bluuebunny/crossref_metadata_2025_split huggingface dataset:
USP4 Positively Regulates RIG-I-Mediated Antiviral Response through Deubiquitination and Stabilization of RIG-I
Authors: Wang Lijuan , Zhao Wei , Zhang Meng , Wang Peng , Zhao Kai , Zhao Xueying , Yang Shangru , Gao Chengjiang 
Published: February 2013

ABSTRACT
Protein ubiquitination plays an essential role in the regulation of retinoic acid-inducible gene I (RIG-I) activation and the antiviral immune response. However, the function of the opposite process of deubiquitination in RIG-I activation remains elusive. In this study, we have identified the deubiquitinating enzyme ubiquitin-specific protease 4 (USP4) as a new regulator for RIG-I activation through deubiquitination and stabilization of RIG-I. USP4 expression was attenuated after virus-induced RIG-I activation. Overexpression of USP4 significantly enhanced RIG-I protein expression and RIG-I-triggered beta interferon (IFN-β) signaling and, at the same time, inhibited vesicular stomatitis virus (VSV) replication. Small interfering RNA (siRNA) knockdown of USP4 expression had an opposite effect. Furthermore, USP4 was found to interact with RIG-I and remove K48-linked polyubiquitination chains from RIG-I. Therefore, we identified USP4 as a new positive regulator for RIG-I that acts through deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I.
3C Protease of Enterovirus 68: Structure-Based Design of Michael Acceptor Inhibitors and Their Broad-Spectrum Antiviral Effects against Picornaviruses
Authors: Tan Jinzhi , George Shyla , Kusov Yuri , Perbandt Markus , Anemüller Stefan , Mesters Jeroen R. , Norder Helene , Coutard Bruno , Lacroix Céline , Leyssen Pieter , Neyts Johan , Hilgenfeld Rolf 
Published: February 2013

ABSTRACT

We have determined the cleavage specificity and the crystal structure of the 3C protease of enterovirus 68 (EV68 3C
pro
). The protease exhibits a typical chymotrypsin fold with a Cys...His...Glu catalytic triad; its three-dimensional structure is closely related to that of the 3C
pro
of rhinovirus 2, as well as to that of poliovirus. The phylogenetic position of the EV68 3C
pro
between the corresponding enzymes of rhinoviruses on the one hand and classical enteroviruses on the other prompted us to use the crystal structure for the design of irreversible inhibitors, with the goal of discovering broad-spectrum antiviral compounds. We synthesized a series of peptidic α,β-unsaturated ethyl esters of increasing length and for each inhibitor candidate, we determined a crystal structure of its complex with the EV68 3C
pro
, which served as the basis for the next design round. To exhibit inhibitory activity, compounds must span at least P3 to P1′; the most potent inhibitors comprise P4 to P1′. Inhibitory activities were found against the purified 3C protease of EV68, as well as with replicons for poliovirus and EV71 (50% effective concentration [EC
50
] = 0.5 μM for the best compound). Antiviral activities were determined using cell cultures infected with EV71, poliovirus, echovirus 11, and various rhinovirus serotypes. The most potent inhibitor, SG85, exhibited activity with EC
50
s of ≈180 nM against EV71 and ≈60 nM against human rhinovirus 14 in a live virus–cell-based assay. Even the shorter SG75, spanning only P3 to P1′, displayed significant activity (EC
50
= 2 to 5 μM) against various rhinoviruses.
Methyltransferase PRMT1 Is a Binding Partner of HBx and a Negative Regulator of Hepatitis B Virus Transcription
Authors: Benhenda Shirine , Ducroux Aurélie , Rivière Lise , Sobhian Bijan , Ward Michael D. , Dion Sarah , Hantz Olivier , Protzer Ulrike , Michel Marie-Louise , Benkirane Monsef , Semmes Oliver J. , Buendia Marie-Annick , Neuveut Christine 
Published: February 2013

ABSTRACT

The hepatitis B virus X protein (HBx) is essential for virus replication and has been implicated in the development of liver cancer. HBx is recruited to viral and cellular promoters and activates transcription by interacting with transcription factors and coactivators. Here, we purified HBx-associated factors in nuclear extracts from HepG2 hepatoma cells and identified protein arginine methyltransferase 1 (PRMT1) as a novel HBx-interacting protein. We showed that PRMT1 overexpression reduced the transcription of hepatitis B virus (HBV), and this inhibition was dependent on the methyltransferase function of PRMT1. Conversely, depletion of PRMT1 correlated with increased HBV transcription. Using a quantitative chromatin immunoprecipitation assay, we found that PRMT1 is recruited to HBV DNA, suggesting a direct effect of PRMT1 on the regulation of HBV transcription. Finally, we showed that HBx expression inhibited PRMT1-mediated protein methylation. Downregulation of PRMT1 activity was further observed in HBV-replicating cells in an
in vivo
animal model. Altogether, our results support the notion that the binding of HBx to PRMT1 might benefit viral replication by relieving the inhibitory activity of PRMT1 on HBV transcription.
An Attenuated Listeria monocytogenes Vector Primes More Potent Simian Immunodeficiency Virus-Specific Mucosal Immunity than DNA Vaccines in Mice
Authors: Im Eung-Jun , Borducchi Erica N. , Provine Nicholas M. , McNally Anna G. , Li Sufen , Frankel Fred R. , Barouch Dan H. 
Published: February 2013

ABSTRACT

A human immunodeficiency virus type 1 (HIV-1) vaccine that induces potent immune responses in the gastrointestinal mucosa would be highly desirable. Here we show that attenuated recombinant
Listeria monocytogenes
, administered orally utilizing its natural route of infection, induces potent mucosal as well as systemic immune responses in mice. Moreover, these responses can be boosted efficiently with replication-incompetent adenoviral vectors.
L. monocytogenes
elicited more potent simian immunodeficiency virus (SIV) Gag-specific CD8
+
T lymphocyte responses in mucosal compartments than DNA vaccines.
The Frequency of CD127
+
Hepatitis C Virus (HCV)-Specific T Cells but Not the Expression of Exhaustion Markers Predicts the Outcome of Acute HCV Infection
Authors: Shin Eui-Cheol , Park Su-Hyung , Nascimbeni Michelina , Major Marian , Caggiari Laura , de Re Valli , Feinstone Stephen M. , Rice Charles M. , Rehermann Barbara 
Published: February 2013

ABSTRACT
T cells are exhausted and overexpress inhibitory molecules in chronic hepatitis C virus (HCV) infection. It is unclear whether this is the cause or consequence of HCV persistence. By studying serial blood and liver samples of chimpanzees during acute infection, we demonstrate that the early expression of the memory precursor marker CD127 on HCV-specific T cells, but not the expression of inhibitory molecules on those T cells or their ligands in the liver, predicts the outcome of acute infection.
Kaposi's Sarcoma-Associated Herpesvirus Latency in Endothelial and B Cells Activates Gamma Interferon-Inducible Protein 16-Mediated Inflammasomes
Authors: Singh Vivek Vikram , Kerur Nagaraj , Bottero Virginie , Dutta Sujoy , Chakraborty Sayan , Ansari Mairaj Ahmed , Paudel Nitika , Chikoti Leela , Chandran Bala 
Published: February 2013

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) infections of endothelial and B cells are etiologically linked with Kaposi's sarcoma (KS) and primary effusion B-cell lymphoma (PEL), respectively. KS endothelial and PEL B cells carry multiple copies of the nuclear episomal latent KSHV genome and secrete a variety of inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. The maturation of IL-1β and IL-18 depends upon active caspase-1, which is regulated by a multiprotein inflammasome complex induced by sensing of danger signals. During primary KSHV infection of endothelial cells, acting as a nuclear pattern recognition receptor, gamma interferon-inducible protein 16 (IFI16) colocalized with the KSHV genome in the nuclei and interacted with ASC and procaspase-1 to form a functional inflammasome (Kerur N et al., Cell Host Microbe 9:363-375, 2011). Here, we demonstrate that endothelial telomerase-immortalized human umbilical cells (TIVE) supporting KSHV stable latency (TIVE-LTC cells) and PEL (cavity-based B-cell lymphoma 1 [BCBL-1]) cells show evidence of inflammasome activation, such as the activation of caspase-1 and cleavage of pro-IL-1β and pro-IL-18. Interaction of ASC with IFI16 but not with AIM2 or NOD-like receptor P3 (NLRP3) was detected. The KSHV latency-associated viral FLIP (vFLIP) gene induced the expression of IL-1β, IL-18, and caspase-1 mRNAs in an NF-κB-dependent manner. IFI16 and cleaved IL-1β were detected in the exosomes released from BCBL-1 cells. Exosomal release could be a KSHV-mediated strategy to subvert IL-1β functions. In fluorescent
in situ
hybridization analyses, IFI16 colocalized with multiple copies of the KSHV genome in BCBL-1 cells. IFI16 colocalization with ASC was also detected in lung PEL sections from patients. Taken together, these findings demonstrated the constant sensing of the latent KSHV genome by IFI16-mediated innate defense and unraveled a potential mechanism of inflammation induction associated with KS and PEL lesions.
Myxoma and Vaccinia Viruses Bind Differentially to Human Leukocytes
Authors: Chan Winnie M. , Bartee Eric C. , Moreb Jan S. , Dower Ken , Connor John H. , McFadden Grant 
Published: February 2013

ABSTRACT

Myxoma virus (MYXV) and vaccinia virus (VACV), two distinct members of the family
Poxviridae
, are both currently being developed as oncolytic virotherapeutic agents. Recent studies have demonstrated that
ex vivo
treatment with MYXV can selectively recognize and kill contaminating cancerous cells from autologous bone marrow transplants without perturbing the engraftment of normal CD34
+
hematopoietic stem and progenitor cells. However, the mechanism(s) by which MYXV specifically recognizes and eliminates the cancer cells in the autografts is not understood. While little is known about the cellular attachment factor(s) exploited by MYXV for entry into any target cells, VACV has been shown to utilize cell surface glycosaminoglycans such as heparan sulfate (HS), the extracellular matrix protein laminin, and/or integrin β1. We have constructed MYXV and VACV virions tagged with the Venus fluorescent protein and compared their characteristics of binding to various human cancer cell lines as well as to primary human leukocytes. We report that the binding of MYXV or VACV to some adherent cell lines could be partially inhibited by heparin, but laminin blocked only VACV binding. In contrast to cultured fibroblasts, the binding of MYXV and VACV to a wide spectrum of primary human leukocytes could not be competed by either HS or laminin. Additionally, MYXV and VACV exhibited very different binding characteristics against certain select human leukocytes, suggesting that the two poxviruses utilize different cell surface determinants for the attachment to these cells. These results indicate that VACV and MYXV can exhibit very different oncolytic tropisms against some cancerous human leukocytes.
Uterine rupture complicating sequential curettage and Bakri balloon tamponade to control secondary PPH
Authors: Ajayi Olukunle Adegboye , Sant Manjusha , Ikhena Sunday , Bako Abdumalik 
Published: February 2013

A 20-year-old para 2 woman had a preterm delivery at 25 weeks and 6 days, readmitted to the hospital 25 days after delivery with severe secondary postpartum haemorrhage (PPH). Uncontrolled by initial conservative management, she underwent uterine curettage followed by Bakri balloon tamponade. She later had laparotomy for continued bleeding. She was found to have uterine rupture and hysterectomy was carried out as a life-saving measure. She was transfused in total with 14 units of blood, 1 unit of platelet, 2 units of cryoprecipitate and 3 units of fresh frozen plasma. The patient had intensive therapy unit care and was discharged home on the sixth postoperative day. The histology report showed ectatic non-constricted vessels as the cause of the secondary PPH. No myometrial tissue, products of conception or evidence of endometritis. The sequential use of uterine curettage and balloon tamponade in the aetiology of uterine rupture is a rare occurrence.
Safety of AS03-adjuvanted split-virion H1N1 (2009) pandemic influenza vaccine: a prospective cohort study
Authors: Nazareth Irwin , Tavares Fernanda , Rosillon Dominique , Haguinet François , Bauchau Vincent 
Published: February 2013

ObjectivesTo assess the safety of an AS03-adjuvanted split virion H1N1 (2009) vaccine (Pandemrix) in persons vaccinated during the national pandemic influenza vaccination campaign in the UK.DesignProspective, cohort, observational, postauthorisation safety study.Setting87 general practices forming part of the Medical Research Council General Practice Research Framework and widely distributed throughout England.ParticipantsA cohort of 9143 individuals aged 7 months to 97 years who received at least one dose of the AS03-adjuvanted H1N1 pandemic vaccine during the national pandemic influenza vaccination campaign in the UK was enrolled. 94% completed the 6-month follow-up. Exclusion criteria were previous vaccination with other H1N1 pandemic vaccine and any child in care.Primary and secondary outcome measuresMedically attended adverse events (MAEs) occurring within 31 days after any dose, serious adverse events (SAEs) and adverse events of special interest (AESIs) following vaccination were collected for all participants. Solicited adverse events (AEs) were assessed in a subset of participants.ResultsMAEs were reported in 1219 participants and SAEs in 113 participants during the 31-day postvaccination period. The most frequently reported MAEs and SAEs were consistent with events expected to be reported during the winter season in this population: lower respiratory tract infections, asthma and pneumonia. The most commonly reported solicited AEs were irritability in young children aged <5 years (61.8%), muscle aches in children aged 5–17 years (61.9%) and adults (46.9%). 18 AESIs, experienced by 14 patients, met the criteria to be considered for the observed-to-expected analyses. AESIs above the expected number were neuritis (1 case within 31 days) and convulsions (8 cases within 181 days). There were 41 deaths during the 181-day period after vaccination, fewer than expected.ConclusionsResults indicate that the AS03-adjuvanted H1N1 pandemic vaccine showed a clinically acceptable reactogenicity and safety profile in all age and risk groups studied.Trial registrationClinicalTrials.gov,NCT00996853.
How big does the effect of an intervention have to be? Application of two novel methods to determine the smallest worthwhile effect of a fall prevention programme: a study protocol
Authors: Franco Marcia Rodrigues , Ferreira Manuela L , Howard Kirsten , Sherrington Catherine , Rose John , Haines Terry P , Ferreira Paulo 
Published: February 2013

IntroductionThis project concerns the identification of the smallest worthwhile effect (SWE) of exercise-based programmes to prevent falls in older people. The SWE is the smallest effect that justifies the costs, risks and inconveniences of an intervention and is used to inform the design and interpretation of systematic reviews and randomised clinical trials.Methods and analysisThis study will comprise two different methodological approaches: the benefit-harm trade-off method and the discrete choice experiment to estimate the SWE of exercise interventions to prevent falls in older people. In the benefit-harm trade-off method, hypothetical scenarios with the benefits, costs, risks and inconveniences associated with the intervention will be presented to each participant. Then, assuming a treatment effect of certain magnitude, the participant will be asked if he or she would choose to have the intervention. The size of the hypothetical benefit will be varied up and down until it is possible to identify the SWE for which the participant would choose to have the intervention. In the discrete choice experiment, the same attributes (benefits, costs, risks and inconveniences) with varying levels will be presented as choice sets, and participants will be asked to choose between these choice sets. With this approach, we will determine the probability that a person will consider the effects of an intervention to be worthwhile, given the particular costs, risks and inconveniences. For each of the two approaches, participants will be interviewed in person and on different occasions. A subsample of the total cohort will participate in both interviews.Ethics and disseminationThis project has received Ethics Approval from the University of Sydney Human Ethics Committee (Protocol number: 14404). Findings will be disseminated through conference presentations, seminars and peer-reviewed scientific journals.
An analysis of the current educational status and future training needs of China's rural doctors in 2011
Authors: Li Xingming , Liu Juyuan , Huang Jianshi , Qian Yunliang , Che Lu 
Published: February 2013

Abstract

Objectives
To analyse the educational status and future training needs of China's rural doctors and provide a basis to improve their future training.

Methods
A cross-sectional epidemiological survey was used for the analysis, and 17 954 rural doctors chosen randomly from the eastern, central and western regions of China in 2009–2010 were surveyed to ascertain their average training time and the methods used for and content of their training.

Results
In general, 8671/17 778 (48.77%) of respondents received less than 12 days of training in a year. Conference sessions seemed to be the major route of training, with 10 150/17 925 respondents (56.62%). Clinical skills, with a response rate of 14 441/17 926 (80.56%), seemed to be the most popular training content. With regard to the general needs for training time received, 6547/18 255 (35.86%) of respondents hoped the average training time received a year would be less than 12 days; on-site guidance from a senior doctor was the most popular training method with response rate of 10 109/17 976 (56.24%), and clinical skills was what rural doctors wished to study the most, with a positive response of 16 744/17 962 (93.22%). Statistically significant differences existed in the current status and training time, training method and training content needs of China's rural doctors.

Conclusions
Our results suggest that the training status and needs of China's rural doctors are still disjointed; measures including the introduction of remote education and clinical further education, extended training time and more clinical skills training should be adopted.
THE MARSDEN–WEINSTEIN REDUCTION STRUCTURE OF INTEGRABLE DYNAMICAL SYSTEMS AND A GENERALIZED EXACTLY SOLVABLE QUANTUM SUPERRADIANCE MODEL
Authors: BOGOLUBOV N. N. , PRYKARPATSKY Y. A. 
Published: February 2013

An approach to describing nonlinear Lax type integrable dynamical systems of modern mathematical and theoretical physics, based on the Marsden–Weinstein reduction method on canonically symplectic manifolds with group symmetry, is proposed. Its natural relationship with the well-known Adler–Kostant–Souriau–Berezin–Kirillov method and the associated R-matrix approach is analyzed. A new generalized exactly solvable spatially one-dimensional quantum superradiance model, describing a charged fermionic medium interacting with external electromagnetic field, is suggested. The Lax type operator spectral problem is presented, the related R-structure is calculated. The Hamilton operator renormalization procedure subject to a physically stable vacuum is described, the quantum excitations and quantum solitons, related with the thermodynamical equilibrity of the model, are discussed.
FLUCTUATIONS IN LIPID BILAYERS: ARE THEY UNDERSTOOD?
Authors: SCHMID FRIEDERIKE 
Published: February 2013

We review recent computer simulation studies of undulating lipid bilayers. Theoretical interpretations of such fluctuating membranes are most commonly based on generalized Helfrich-type elastic models, with additional contributions of local "protrusions" and/or density fluctuations. Such models provide an excellent basis for describing the fluctuations of tensionless bilayers in the fluid Lαphase at a quantitative level.However, this description is found to fail for membranes in the gel phase and for membranes subject to high tensions. The fluctuations of tilted gel membranes (Lβ′phase) show a signature of the modulated ripple structure Pβ′, which is a nearby phase observed in the pretransition regime between the Lαand Lβ′state. This complicates a quantitative analysis on mesoscopic length scales. In the case of fluid membranes under tension, the large-wavelength fluctuation modes are found to be significantly softer than predicted by theory.In the latter context, we also address the general problem of the relation between frame tension and the fluctuation tension, which has been discussed somewhat controversially in recent years. Simulations of very simple model membranes with fixed area show that the fluctuations should be controlled by the frame tension, and not by the internal tension.
Loss of Continuity in the Thin Epicardial Layer Because of Endomysial Fibrosis Increases the Complexity of Atrial Fibrillatory Conduction
Authors: Verheule Sander , Tuyls Els , Gharaviri Ali , Hulsmans Sarah , van Hunnik Arne , Kuiper Marion , Serroyen Jan , Zeemering Stef , Kuijpers Nico H.L. , Schotten Ulrich 
Published: February 2013

Background—
The transition from persistent to permanent atrial fibrillation (AF) is associated with increased complexity of fibrillatory conduction. We have investigated the spatial distribution of fibrillation waves and structural alterations in the atrial free walls in a goat model of AF.

Methods and Results—
AF was maintained for 3 weeks (short term [ST], persistent AF) or 6 months (long term [LT], permanent AF). Fibrillation patterns were assessed with epicardial mapping. The origin of fibrillation waves and sites of conduction abnormalities were more homogeneously distributed in LT than in ST goats. Histologically, the total area fraction occupied by fibrous tissue and the degree of perimysial fibrosis (separation between myocyte bundles) were not significantly different between groups. However, endomysial fibrosis (distance between myocytes within bundles) was significantly larger in LT goats, particularly in the outer millimeter of the atria. By contrast, myocyte diameters were larger in LT goats throughout the atrial walls. High-resolution optical mapping showed that epicardial wavefront expansion was slower and more anisotropic in LT than in ST goats. Finally, a mathematical model of a simplified atrial architecture confirmed the potential impact of epicardial endomysial fibrosis on AF complexity.

Conclusions—
Altered propagation after 6 months of AF is consistent with homogeneous structural remodeling in the outer millimeter of the atria. Loss of continuity of the epicardial layer because of endomysial fibrosis may reduce its synchronizing effect, thereby increasing the complexity of fibrillatory conduction pathways. The exact distribution of fibrosis may be more important for the occurrence of conduction disturbances than the overall quantity.