bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6
Authors: Chan Stephanie T. , Lee Jiyoung , Narula Mansi , Ou J.-H. James 
Published: September 2016

ABSTRACT
Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor molecule that mediates the TNFR family and interleukin-1 (IL-1)/Toll-like receptor (TLR) signaling cascades. These pathways are important for the host to control viral infections. In this report, we demonstrated that hepatitis C virus (HCV) depleted TRAF6 from its host cells through a posttranslational mechanism. This depletion was independent of proteasomes, as it was not affected by the proteasome inhibitor MG132, but it was suppressed by bafilomycin A1, which led to the association of TRAF6 with autophagosomes. As bafilomycin A1 is a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, these results suggested that HCV depleted TRAF6 via autophagy. The degradation of TRAF6 was apparently mediated by the p62 sequestosome protein, which is a factor important for selective autophagy, as it could bind to TRAF6 and its silencing stabilized TRAF6. The depletion of TRAF6 suppressed activation of NF-κB and induction of proinflammatory cytokines and enhanced HCV replication. In contrast, the overexpression of TRAF6 suppressed HCV replication. These results revealed a novel mechanism that was used by HCV to disrupt the host innate immune responses for viral replication and persistence.

IMPORTANCE
HCV can cause severe liver diseases and is one of the most important human pathogens. It establishes chronic infections in the great majority of patients that it infects, indicating that it has evolved sophisticated mechanisms to evade host immunity. TRAF6 is an important signaling molecule that mediates activation of NF-κB and expression of proinflammatory cytokines and interferons. In this study, we found that HCV infection suppressed the host innate immune response through the induction of autophagic degradation of TRAF6. This finding provided important information for further understanding how HCV evades host immunity to establish persistence.
A Tale of Two PMLs: Elements Regulating a Differential Substrate Recognition by the ICP0 E3 Ubiquitin Ligase of Herpes Simplex Virus 1
Authors: Zheng Yi , Samrat Subodh Kumar , Gu Haidong 
Published: September 2016

ABSTRACT

Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an α gene product required for viral replication at low multiplicities of infection. Upon entry, nuclear domain 10 (ND10) converges at the incoming DNA and represses viral gene expression. ICP0 contains a RING-type E3 ubiquitin ligase that degrades the ND10 organizer PML and disperses ND10 to alleviate the repression. In the present study, we focused on understanding the regulation of ICP0 E3 ligase activity in the degradation of different ICP0 substrates. We report the following. (i) A SUMO interaction motif located at ICP0 residues 362 to 364 is required for the degradation of PML isoforms II, IV, and VI but not isoform I. This differentiation mechanism exists in both HEp-2 and U2OS cells, regardless of the cell's permissiveness to the ICP0-null virus. (ii) Physical interaction between SIM
362–364
and PML II is necessary but not sufficient for PML II degradation. Both proximal sequences surrounding SIM
362–364
and distal sequences located at the ICP0 C terminus enhance the degradation of PML II. (iii) The ICP0 C terminus is dispensable for PML I degradation. Instead, bipartite PML I binding domains located in the N-terminal half of ICP0 coordinate to promote the degradation of PML I. (iv) The stability of ICP0, but not its ND10 fusion ability, affects the rate of PML I degradation. Taken together, our results show that ICP0 uses at least two regulatory mechanisms to differentiate its substrates. The disparate recognition of the ICP0 E3 substrates may be related to the different roles these substrates may play in HSV-1 infection.

IMPORTANCE
Viruses have a limited genetic coding capacity but must encounter a multilayered comprehensive host defense. To establish a successful infection, viruses usually produce multifunctional proteins to coordinate the counteractions. Here we report that an HSV-1 protein, ICP0, can recognize individual host factors and target them differently for destruction. We identified elements that are important for the ICP0 E3 ubiquitin ligase to differentially recognize two of its substrates, PML I and PML II. This is the first study that has systematically investigated how ICP0 discriminates two similar molecules by very different mechanisms. This work lays the foundation for understanding the role of host defensive factors and the mechanisms viruses use to take advantage of some host proteins while destroying others.
Ubiquitination Upregulates Influenza Virus Polymerase Function
Authors: Kirui James , Mondal Arindam , Mehle Andrew 
Published: September 2016

ABSTRACT
The influenza A virus polymerase plays an essential role in the virus life cycle, directing synthesis of viral mRNAs and genomes. It is a trimeric complex composed of subunits PA, PB1, and PB2 and associates with viral RNAs and nucleoprotein (NP) to form higher-order ribonucleoprotein (RNP) complexes. The polymerase is regulated temporally over the course of infection to ensure coordinated expression of viral genes as well as replication of the viral genome. Various host factors and processes have been implicated in regulation of the IAV polymerase function, including posttranslational modifications; however, the mechanisms are not fully understood. Here we demonstrate that ubiquitination plays an important role in stimulating polymerase activity. We show that all protein subunits in the RNP are ubiquitinated, but ubiquitination does not significantly alter protein levels. Instead, ubiquitination and an active proteasome enhance polymerase activity. Expression of ubiquitin upregulates polymerase function in a dose-dependent fashion, causing increased accumulation of viral RNA (vRNA), cRNA, and mRNA and enhanced viral gene expression during infection. Ubiquitin expression directly affects polymerase activity independent of nucleoprotein (NP) or ribonucleoprotein (RNP) assembly. Ubiquitination and the ubiquitin-proteasome pathway play key roles during multiple stages of influenza virus infection, and data presented here now demonstrate that these processes modulate viral polymerase activity independent of protein degradation.

IMPORTANCE
The cellular ubiquitin-proteasome pathway impacts steps during the entire influenza virus life cycle. Ubiquitination suppresses replication by targeting viral proteins for degradation and stimulating innate antiviral signaling pathways. Ubiquitination also enhances replication by facilitating viral entry and virion disassembly. We identify here an addition proviral role of the ubiquitin-proteasome system, showing that all of the proteins in the viral replication machinery are subject to ubiquitination and this is crucial for optimal viral polymerase activity. Manipulation of the ubiquitin machinery for therapeutic benefit is therefore likely to disrupt the function of multiple viral proteins at stages throughout the course of infection.
Rolling open Earth’s deepest forearc basin
Authors: Pownall Jonathan M. , Hall Robert , Lister Gordon S. 
Published: September 2016

Abstract
The Weber Deep—a 7.2-km-deep forearc basin within the tightly curved Banda arc of eastern Indonesia—is the deepest point of the Earth’s oceans not within a trench. Several models have been proposed to explain the tectonic evolution of the Banda arc in the context of the ongoing (ca. 23 Ma–present) Australia–Southeast Asia collision, but no model explicitly accounts for how the Weber Deep achieved its anomalous depth. Here we propose that the Weber Deep formed by forearc extension driven by eastward subduction rollback. Substantial lithospheric extension in the upper plate was accommodated by a major, previously unidentified, low-angle normal fault system we name the “Banda detachment.” High-resolution bathymetry data reveal that the Banda detachment is exposed underwater over much of its 120 km down-dip and 450 km lateral extent, having produced the largest bathymetric expression of any fault discernable in the world’s oceans. The Banda arc is a modern analogue for highly extended terranes preserved in the many regions that may similarly have “rolled open” behind migrating subduction zones.
Therapeutic efficacy and safety of ACE inhibitors in the hypertensive paediatric population: a review
Authors: Snauwaert Evelien , Vande Walle Johan , De Bruyne Pauline 
Published: September 2016

PurposeSince 1997, strong incentives have been introduced worldwide to improve access to safe and effective medicines addressing the therapeutic needs of children. ACE inhibitors, the most prescribed antihypertensive drugs in the paediatric population, are one of the prototype drugs targeted by the legislation initiatives. Our purpose in assembling this review is to evaluate and describe the current evidence for the efficacy and safety profile of ACE inhibitors in the paediatric population.MethodsThe authors made a descriptive review of the literature from 1980 to 2015 using the following search terms: hypertension, child, paediatric, ACE (inhibitors), renin–angiotensin aldosterone system, captopril, lisinopril, enalapril, ramipril and fosinopril.ResultsA total of 16 studies evaluating efficacy and safety of ACE inhibitors were included in this review. The included studies demonstrate that ACE inhibitors have the potency to decrease the systolic and/or diastolic blood pressure with an overall favourable safety profile in a short-term period. More importantly, the incentives resulted in an improvement of the overall availability of paediatric labelling, dosing and safety information for ACE inhibitors. However, they failed to fulfil several of paediatric needs: absence of long-term safety data on growth and maturation, absence of commercially available child-friendly formulations and incomplete evaluation of the entire paediatric hypertension population.ConclusionAdditional efforts are needed to close the gap between the availability of drugs that are labelled and indicated for paediatric use and the actual drug usage in children, especially in young children, neonates and children with severe hypertension, renal transplantation or severe renal impairment.
Does sports participation (including level of performance and previous injury) increase risk of osteoarthritis? A systematic review and meta-analysis
Authors: Tran Gui , Smith Toby O , Grice Adam , Kingsbury Sarah R , McCrory Paul , Conaghan Philip G 
Published: September 2016

BackgroundTo assess the relationship between sport and osteoarthritis (OA), and specifically to determine whether previous participation, in terms of level (elite or non-elite), type of sport, intensity or previous injury, was associated with OA.MethodsThis systematic review was developed using PRISMA guidelines. Databases were searched (to May 2016). Narrative review and meta-analysis (with risk ratio (RR) and 95% CIs) approaches were undertaken where appropriate. Study quality was assessed using GRADE.Results46 studies were included. Narratively, 31 studies reported an increased risk of OA, with 19 demonstrating an increased risk in elite athletes. There was an increased risk after sports exposure (irrespective of type; RR 1.37; 95% CI 1.14 to 1.64; 21 studies). It remained uncertain whether there was a difference in risk of OA between elite and non-elite athletes (RR 1.37; 95% CI 0.84 to 2.22; 17 studies). The risk was higher in soccer (RR 1.42; 95% CI 1.14 to 1.77; 15 studies) but lower in runners (RR 0.86; 95% CI 0.53 to 1.41; 12 studies). 9 studies showed an association with the intensity of sport undertaken and OA. 5 studies demonstrated a higher prevalence of OA following meniscectomies and anterior cruciate ligament tears. Overall, the evidence was of GRADE ‘very low’ quality.ConclusionsThere was very low-quality evidence to support an increased relationship between sports participation and OA in elite participants. It is unclear whether there is a difference in risk between elite and non-elite participants with further prospective studies needed to evaluate this. Pooled findings suggested that significant injuries were associated with OA in soccer players.
Predictive value of miR-210 as a novel biomarker for pre-eclampsia: a systematic review protocol
Authors: Nikuei Pooneh , Davoodian Nahid , Tahamtan Iman , Keshtkar Abbas Ali 
Published: September 2016

IntroductionPre-eclampsia (PE) is a serious condition affecting 3–5% of all pregnancies worldwide. However, underlying molecular pathogenesis of this disease has largely remained unknown. Recently, several studies have indicated the possibility role of microRNAs, especially miR-210, in the aetiology of PE. The aim of this systematic review is to assess the possible role of miR-210 as a novel biomarker for the prediction of PE.Methods and analysisUsing a combination of mesh terms ‘preeclampsia’, ‘microRNA’ and their equivalents, an electronic search will be performed for all observational studies (cross sectional, case–control and cohort) in PubMed, Web of Science, Scopus, Embase, Cochrane, LILACS and OvidSP MEDLINE from January 2005 to December 2015. Furthermore, other sources are searched, including grey literature, reference lists of relevant primary studies as well as key journals. Study selection, data extraction and quality assessment of studies will be performed independently by 2 reviewers, and any disagreement will be resolved by consensus. If sufficient data are available, it will be combined by either fixed or random effects models. We will investigate the source)s(and degree of heterogeneity using ‘Heterogeneity χ2’ and I2. Heterogeneity would be investigated through either subgroup analysis or metaregression. Stata V.11.1 will be used for data analysis.Ethics and disseminationThe results of this study are disseminated in peer-reviewed journal articles and academic presentations. Formal ethical approval is not required, since the secondary data will be collected.Trial registration numberCRD42015032345.
A collaborative improvement project by an NHS Emergency Department and Scottish Ambulance Paramedics to improve the identification and delivery of sepsis 6.
Authors: Carberry Martin , Harden John 
Published: September 2016

Early identification of patients with sepsis is key to the delivery of the sepsis 6 bundle including antibiotic therapy within an hour.[1-3] Demand versus capacity challenges in the Emergency Department (ED) led to delays in antibiotic and sepsis 6 delivery. An alerting tool was developed that provided criteria for Scottish Ambulance Service (SAS) Paramedics to alert the ED of potential sepsis patients.Data from patients presenting to the ED prior to the alerting process commencing (n=50) and during alerting (n=50) were analysed, a questionnaire was used to ascertain feedback from all staff groups; nurses doctors, and paramedics (n=38). Mean Time to triage improved by 82% from 17 minutes to 3 minutes (p=0.01), time to first antibiotic improved by 39% from 49 minutes to 30 minutes. Overall 78% of patients received antibiotics within an hour of leaving their home; no significant increase in workload was reported by staff.In conclusion alerting by paramedics of potential sepsis patients reduced the time taken to deliver the Sepsis 6 Bundle. Process reliability has been sustained over several months. This process has been spread to seven regional ambulance stations in Lanarkshire Scotland.
The impact of critically ill children on paediatric ED medication timeliness
Authors: Michelson Kenneth A , Bachur Richard G , Levy Jason A 
Published: September 2016

ObjectivesThe presence of critically ill patients may impact care for other ED patients. We sought to evaluate whether the presence of a critically ill child was associated with the time to (1) receipt of the first medication among other patients, and (2) administration of diagnosis-specific medications.MethodsWe performed a retrospective cohort study of all paediatric ED visits over 3 years. Patients were exposed if they arrived during the first hour of a critically ill patient's care. The primary outcome was the time from arrival to first medication administration. Secondary outcomes were time to corticosteroids in asthma and time to antibiotics for fever/neutropenia. We modelled times to medication using median regression, adjusting for demographics, arrival time and weekday, and census (number of patients in the ED).ResultsWe analysed 170 112 visits. Median times to first medication for those exposed to 0, 1 and >1 simultaneous critically ill patients were 90 min (IQR 54–146), 96 min (IQR 58–157) and 113 min (IQR 72–166), respectively (p<0.001). The increase in time to corticosteroids among exposed patients versus unexposed was 6 min (IQR 2–14, p=0.11) and in time to antibiotic for fever/neutropenia was −4 min (IQR −4 to −11, p=0.13). Modelled time to first medication increased 3.1 min (95% CI 0.5 to 5.7) among all exposed patients (p=0.02). Time to first medication increased 15.3 min (95% CI 14.7 to 15.9) for each 10 patient increase in census.ConclusionsThe presence of critically ill patients was associated with a delay in medication administration to others. Census independently predicted medication delays.
The Information Systems Group at HPI
Authors: Naumann Felix , Krestel Ralf 
Published: September 2016

The Hasso Plattner Institute (HPI) is a private computer science institute funded by the eponymous SAP co-founder. It is affiliated with the University of Potsdam in Germany and is dedicated to research and teaching, awarding B.Sc., M.Sc., and Ph.D. degrees.
The Information Systems group was founded in 2006, currently has around ten Ph.D. students and about 15 masters students actively involved in our research activities. Our initial and still ongoing research focus has been the area of data cleansing and duplicate detection. More recently we have become active in the area of text mining to extract structured information from text, and even more recently in data profiling, i.e., the task of discovering various metadata and dependencies from a data instance.
RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients
Authors: Kato Shumei , Subbiah Vivek , Marchlik Erica , Elkin Sheryl K. , Carter Jennifer L. , Kurzrock Razelle 
Published: September 2016

Abstract
Purpose: Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple cancers may facilitate clinical trial development targeting RET.
Experimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments–certified targeted next-generation sequencing of 182 or 236 gene panels.
Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novel SQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-associated genes [59.1% (52/88)], cell cycle–associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)]. RET fusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.
Conclusions: RET aberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients with RET anomalies will require customized combination strategies. Clin Cancer Res; 23(8); 1988–97. ©2016 AACR.
Circulating protein Z concentration, PROZ variants, and unexplained cerebral infarction in young and middle-aged adults
Authors: Zhang Lili , Segal Alan Z. , Leifer Dana , Silverstein Roy L. , Gerber Linda M. , Devereux Richard B. , Kizer Jorge R. 
Published: September 2016

SummaryProtein Z (PZ) is a vitamin K–dependent plasma protein that exhibits both pro- and anticoagulant properties. Both low and high PZ levels have been linked to ischaemic stroke. Although PZ-lowering gene variants have been found to be less common in ischaemic stroke, the relationship remains unclear. We investigated PZ levels and PROZ variants in a multi-ethnic case-control study of unexplained stroke in participants aged 18 to 64. Plasma PZ was measured in cases (≥2 months post-stroke) and controls. PZ polymorphisms G79A (rs3024735) and A13G (2273971) were genotyped. A combined genetic score (0–4 minor alleles) was created assuming additive effects. A total of 715 individuals (1:1.4 cases:controls) was included. Analyses revealed evidence of a non-linear association. After adjusting for demographic and clinical covariates, PZ levels >2.5 µg/ml (90th %ile) were significantly associated with cryptogenic stroke (OR 2.41 [95 % CI 1.34, 4.34]) as compared with lower levels. Higher genetic score was related to progressively lower levels of PZ, and the presence of four minor alleles was associated with lower odds of stroke (adjusted OR 0.26 [95 % CI 0.07, 0.96]) versus 0 minor alleles. In this multi-ethnic study of young and middle-aged adults, there was evidence of a nonlinear positive association between PZ level and unexplained stroke, with a directionally consistent association for genetic variants related to PZ levels and cryptogenic stroke. These findings support elevated PZ levels as a risk factor for cryptogenic stroke.