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in vivo two-photon imaging of dendritic spines in marmoset neocortex(1,2,3).two-photon microscopy in combination with a technique involving the artificial expression of fluorescent protein has enabled the direct observation of dendritic spines in living brains. however, the application of this method to primate brains has been hindered by the lack of appropriate labeling techniques for visualizing dendritic spines. here, we developed an adeno-associated virus vector-based fluorescent protein expression system for visualizing dendritic spines in vivo in the marmoset neoc ...201526465000
retargeting oncolytic vesicular stomatitis virus to human t-cell lymphotropic virus type 1-associated adult t-cell leukemia.adult t cell leukemia/lymphoma (atl) is an aggressive cancer of cd4/cd25(+) t lymphocytes, the etiological agent of which is human t-cell lymphotropic virus type 1 (htlv-1). atl is highly refractory to current therapies, making the development of new treatments a high priority. oncolytic viruses such as vesicular stomatitis virus (vsv) are being considered as anticancer agents since they readily infect transformed cells compared to normal cells, the former appearing to exhibit defective innate i ...201526378177
regulation of cell death by iaps and their antagonists.inhibitors of apoptosis (iaps) family of genes encode baculovirus iap-repeat domain-containing proteins with antiapoptotic function. these proteins also contain ring or ubc domains and act by binding to major proapoptotic factors and ubiquitylating them. high levels of iaps inhibit caspase-mediated apoptosis. for these cells to undergo apoptosis, iap function must be neutralized by iap-antagonists. mammalian iap knockouts do not exhibit obvious developmental phenotypes, but the cells are more se ...201526431568
fiat luc: bioluminescence imaging reveals in vivo viral replication dynamics. 201526356297
kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor 1 interacts with a member of the interferon-stimulated gene 15 pathway.kaposi's sarcoma-associated herpesvirus (kshv) is a gammaherpesvirus known to establish lifelong latency in the human host. we and others have previously shown that three kshv homologs of cellular interferon regulatory factors (irfs), known as viral irfs (virfs), participate in evasion of the host interferon (ifn) response. we report that virf1 interacts with the cellular interferon-stimulated gene 15 (isg15) e3 ligase, herc5, in the context of toll-like receptor 3 (tlr3) activation and ifn indu ...201526355087
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
pros and cons of antigen-presenting cell targeted tumor vaccines.in therapeutic antitumor vaccination, dendritic cells play the leading role since they decide if, how, when, and where a potent antitumor immune response will take place. since the disentanglement of the complexity and merit of different antigen-presenting cell subtypes, antitumor immunotherapeutic research started to investigate the potential benefit of targeting these subtypes in situ. this review will discuss which antigen-presenting cell subtypes are at play and how they have been targeted a ...201526583156
viral interference and persistence in mosquito-borne flaviviruses.mosquito-borne flaviviruses are important pathogens for humans, and the detection of two or more flaviviruses cocirculating in the same geographic area has often been reported. however, the epidemiological impact remains to be determined. mosquito-borne flaviviruses are primarily transmitted through aedes and culex mosquitoes; these viruses establish a life-long or persistent infection without apparent pathological effects. this establishment requires a balance between virus replication and the ...201526583158
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
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
rnai and antiviral defense in the honey bee.honey bees play an important agricultural and ecological role as pollinators of numerous agricultural crops and other plant species. therefore, investigating the factors associated with high annual losses of honey bee colonies in the us is an important and active area of research. pathogen incidence and abundance correlate with colony collapse disorder- (ccd-) affected colonies in the us and colony losses in the us and in some european countries. honey bees are readily infected by single-strande ...201526798663
the phosphatidylserine and phosphatidylethanolamine receptor cd300a binds dengue virus and enhances infection.dengue virus (denv) is the etiological agent of the major human arboviral disease. we previously demonstrated that the tim and tam families of phosphatidylserine (ptdser) receptors involved in the phagocytosis of apoptotic cells mediate denv entry into target cells. we show here that human cd300a, a recently identified phospholipid receptor, also binds directly denv particles and enhances viral entry. cd300a facilitates infection of the four denv serotypes, as well as of other mosquito-borne vir ...201526468529
aberrant regulation of synchronous network activity by the attention-deficit/hyperactivity disorder-associated human dopamine d4 receptor variant d4.7 in the prefrontal cortex.the hd4.7 variant has been linked to attention-deficit/hyperactivity disorder (adhd); however, the underlying mechanism is unknown. we found that activation of hd4.7 induced over-suppression of glutamatergic excitatory network bursts and under-suppression of gabaergic inhibitory network bursts in the prefrontal cortex (pfc) circuitry. methylphenidate, a psychostimulant drug used to treat adhd, normalized the effects of hd4.7 on synchronous network bursts in pfc pyramidal neurons. the findings of ...201526541360
direct pcr of indigenous and invasive mosquito species: a time- and cost-effective technique of mosquito barcoding.millions of people die each year as a result of pathogens transmitted by mosquitoes. however, the morphological identification of mosquito species can be difficult even for experts. the identification of morphologically indistinguishable species, such as members of the anopheles maculipennis complex (diptera: culicidae), and possible hybrids, such as culex pipiens pipiens/culex pipiens molestus (diptera: culicidae), presents a major problem. in addition, the detection and discrimination of newly ...201526663040
characterization of a novel human-specific sting agonist that elicits antiviral activity against emerging alphaviruses.pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. in light of this we sought to identify small molecules capable of activating the type i interferon (ifn) response by way of the transcription factor ifn regulatory factor 3 (irf3). a high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-n-(furan-2- ...201526646986
detection of persistent chikungunya virus rna but not infectious virus in experimental vertical transmission in aedes aegypti from malaysia.vertical transmission may contribute to the maintenance of arthropod-borne viruses, but its existence in chikungunya virus (chikv) is unclear. experimental vertical transmission of infectious clones of chikv in aedes aegypti mosquitoes from malaysia was investigated. eggs and adult progeny from the second gonotrophic cycles of infected parental mosquitoes were tested. using polymerase chain reaction (pcr), 56.3% of pooled eggs and 10% of adult progeny had detectable chikv rna, but no samples had ...201526598564
mtor is essential for corticosteroid effects on hippocampal ampa receptor function and fear memory.glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. we examined how corticosterone regulates ampa receptors (ampars), which are crucial for synaptic plasticity and memory formation. combining a live imaging fluorescent recovery after photobleaching approach with the use of the ph-sensitive gfp-ampar tagging revealed that corticosterone enhances the ampar mobile fraction and increases synaptic trapping of am ...201526572647
self-assembling protein nanoparticles in the design of vaccines.for over 100 years, vaccines have been one of the most effective medical interventions for reducing infectious disease, and are estimated to save millions of lives globally each year. nevertheless, many diseases are not yet preventable by vaccination. this large unmet medical need demands further research and the development of novel vaccines with high efficacy and safety. compared to the 19th and early 20th century vaccines that were made of killed, inactivated, or live-attenuated pathogens, mo ...201526862374
chikungunya nsp2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine.chikungunya virus is the pathogenic alphavirus that causes chikungunya fever in humans. in the last decade millions of cases have been reported around the world from africa to asia to the americas. the alphavirus nsp2 protein is multifunctional and is considered to be pivotal to viral replication, as the nsp2 protease activity is critical for proteolytic processing of the viral polyprotein during replication. classically the alphavirus nsp2 protease is thought to be papain-like with the enzyme r ...201526597768
conformational ensemble of the poliovirus 3cd precursor observed by md simulations and confirmed by saxs: a strategy to expand the viral proteome?the genomes of rna viruses are relatively small. to overcome the small-size limitation, rna viruses assign distinct functions to the processed viral proteins and their precursors. this is exemplified by poliovirus 3cd protein. 3c protein is a protease and rna-binding protein. 3d protein is an rna-dependent rna polymerase (rdrp). 3cd exhibits unique protease and rna-binding activities relative to 3c and is devoid of rdrp activity. the origin of these differences is unclear, since crystal structur ...201526610545
design, synthesis, and antiviral activity of novel ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates.a novel series of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates was synthesized through the kabachnik-fields reaction using i2 as catalyst followed by copper-catalyzed cycloaddition of the azide-alkyne reaction (cuaac). all structures of the newly prepared compounds were characterized by (1) h nmr, (13) c nmr, and hrms spectra. the structures of 2e, 2f, 3d, and 3g were further confirmed by x-ray diffraction analysis. these compounds were tested against various strains of dna and rna ...201526575425
chikungunya virus replication in salivary glands of the mosquito aedes albopictus.chikungunya virus (chikv) is an emerging arbovirus transmitted to humans by mosquitoes such as aedes albopictus. to be transmitted, chikv must replicate in the mosquito midgut, then disseminate in the hemocele and infect the salivary glands before being released in saliva. we have developed a standardized protocol to visualize viral particles in the mosquito salivary glands using transmission electron microscopy. here we provide direct evidence for chikv replication and storage in ae. albopictus ...201526593936
both rig-i and mda5 detect alphavirus replication in concentration-dependent mode.alphaviruses are a family of positive-strand rna viruses that circulate on all continents between mosquito vectors and vertebrate hosts. despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus-host interaction are insufficiently understood. in this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating alphaviruses. our new da ...201526550947
region-specific dendritic simplification induced by aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.dendritic simplification, a key feature of the neurodegenerative triad of alzheimer's disease (ad) in addition to spine changes and neuron loss, occurs in a region-specific manner. however, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.201526541821
beclin 1-vps34 complex architecture: understanding the nuts and bolts of therapeutic targets.autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. dysregulation of autophagy is linked to a growing number of human diseases. the beclin 1-vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. manipulation of autophagy, in particular via modulation of the action of the beclin 1-vps34 complexes, is considered a ...201526692106
an odyssey in antiviral drug development-50 years at the rega institute: 1964-2014. 201526713268
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
recovery of recombinant crimean congo hemorrhagic fever virus reveals a function for non-structural glycoproteins cleavage by furin.crimean congo hemorrhagic fever virus (cchfv) is a negative-strand rna virus of the family bunyaviridae (genus: nairovirus). in humans, cchfv causes fever, hemorrhage, severe thrombocytopenia, and high fatality. a major impediment in precisely determining the basis of cchfv's high pathogenicity has been the lack of methodology to produce recombinant cchfv. we developed a reverse genetics system based on transfecting plasmids into bsr-t7/5 and huh7 cells. in our system, bacteriophage t7 rna polym ...201525933376
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
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
a neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes.mosquitoes are natural vectors for many etiologic agents of human viral diseases. mosquito-borne flaviviruses can persistently infect the mosquito central nervous system without causing dramatic pathology or influencing the mosquito behavior and lifespan. the mechanism by which the mosquito nervous system resists flaviviral infection is still largely unknown. here we report that an aedes aegypti homologue of the neural factor hikaru genki (aahig) efficiently restricts flavivirus infection of the ...201525915054
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
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
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
understanding west nile virus ecology in europe: culex pipiens host feeding preference in a hotspot of virus emergence.understanding wildlife disease ecology is becoming an urgent need due to the continuous emergence and spread of several wildlife zoonotic diseases. west nile virus (wnv) is the most widespread arthropod-borne virus in the world, and in recent decades there has been an increase both in geographic range, and in the frequency of symptomatic infections in humans and wildlife. the principal vector for wnv in europe is the common house culex pipiens mosquito, which feeds on a wide variety of vertebrat ...201525888754
structural basis of arc binding to synaptic proteins: implications for cognitive disease.arc is a cellular immediate-early gene (ieg) that functions at excitatory synapses and is required for learning and memory. we report crystal structures of arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (hiv) gag protein. analysis indicates arc originated from the ty3/gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. the arc n-terminal lobe evolved a unique hydrophobic pocket ...201525864631
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
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
catch me if you can: the link between autophagy and viruses. 201525811485
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
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 interferon-stimulated gene ifi27l2a restricts west nile virus infection and pathogenesis in a cell-type- and region-specific manner.the mammalian host responds to viral infections by inducing expression of hundreds of interferon-stimulated genes (isgs). while the functional significance of many isgs has yet to be determined, their cell type and temporal nature of expression suggest unique activities against specific pathogens. using a combination of ectopic expression and gene silencing approaches in cell culture, we previously identified ifi27l2a as a candidate antiviral isg within neuronal subsets of the central nervous sy ...201526699642
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