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trehalose, an mtor-independent inducer of autophagy, inhibits human cytomegalovirus infection in multiple cell types.human cytomegalovirus (hcmv) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. previous studies have shown that the induction of autophagy can inhibit the replication of several different types of dna and rna viruses. the goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of hcmv. most prior studies have used agents that induce autop ...201526559848
hiv vaccine: recent advances, current roadblocks, and future directions.hiv/aids is a leading cause of mortality and morbidity worldwide. in spite of successful interventions and treatment protocols, an hiv vaccine would be the ultimate prevention and control strategy. ever since identification of hiv/aids, there have been meticulous efforts for vaccine development. the specific aim of this paper is to review recent vaccine efficacy trials and associated advancements and discuss the current challenges and future directions. recombinant dna technologies greatly facil ...201526579546
parp9-dtx3l ubiquitin ligase targets host histone h2bj and viral 3c protease to enhance interferon signaling and control viral infection.enhancing the response to interferon could offer an immunological advantage to the host. in support of this concept, we used a modified form of the transcription factor stat1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. we found that the improvement depended on expression of a parp9-dtx3l complex with distinct domains for interaction with stat1 and for activity as an e3 ubiquitin ligase that ...201526479788
virus-based nanoparticles as versatile nanomachines.nanoscale engineering is revolutionizing the way we prevent, detect, and treat diseases. viruses have played a special role in these developments because they can function as prefabricated nanoscaffolds that have unique properties and are easily modified. the interiors of virus particles can encapsulate and protect sensitive compounds, while the exteriors can be altered to display large and small molecules in precisely defined arrays. these properties of viruses, along with their innate biocompa ...201526958921
intracellular mono-adp-ribosylation in signaling and disease.a key process in the regulation of protein activities and thus cellular signaling pathways is the modification of proteins by post-translational mechanisms. knowledge about the enzymes (writers and erasers) that attach and remove post-translational modifications, the targets that are modified and the functional consequences elicited by specific modifications, is crucial for understanding cell biological processes. moreover detailed knowledge about these mechanisms and pathways helps to elucidate ...201526426055
infectious bronchitis coronavirus inhibits stat1 signaling and requires accessory proteins for resistance to type i interferon activity.the innate immune response is the first line of defense against viruses, and type i interferon (ifn) is a critical component of this response. similar to other viruses, the gammacoronavirus infectious bronchitis virus (ibv) has evolved under evolutionary pressure to evade and counteract the ifn response to enable its survival. previously, we reported that ibv induces a delayed activation of the ifn response. in the present work, we describe the resistance of ibv to ifn and the potential role of ...201526401035
antiviral potential of algae polysaccharides isolated from marine sources: a review.from food to fertilizer, algal derived products are largely employed in assorted industries, including agricultural, biomedical, food, and pharmaceutical industries. among different chemical compositions isolated from algae, polysaccharides are the most well-established compounds, which were subjected to a variety of studies due to extensive bioactivities. over the past few decades, the promising results for antiviral potential of algae-derived polysaccharides have advocated them as inordinate c ...201526484353
colorimetric detection of dengue by single tube reverse-transcription-loop-mediated isothermal amplification.dengue is usually diagnosed by isolation of the virus, serology or molecular diagnostic methods. several commercial kits for the diagnosis of dengue are existing, but concerns have arisen regarding to the affordability and performance characteristics of these kits. hence, the loop-mediated isothermal amplification (lamp) is potentially ideal to be used especially in resource limited environments. serum was collected from healthy donors and patients diagnosed with dengue infection. rna extracted ...201526384248
hur displaces polypyrimidine tract binding protein to facilitate la binding to the 3' untranslated region and enhances hepatitis c virus replication.hur is a ubiquitous, rna binding protein that influences the stability and translation of several cellular mrnas. here, we report a novel role for hur, as a regulator of proteins assembling at the 3' untranslated region (utr) of viral rna in the context of hepatitis c virus (hcv) infection. hur relocalizes from the nucleus to the cytoplasm upon hcv infection, interacts with the viral polymerase (ns5b), and gets redistributed into compartments of viral rna synthesis. depletion in hur levels leads ...201526339049
structural and functional characterization of anti-a33 antibodies reveal a potent cross-species orthopoxviruses neutralizer.vaccinia virus a33 is an extracellular enveloped virus (eev)-specific type ii membrane glycoprotein that is essential for efficient eev formation and long-range viral spread within the host. a33 is a target for neutralizing antibody responses against eev. in this study, we produced seven murine anti-a33 monoclonal antibodies (mabs) by immunizing mice with live vacv, followed by boosting with the soluble a33 homodimeric ectodomain. five a33 specific mabs were capable of neutralizing eev in the pr ...201526325270
selective effects of pde10a inhibitors on striatopallidal neurons require phosphatase inhibition by darpp-32(1,2,3).type 10a phosphodiesterase (pde10a) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (msns), which express d1 and d2 dopamine receptors, respectively. pde10a inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. we analyzed the effects of pde10a inhibition in vivo by immunohistochemistry, and imaged camp, camp-dependent protein kinase a (pka), and cgmp si ...201526465004
flavivirus sfrna suppresses antiviral rna interference in cultured cells and mosquitoes and directly interacts with the rnai machinery.productive arbovirus infections require mechanisms to suppress or circumvent the cellular rna interference (rnai) pathway, a major antiviral response in mosquitoes. in this study, we demonstrate that two flaviviruses, dengue virus and kunjin virus, significantly repress sirna-mediated rnai in infected human cells as well as during infection of the mosquito vector culex quinquefasciatus. arthropod-borne flaviviruses generate a small structured non-coding rna from the viral 3' utr referred to as s ...201526331679
cd8 t-cell priming upon mrna vaccination is restricted to bone-marrow-derived antigen-presenting cells and may involve antigen transfer from myocytes.self-amplifying mrnas (sam(®) ) are a novel class of nucleic acid vaccines, delivered by a non-viral delivery system. they are effective at eliciting potent and protective immune responses and are being developed as a platform technology with potential to be used for a broad range of targets. however, their mechanism of action has not been fully elucidated. to date, no evidence of in vivo transduction of professional antigen-presenting cells (apcs) by sam vector has been reported, while the anti ...201526173587
x-ray structural and functional studies of the three tandemly linked domains of non-structural protein 3 (nsp3) from murine hepatitis virus reveal conserved functions.murine hepatitis virus (mhv) has long served as a model system for the study of coronaviruses. non-structural protein 3 (nsp3) is the largest nsp in the coronavirus genome, and it contains multiple functional domains that are required for coronavirus replication. despite the numerous functional studies on mhv and its nsp3 domain, the structure of only one domain in nsp3, the small ubiquitin-like domain 1 (ubl1), has been determined. we report here the x-ray structure of three tandemly linked dom ...201526296883
comparative mapping of host-pathogen protein-protein interactions.pathogens usurp a variety of host pathways via protein-protein interactions to ensure efficient pathogen replication. despite the existence of an impressive toolkit of systematic and unbiased approaches, we still lack a comprehensive list of these ppis and an understanding of their functional implications. here, we highlight the importance of harnessing genetic diversity of hosts and pathogens for uncovering the biochemical basis of pathogen restriction, virulence, fitness, and pathogenesis. we ...201526275922
hexokinase 2 controls cellular stress response through localization of an rna-binding protein.subcellular localization of rna-binding proteins is a key determinant of their ability to control rna metabolism and cellular stress response. using an rnai-based kinome-wide screen, we identified hexokinase 2 (hk2) as a regulator of the cytoplasmic accumulation of hnrnp a1 in response to hypertonic stress and human rhinovirus infection (hrv). we show that inhibition of hk2 expression or pharmacological inhibition of hk2 activity blocks the cytoplasmic accumulation of heterogeneous nuclear ribon ...201526247723
oncolytic potency of her-2 retargeted vsv-fh hybrid viruses: the role of receptor ligand affinity.the hybrid oncolytic vesicular stomatitis virus (vsv-fh) deleted for its g glycoprotein and displaying the measles virus (mv) envelope glycoproteins (hemagglutinin h and fusion f) is fusogenic, infects cells via any of the three mv receptors and has potent oncolytic activity against subcutaneous and disseminated myeloma tumors. to tailor vsv-fh as an oncolytic virus for ovarian cancer, we ablated its natural tropism and retargeted the virus by display of a single-chain antibody (scfv) with speci ...201527119107
potential antileukemia effect and structural analyses of srpk inhibition by n-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)isonicotinamide (srpin340).dysregulation of pre-mrna splicing machinery activity has been related to the biogenesis of several diseases. the serine/arginine-rich protein kinase family (srpks) plays a critical role in regulating pre-mrna splicing events through the extensive phosphorylation of splicing factors from the family of serine/arginine-rich proteins (sr proteins). previous investigations have described the overexpression of srpk1 and srpk2 in leukemia and other cancer types, suggesting that they would be useful ta ...201526244849
analysis of site-specific n-glycan remodeling in the endoplasmic reticulum and the golgi.the hallmark of n-linked protein glycosylation is the generation of diverse glycan structures in the secretory pathway. dynamic, non-template-driven processes of n-glycan remodeling in the endoplasmic reticulum and the golgi provide the cellular setting for structural diversity. we applied newly developed mass spectrometry-based analytics to quantify site-specific n-glycan remodeling of the model protein pdi1p expressed in insect cells. molecular dynamics simulation, mutational analysis, kinetic ...201526240167
mammalian synthetic circuits with rna binding proteins for rna-only delivery.synthetic regulatory circuits encoded in rna rather than dna could provide a means to control cell behavior while avoiding potentially harmful genomic integration in therapeutic applications. we create post-transcriptional circuits using rna-binding proteins, which can be wired in a plug-and-play fashion to create networks of higher complexity. we show that the circuits function in mammalian cells when encoded in modified mrna or self-replicating rna.201526237515
autophagy knocked down by high-risk hpv infection and uterine cervical carcinogenesis.cervical cancer is a leading cause of cancer death among women in the world. the specific etiopathogenesis of cervical cancer is indeed complex. even so, we should make arduous efforts to have a precise understanding of the complicate cellular/molecular mechanisms underlying initiation, progression and/or prevention of the cervical cancer. the high-risk human papillomavirus (hrhpv) is considered as the major causative agent of cervical cancer. but with the existence of hrhpv only is not sufficie ...201526379821
ultraviolet light (uv) inactivation of porcine parvovirus in liquid plasma and effect of uv irradiated spray dried porcine plasma on performance of weaned pigs.a novel ultraviolet light irradiation (uv-c, 254 nm) process was designed as an additional safety feature for manufacturing of spray dried porcine plasma (sdpp). in exp. 1, three 10-l batches of bovine plasma were inoculated with 10(5.2 ± 0.12) tissue culture infectious dose 50 (tcid50) of porcine parvovirus (ppv) per ml of plasma and subjected to uv-c ranging from 0 to 9180 j/l. no viable ppv was detected in bovine plasma by micro-titer assay in sk6 cell culture after uv-c at 2295 j/l. in exp. ...201526171968
unraveling host-vector-arbovirus interactions by two-gene high resolution melting mosquito bloodmeal analysis in a kenyan wildlife-livestock interface.the blood-feeding patterns of mosquitoes are directly linked to the spread of pathogens that they transmit. efficient identification of arthropod vector bloodmeal hosts can identify the diversity of vertebrate species potentially involved in disease transmission cycles. while molecular bloodmeal analyses rely on sequencing of cytochrome b (cyt b) or cytochrome oxidase 1 gene pcr products, recently developed bloodmeal host identification based on high resolution melting (hrm) analyses of cyt b pc ...201526230507
quantitative proteomics identifies serum response factor binding protein 1 as a host factor for hepatitis c virus entry.hepatitis c virus (hcv) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor cd81. how cd81 governs hcv entry is poorly characterized, and cd81 protein interactions after virus binding remain elusive. we have developed a quantitative proteomics protocol to identify hcv-triggered cd81 interactions and found 26 dynamic binding partners. at least six of these proteins promote hcv infection, as indicated by rnai. we further characterized ser ...201526212323
effect of osmotic pressure on the stability of whole inactivated influenza vaccine for coating on microneedles.enveloped virus vaccines can be damaged by high osmotic strength solutions, such as those used to protect the vaccine antigen during drying, which contain high concentrations of sugars. we therefore studied shrinkage and activity loss of whole inactivated influenza virus in hyperosmotic solutions and used those findings to improve vaccine coating of microneedle patches for influenza vaccination. using stopped-flow light scattering analysis, we found that the virus underwent an initial shrinkage ...201526230936
antiviral phosphorodiamidate morpholino oligomers are protective against chikungunya virus infection on cell-based and murine models.chikungunya virus (chikv) infection in human is associated with debilitating and persistent arthralgia and arthritis. currently, there is no specific vaccine or effective antiviral available. anti-chikv phosphorodiamidate morpholino oligomer (cpmo) was evaluated for its antiviral efficacy and cytotoxcity in human cells and neonate murine model. two cpmos were designed to block translation initiation of a highly conserved sequence in chikv non-structural and structural polyprotein, respectively. ...201526224141
herpes simplex virus 1 suppresses the function of lung dendritic cells via caveolin-1.caveolin-1 (cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. several viruses exploit caveolae to facilitate viral infections. however, the roles of cav-1 in herpes simplex virus 1 (hsv-1) infection have not fully been elucidated. here, we report that cav-1 downregulates the expression of inducible nitric oxide synthase (inos) and the production of nitric oxide (no) in dendritic cells (dcs) during hsv-1 infection. as a result, ca ...201526018534
viral membrane channels: role and function in the virus life cycle.viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. these proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating to viral release. in addition, the ion channel activity of viroporin causes disruption in the cellular ion homeostasis, in particular the calcium ion. fluctuation in the calcium level triggers the activation of t ...201526110585
the effect of oral administration of dsrna on viral replication and mortality in bombus terrestris.israeli acute paralysis virus (iapv), a single-stranded rna virus, has a worldwide distribution and affects honeybees as well as other important pollinators. iapv infection in honeybees has been successfully repressed by exploiting the rna interference (rnai) pathway of the insect's innate immune response with virus-specific double stranded rna (dsrna). here we investigated the effect of iapv infection in the bumblebee bombus terrestris and its tissue tropism. b. terrestris is a common pollinato ...201526110584
designing herpes viruses as oncolytics.oncolytic herpes simplex virus (ohsv) was one of the first genetically-engineered oncolytic viruses. because herpes simplex virus (hsv) is a natural human pathogen that can cause serious disease, it is incumbent that it be genetically-engineered or significantly attenuated for safety. here we present a detailed explanation of the functions of hsv-1 genes frequently mutated to endow oncolytic activity. these genes are non-essential for growth in tissue culture cells but are important for growth i ...201526462293
going viral with fluorescent proteins.many longstanding questions about dynamics of virus-cell interactions can be answered by combining fluorescence imaging techniques with fluorescent protein (fp) tagging strategies. successfully creating a fp fusion with a cellular or viral protein of interest first requires selecting the appropriate fp. however, while viral architecture and cellular localization often dictate the suitability of a fp, a fp's chemical and physical properties must also be considered. here, we discuss the challenges ...201526202231
serological evidence of chikungunya virus among acute febrile patients in southern mozambique.in the last two decades, chikungunya virus (chikv) has rapidly expanded to several geographical areas, causing frequent outbreaks in sub-saharan africa, south east asia, south america, and europe. therefore, the disease remains heavily neglected in mozambique, and no recent study has been conducted.201526473605
mouse superkiller-2-like helicase ddx60 is dispensable for type i ifn induction and immunity to multiple viruses.ifn-α/β allow cells to fight virus infection by inducing the expression of many genes that encode effectors of antiviral defense. one of these, the ski2-like dexh-box helicase ddx60, was recently implicated in resistance of human cells to hepatitis c virus, as well as in induction of ifn-α/β by retinoic acid inducible gene 1-like receptors (rlrs) that detect the presence of rna viruses in a cell-intrinsic manner. here, we sought to investigate the role of ddx60 in ifn-α/β induction and in resist ...201526457795
simultaneous determination of sample thickness, tilt, and electron mean free path using tomographic tilt images based on beer-lambert law.cryo-electron tomography (cryo-et) is an emerging technique that can elucidate the architecture of macromolecular complexes and cellular ultrastructure in a near-native state. some important sample parameters, such as thickness and tilt, are needed for 3-d reconstruction. however, these parameters can currently only be determined using trial 3-d reconstructions. accurate electron mean free path plays a significant role in modeling image formation process essential for simulation of electron micr ...201526433027
hur and ago2 bind the internal ribosome entry site of enterovirus 71 and promote virus translation and replication.ev71 (enterovirus 71) rna contains an internal ribosomal entry site (ires) that directs cap-independent initiation of translation. ires-dependent translation requires the host's translation initiation factors and ires-associated trans-acting factors (itafs). we reported recently that mrna decay factor auf1 is a negative-acting itaf that binds ires stem-loop ii. we also reported that the small rna-processing enzyme dicer produces at least four small rnas (vsrnas) from the ev71 ires. one of these, ...201526451954
serum levels of inflammatory cytokines in rift valley fever patients are indicative of severe disease.rift valley fever (rvf) is a mosquito-borne viral zoonosis affecting domestic and wild ruminants, camels and humans. outbreaks of rvf are characterized by a sudden onset of abortions and high mortality amongst domestic ruminants. humans develop disease ranging from a mild flu-like illness to more severe complications including hemorrhagic syndrome, ocular and neurological lesions and death. during the rvf outbreak in south africa in 2010/11, a total of 278 human cases were laboratory confirmed, ...201526437779
neuroanatomy goes viral!the nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. unraveling this specificity is the task of neuroanatomy. in this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the golgi method to electron microscopy. an ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in t ...201526190977
interleukin-10 is a critical regulator of white matter lesion containment following viral induced demyelination.neurotropic coronavirus induces an acute encephalomyelitis accompanied by focal areas of demyelination distributed randomly along the spinal column. the initial areas of demyelination increase only slightly after the control of infection. these circumscribed focal lesions are characterized by axonal sparing, myelin ingestion by macrophage/microglia, and glial scars associated with hypertrophic astrocytes, which proliferate at the lesion border. accelerated virus control in mice lacking the anti- ...201526132901
viroporins, examples of the two-stage membrane protein folding model.viroporins are small, α-helical, hydrophobic virus encoded proteins, engineered to form homo-oligomeric hydrophilic pores in the host membrane. viroporins participate in multiple steps of the viral life cycle, from entry to budding. as any other membrane protein, viroporins have to find the way to bury their hydrophobic regions into the lipid bilayer. once within the membrane, the hydrophobic helices of viroporins interact with each other to form higher ordered structures required to correctly p ...201526131957
isolation and full-length genome analysis of mosquito-borne manzanilla virus from yunnan province, china.there have been four strains on manzanilla virus (manv) identified to date. here, we identify a novel manv strain (dhl10m107) isolated from culex tritaeniorhynchus giles mosquitoes from ruili city, dehong prefecture, yunnan province, in the people's republic of china.201526100251
impact of vesicular stomatitis virus m proteins on different cellular functions.three different matrix (m) proteins termed m1, m2 and m3 have been described in cells infected with vesicular stomatitis virus (vsv). individual expression of vsv m proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. analogous to viroporins, m1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membra ...201526091335
calcium flux-independent nmda receptor activity is required for aβ oligomer-induced synaptic loss.synaptic loss is one of the major features of alzheimer's disease (ad) and correlates with the degree of dementia. n-methyl-d-aspartate receptors (nmdars) have been shown to mediate downstream effects of the β-amyloid peptide (aβ) in ad models. nmdars can trigger intracellular cascades via ca(2+) entry, however, also ca(2+)-independent (metabotropic) functions of nmdars have been described. we aimed to determine whether ionotropic or metabotropic nmdar signaling is required for the induction of ...201526086964
lentiviral protein transfer vectors are an efficient vaccine platform and induce a strong antigen-specific cytotoxic t cell response.to induce and trigger innate and adaptive immune responses, antigen-presenting cells (apcs) take up and process antigens. retroviral particles are capable of transferring not only genetic information but also foreign cargo proteins when they are genetically fused to viral structural proteins. here, we demonstrate the capacity of lentiviral protein transfer vectors (ptvs) for targeted antigen transfer directly into apcs and thereby induction of cytotoxic t cell responses. targeting of lentiviral ...201526085166
circumsporozoite protein as a potential target for antimalarials.since the discovery of circumsporozoite protein (csp), a major sporozoite surface antigen, by ruth nussenzweig and victor nussenzweig in the early 1980s, the role of csp in protection against malaria has been extensively investigated. several monoclonal antibodies against csp have been generated to date, with some of them mediating antimalarial protection upon passive transfer into animals. genetically engineered transgenic mosquitoes producing the anti-csp antibody have recently been generated ...201526081442
important role of the il-32 inflammatory network in the host response against viral infection.the pro-inflammatory cytokine interleukin (il)-32 has gained much attention recently because of its important role in the inflammatory network. since the discovery of il-32 in 2005, our appreciation for its diverse roles continues to grow. recent studies have discovered the antiviral effects induced by il-32 and its associated regulatory mechanisms. the interactions between il-32 and various cytokines including cyclooxygenase 2 (cox-2), inducible nitric oxide synthase (inos), interferon (ifn)-λ1 ...201526087456
antiviral activity of silymarin against chikungunya virus.the mosquito-borne chikungunya virus (chikv) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. although there are several studies to evaluate the efficacy of drugs against chikv, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. here, we investigated the antiviral activity of three t ...201526078201
amino-terminal arginylation targets endoplasmic reticulum chaperone bip for autophagy through p62 binding.we show that ate1-encoded arg-transfer rna transferase (r-transferase) of the n-end rule pathway mediates n-terminal arginylation of multiple endoplasmic reticulum (er)-residing chaperones, leading to their cytosolic relocalization and turnover. n-terminal arginylation of bip (also known as grp78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses to cytosolic foreign dna or proteasomal inhibition, associated with increased ubiquitylation. ...201526075355
comparison of α-glucosyl hesperidin of citrus fruits and epigallocatechin gallate of green tea on the loss of rotavirus infectivity in cell culture.a number of secondary plant metabolites (e.g., flavonoids) possess antiviral/antimicrobial activity. most flavonoids, however, are difficult to study, as they are immiscible in water-based systems. the relatively new semisynthetic α-glucosyl hesperitin (gh), and the natural plant product epigallocatechin gallate (egcg) are unique among most flavonoids, as these flavonoids are highly soluble. the antiviral activity of these plant metabolites were investigated using the rotavirus as a model enteri ...201525972850
distinct immune responses in resistant and susceptible strains of mice during neurovirulent alphavirus encephalomyelitis.susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. neuroadapted sindbis virus (nsv) causes uniformly fatal disease in adult c57bl/6 (b6) mice, but adult balb/c (bc) mice recover from infection. in b6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. to identify the immunological determinants of host susceptibility to fatal nsv-induced encephalomyelitis, we compared virus ...201526041298
new insights into the understanding of hepatitis c virus entry and cell-to-cell transmission by using the ionophore monensin a.in our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular ph, on the hepatitis c virus (hcv) life cycle. we showed that monensin inhibits hcv entry in a pangenotypic and dose-dependent manner. monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. interestingly, we demonstrated that hcv cell-to-cell transmission is dependent on the vesicular ph. using the se ...201526041282
sequence-independent characterization of viruses based on the pattern of viral small rnas produced by the host.virus surveillance in vector insects is potentially of great benefit to public health. large-scale sequencing of small and long rnas has previously been used to detect viruses, but without any formal comparison of different strategies. furthermore, the identification of viral sequences largely depends on similarity searches against reference databases. here, we developed a sequence-independent strategy based on virus-derived small rnas produced by the host response, such as the rna interference ...201526040701
the interferon-inducible mouse apolipoprotein l9 and prohibitins cooperate to restrict theiler's virus replication.apolipoprotein l9b (apol9b) is an interferon-stimulated gene (isg) that has antiviral activity and is weakly expressed in primary mouse neurons as compared to other cell types. here, we show that both apol9 isoforms (apol9b and apol9a) inhibit replication of theiler's murine encephalomyelitis virus (tmev) but not replication of vesicular stomatitis virus (vsv), murid herpesvirus-4 (muhv-4), or infection by a lentiviral vector. apol9 genes are strongly expressed in mouse liver and, to a lesser ex ...201526196674
knockout silkworms reveal a dispensable role for juvenile hormones in holometabolous life cycle.insect juvenile hormones (jhs) prevent precocious metamorphosis and allow larvae to undergo multiple rounds of status quo molts. however, the roles of jhs during the embryonic and very early larval stages have not been fully understood. we generated and characterized knockout silkworms (bombyx mori) with null mutations in jh biosynthesis or jh receptor genes using genome-editing tools. we found that embryonic growth and morphogenesis are largely independent of jhs in bombyx and that, even in the ...201526195792
using the hepatitis c virus rna-dependent rna polymerase as a model to understand viral polymerase structure, function and dynamics.viral polymerases replicate and transcribe the genomes of several viruses of global health concern such as hepatitis c virus (hcv), human immunodeficiency virus (hiv) and ebola virus. for this reason they are key targets for therapies to treat viral infections. although there is little sequence similarity across the different types of viral polymerases, all of them present a right-hand shape and certain structural motifs that are highly conserved. these features allow their functional properties ...201526193306
proteomic analysis of purified turkey adenovirus 3 virions.turkey adenovirus 3 (tadv-3) causes high mortality and significant economic losses to the turkey industry. however, little is known about the molecular determinants required for viral replication and pathogenesis. moreover, tadv-3 does not grow well in cell culture, thus detailed structural studies of the infectious particle is particularly challenging. to develop a better understanding of virus-host interactions, we performed a comprehensive proteomic analysis of proteinase k treated purified t ...201526159706
a genome-wide rnai screening method to discover novel genes involved in virus infection.systematic and comprehensive analysis of host cell proteins involved in virus infection has been difficult in large part due to the lack of robust unbiased methods for their identification. recent technological breakthroughs allowing development of cell-based genetic screens have greatly facilitated our understanding of virus-host interactions. these include instrumentation for processing in microtiter plates (e.g., 384 well), coupled with sensitive readers and off-the-shelf analysis and informa ...201526164699
hunting viral receptors using haploid cells.viruses have evolved intricate mechanisms to gain entry into the host cell. identification of host proteins that serve as viral receptors has enabled insights into virus particle internalization, host and tissue tropism, and viral pathogenesis. in this review we discuss the most commonly employed methods for virus receptor discovery, specifically highlighting the use of forward genetic screens in human haploid cells. the ability to generate true knockout alleles at high saturation provides a sen ...201526958914
ebola virus entry into host cells: identifying therapeutic strategies.filoviruses cause severe hemorrhagic fever in humans. the archetypal virus of this group, ebola virus, is responsible for the current filovirus epidemic in west africa. filoviruses infect most mammalian cells, resulting in broad species tropism and likely contributing to rapid spread of virus throughout the body. a thorough understanding of filovirus entry events will facilitate the development of therapeutics against these critical steps in the viral life cycle. this review summarizes the curre ...201526509109
double-stranded rna is detected by immunofluorescence analysis in rna and dna virus infections, including those by negative-stranded rna viruses.early biochemical studies of viral replication suggested that most viruses produce double-stranded rna (dsrna), which is essential for the induction of the host immune response. however, it was reported in 2006 that dsrna could be detected by immunofluorescence antibody staining in double-stranded dna and positive-strand rna virus infections but not in negative-strand rna virus infections. other reports in the literature seemed to support these observations. this suggested that negative-strand r ...201526136565
elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. a number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to t ...201526025608
the baculovirus antiapoptotic p35 protein functions as an inhibitor of the host rna interference antiviral response.rna interference (rnai) is considered an ancient antiviral defense in diverse organisms, including insects. virus infections generate double-strand rnas (dsrnas) that trigger the rnai machinery to process dsrnas into virus-derived short interfering rnas (vsirnas), which target virus genomes, mrnas, or replication intermediates. viruses, in turn, have evolved viral suppressors of rnai (vsrs) to counter host antiviral rnai. following recent discoveries that insects mount an rnai response against d ...201526018163
astaxanthin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ros/mapk pathway in mice.hepatic ischemia reperfusion (ir) is an important issue in complex liver resection and liver transplantation. the aim of the present study was to determine the protective effect of astaxanthin (asx), an antioxidant, on hepatic ir injury via the reactive oxygen species/mitogen-activated protein kinase (ros/mapk) pathway.201526023842
full length and protease domain activity of chikungunya virus nsp2 differ from other alphavirus nsp2 proteases in recognition of small peptide substrates.alphavirus nsp2 proteins are multifunctional and essential for viral replication. the protease role of nsp2 is critical for virus replication as only the virus protease activity is used for processing of the viral non-structural polypeptide. chikungunya virus is an emerging disease problem that is becoming a world-wide health issue. we have generated purified recombinant chikungunya virus nsp2 proteins, both full length and a truncated protease domain from the c-terminus of the nsp2 protein. enz ...201526182358
virus-induced translational arrest through 4ebp1/2-dependent decay of 5'-top mrnas restricts viral infection.the mosquito-transmitted bunyavirus, rift valley fever virus (rvfv), is a highly successful pathogen for which there are no vaccines or therapeutics. translational arrest is a common antiviral strategy used by hosts. in response, rvfv inhibits two well-known antiviral pathways that attenuate translation during infection, pkr and type i ifn signaling. despite this, translational arrest occurs during rvfv infection by unknown mechanisms. here, we find that rvfv infection triggers the decay of core ...201526038567
inhibition of cav3.2 t-type calcium channels by its intracellular i-ii loop.voltage-dependent calcium channels (cav) of the t-type family (cav3.1, cav3.2, and cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. enhanced t-type channel activity, especially cav3.2, contributes to disease states, including absence epilepsy. interestingly, the intracellular loop connecting domains i and ii (i-ii loop) of cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating t ...201525931121
cross-species comparative analysis of dicer proteins during sindbis virus infection.in plants and invertebrates rna silencing is a major defense mechanism against virus infections. the first event in rna silencing is dicing of long double stranded rnas into small interfering rnas (sirnas). the dicer proteins involved in this process are phylogenetically conserved and have the same domain organization. accordingly, the production of viral derived sirnas has also been observed in the mouse, but only in restricted cell types. to gain insight on this restriction, we compare the dic ...201526024431
development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors.it is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (rcl) in lentiviral vector products prior to use in clinical trials. immune design previously described an hiv-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (vp02). vp02 is enveloped with e1001, a modified sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (dc-sign) expressed on dendrit ...201526029728
endogenous sirnas and pirnas derived from transposable elements and genes in the malaria vector mosquito anopheles gambiae.the sirna and pirna pathways have been shown in insects to be essential for regulation of gene expression and defence against exogenous and endogenous genetic elements (viruses and transposable elements). the vast majority of endogenous small rnas produced by the sirna and pirna pathways originate from repetitive or transposable elements (te). in d. melanogaster, te-derived endogenous sirnas and pirnas are involved in genome surveillance and maintenance of genome integrity. in the medically rele ...201525879960
ltp-triggered cholesterol redistribution activates cdc42 and drives ampa receptor synaptic delivery.neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. however, little is known about the contribution of lipid metabolism during these processes. in this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (ltp). we found that n-methyl-d-aspartate-type glutamate receptor (nmdar) activation during ltp induction leads to a rapid and ...201525753037
a small antigenic determinant of the chikungunya virus e2 protein is sufficient to induce neutralizing antibodies which are partially protective in mice.the mosquito-borne chikungunya virus (chikv) causes high fever and severe joint pain in humans. it is expected to spread in the future to europe and has recently reached the usa due to globalization, climate change and vector switch. despite this, little is known about the virus life cycle and, so far, there is no specific treatment or vaccination against chikungunya infections. we aimed here to identify small antigenic determinants of the chikv e2 protein able to induce neutralizing immune resp ...201525905779
the brainstem oscillator for whisking and the case for breathing as the master clock for orofacial motor actions.whisking and sniffing are predominant aspects of exploratory behavior in rodents. we review evidence that these motor rhythms are coordinated by the respiratory patterning circuitry in the ventral medulla. a recently described region in the intermediate reticular zone of the medulla functions as an autonomous whisking oscillator, whose neuronal output is reset upon each breath by input from the pre-bötzinger complex. based on similarities between this neuronal circuit architecture and that of ot ...201525876629
electron tomography analysis of tick-borne encephalitis virus infection in human neurons.tick-borne encephalitis virus (tbev) causes serious, potentially fatal neurological infections that affect humans in endemic regions of europe and asia. neurons are the primary target for tbev infection in the central nervous system. however, knowledge about this viral infection and virus-induced neuronal injury is fragmental. here, we directly examined the pathology that occurs after tbev infection in human primary neurons. we exploited the advantages of advanced high-pressure freezing and free ...201526073783
spinoculation enhances hbv infection in ntcp-reconstituted hepatocytes.hepatitis b virus (hbv) infection and its sequelae remain a major public health burden, but both hbv basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. recently, sodium taurocholate cotransporting polypeptide (ntcp) has been identified as the hbv receptor. we herein report that we established a ntcp-complemented hepg2 cell line (hepg2-ntcp12) that supports hbv infection, albeit at a low infectivity level followin ...201526070202
rnasek is required for internalization of diverse acid-dependent viruses.viruses must gain entry into cells to establish infection. in general, viruses enter either at the plasma membrane or from intracellular endosomal compartments. viruses that use endosomal pathways are dependent on the cellular factors that control this process; however, these genes have proven to be essential for endogenous cargo uptake, and thus are of limited value for therapeutic intervention. the identification of genes that are selectively required for viral uptake would make appealing drug ...201526056282
fragile x proteins fmrp and fxr2p control synaptic glua1 expression and neuronal maturation via distinct mechanisms.fragile x mental retardation protein (fmrp) and its autosomal paralog fxr2p are selective neuronal rna-binding proteins, and mice that lack either protein exhibit cognitive deficits. although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. in the present study, we discovered that fxr2p (also known as fxr2) is important for neuronal dendritic development. fmrp and fxr2p additively promote the maturation of new neur ...201526051932
discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3a.there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. to discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (ev71) to screen an fda-approved drug library. itraconazole (itz), a triazole antifungal agent, was identified as an effective inhi ...201525691649
the transcription factor foxk participates with nup98 to regulate antiviral gene expression.upon infection, pathogen recognition leads to a rapidly activated gene expression program that induces antimicrobial effectors to clear the invader. we recently found that nup98 regulates the expression of a subset of rapidly activated antiviral genes to restrict disparate rna virus infections in drosophila by promoting rna polymerase occupancy at the promoters of these antiviral genes. how nup98 specifically targets these loci was unclear; however, it is known that nup98 participates with trans ...201525852164
dissection of amino-terminal functional domains of murine coronavirus nonstructural protein 3.coronaviruses, the largest rna viruses, have a complex program of rna synthesis that entails genome replication and transcription of subgenomic mrnas. rna synthesis by the prototype coronavirus mouse hepatitis virus (mhv) is carried out by a replicase-transcriptase composed of 16 nonstructural protein (nsp) subunits. among these, nsp3 is the largest and the first to be inserted into the endoplasmic reticulum. nsp3 comprises multiple structural domains, including two papain-like proteases (plps) ...201525810552
in vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin.we have described a novel antidepressant peptide, spadin, that acts by blocking the twik-related-potassium channel, type 1 (trek-1). here, we examined possible mechanisms of action of spadin at both molecular and cellular levels.201525598009
generation of a safe and effective live viral vaccine by virus self-attenuation using species-specific artificial microrna.vaccination with live attenuated vaccines (lavs) is an effective way for prevention of infectious disease. while several methods are employed to create them, efficacy and safety are still a challenge. in this study, we evaluated the feasibility of creating a self-attenuated rna virus expressing a functional species-specific artificial microrna. using influenza virus as a model, we produced an attenuated virus carrying a mammalian-specific mir-93 expression cassette that expresses a viral nucleop ...201525858415
emerging role of natural killer cells in oncolytic virotherapy.natural killer (nk) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. the ability of nk cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. therapies with nk cells involve activation of endogenous nk cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. to exploit the diverse functional abil ...201527471713
virus-induced dormancy in the archaeon sulfolobus islandicus.we investigated the interaction between sulfolobus spindle-shaped virus (ssv9) and its native archaeal host sulfolobus islandicus. we show that upon exposure to ssv9, s. islandicus strain rjw002 has a significant growth delay where the majority of cells are dormant (viable but not growing) for 24 to 48 hours postinfection (hpi) compared to the growth of controls without virus. we demonstrate that in this system, dormancy (i) is induced by both active and inactive virus particles at a low multipl ...201525827422
autophagy mediates tolerance to staphylococcus aureus alpha-toxin.resistance and tolerance are two defense strategies employed by the host against microbial threats. autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant staphylococcus aureus usa300 is to mediate tolerance rather than resistance. atg16l1 hypomorphic mice (atg16l1(hm)), which have reduced autophagy, were ...201525816775
parallel epigenomic and transcriptomic responses to viral infection in honey bees (apis mellifera).populations of honey bees are declining throughout the world, with us beekeepers losing 30% of their colonies each winter. though multiple factors are driving these colony losses, it is increasingly clear that viruses play a major role. however, information about the molecular mechanisms mediating antiviral immunity in honey bees is surprisingly limited. here, we examined the transcriptional and epigenetic (dna methylation) responses to viral infection in honey bee workers. one-day old worker ho ...201525811620
antiviral and immunoregulatory effects of indoleamine-2,3-dioxygenase in hepatitis c virus infection.in patients with hepatitis c virus (hcv) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (ido) has been reported. ido - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. the molecular mechanism of ido induction in hcv infection and its role in the antiviral immune response remain unknown. using primary human hepatocytes, we show that hcv infection stimulates ido expression. ido gene inductio ...201525792183
the hub protein loquacious connects the microrna and short interfering rna pathways in mosquitoes.aedes aegypti mosquitoes vector several arboviruses of global health significance, including dengue viruses and chikungunya virus. rna interference (rnai) plays an important role in antiviral immunity, gene regulation and protection from transposable elements. double-stranded rna binding proteins (dsrbps) are important for efficient rnai; in drosophila functional specialization of the mirna, endo-sirna and exo-sirna pathway is aided by the dsrbps loquacious (loqs-pb, loqs-pd) and r2d2, respectiv ...201525765650
simultaneous recording of fluorescence and electrical signals by photometric patch electrode in deep brain regions in vivo.despite its widespread use, high-resolution imaging with multiphoton microscopy to record neuronal signals in vivo is limited to the surface of brain tissue because of limited light penetration. moreover, most imaging studies do not simultaneously record electrical neural activity, which is, however, crucial to understanding brain function. accordingly, we developed a photometric patch electrode (pme) to overcome the depth limitation of optical measurements and also enable the simultaneous recor ...201525761950
residue-level resolution of alphavirus envelope protein interactions in ph-dependent fusion.alphavirus envelope proteins, organized as trimers of e2-e1 heterodimers on the surface of the pathogenic alphavirus, mediate the low ph-triggered fusion of viral and endosomal membranes in human cells. the lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. in this work, we performed constant ph molecular dynamics based on an atomic model of the alphav ...201525646410
activation of tomato bushy stunt virus rna-dependent rna polymerase by cellular heat shock protein 70 is enhanced by phospholipids in vitro.similar to other positive-strand rna viruses, tombusviruses are replicated by the membrane-bound viral replicase complex (vrc). the vrc consists of the p92 virus-coded rna-dependent rna polymerase (rdrp), the viral p33 rna chaperone, and several co-opted host proteins. in order to become a functional rdrp after its translation, the p92 replication protein should be incorporated into the vrc, followed by its activation. we have previously shown in a cell-free yeast extract-based assay that the ac ...201525762742
role of zinc-finger anti-viral protein in host defense against sindbis virus.accumulating evidence indicates that type i interferon (ifn) mediates the host protective response to rna viruses. however, the anti-viral effector molecules involved in this response have not been fully identified. here, we show that zinc-finger anti-viral protein (zap), an ifn-inducible gene, plays a critical role in the elimination of sindbis virus (sinv) in vitro and in vivo. the loss of zap greatly enhances the replication of sinv but does not inhibit type i ifn production in primary mouse ...201525758257
mechanisms of innate immune evasion in re-emerging rna viruses.recent outbreaks of ebola, west nile, chikungunya, middle eastern respiratory and other emerging/re-emerging rna viruses continue to highlight the need to further understand the virus-host interactions that govern disease severity and infection outcome. as part of the early host antiviral defense, the innate immune system mediates pathogen recognition and initiation of potent antiviral programs that serve to limit virus replication, limit virus spread and activate adaptive immune responses. conc ...201525765605
the α2,3-sialyltransferase encoded by myxoma virus is a virulence factor that contributes to immunosuppression.myxoma virus (myxv) induces a lethal disease called myxomatosis in european rabbits. myxv is one of the rare viruses that encodes an α2,3-sialyltransferase through its m138l gene. in this study, we showed that although the absence of the enzyme was not associated with any in vitro deficit, the m138l deficient strains are highly attenuated in vivo. indeed, while all rabbits infected with the parental and the revertant strains died within 9 days post-infection from severe myxomatosis, all but one ...201525705900
the laminin receptor is a cellular attachment receptor for classical swine fever virus.classical swine fever virus (csfv) is the causative agent of classical swine fever (csf), a highly contagious, economically important viral disease in many countries. the e(rns) and e2 envelope glycoproteins are responsible for the binding to and entry into the host cell by csfv. to date, only one cellular receptor, heparan sulfate (hs), has been identified as being involved in csfv attachment. hs is also present on the surface of various cells that are nonpermissive to csfv. hence, there must b ...201525694590
a basic cluster in the n terminus of yellow fever virus ns2a contributes to infectious particle production.the flavivirus ns2a protein is involved in the assembly of infectious particles. to further understand its role in this process, a charged-to-alanine scanning analysis was performed on ns2a encoded by an infectious cdna clone of yellow fever virus (yfv). fifteen mutants containing single, double, or triple charged-to-alanine changes were tested. five of them did not produce infectious particles, whereas efficient rna replication was detectable for two of the five ns2a mutants (r22a-k23a-r24a and ...201525694595
neurological sequelae induced by alphavirus infection of the cns are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine.recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. infection of mice with the prototypic alphavirus, sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. infectious virus is cleared from the brain within a week after infection, but viral rna is cleared slowly and persists for the life of the animal. however, no studies hav ...201525645378
the role of misshapen nck-related kinase (mink), a novel ste20 family kinase, in the ires-mediated protein translation of human enterovirus 71.human enterovirus 71 (ev71) commonly causes hand, foot and mouth disease in young children, and occasional occurrences of neurological complications can be fatal. in this study, a high-throughput cell-based screening on the serine/threonine kinase sirna library was performed to identify potential antiviral agents against ev71 replication. among the hits, misshapen/niks-related kinase (mink) was selected for detailed analysis due to its strong inhibitory profile and novelty. in the investigation ...201525747578
xrn1 stalling in the 5' utr of hepatitis c virus and bovine viral diarrhea virus is associated with dysregulated host mrna stability.we demonstrate that both hepatitis c virus (hcv) and bovine viral diarrhea virus (bvdv) contain regions in their 5' utrs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease xrn1, resulting in dramatic changes in the stability of cellular mrnas. we used biochemical assays, virus infections, and transfection of the hcv and bvdv 5' untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-v ...201525747802
selective inactivation of usp18 isopeptidase activity in vivo enhances isg15 conjugation and viral resistance.protein modification by the ubiquitin-like protein isg15 is an interferon (ifn) effector system, which plays a major role in antiviral defense. isg15 modification is counteracted by the isopeptidase usp18, a major negative regulator of ifn signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. to dissect enzymatic and nonenzymatic functions of usp18 in vivo, we generated knock-in mice (usp18(c61a/c61a)) expressing enzymatically inactive usp18. usp ...201525605921
adp-ribosylation factor 6 (arf6) bidirectionally regulates dendritic spine formation depending on neuronal maturation and activity.recent studies have reported conflicting results regarding the role of arf6 in dendritic spine development, but no clear answer for the controversy has been suggested. we found that adp-ribosylation factor 6 (arf6) either positively or negatively regulates dendritic spine formation depending on neuronal maturation and activity. arf6 activation increased the spine formation in developing neurons, whereas it decreased spine density in mature neurons. genome-wide microarray analysis revealed that a ...201525605715
catch me if you can: the link between autophagy and viruses. 201525811485
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