fewer sessions (+0.86 kg (0.71 kg)).ConclusionsThese results support culturally relevant dance as a successful exercise intervention to promote HbA1c control, compared with usual care.Trial registration numberNCT02061618.
Validation of the multivariable In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule within an all-payer inpatient administrative claims database
Authors: Coleman Craig I , Kohn Christine G , Crivera Concetta , Schein Jeffrey R , Peacock W Frank 
Published: October 2015

ObjectiveTo validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) prediction rule, in a database consisting only of inpatient claims.DesignRetrospective claims database analysis.SettingThe 2012 Healthcare Cost and Utilization Project National Inpatient Sample.ParticipantsPulmonary embolism (PE) admissions were identified by an International Classification of Diseases, ninth edition (ICD-9) code either in the primary position or secondary position when accompanied by a primary code for a PE complication. The multivariable IMPACT rule, which includes age and 11 comorbidities, was used to estimate patients’ probability of in-hospital mortality and classify them as low or higher risk (≤1.5% deemed low risk).Primary and secondary outcome measuresThe rule's sensitivity, specificity, positive and negative predictive values (PPV and NPV) and area under the receiver operating characteristic curve statistic for predicting in-hospital mortality with accompanying 95% CIs.ResultsA total of 34 108 admissions for PE were included, with a 3.4% in-hospital case-fatality rate. IMPACT classified 11 025 (32.3%) patients as low risk, and low risk patients had lower in-hospital mortality (OR, 0.17, 95% CI 0.13 to 0.21), shorter length of stay (−1.2 days, p<0.001) and lower total treatment costs (−$3074, p<0.001) than patients classified as higher risk. IMPACT had a sensitivity of 92.4%, 95% CI 90.7 to 93.8 and specificity of 33.2%, 95% CI 32.7 to 33.7 for classifying mortality risk. It had a high NPV (>99%), low PPV (4.6%) and an AUC of 0.74, 95% CI 0.73 to 0.76.ConclusionsThe IMPACT rule appeared valid when used in this all payer, inpatient only administrative claims database. Its high sensitivity and NPV suggest the probability of in-hospital death in those classified as low risk by IMPACT was minimal.