bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Host E3-Ubiquitin Ligase TRIM6 Ubiquitinates the Ebola Virus VP35 Protein and Promotes Virus Replication
Authors: Bharaj Preeti , Atkins Colm , Luthra Priya , Giraldo Maria Isabel , Dawes Brian E. , Miorin Lisa , Johnson Jeffrey R. , Krogan Nevan J. , Basler Christopher F. , Freiberg Alexander N. , Rajsbaum Ricardo 
Published: July 2017

ABSTRACT

Ebola virus (EBOV), a member of the
Filoviridae
family, is a highly pathogenic virus that causes severe hemorrhagic fever in humans and is responsible for epidemics throughout sub-Saharan, central, and West Africa. The EBOV genome encodes VP35, an important viral protein involved in virus replication by acting as an essential cofactor of the viral polymerase as well as a potent antagonist of the host antiviral type I interferon (IFN-I) system. By using mass spectrometry analysis and coimmunoprecipitation assays, we show here that VP35 is ubiquitinated on lysine 309 (K309), a residue located on its IFN antagonist domain. We also found that VP35 interacts with TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family. We recently reported that TRIM6 promotes the synthesis of unanchored K48-linked polyubiquitin chains, which are not covalently attached to any protein, to induce efficient antiviral IFN-I-mediated responses. Consistent with this notion, VP35 also associated noncovalently with polyubiquitin chains and inhibited TRIM6-mediated IFN-I induction. Intriguingly, we also found that TRIM6 enhances EBOV polymerase activity in a minigenome assay and TRIM6 knockout cells have reduced replication of infectious EBOV, suggesting that VP35 hijacks TRIM6 to promote EBOV replication through ubiquitination. Our work provides evidence that TRIM6 is an important host cellular factor that promotes EBOV replication, and future studies will focus on whether TRIM6 could be targeted for therapeutic intervention against EBOV infection.

IMPORTANCE
EBOV belongs to a family of highly pathogenic viruses that cause severe hemorrhagic fever in humans and other mammals with high mortality rates (40 to 90%). Because of its high pathogenicity and lack of licensed antivirals and vaccines, EBOV is listed as a tier 1 select-agent risk group 4 pathogen. An important mechanism for the severity of EBOV infection is its suppression of innate immune responses. The EBOV VP35 protein contributes to pathogenesis, because it serves as an essential cofactor of the viral polymerase as well as a potent antagonist of innate immunity. However, how VP35 function is regulated by host cellular factors is poorly understood. Here, we report that the host E3-ubiquitin ligase TRIM6 promotes VP35 ubiquitination and is important for efficient virus replication. Therefore, our study identifies a new host factor, TRIM6, as a potential target in the development of antiviral drugs against EBOV.
Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D
Authors: Lei Xiaobo , Zhang Zhenzhen , Xiao Xia , Qi Jianli , He Bin , Wang Jianwei 
Published: July 2017

ABSTRACT

Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD
1–193
). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD
1–275
). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.

IMPORTANCE
Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1β (IL-1β) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD
1–275
(p30) inhibits EV71 replication whereas GSDMD
1–193
does not. These results reveal a new strategy for EV71 to evade the antiviral response.
Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease
Authors: Jiang Yike , Patel Chaya D. , Manivanh Richard , North Brian , Backes Iara M. , Posner David A. , Gilli Francesca , Pachner Andrew R. , Nguyen Lananh N. , Leib David A. 
Published: July 2017

ABSTRACTWhile antibody responses to neurovirulent pathogens are critical for clearance, the extent to which antibodies access the nervous system to ameliorate infection is poorly understood. In this study on herpes simplex virus 1 (HSV-1), we demonstrate that HSV-specific antibodies are present during HSV-1 latency in the nervous systems of both mice and humans. We show that antibody-secreting cells entered the trigeminal ganglion (TG), a key site of HSV infection, and persisted long after the establishment of latent infection. We also demonstrate the ability of passively administered IgG to enter the TG independently of infection, showing that the naive TG is accessible to antibodies. The translational implication of this finding is that human fetal neural tissue could contain HSV-specific maternally derived antibodies. Exploring this possibility, we observed HSV-specific IgG in HSV DNA-negative human fetal TG, suggesting passive transfer of maternal immunity into the prenatal nervous system. To further investigate the role of maternal antibodies in the neonatal nervous system, we established a murine model to demonstrate that maternal IgG can access and persist in neonatal TG. This maternal antibody not only prevented disseminated infection but also completely protected the neonate from neurological disease and death following HSV challenge. Maternal antibodies therefore have a potent protective role in the neonatal nervous system against HSV infection. These findings strongly support the concept that prevention of prenatal and neonatal neurotropic infections can be achieved through maternal immunization.IMPORTANCEHerpes simplex virus 1 is a common infection of the nervous system that causes devastating neonatal disease. Using mouse and human tissue, we discovered that antiviral antibodies accumulate in neural tissue after HSV-1 infection in adults. Similarly, these antibodies pass to the offspring during pregnancy. We found that antiviral maternal antibodies can readily access neural tissue of the fetus and neonate. These maternal antibodies then protect neonatal mice against HSV-1 neurological infection and death. These results underscore the previously unappreciated role of maternal antibodies in protecting fetal and newborn nervous systems against infection. These data suggest that maternal immunization would be efficacious at preventing fetal/neonatal neurological infections.
AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA
Authors: Nakaya Yuki , Lilue Jingtao , Stavrou Spyridon , Moran Eileen A. , Ross Susan R. 
Published: July 2017

ABSTRACT
Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA.

IMPORTANCE
Autoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease.
Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial
Authors: Lipman Grant S , Shea Kate , Christensen Mark , Phillips Caleb , Burns Patrick , Higbee Rebecca , Koskenoja Viktoria , Eifling Kurt , Krabak Brian J 
Published: July 2017

BackgroundDespite concerns that non-steroidal anti-inflammatory drugs (NSAIDs) contribute to acute kidney injury (AKI), up to 75% of ultramarathon runners ingest these during competition. The effect of NSAID on AKI incidence in ultramarathon runners is unclear.MethodsMultisite randomised double-blind placebo-controlled trial in the Gobi, Atacama, Ecuador and Sri Lankan deserts to determine whether ibuprofen (400 mg every 4 hours) would be non-inferior to placebo during a 50-mile (80 km) foot race. The primary outcome was incidence of AKI defined as severity categories of ‘risk’ of injury of 1.5× baseline creatinine (Cr) or ‘injury’ as 2× Cr, combined to calculate total incidence at the finish line. Non-inferiority margin for difference in AKI rates was defined as 15%.ResultsEighty-nine participants (47% ibuprofen and 53% placebo) were enrolled with similar demographics between groups. The overall incidence of AKI was 44%. Intent-to-treat analysis found 22 (52%) ibuprofen versus 16 (34%) placebo users developed AKI (18% difference, 95% CI –4% to 41%; OR 2.1, 95% CI 0.9 to 5.1) with a number needed to harm of 5.5. Greater severity of AKI was seen with ibuprofen compared with placebo (risk=38% vs 26%; 95% CI –9% to 34%; injury=14% vs 9%; 95% CI –10% to 21%). Slower finishers were less likely to encounter AKI (OR 0.67, 95% CI 0.47 to 0.98) and greater weight loss (−1.3%) increased AKI (OR 1.24, 95% CI 1.00 to 1.63).ConclusionThere were increased rates of AKI in those who took ibuprofen, and although not statistically inferior to placebo by a small margin, there was a number needed to harm of 5.5 people to cause 1 case of AKI. Consideration should therefore be taken before ingesting NSAID during endurance running as it could exacerbate renal injury.Trial registration numberNCT02272725.
The intervention effect of local alcohol licensing policies on hospital admission and crime: a natural experiment using a novel Bayesian synthetictime-series method
Authors: de Vocht Frank , Tilling Kate , Pliakas Triantafyllos , Angus Colin , Egan Matt , Brennan Alan , Campbell Rona , Hickman Matthew 
Published: July 2017

BackgroundControl of alcohol licensing at local government level is a key component of alcohol policy in England. There is, however, only weak evidence of any public health improvement. We used a novel natural experiment design to estimate the impact of new local alcohol licensing policies on hospital admissions and crime.MethodsWe used Home Office licensing data (2007–2012) to identify (1) interventions: local areas where both a cumulative impact zone and increased licensing enforcement were introduced in 2011; and (2) controls: local areas with neither. Outcomes were 2009–2015 alcohol-related hospital admissions, violent and sexual crimes, and antisocial behaviour. Bayesian structural time series were used to create postintervention synthetic time series (counterfactuals) based on weighted time series in control areas. Intervention effects were calculated from differences between measured and expected trends. Validation analyses were conducted using randomly selected controls.Results5 intervention and 86 control areas were identified. Intervention was associated with an average reduction in alcohol-related hospital admissions of 6.3% (95% credible intervals (CI) −12.8% to 0.2%) and to lesser extent with a reduced in violent crimes, especially up to 2013 (–4.6%, 95% CI −10.7% to 1.4%). There was weak evidence of an effect on sexual crimes up 2013 (–8.4%, 95% CI −21.4% to 4.6%) and insufficient evidence of an effect on antisocial behaviour as a result of a change in reporting.ConclusionModerate reductions in alcohol-related hospital admissions and violent and sexual crimes were associated with introduction of local alcohol licensing policies. This novel methodology holds promise for use in other natural experiments in public health.
A glossary of terms for understanding political aspects in the implementation of Health in All Policies (HiAP)
Authors: Oneka Goldameir , Vahid Shahidi Faraz , Muntaner Carles , Bayoumi Ahmed M , Mahabir Deb Finn , Freiler Alix , O’Campo Patricia , Shankardass Ketan 
Published: July 2017

Health in All Policies (HiAP) is a strategy that seeks to integrate health considerations into the development, implementation and evaluation of policies across various non-health sectors of the government. Over the past 15 years, there has been an increase in the uptake of HiAP by local, regional and national governments. Despite the growing popularity of this approach, most existing literature on HiAP implementation remains descriptive rather than explanatory in its orientation. Moreover, prior research has focused on the more technical aspects of the implementation process. Thus, studies that aim to ‘build capacity to promote, implement and evaluate HiAP’ abound. Conversely, there is little emphasis on the political aspects of HiAP implementation. Neglecting the role of politics in shaping the use of HiAP is problematic, since health and the strategies by which it is promoted are partially political.This glossary addresses the politics gap in the existing literature by drawing on theoretical concepts from political, policy, and public health sciences to articulate a framework for studying how political mechanisms influence HiAP implementation. To this end, the glossary forms part of an on-going multiple explanatory case study of HiAP implementation, HARMONICS (HiAP Analysis using Realist Methods on International Case Studies, harmonics-hiap.ca), and is meant to expand on a previously published glossary addressing the topic of HiAP implementation more broadly. Collectively, these glossaries offer a conceptual toolkit for understanding how politics explains implementation outcomes of HiAP.
Synthesis and Analysis of Electronically Adjustable Fractional-Order Low-Pass Filter
Authors: Dvorak Jan , Langhammer Lukas , Jerabek Jan , Koton Jaroslav , Sotner Roman , Polak Josef 
Published: July 2017

A proposal of a fractional ([Formula: see text])-order low-pass filter is presented in this paper. The proposed filter operates in the current-mode and it is designed using Multi-Output Current Followers (MO-CFs), Dual-Output Current Follower (DO-CF), Dual-Output Adjustable Current Amplifier (DO-ACA) and Adjustable Current Amplifiers (ACAs) as active elements within the presented topology of the filter. The filter possesses ability to electronically control its order and also the pole frequency by changing the current gain of current amplifiers (ACAs) already present in the structure. Three different values of the order and pole frequency of the proposed low-pass filter were tested as an example. Design of the proposed filter is supported by simulation and experimental results. Simulations of the circuit are carried out in PSPICE simulator with behavioral models of used active elements. The experimental laboratory measurements are performed with the help of available devices forming equivalent circuits. Simulations and experimental results of the electronical control of the order and pole frequency are compared in this contribution.
Phase I Trial of Intravenous Oncolytic Vaccinia Virus (GL-ONC1) with Cisplatin and Radiotherapy in Patients with Locoregionally Advanced Head and Neck Carcinoma
Authors: Mell Loren K. , Brumund Kevin T. , Daniels Gregory A. , Advani Sunil J. , Zakeri Kaveh , Wright Mary E. , Onyeama Sara-Jane , Weisman Robert A. , Sanghvi Parag R. , Martin Peter J. , Szalay Aladar A. 
Published: July 2017

AbstractPurpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III–IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1–2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy. Clin Cancer Res; 23(19); 5696–702. ©2017 AACR.
Prognostic Impact of Circulating Tumor Cells for Breast Cancer Patients Treated in the Neoadjuvant "Geparquattro" Trial
Authors: Riethdorf Sabine , Müller Volkmar , Loibl Sibylle , Nekljudova Valentina , Weber Karsten , Huober Jens , Fehm Tanja , Schrader Iris , Hilfrich Jörn , Holms Frank , Tesch Hans , Schem Christian , von Minckwitz Gunter , Untch Michael , Pantel Klaus 
Published: July 2017

Abstract
Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTC) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro.
Experimental Design: Data on CTCs enumerated with the CellSearch system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free survival (DFS) and overall survival (OS) were analyzed by nonparametric Kaplan–Meier estimates and parametric Cox regression.
Results: After a median follow-up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (P = 0.031 and P &lt; 0.0001, respectively) and OS (P = 0.0057 and P &lt; 0.0001, respectively), whereas CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL, and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathologic complete response (pCR) exhibited the best prognosis, whereas those with CTCs and less tumor response were at high risk of tumor relapse. In HER2 (ERBB2)-positive and triple-negative patients, ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS.
Conclusions: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome, and combined with pCR, it could be helpful to stratify breast cancer patients for therapeutic interventions. Clin Cancer Res; 23(18); 5384–93. ©2017 AACR.
Molecular Effects of Stromal-Selective Targeting by uPAR-Retargeted Oncolytic Virus in Breast Cancer
Authors: Jing Yuqi , Chavez Valery , Ban Yuguang , Acquavella Nicolas , El-Ashry Doraya , Pronin Alexey , Chen Xi , Merchan Jaime R. 
Published: July 2017

AbstractThe tumor microenvironment (TME) is a relevant target for novel biological therapies. MV-m-uPA and MV-h-uPA are fully retargeted, species-specific, oncolytic measles viruses (MV) directed against murine or human urokinase receptor (PLAUR/uPAR), expressed in tumor and stromal cells. The effects of stromal-selective targeting by uPAR-retargeted MVs were investigated. In vitro infection, virus-induced GFP expression, and cytotoxicity by MV-h-uPA and MV-m-uPA were demonstrated in human and murine cancer cells and cancer-associated fibroblasts in a species-specific manner. In a murine fibroblast/human breast cancer 3D coculture model, selective fibroblast targeting by MV-m-uPA inhibited breast cancer cell growth. Systemic administration of murine-specific MV-m-uPA in mice bearing human MDA-MB-231 xenografts was associated with a significant delay in tumor progression and improved survival compared with controls. Experiments comparing tumor (MV-h-uPA) versus stromal (MV-m-uPA) versus combined virus targeting showed that tumor and stromal targeting was associated with improved tumor control over the other groups. Correlative studies confirmed in vivo viral targeting of tumor stroma by MV-m-uPA, increased apoptosis, and virus-induced differential regulation of murine stromal genes associated with inflammatory, angiogenesis, and survival pathways, as well as indirect regulation of human cancer pathways, indicating viral-induced modulation of tumor–stroma interactions. These data demonstrate the feasibility of stromal-selective targeting by an oncolytic MV, virus-induced modulation of tumor–stroma pathways, and subsequent tumor growth delay. These findings further validate the critical role of stromal uPAR in cancer progression and the potential of oncolytic viruses as antistromal agents.Implications: The current report demonstrates for the first time the biological, in vitro, and in vivo antitumor and molecular effects of stromal selective targeting by an oncolytic virus. Mol Cancer Res; 15(10); 1410–20. ©2017 AACR.
Improving the Armamentarium of PI3K Inhibitors with Isoform-Selective Agents: A New Light in the Darkness
Authors: Rodon Jordi , Tabernero Josep 
Published: July 2017

Abstract
Summary: Excitement and drug-development efforts aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway have declined due to the limited clinical performance of these inhibitors as monotherapies. New, more isoform-selective treatments, such as taselisib, promise to both expand the therapeutic window and increase efficacy. Cancer Discov; 7(7); 666–9. ©2017 AACR.
See related article by Juric et al., p. 704.