bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses
Authors: Poddar Subhajit , Hyde Jennifer L. , Gorman Matthew J. , Farzan Michael , Diamond Michael S. 
Published: July 2016

ABSTRACT

Host cells respond to viral infections by producing type I interferon (IFN), which induces the expression of hundreds of interferon-stimulated genes (ISGs). Although ISGs mediate a protective state against many pathogens, the antiviral functions of the majority of these genes have not been identified. IFITM3 is a small transmembrane ISG that restricts a broad range of viruses, including orthomyxoviruses, flaviviruses, filoviruses, and coronaviruses. Here, we show that alphavirus infection is increased in
Ifitm3
−/−
and
Ifitm
locus deletion (
Ifitm-del
) fibroblasts and, reciprocally, reduced in fibroblasts transcomplemented with Ifitm3. Mechanistic studies showed that Ifitm3 did not affect viral binding or entry but inhibited pH-dependent fusion. In a murine model of chikungunya virus arthritis,
Ifitm3
−/−
mice sustained greater joint swelling in the ipsilateral ankle at days 3 and 7 postinfection, and this correlated with higher levels of proinflammatory cytokines and viral burden. Flow cytometric analysis suggested that
Ifitm3
−/−
macrophages from the spleen were infected at greater levels than observed in wild-type (WT) mice, results that were supported by experiments with
Ifitm3
−/−
bone marrow-derived macrophages.
Ifitm3
−/−
mice also were more susceptible than WT mice to lethal alphavirus infection with Venezuelan equine encephalitis virus, and this was associated with greater viral burden in multiple organs. Collectively, our data define an antiviral role for Ifitm3 in restricting infection of multiple alphaviruses.

IMPORTANCE
The interferon-induced transmembrane protein 3 (IFITM3) inhibits infection of multiple families of viruses in cell culture. Compared to other viruses, much less is known about the antiviral effect of IFITM3 on alphaviruses. In this study, we characterized the antiviral activity of mouse Ifitm3 against arthritogenic and encephalitic alphaviruses using cells and animals with a targeted gene deletion of
Ifitm3
as well as deficient cells transcomplemented with Ifitm3. Based on extensive virological analysis, we demonstrate greater levels of alphavirus infection and disease pathogenesis when Ifitm3 expression is absent. Our data establish an inhibitory role for Ifitm3 in controlling infection of alphaviruses.
Exocytosis of Varicella-Zoster Virus Virions Involves a Convergence of Endosomal and Autophagy Pathways
Authors: Buckingham Erin M. , Jarosinski Keith W. , Jackson Wallen , Carpenter John E. , Grose Charles 
Published: July 2016

ABSTRACT
Varicella-zoster virus (VZV) is an extremely cell-associated herpesvirus with limited egress of viral particles. The induction of autophagy in VZV-infected monolayers is easily detectable; inhibition of autophagy leads to decreased VZV glycoprotein biosynthesis and diminished viral titers. To explain how autophagic flux could exert a proviral effect on the VZV infectious cycle, we postulated that the VZV exocytosis pathway following secondary envelopment may converge with the autophagy pathway. This hypothesis depended on known similarities between VZV gE and autophagy-related (Atg) Atg9/Atg16L1 trafficking pathways. Investigations were carried out with highly purified fractions of VZV virions. When the virion fraction was tested for the presence of autophagy and endosomal proteins, microtubule-associated protein 1 light chain (MAP1LC3B) and Ras-like GTPase 11 (Rab11) were detected. By two-dimensional (2D) and 3D imaging after immunolabeling, both proteins also colocalized with VZV gE in a proportion of cytoplasmic vesicles. When purified VZV virions were enumerated after immunoelectron microscopy, gold beads were detected on viruses following incubation with antibodies to VZV gE (∼100%), Rab11 (50%), and LC3B (30%). Examination of numerous electron micrographs demonstrated that enveloped virions were housed in single-membraned vesicles; viral particles were not observed in autophagosomes. Taken together, our data suggested that some viral particles after secondary envelopment accumulated in a heterogeneous population of single-membraned vesicular compartments, which were decorated with components from both the endocytic pathway (Rab11) and the autophagy pathway (LC3B). The latter cytoplasmic viral vesicles resembled an amphisome.

IMPORTANCE
VZV infection leads to increased autophagic flux, while inhibition of autophagy leads to a marked reduction in virus spread. In this investigation of the proviral role of autophagy, we found evidence for an intersection of viral exocytosis and autophagy pathways. Specifically, both LC3-II and Rab11 proteins copurified with some infectious VZV particles. The results suggested that a subpopulation of VZV particles were carried to the cell surface in single-walled vesicles with attributes of an amphisome, an organelle formed from the fusion of an endosome and an autophagosome. Our results also addressed the interpretation of autophagy/xenophagy results with mutated herpes simplex virus lacking its ICP34.5 neurovirulence gene (HSVΔ34.5). The VZV genome lacks an ICP34.5 ortholog, yet we found no evidence of VZV particles housed in a double-membraned autophagosome. In other words, xenophagy, a degradative process documented after infection with HSVΔ34.5, was not observed in VZV-infected cells.
Deep Sequencing of Distinct Preparations of the Live Attenuated Varicella-Zoster Virus Vaccine Reveals a Conserved Core of Attenuating Single-Nucleotide Polymorphisms
Authors: Depledge Daniel P. , Yamanishi Koichi , Gomi Yasuyuki , Gershon Anne A. , Breuer Judith 
Published: July 2016

ABSTRACT
The continued success of the live attenuated varicella-zoster virus vaccine in preventing varicella-zoster and herpes zoster is well documented, as are many of the mutations that contribute to the attenuation of the vOka virus for replication in skin. At least three different preparations of vOka are marketed. Here, we show using deep sequencing of seven batches of vOka vaccine (including ZostaVax, VariVax, VarilRix, and the Oka/Biken working seed) from three different manufacturers (VariVax, GSK, and Biken) that 137 single-nucleotide polymorphism (SNP) mutations are present in all vaccine batches. This includes six sites at which the vaccine allele is fixed or near fixation, which we speculate are likely to be important for attenuation. We also show that despite differences in the vaccine populations between preparations, batch-to-batch variation is minimal, as is the number and frequency of mutations unique to individual batches. This suggests that the vaccine manufacturing processes are not introducing new mutations and that, notwithstanding the mixture of variants present, VZV live vaccines are extremely stable.

IMPORTANCE
The continued success of vaccinations to prevent chickenpox and shingles, combined with the extremely low incidence of adverse reactions, indicates the quality of these vaccines. The vaccine itself is comprised of a heterogeneous live attenuated virus population and thus requires deep-sequencing technologies to explore the differences and similarities in the virus populations between different preparations and batches of the vaccines. Our data demonstrate minimal variation between batches, an important safety feature, and provide new insights into the extent of the mutations present in this attenuated virus.
Epstein-Barr Virus Oncoprotein LMP1 Mediates Epigenetic Changes in Host Gene Expression through PARP1
Authors: Martin Kayla A. , Lupey Lena N. , Tempera Italo 
Published: July 2016

ABSTRACT
The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV replication during latency. In this study, we detail the mechanisms that drive cellular PARylation during latent EBV infection and the effects of PARylation on host gene expression and cellular function. EBV-infected B cells had higher PAR levels than EBV-negative B cells. Moreover, cellular PAR levels were up to 2-fold greater in type III than type I latently infected EBV B cells. We identified a positive association between expression of the EBV genome-encoded latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1. PARP1 regulates gene expression by numerous mechanisms, including modifying chromatin structure and altering the function of chromatin-modifying enzymes. Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis, we explored the model that disruption in cellular PARylation, driven by LMP1 expression, subsequently promotes epigenetic alterations to elicit changes in host gene expression. PARP1 inhibition resulted in the accumulation of the repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition of PARP1, or abrogation of PARP1 expression, also suppressed the expression of LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an essential role for PARP1 activity in LMP1-induced gene expression and cellular transformation associated with LMP1. In summary, we identified a novel mechanism by which LMP1 drives expression of host tumor-promoting genes by blocking generation of the inhibitory histone modification H3K27me3 through PARP1 activation.

IMPORTANCE
EBV is causally linked to several malignancies and is responsible for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential for promoting viral tumorigenesis by aberrant activation of several well-known intracellular signaling pathways. We have identified and defined an additional novel molecular mechanism by which LMP1 regulates the expression of tumor-promoting host genes. We found that LMP1 activates the cellular protein PARP1, leading to a decrease in a repressive histone modification, accompanied by induction in expression of multiple cancer-related genes. PARP1 inhibition or depletion led to a decrease in LMP1-induced cellular transformation. Therefore, targeting PARP1 activity may be an effective treatment for EBV-associated malignancies.
Concurrence of Iridovirus, Polyomavirus, and a Unique Member of a New Group of Fish Papillomaviruses in Lymphocystis Disease-Affected Gilthead Sea Bream
Authors: López-Bueno Alberto , Mavian Carla , Labella Alejandro M. , Castro Dolores , Borrego Juan J. , Alcami Antonio , Alejo Alí 
Published: July 2016

ABSTRACT

Lymphocystis disease is a geographically widespread disease affecting more than 150 different species of marine and freshwater fish. The disease, provoked by the iridovirus lymphocystis disease virus (LCDV), is characterized by the appearance of papillomalike lesions on the skin of affected animals that usually self-resolve over time. Development of the disease is usually associated with several environmental factors and, more frequently, with stress conditions provoked by the intensive culture conditions present in fish farms. In gilthead sea bream (
Sparus aurata
), an economically important cultured fish species in the Mediterranean area, a distinct LCDV has been identified but not yet completely characterized. We have used direct sequencing of the virome of lymphocystis lesions from affected
S. aurata
fish to obtain the complete genome of a new LCDV-Sa species that is the largest vertebrate iridovirus sequenced to date. Importantly, this approach allowed us to assemble the full-length circular genome sequence of two previously unknown viruses belonging to the papillomaviruses and polyomaviruses, termed Sparus aurata papillomavirus 1 (SaPV1) and Sparus aurata polyomavirus 1 (SaPyV1), respectively. Epidemiological surveys showed that lymphocystis disease was frequently associated with the concurrent appearance of one or both of the new viruses. SaPV1 has unique characteristics, such as an intron within the L1 gene, and as the first member of the
Papillomaviridae
family described in fish, provides evidence for a more ancient origin of this family than previously thought.

IMPORTANCE
Lymphocystis disease affects marine and freshwater fish species worldwide. It is characterized by the appearance of papillomalike lesions on the skin that contain heavily enlarged cells (lymphocysts). The causative agent is the lymphocystis disease virus (LCDV), a large icosahedral virus of the family
Iridoviridae
. In the Mediterranean area, the gilthead sea bream (
Sparus aurata
), an important farmed fish, is frequently affected. Using next-generation sequencing, we have identified within
S. aurata
lymphocystis lesions the concurrent presence of an additional LCDV species (LCDV-Sa) as well as two novel viruses. These are members of polyomavirus and papillomavirus families, and here we report them to be frequently associated with the presence of lymphocysts in affected fish. Because papillomaviruses have not been described in fish before, these findings support a more ancient origin of this virus family than previously thought and evolutionary implications are discussed.
The PB2 Subunit of the Influenza A Virus RNA Polymerase Is Imported into the Mitochondrial Matrix
Authors: Long Joshua C. D. , Fodor Ervin 
Published: July 2016

ABSTRACT

The polymerase basic 2 (PB2) subunit of the RNA polymerase complex of seasonal human influenza A viruses has been shown to localize to the mitochondria. Various roles, including the regulation of apoptosis and innate immune responses to viral infection, have been proposed for mitochondrial PB2. In particular, PB2 has been shown to inhibit interferon expression by associating with the mitochondrial antiviral signaling (MAVS) protein, which acts downstream of RIG-I and MDA-5 in the interferon induction pathway. However, in spite of a growing body of literature on the potential roles of mitochondrial PB2, the exact location of PB2 in mitochondria has not been determined. Here, we used enhanced
a
scorbate
pe
ro
x
idase (APEX)-tagged PB2 proteins and electron microscopy to study the localization of PB2 in mitochondria. We found that PB2 is imported into mitochondria, where it localizes to the mitochondrial matrix. We also demonstrated that MAVS is not required for the import of PB2 into mitochondria by showing that PB2 associates with mitochondria in MAVS knockout mouse embryo fibroblasts. Instead, we found that amino acid residue 9 in the N-terminal mitochondrial targeting sequence is a determinant of the mitochondrial import of PB2, differentiating the localization of PB2 of human from that of avian influenza A virus strains. We also showed that a virus encoding nonmitochondrial PB2 is attenuated in mouse embryonic fibroblasts (MEFs) compared with an isogenic virus encoding mitochondrial PB2, in a MAVS-independent manner, suggesting a role for PB2 within the mitochondrial matrix. This work extends our understanding of the interplay between influenza virus and mitochondria.

IMPORTANCE
The PB2 subunit of the influenza virus RNA polymerase is a major determinant of viral pathogenicity. However, the molecular mechanisms of how PB2 determines pathogenicity remain poorly understood. PB2 associates with mitochondria and inhibits the function of the mitochondrial antiviral signaling protein MAVS, implicating PB2 in the regulation of innate immune responses. We found that PB2 is imported into the mitochondrial matrix and showed that amino acid residue 9 is a determinant of mitochondrial import. The presence of asparagine or threonine in over 99% of all human seasonal influenza virus pre-2009 H1N1, H2N2, and H3N2 strains is compatible with mitochondrial import, whereas the presence of an aspartic acid in over 95% of all avian influenza viruses is not, resulting in a clear distinction between human-adapted and avian influenza viruses. These findings provide insights into the interplay between influenza virus and mitochondria and suggest mechanisms by which PB2 could affect pathogenicity.
Historical and Critical Review on Biophysical Economics
Authors: Adigüzel Yekbun 
Published: July 2016

Biophysical economics is initiated with the long history of the relation of economics with ecological basis and biophysical perspectives of the physiocrats. It inherently has social, economic, biological, environmental, natural, physical, and scientific grounds. Biological entities in economy like the resources, consumers, populations, and parts of production systems, etc. could all be dealt by biophysical economics. Considering this wide scope, current work is a “biophysical economics at a glance” rather than a comprehensive review of the full range of topics that may just be adequately covered in a book-length work. However, the sense of its wide range of applications is aimed to be provided to the reader in this work. Here, modern approaches and biophysical growth theory are presented after the long history and an overview of the concepts in biophysical economics. Examples of the recent studies are provided at the end with discussions. This review is also related to the work by Cleveland, “Biophysical Economics: From Physiocracy to Ecological Economics and Industrial Ecology” [C. J. Cleveland, in Advances in Bioeconomics and Sustainability: Essay in Honor of Nicholas Gerogescu-Roegen, eds. J. Gowdy and K. Mayumi (Edward Elgar Publishing, Cheltenham, England, 1999), pp. 125–154.]. Relevant parts include critics and comments on the presented concepts in a parallelized fashion with the Cleveland’s work.
Paralic reservoirs
Authors: Reynolds Antony D. 
Published: July 2016

Abstract
Paralic environments, deltas, estuaries and shoreline-shelf systems respond sensitively to changes in sea-level and sediment supply, commonly by shifts in facies belts across sequence stratigraphic surfaces. As a result, they are often interleaved in highly layered successions. Layering and a wide range of associated sandbody types control the distinctive nature of paralic oil and gas fields. Layering results in stacked reservoirs. Thick extensive sandstones have structurally defined spill points, large aquifers and good reservoir properties. Such sands have high recovery, good reservoir performance and form primary completion targets. By contrast, thin, laterally restricted, isolated sandstones have low recovery factors and poor performance. Each isolated sand may have its own hydrocarbon contacts and a distinct outline that reflects both structural and stratigraphic trapping. Such sands form secondary completion targets. Fault compartmentalization is a recurring risk. Sealing faults increase the number of reservoir compartments and may decrease performance and recovery. They can also generate traps. Sedimentology is pivotal in describing heterogeneity in paralic reservoirs at all scales. Established techniques are likely to be complemented in the future by forward stratigraphic modelling, integration with palynology and more studies of surveillance data to show how sedimentological variability controls fluid movement in real reservoirs.
Rift–drift transition in a magma-rich system: the Gop Rift–Laxmi Basin case study, West India
Authors: Nemčok M. , Rybár S. 
Published: July 2016

Abstract
This paper studies the magma-rich Gop Rift–Laxmi Basin, West India, which underwent the mantle first–crust second break-up mode. It draws from reflection seismic and gravity data from this abandoned system. Seismic images document that the crustal necking was associated with the development of seawards-dipping reflector wedges deformed by landwards-dipping detachment faults. A wide crustal necking zone indicates that the ductile lower crust was still present during necking. Observed uneven detachment fault spacing indicates the effect of upper-crustal anisotropy. Comparison of the seismic images through progressively more mature stages of the rift–drift transition documents that the final stages of thinning represented the time period when the upper-crustal wide and symmetrical rift architecture changed to the asymmetrical one, and the decoupled system to the coupled one. It further indicates that the last crustal layer was broken with a convex-up fault that was associated with an excess magmatic event. The fault propagation represented the first spontaneous deformation unaffected by the pre-existing anisotropy. Subsequent drift of the two plates was associated with melt-assisted spreading and spontaneous faulting. The faulting geometry and sequence controlled which of the conjugate margins ended up with a volcanic outer high, representing the record of the break-up-locating excess magmatism.
Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction
Authors: Bohula Erin A. , Bonaca Marc P. , Braunwald Eugene , Aylward Philip E. , Corbalan Ramon , De Ferrari Gaetano M. , He Ping , Lewis Basil S. , Merlini Piera A. , Murphy Sabina A. , Sabatine Marc S. , Scirica Benjamin M. , Morrow David A. 
Published: July 2016

Background:
Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar.

Methods:
We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2°P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348; MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding.

Results:

The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the individual components (
P
for trend <0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1–2 risk indicators; 61%) had a 2.1% absolute risk reduction (
P
<0.001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups (
P
for trend<0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients.

Conclusions:
Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00526474.