PMID(sorted descending)
mhc class ii-alpha chain knockout mice support increased viral replication that is independent of their lack of mhc class ii cell surface expression and associated immune function deficiencies.mhcii molecules are heterodimeric cell surface proteins composed of an α and β chain. these molecules are almost exclusively expressed on thymic epithelium and antigen presenting cells (apcs) and play a central role in the development and function of cd4 t cells. various mhc-ii knockout mice have been generated including mhc-iiaα(-/-) (i-aα(-/-)), mhc-iiaβ(-/-) (i-β(-/-)) and the double knockout (i-aαxβ(-/-)). here we report a very striking observation, namely that alphaviruses including the avi ...201323840854
visualization of dc-sign-mediated entry pathway of engineered lentiviral vectors in target cells.dendritic cells (dcs) are potent antigen-presenting cells and therefore have enormous potential as vaccine targets. we have previously developed an engineered lentiviral vector (lv) that is pseudotyped with a mutated sindbis virus glycoprotein (svgmu), which is capable of targeting dcs through dendritic cell-specific icam3-grabbing nonintegrin (dc-sign), a receptor that is predominantly expressed by dcs. in this study, we aimed to elucidate the internalization and trafficking mechanisms of this ...201323840690
specific nucleotide changes in the subgenomic promoter region influence infectivity of the sindbis virus.transcription of the subgenomic mrna of sindbis virus (sinv) is initiated at a subgenomic promoter (sp). alignment of sinv sequences identified a 68-nucleotide conserved domain spanning -19 to +49 relative to the subgenomic mrna start site. nucleotide t or c is present at -18 or +49 in all known sinvs while a sindbis-like virus xj-160 has an a or t at a corresponding position. our results indicate that deletion or substitution of the t at +49 decreased the activity of sp, while substituting t fo ...201323838061
degradation of high affinity hud targets releases kv1.1 mrna from mir-129 repression by mtorc1.little is known about how a neuron undergoes site-specific changes in intrinsic excitability during neuronal activity. we provide evidence for a novel mechanism for mtorc1 kinase-dependent translational regulation of the voltage-gated potassium channel kv1.1 messenger rna (mrna). we identified a microrna, mir-129, that repressed kv1.1 mrna translation when mtorc1 was active. when mtorc1 was inactive, we found that the rna-binding protein, hud, bound to kv1.1 mrna and promoted its translation. un ...023836929
monitoring neuronal excitability at the synapse.mammalian target of rapamycin (mtor) is a key player at the synapse regulating local translation and long-lasting synaptic plasticity. now, a new study by sosanya et al. (2013. j. cell biol. investigates the molecular mechanism of how mtor suppresses local protein synthesis of a key potassium channel at activated synapses.023836926
beclin 1 and nuclear factor-κbp65 are upregulated in hepatocellular carcinoma.there are no sensitive and specific biomarkers that aid in the clinical diagnosis and prognosis of hepatocellular carcinoma (hcc). the aim of the present study was to determine the mrna and protein expression levels of beclin 1 (becn1) and nuclear factor-κb (nf-κb)p65 in patients with hcc, to evaluate their value as potential diagnostic and prognostic biomarkers. immunohistochemistry and in situ hybridization were used to detect the expression of hepatic becn1 and nf-kbp65 in patients with hcc, ...201323833647
neuro-invasion of chandipura virus mediates pathogenesis in experimentally infected mice.neuro-tropism is a major feature in many viral infections. chandipura virus produces neurological symptoms in naturally infected young children and experimentally infected suckling mice. this study was undertaken to find out the neuro-invasive behaviour of chandipura virus in suckling mice. the suckling mice were infected with the virus via footpad injection. different tissues were collected at 24-h intervals up to 96-h post infection and processed for virus quantification and histological study ...201323826408
reconstruction of h3n2 influenza virus based virosome in-vitro.virosomes are virus like particles (vlp) assembled in-vitro. influenza virosomes maintain the cell binding and membrane fusion activity of the wild type virus but are devoid of viral genetic material or internal proteins. influenza virosomes mimic the natural antigen presentation route of the influenza virus.023825736
zebrafish isg15 exerts a strong antiviral activity against rna and dna viruses and regulates the interferon response.isg15, a 15-kda interferon-induced protein that participates in antiviral defenses of mammals, is highly conserved among vertebrates. in fish, as in mammals, viral infection and interferon treatment induce isg15 expression. the two ubiquitin-like domains of isg15 and the presence of a consensus lrlrgg sequence in the c-terminal region, which is required for the covalent conjugation to a substrate protein, are also conserved in fish. our data demonstrate that overexpression of zebrafish isg15 (zf ...201323824820
flaviviruses are sensitive to inhibition of thymidine synthesis pathways.dengue virus has emerged as a global health threat to over one-third of humankind. as a positive-strand rna virus, dengue virus relies on the host cell metabolism for its translation, replication, and egress. therefore, a better understanding of the host cell metabolic pathways required for dengue virus infection offers the opportunity to develop new approaches for therapeutic intervention. in a recently described screen of known drugs and bioactive molecules, we observed that methotrexate and f ...201323824813
a genome-wide rnai screen reveals that mrna decapping restricts bunyaviral replication by limiting the pools of dcp2-accessible targets for cap-snatching.bunyaviruses are an emerging group of medically important viruses, many of which are transmitted from insects to mammals. to identify host factors that impact infection, we performed a genome-wide rnai screen in drosophila and identified 131 genes that impacted infection of the mosquito-transmitted bunyavirus rift valley fever virus (rvfv). dcp2, the catalytic component of the mrna decapping machinery, and two decapping activators, ddx6 and lsm7, were antiviral against disparate bunyaviruses in ...023824541
transfer and expression of small interfering rnas in mammalian cells using lentiviral vectors.rna interference is a convenient tool for modulating gene expression. the widespread application of rna interference is made difficult because of the imperfections of the methods used for efficient target cell delivery of whatever genes are under study. one of the most convenient and efficient gene transfer and expression systems is based on the use of lentiviral vectors, which direct the synthesis of small hairpin rnas (shrnas), the precursors of sirnas. the application of these systems enables ...023819033
mature neurons: equipped for survival.neurons completely transform how they regulate cell death over the course of their lifetimes. developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. however, the regulatory balance between life and death shifts as neurons mature beyond early development. mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. this dramatic ...201323807218
induction of apoptosis in mcf-7 cells by the hemagglutinin-neuraminidase glycoprotein of newcastle disease virus malaysian strain af2240.newcastle disease virus (ndv) exerts its naturally occurring oncolysis possibly through the induction of apoptosis. we hypothesized that the binding of the virus to the cell via the hemagglutinin-neuraminidase (hn) glycoprotein may be sufficient to not only induce apoptosis but to induce a higher apoptosis level than the parental ndv af2240 virus. ndv af2240 induction of apoptosis in mcf-7 human breast cancer cells was analyzed and quantified. in addition, the complete hn gene of ndv strain af22 ...201323807159
novel gene delivery systems.gene therapy is an emerging field in medical and pharmaceutical sciences because of its potential in treating chronic diseases like cancer, viral infections, myocardial infarctions, and genetic disorders. application of gene therapy is limited because of lack of suitable methods for proper introduction of genes into cells and therefore, this is an area of interest for most of the researchers. to achieve successful gene therapy, development of proper gene delivery systems could be one of the most ...023799200
understanding and altering cell tropism of vesicular stomatitis virus.vesicular stomatitis virus (vsv) is a prototypic nonsegmented negative-strand rna virus. vsv's broad cell tropism makes it a popular model virus for many basic research applications. in addition, a lack of preexisting human immunity against vsv, inherent oncotropism and other features make vsv a widely used platform for vaccine and oncolytic vectors. however, vsv's neurotropism that can result in viral encephalitis in experimental animals needs to be addressed for the use of the virus as a safe ...201323796410
synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides and discovery of a highly potent and less toxic nrti.the synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. electrophilic glycosidation between 16 and the silylated nucleobases (n (4)-acetylcytosine, n (6)-benzoyladenine and n (2)-acetyl-o (6)-diphenylcarbamoylguanine) was carried out in the presence of n-iodosuccinimide (nis) leading to the exclusive formation of the desired β-anomers 29, 33 and 36. anti-hiv studie ...201123795238
imaging of the alphavirus capsid protein during virus replication.alphaviruses are enveloped viruses with highly organized structures. the nucleocapsid (nc) core contains a capsid protein lattice enclosing the plus-sense rna genome, and it is surrounded by a lipid bilayer containing a lattice of the e1 and e2 envelope glycoproteins. capsid protein is synthesized in the cytoplasm and particle budding occurs at the plasma membrane (pm), but the traffic and assembly of viral components and the exit of virions from host cells are not well understood. to visualize ...201323785213
encephalomyocarditis virus disrupts stress granules, the critical platform for triggering antiviral innate immune response to stress, cells induce ribonucleoprotein aggregates, termed stress granules (sgs). sgs are transient loci containing translation-stalled mrna, which is eventually degraded or recycled for translation. infection of some viruses, including influenza a virus with a deletion of nonstructural protein 1 (iavδns1), induces sg-like protein aggregates. previously, we showed that iavδns1-induced sgs are required for efficient induction of type i interferon (ifn). here, we investigated sg form ...201323785203
point mutations in the paramyxovirus f protein that enhance fusion activity shift the mechanism of complement-mediated virus neutralization.parainfluenza virus 5 (piv5) activates and is neutralized by the alternative pathway (ap) in normal human serum (nhs) but not by heat-inactivated (hi) serum. we have tested the relationship between the fusion activity within the piv5 f protein, the activation of complement pathways, and subsequent complement-mediated virus neutralization. recombinant piv5 viruses with enhanced fusion activity were generated by introducing point mutations in the f fusogenic peptide (g3a) or at a distal site near ...201323785199
a short hairpin rna screen of interferon-stimulated genes identifies a novel negative regulator of the cellular antiviral response.the type i interferon (ifn) signaling pathway restricts infection of many divergent families of rna and dna viruses by inducing hundreds of ifn-stimulated genes (isgs), some of which have direct antiviral activity. we screened 813 short hairpin rna (shrna) constructs targeting 245 human isgs using a flow cytometry approach to identify genes that modulated infection of west nile virus (wnv) in ifn-β-treated human cells. thirty isgs with inhibitory effects against wnv were identified, including se ...201323781071
prenylome profiling reveals s-farnesylation is crucial for membrane targeting and antiviral activity of zap long-isoform.s-prenylation is an important lipid modification that targets proteins to membranes for cell signaling and vesicle trafficking in eukaryotes. as s-prenylated proteins are often key effectors for oncogenesis, congenital disorders, and microbial pathogenesis, robust proteomic methods are still needed to biochemically characterize these lipidated proteins in specific cell types and disease states. here, we report that bioorthogonal proteomics of macrophages with an improved alkyne-isoprenoid chemic ...201323776219
[the concept of emerging viral diseases: what risk for reunion island?].in reunion island, the risk of emerging infectious diseases lies mainly in several viral zoonoses: west nile fever, sindbis virus, nipah virus, wesselsbron virus, rift valley fever and japanese encephalitis. there morbidity and consequences are more or less important but they all have a non-negligible epidemic potential, so they have to be monitored. indeed, the struggle against these emerging infectious diseases requires an early detection of the cases, thus a surveillance system capable of det ...201323765703
template rna length determines the size of replication complex spherules for semliki forest virus.the replication complexes of positive-strand rna viruses are always associated with cellular membranes. the morphology of the replication-associated membranes is altered in different ways in different viral systems, but many viruses induce small membrane invaginations known as spherules as their replication sites. we show here that for semliki forest virus (sfv), an alphavirus, the size of the spherules is tightly connected with the length of the replicating rna template. cells with different mo ...201323760239
cytoplasmic rna viruses as potential vehicles for the delivery of therapeutic small rnas.viral vectors have become the best option for the delivery of therapeutic genes in conventional and rna interference-based gene therapies. the current viral vectors for the delivery of small regulatory rnas are based on dna viruses and retroviruses/lentiviruses. cytoplasmic rna viruses have been excluded as viral vectors for rnai therapy because of the nuclear localization of the microprocessor complex and the potential degradation of the viral rna genome during the excision of any virus-encoded ...201323759022
the relationship between metabolism and the autophagy machinery during the innate immune response.the innate immune response is shaped by multiple factors, including both traditional autophagy and lc3-associated phagocytosis (lap). as the autophagic machinery is engaged during times of nutrient stress, arising from scarcity or pathogens, we examine how autophagy, specifically lap, and cellular metabolism together influence macrophage function and the innate immune response.023747248
inhibition of human immunodeficiency virus type-1 through an obligatory intracellular pathogen, human immunodeficiency virus type-1 (hiv) is dependent upon its ability to exploit host cell machinery for replication and dissemination, and to circumvent cellular processes that prevent its growth. one such intracellular process is autophagy, a component of the host defense against hiv with roles in innate immune signaling, adaptive immunity and intracellular degradation of hiv. during permissive infection, hiv down-modulates autophagy, promoting its ow ...201323747172
possible role of a cell surface carbohydrate in evolution of resistance to viral infections in old world primates.due to inactivation of the α1,3-galactosyltransferase gene (ggta1, or the α1,3gt gene) approximately 28 million years ago, the carbohydrate αgal (galα1,3galβ1,4glcnac) is not expressed on the cells of old world monkeys and apes (including humans) but is expressed in all other mammals. the proposed selective advantage of this mutation for these primates is the ability to produce anti-gal antibodies, which may be an effective immune component in neutralizing αgal-expressing pathogens. however, los ...201323740988
sumoylation, arc and the regulation homeostatic synaptic scaling: implications in health and disease.neurons compensate for changes in network activity by altering the sensitivity of transmission across collections of synapses by up- or downregulating the number of synaptic ampa receptors. we recently reported that, in parallel to increasing ampa receptor surface expression, suppression of network activity with ttx increases protein sumoylation by decreasing levels of the desumoylating enzyme senp1. sumoylation of the immediate early gene product arc is required for synaptic scaling. these resu ...201223739045
inducible interleukin 32 (il-32) exerts extensive antiviral function via selective stimulation of interferon λ1 (ifn-λ1).interleukin (il)-32 has been recognized as a proinflammatory cytokine that participates in responses to viral infection. however, little is known about how il-32 is induced in response to viral infection and the mechanisms of il-32-mediated antiviral activities. we discovered that il-32 is elevated by hepatitis b virus (hbv) infection both in vitro and in vivo and that hbv induced il-32 expression at the level of both transcription and post-transcription. furthermore, microrna-29b was found to b ...201323729669
the drosophila imd pathway in the activation of the humoral immune response.the imd pathway signaling plays a pivotal role in the drosophila defense against bacteria. during the last two decades, significant progress has been made in identifying the components and deciphering the molecular mechanisms underlying this pathway, including the means of bacterial sensing and signal transduction. while these findings have contributed to the understanding of the immune signaling in insects, they have also provided new insights in studying the mammalian nf-κb signaling pathways. ...201323721820
comparative analysis of the genome sequences and replication profiles of chikungunya virus isolates within the east, central and south african (ecsa) lineage.a comparative analysis of the genomic and replication profiles of different geographical chikungunya virus (chikv) isolates of the east, central and south african (ecsa) lineage was performed.201323721429
activity increase in respiratory chain complexes by rubella virus with marginal induction of oxidative stress.mitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. a highly complex interaction with mitochondria is exerted by rubella virus (rv), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial activity. we aimed in this study to provide a more comprehensive picture of the activity of mitochondrial respiratory chain complexes i to iv. their activities were compared among three ...201323720730
natural variation in the heparan sulfate binding domain of the eastern equine encephalitis virus e2 glycoprotein alters interactions with cell surfaces and virulence in mice.recently, we compared amino acid sequences of the e2 glycoprotein of natural north american eastern equine encephalitis virus (na-eeev) isolates and demonstrated that naturally circulating viruses interact with heparan sulfate (hs) and that this interaction contributes to the extreme neurovirulence of eeev (c. l. gardner, g. d. ebel, k. d. ryman, and w. b. klimstra, proc. natl. acad. sci. u. s. a., 108:16026-16031, 2011). in the current study, we have examined the contribution to hs binding of e ...201323720725
functional characterization of the alphavirus tf protein.alphavirus dogma has long dictated the production of a discrete set of structural proteins during infection of a cell: capsid, pe2, 6k, and e1. however, bioinformatic analyses of alphavirus genomes (a. e. firth, b. y. chung, m. n. fleeton, and j. f. atkins, virol. j. 5:108, 2008) suggested that a ribosomal frameshifting event occurs during translation of the alphavirus structural polyprotein. specifically, a frameshift event is suggested to occur during translation of the 6k gene, yielding produ ...201323720714
recombination of replicon and helper rnas and the emergence of propagation-competent vectors upon sindbis virus vector production.sindbis vectors have shown remarkable antitumor efficacy and tumor-targeting capacity in animal models and hold promise for cancer therapy. different packaging systems are used to produce propagation-incompetent sindbis vectors. however, the vectors produced using either dh-bb single helper rna or split helper rna can spread in permissive cell cultures. we investigated the mechanisms of vector spreading and show, here, that recombination occurs between the replicon and dh-bb helper rna, leading ...201323716190
role of the phosphatidylserine receptor tim-1 in enveloped-virus entry.the cell surface receptor t cell immunoglobulin mucin domain 1 (tim-1) dramatically enhances filovirus infection of epithelial cells. here, we showed that key phosphatidylserine (ptdser) binding residues of the tim-1 igv domain are critical for ebola virus (ebov) entry through direct interaction with ptdser on the viral envelope. ptdser liposomes but not phosphatidylcholine liposomes competed with tim-1 for ebov pseudovirion binding and transduction. further, annexin v (anxv) substituted for the ...201323698310
in vivo bioluminescent imaging of influenza a virus infection and characterization of novel cross-protective monoclonal antibodies.influenza a virus is a major human pathogen responsible for seasonal epidemics as well as pandemic outbreaks. due to the continuing burden on human health, the need for new tools to study influenza virus pathogenesis as well as to evaluate new therapeutics is paramount. we report the development of a stable, replication-competent luciferase reporter influenza a virus that can be used for in vivo imaging of viral replication. this imaging is noninvasive and allows for the longitudinal monitoring ...201323698304
postexit surface engineering of retroviral/lentiviral vectors.gene delivery vectors based on retroviral or lentiviral particles are considered powerful tools for biomedicine and biotechnology applications. such vectors require modification at the genomic level in the form of rearrangements to allow introduction of desired genes and regulatory elements (genotypic modification) as well as engineering of the physical virus particle (phenotypic modification) in order to mediate efficient and safe delivery of the genetic information to the target cell nucleus. ...201323691494
antimicrobial autophagy: a conserved innate immune response in drosophila.autophagy is a highly conserved degradative pathway that has rapidly emerged as a critical component of immunity and host defense. studies have implicated autophagy genes in restricting the replication of a diverse array of pathogens, including bacteria, viruses and protozoans. however, in most cases, the in vivo role of antimicrobial autophagy against pathogens has been undefined. drosophila provides a genetically tractable model system that can be easily adapted to study autophagy in innate im ...201323689401
iron absorption in drosophila melanogaster.the way in which drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. to describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. here we review studies on the divalent metal transporter-1 homolog malvolio (iron import), the recent discovery that multicopper o ...201323686013
[updated inventory of mosquitoes (diptera: culicidae) of the island of la réunion, indian ocean].a literature analysis coupled with new entomological surveys conducted between 2009 and 2012 led to changes in the list of mosquito species present on the island of la réunion. using morphological criteria, orthopodomyia arboricollis is replaced by or. reunionensis. on the basis of morphometrical and genetic criteria, culex univittatus is replaced by cx. neavei. cx. poicilipes, which was already reported missing 40 years ago, has not been found again. anopheles arabiensis is confirmed as the onl ...201323681758
viruses and antiviral immunity in drosophila.viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. a wide variety of viruses infect invertebrates, including both natural pathogens that are insect-restricted, and viruses that are transmitted to vertebrates. studies using the powerful tools in the model organism drosophila have expanded our understanding of antiviral defenses against diverse viruses. in this review, we will cover three major areas. first, we will ...201323680639
mosquito-borne arbovirus surveillance at selected sites in diverse ecological zones of kenya; 2007 - 2012.increased frequency of arbovirus outbreaks in east africa necessitated the determination of distribution of risk by entomologic arbovirus surveillance. a systematic vector surveillance programme spanning 5 years and covering 11 sites representing seven of the eight provinces in kenya and located in diverse ecological zones was carried out.201323663381
macroautophagy--friend or foe of viral replication? 201323661081
anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal nos phosphorylation.stimulation of β3-adrenoreceptors (β3-ar) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nnos) dependent manner. nnos can be regulated by post-translational modification of stimulatory phosphorylation residue ser1412 and inhibitory residue ser847. however, the role of phosphorylation of these residues in cardiomyocytes and β3-ar protective signaling has yet to be explored.201323643588
malaria infection does not affect the sensitivity of peripheral receptor neurons in anopheles stephensi.mosquitoes transmit many important diseases including malaria, dengue and yellow fever. disease transmission from one vertebrate host to another depends on repeated blood feedings by single mosquitoes. in order for the mosquito to acquire the blood that it needs to complete oogenesis, the insect must locate a suitable host. olfactory cues (including carbon dioxide) released by the host and detected by the mosquito are the primary signals that vector insects use for host location. previous studie ...201323642231
fatal neurological respiratory insufficiency is common among viral encephalitides.neurological respiratory insufficiency strongly correlates with mortality among rodents infected with west nile virus (wnv), which suggests that this is a primary mechanism of death in rodents and possibly fatal west nile neurological disease in human patients.201323641019
self replicating gene vaccine carrying p1-2a gene of fmdv serotype o and its effects on the immune responses of cattle.dna vaccines are considered as alternatives to live attenuated ones for those diseases like foot-and-mouth disease (fmd) where the production and application of live vaccines have been found unsuccessful. however, stability of dna and the quantity of antigen expressed are the major limitation with naked dna vaccines. to address these issues self replicating gene vaccine construct was made for foot-and-mouth disease virus (fmdv) type 'o' and studied. the vector for vaccine construct, designated a ...201123637502
reemergence of chikungunya virus in indian subcontinent.chikungunya virus (chikv), a reemerging arboviral disease of public health concern is characterized by a triad of fever, rash and arthralgia. it was responsible for a number of epidemics in asia and africa. the severity of the current epidemic can be judged by the fact that an estimated 1.38 million people in india and one-third of the la reunion population (by april 2006) were affected by chikv. aedes aegypti and aedes albopictus are the major mosquitoes transmitting chikv in asia. various neur ...201023637474
cross-inhibition of chikungunya virus fusion and infection by alphavirus e1 domain iii proteins.alphaviruses are small enveloped rna viruses that include important emerging human pathogens, such as chikungunya virus (chikv). these viruses infect cells via a low-ph-triggered membrane fusion reaction, making this step a potential target for antiviral therapies. the e1 fusion protein inserts into the target membrane, trimerizes, and refolds to a hairpin-like conformation in which the combination of e1 domain iii (diii) and the stem region (diii-stem) pack against a core trimer composed of e1 ...201323637415
hypervariable domain of nonstructural protein nsp3 of venezuelan equine encephalitis virus determines cell-specific mode of virus replication.venezuelan equine encephalitis virus (veev) is one of the most pathogenic members of the alphavirus genus in the togaviridae family. this genus is divided into the old world and new world alphaviruses, which demonstrate profound differences in pathogenesis, replication, and virus-host interactions. veev is a representative member of the new world alphaviruses. the biology of this virus is still insufficiently understood, particularly the function of its nonstructural proteins in rna replication ...201323637407
hierarchy of orofacial rhythms revealed through whisking and breathing.whisking and sniffing are predominant aspects of exploratory behaviour in rodents. yet the neural mechanisms that generate and coordinate these and other orofacial motor patterns remain largely uncharacterized. here we use anatomical, behavioural, electrophysiological and pharmacological tools to show that whisking and sniffing are coordinated by respiratory centres in the ventral medulla. we delineate a distinct region in the ventral medulla that provides rhythmic input to the facial motor neur ...201323624373
nmda receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss.aggregates of amyloid-beta (aβ) and tau are hallmarks of alzheimer's disease (ad) leading to neurodegeneration and synaptic loss. while increasing evidence suggests that inhibition of n-methyl-d-aspartate receptors (nmdars) may mitigate certain aspects of ad neuropathology, the precise role of different nmdar subtypes for aβ- and tau-mediated toxicity remains to be elucidated. using mouse organotypic hippocampal slice cultures from arcaβ transgenic mice combined with sindbis virus-mediated expre ...201323618906
a mobile genetic element with unknown function found in distantly related viruses.the genetic element s2m seems to represent one of very few examples of mobile genetic elements in viruses. the function remains obscure and a scattered taxonomical distribution has been reported by numerous groups.201323618040
human cases of sindbis fever in south africa, 2006-2010.sindbis virus (sinv), the prototype positive-sense rna alphavirus, causes febrile arthritis and is present throughout afro-eurasia. little is known of the epidemiology of sindbis fever due to insufficient surveillance in most endemic countries. the epidemiological features of sindbis fever in humans in south africa are described here based on a retrospective study of suspected arbovirus cases submitted for laboratory investigation from 2006 to 2010. cases were detected annually mostly during the ...201423611492
intracellular pathogen detection by rig-i-like receptors.the rig-i-like receptors (rlrs) rig-i, mda5, and lgp2 trigger innate immune responses against viral infections that serve to limit virus replication and to stimulate adaptive immunity. rlrs are cytosolic sensors for virus-derived rna and thus responsible for intracellular immune surveillance against infection. rlr signaling requires the adapter protein mavs to induce type i interferon, interferon-stimulated genes, and proinflammatory cytokines. this review focuses on the molecular and cell biolo ...201323611287
the protective roles of autophagy in ischemic preconditioning.autophagy, a process for the degradation of protein aggregates and dysfunctional organelles, is required for cellular homeostasis and cell survival in response to stress and is implicated in endogenous protection. ischemic preconditioning is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion through the up-regulation of endogenous protective mechanisms. emerging evidence shows that autophagy is associated with the protective effect of ischemic p ...201323603984
membrane curvature in flaviviruses.coordinated interplay between membrane proteins and the lipid bilayer is required for such processes as transporter function and the entrance of enveloped viruses into host cells. in this study, three-dimensional cryo-electron microscopy density maps of mature and immature flaviviruses were analyzed to assess the curvature of the membrane leaflets and its relation to membrane-bound viral glycoproteins. the overall morphology of the viral membrane is determined by the icosahedral scaffold compose ...201323602814
virus-induced cd8+ t cells accelerate the onset of experimental autoimmune encephalomyelitis: implications for how viral infections might trigger multiple sclerosis exacerbations.viral infections can exacerbate multiple sclerosis (ms) through poorly defined mechanisms. we developed an experimental system whereby infection with an asymptomatic neurotropic alphavirus caused a transient acceleration of experimental autoimmune encephalomyelitis (eae) without altering the expansion or differentiation of autoreactive cd4+ t cells. instead, this effect on the clinical course of eae depended on cd8+ t cells that neither participate in viral clearance nor induce neuropathology in ...201323602715
viral precursor polyproteins: keys of regulation from replication to maturation.many viruses use a replication strategy involving the translation of a large polyprotein, which is cleaved by viral and/or cellular proteases. several of these viruses severely impact human health around the globe, including hiv, hcv, dengue virus, and west nile virus. this method of genome organization has many benefits to the virus such as condensation of genetic material, as well as temporal and spatial regulation of protein activity depending on polyprotein cleavage state. the study of polyp ...201323602469
role for subgenomic mrna in host translation inhibition during sindbis virus infection of mammalian cells.sindbis virus subgenomic mrna is efficiently translated in infected vertebrate cells whereas host translation is shut-off. deletions in the 5'utr of the subgenomic mrna were made to investigate its role in viral gene expression. deletion of nucleotides 1-10 and 11-20 caused a small plaque phenotype, reduced levels of subgenomic mrna and structural proteins, and increased expression of nonstructural proteins. whereas deletion 1-10 virus inhibited cellular protein synthesis, deletion 11-20 did so ...201323601784
virus infections in the nervous system.virus infections usually begin in peripheral tissues and can invade the mammalian nervous system (ns), spreading into the peripheral (pns) and more rarely the central (cns) nervous systems. the cns is protected from most virus infections by effective immune responses and multilayer barriers. however, some viruses enter the ns with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. ...023601101
do viruses require the cytoskeleton?it is generally thought that viruses require the cytoskeleton during their replication cycle. however, recent experiments in our laboratory with rubella virus, a member of the family togaviridae (genus rubivirus), revealed that replication proceeded in the presence of drugs that inhibit microtubules. this study was done to expand on this observation.201323597412
isg15: leading a double life as a secreted molecule.isg15 is a well-known intracellular ubiquitin-like molecule involved in isgylation. however, a recent study has revived the notion first put forward two decades ago that isg15 is also a secreted molecule. human neutrophils, monocytes and lymphocytes can release isg15, even though this protein has no detectable signal peptide sequence. isg15 has also been found in the secretory granules of granulocytes. the mechanism underlying isg15 secretion is unknown. secreted isg15 acts on at least t and nat ...201323579383
structural analyses at pseudo atomic resolution of chikungunya virus and antibodies show mechanisms of neutralization.a 5.3 å resolution, cryo-electron microscopy (cryoem) map of chikungunya virus-like particles (vlps) has been interpreted using the previously published crystal structure of the chikungunya e1-e2 glycoprotein heterodimer. the heterodimer structure was divided into domains to obtain a good fit to the cryoem density. differences in the t = 4 quasi-equivalent heterodimer components show their adaptation to different environments. the spikes on the icosahedral 3-fold axes and those in general positi ...201323577234
the role of innate versus adaptive immune responses in a mouse model of o'nyong-nyong virus infection.o'nyong-nyong virus (onnv), an alphavirus closely related to chikungunya virus (chikv), has caused three major epidemics in africa since 1959. both onnv and chikv produce similar syndromes with fever, rash, and debilitating arthralgia. to determine the roles of the innate and adaptive immune responses, we infected different knockout mice with two strains of onnv (sg650 and mp30). wild-type, rag1 ko, and ifnγr ko mice showed no signs of illness or viremia. the stat1 ko and a129 mice exhibited 50- ...201323568285
effect of larval density and sindbis virus infection on immune responses in aedes aegypti.stressful environmental conditions during mosquito larval development may enhance susceptibility of adult mosquitoes to viral pathogens. although anti-viral defense system in mosquitoes remains uncertain, stress-related enhancement of mosquito susceptibility to viral pathogens may be due to alteration of signaling pathways such as the toll and immune deficiency (imd) pathways. to test the influence of larval density and sindbis virus (sinv) infection on mosquito toll/imd pathways, 100 or 200 aed ...201323562781
autophagy as an innate immune modulator.autophagy is a fundamental cellular process in eukaryotic cells for maintaining homeostasis by degrading cellular proteins and organelles. recently, the roles of autophagy have been expanded to immune systems, which in turn modulate innate immune responses. more specifically, autophagy acts as a direct effector for protection against pathogens, as well as a modulator of pathogen recognition and downstream signaling in innate immune responses. in addition, autophagy controls autoimmunity and infl ...201323559894
knockdown of pirna pathway proteins results in enhanced semliki forest virus production in mosquito cells.the exogenous sirna pathway is important in restricting arbovirus infection in mosquitoes. less is known about the role of the piwi-interacting rna pathway, or pirna pathway, in antiviral responses. viral pirna-like molecules have recently been described following infection of mosquitoes and derived cell lines with several arboviruses. the pirna pathway has thus been suggested to function as an additional small rna-mediated antiviral response to the known infection-induced sirna response. here w ...201323559478
postsynaptic kainate receptor recycling and surface expression are regulated by metabotropic autoreceptor signalling.kainate receptors (kars) play fundamentally important roles in controlling synaptic function and regulating neuronal excitability. postsynaptic kars contribute to excitatory neurotransmission but the molecular mechanisms underlying their activity-dependent surface expression are not well understood. strong activation of kars in cultured hippocampal neurons leads to the downregulation of postsynaptic kars via endocytosis and degradation. in contrast, low-level activation augments postsynaptic kar ...201323556457
a ubiquitin-specific protease possesses a decisive role for adenovirus replication and oncogene-mediated transformation.adenoviral replication depends on viral as well as cellular proteins. however, little is known about cellular proteins promoting adenoviral replication. in our screens to identify such proteins, we discovered a cellular component of the ubiquitin proteasome pathway interacting with the central regulator of adenoviral replication. our binding assays mapped a specific interaction between the n-terminal domains of both viral e1b-55k and usp7, a deubiquitinating enzyme. rna interference-mediated dow ...201323555268
regulation of stress granules and p-bodies during rna virus infection.rna granules are structures within cells that play major roles in gene expression and homeostasis. two principle kinds of rna granules are conserved from yeast to mammals: stress granules (sgs), which contain stalled translation initiation complexes, and processing bodies (p-bodies, pbs), which are enriched with factors involved in rna turnover. since rna granules are associated with silenced transcripts, viruses subvert rna granule function for replicative advantages. this review, focusing on r ...201323554219
chikungunya virus host range e2 transmembrane deletion mutants induce protective immunity against challenge in c57bl/6j mice.a vaccine against chikungunya virus (chikv), a reemerging pathogenic arbovirus, has been made by attenuating wild-type (wt) virus via truncation of the transmembrane domain (tmd) of e2 and selecting for host range (hr) mutants. mice are a standard model system for chikv disease and display the same symptoms of the disease seen in humans. groups of mice were inoculated with one of three chikv hr mutants to determine the ability of each mutant strain to elicit neutralizing antibody and protective ...201323552427
striatal neurones have a specific ability to respond to phasic dopamine release.the camp/protein kinase a (pka) signalling cascade is ubiquitous, and each step in this cascade involves enzymes that are expressed in multiple isoforms. we investigated the effects of this diversity on the integration of the pathway in the target cell by comparing prefrontal cortical neurones with striatal neurones which express a very specific set of signalling proteins. the prefrontal cortex and striatum both receive dopaminergic inputs and we analysed the dynamics of the camp/pka signal trig ...201323551948
rna-based mechanisms regulating host-virus interactions.rna interference (rnai) is an ancient process by which non-coding rnas regulate gene expression in a sequence-specific manner. the core components of rnai are small regulatory rnas, approximately 21-30 nucleotides in length, including small interfering rnas (sirnas) and micrornas (mirnas). the past two decades have seen considerable progress in our understanding of the molecular mechanisms underlying the biogenesis of sirnas and mirnas. recent advances have also revealed the crucial regulatory r ...023550641
evolution of sindbis virus with a low-methionine-resistant phenotype is dependent both on a pre-existing mutation and on the methionine concentration in the medium.svlm21 is a mutant of sindbis virus which was isolated by serial passage of virus in mosquito cells maintained in low-methionine medium; it therefore has a low-methionine-resistant (lmr) phenotype. this phenotype requires mutations at nts 319 and 321; these mutations result in arg to leu and ser to cys changes at positions 87 and 88 respectively in the viral methyl transferase, nsp1. to better understand the genesis of svlm21, we carried out serial passages of viruses having only one of these am ...201323544150
molecular determinants of mouse neurovirulence and mosquito infection for western equine encephalitis virus.western equine encephalitis virus (weev) is a naturally occurring recombinant virus derived from ancestral sindbis and eastern equine encephalitis viruses. we previously showed that infection by weev isolates mcmillan (mcm) and imp-181 (imp) results in high (∼90-100%) and low (0%) mortality, respectively, in outbred cd-1 mice when virus is delivered by either subcutaneous or aerosol routes. however, relatively little is known about specific virulence determinants of weev. we previously observed ...201323544138
mda5 localizes to stress granules, but this localization is not required for the induction of type i interferon.virus infection can initiate a type i interferon (ifn-α/β) response via activation of the cytosolic rna sensors retinoic acid-inducible gene-i (rig-i) and melanoma differentiation-associated gene 5 (mda5). furthermore, it can activate kinases that phosphorylate eukaryotic translation initiation factor 2α (eif2α), which leads to inhibition of (viral) protein translation and formation of stress granules (sg). most viruses have evolved mechanisms to suppress these cellular responses. here, we show ...201323536668
the receptor attachment function of measles virus hemagglutinin can be replaced with an autonomous protein that binds her2/neu while maintaining its fusion-helper function.cell entry of enveloped viruses is initiated by attachment to the virus receptor followed by fusion between the virus and host cell membranes. measles virus (mv) attachment to its receptor is mediated by the hemagglutinin (h), which is thought to produce conformational changes in the membrane fusion protein (f) that trigger insertion of its fusion peptide into the target cell membrane. here, we uncoupled receptor attachment and the fusion-helper function of h by introducing y481a, r533a, s548l, ...201323536664
adaptation of enterovirus 71 to adult interferon deficient mice.non-polio enteroviruses, including enterovirus 71 (ev71), have caused severe and fatal cases of hand, foot and mouth disease (hfmd) in the asia-pacific region. the development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. in this study, a mouse adapted ev71 strain was produced by conducting serial passages through a129 (α/β interferon (ifn) receptor deficient) and ag129 (α/β, γ ifn receptor deficient) mice. a b2 sub genotype of ...201323527208
baculovirus-mediated gene transfer in butterfly wings in vivo: an efficient expression system with an anti-gp64 antibody.candidate genes for color pattern formation in butterfly wings have been known based on gene expression patterns since the 1990s, but their functions remain elusive due to a lack of a functional assay. several methods of transferring and expressing a foreign gene in butterfly wings have been reported, but they have suffered from low success rates or low expression levels. here, we developed a simple, practical method to efficiently deliver and express a foreign gene using baculovirus-mediated ge ...201323522444
lipidome analysis of rotavirus-infected cells confirms the close interaction of lipid droplets with viroplasms.rotaviruses (rvs) cause acute gastroenteritis in infants and young children, and are globally distributed. within the infected host cell, rvs establish replication complexes in viroplasms ('viral factories') to which lipid droplet organelles are recruited. to further understand this recently discovered phenomenon, the lipidomes of rv-infected and uninfected ma104 cells were investigated. cell lysates were subjected to equilibrium ultracentrifugation through iodixanol gradients. fourteen differen ...201323515026
a tyrosine-to-histidine switch at position 18 of the ross river virus e2 glycoprotein is a determinant of virus fitness in disparate hosts.arthritogenic alphaviruses are human pathogens maintained in nature through alternating replication in vertebrates and mosquitoes. using chimeric viruses, we previously reported that replacement of the pe2 coding region of the t48 strain of ross river virus (rrv-t48) with that from the attenuated dc5692 strain, which differ by 7 amino acids, resulted in an attenuated disease phenotype in a mouse model of rrv-induced rheumatic disease. here, we demonstrate that introduction of one of these amino ...201323514884
structure and antimicrobial properties of monensin a and its derivatives: summary of the this paper structural and microbiological studies on the ionophorous antibiotic monensin a and its derivatives have been collected. monensin a is an ionophore which selectively complexes and transports sodium cation across lipid membranes, and therefore it shows a variety of biological properties. this antibiotic is commonly used as coccidiostat and nonhormonal growth promoter. the paper focuses on both the latest and earlier achievements concerning monensin a antimicrobial activity. the acti ...201323509771
antiviral type i and type iii interferon responses in the central nervous system.the central nervous system (cns) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. this organ is partly protected by the blood-brain barrier (bbb) from toxic substances and pathogens carried in the bloodstream. yet, neurotropic viruses can reach the cns either by crossing the bbb after viremia, or by exploiting motile infected cells as trojan horses, or by using axonal transport. type i and type iii interferons (ifns) are cy ...201323503326
moving h5n1 studies into the era of systems biology.the dynamics of h5n1 influenza virus pathogenesis are multifaceted and can be seen as an emergent property that cannot be comprehended without looking at the system as a whole. in past years, most of the high-throughput studies on h5n1-host interactions have focused on the host transcriptomic response, at the cellular or the lung tissue level. these studies pointed out that the dynamics and magnitude of the innate immune response and immune cell infiltration is critical to h5n1 pathogenesis. how ...201323499671
dendritic cell immunoreceptor regulates chikungunya virus pathogenesis in mice.chikungunya virus (chikv) is a mosquito-borne alphavirus responsible for recent epidemic outbreaks of debilitating disease in humans. alphaviruses are known to interact with members of the c-type lectin receptor family of pattern recognition proteins, and given that the dendritic cell immunoreceptor (dcir) is known to act as a negative regulator of the host inflammatory response and has previously been associated with rheumatoid arthritis, we evaluated dcir's role in response to chikv infection. ...201323487448
sustained activation of akt elicits mitochondrial dysfunction to block plasmodium falciparum infection in the mosquito host.the overexpression of activated, myristoylated akt in the midgut of female transgenic anopheles stephensi results in resistance to infection with the human malaria parasite plasmodium falciparum but also decreased lifespan. in the present study, the understanding of mitochondria-dependent midgut homeostasis has been expanded to explain this apparent paradox in an insect of major medical importance. given that akt signaling is essential for cell growth and survival, we hypothesized that sustained ...201323468624
the role of b cells and humoral immunity in mycobacterium tuberculosis infection.tuberculosis (tb) remains a serious threat to public health, causing 2 million deaths annually world-wide. the control of tb has been hindered by the requirement of long duration of treatment involving multiple chemotherapeutic agents, the increased susceptibility to mycobacterium tuberculosis infection in the hiv-infected population, and the development of multi-drug resistant and extensively resistant strains of tubercle bacilli. an efficacious and cost-efficient way to control tb is the devel ...201323468112
immune responses of a native and an invasive bird to buggy creek virus (togaviridae: alphavirus) and its arthropod vector, the swallow bug (oeciacus vicarius).invasive species often display different patterns of parasite burden and virulence compared to their native counterparts. these differences may be the result of variability in host-parasite co-evolutionary relationships, the occurrence of novel host-parasite encounters, or possibly innate differences in physiological responses to infection between invasive and native hosts. here we examine the adaptive, humoral immune responses of a resistant, native bird and a susceptible, invasive bird to an a ...201323460922
acute bdnf treatment upregulates glur1-sap97 and glur2-grip1 interactions: implications for sustained ampa receptor expression.brain-derived neurotrophic factor (bdnf) plays several prominent roles in synaptic plasticity and in learning and memory formation. reduced bdnf levels and altered bdnf signaling have been reported in several brain diseases and behavioral disorders, which also exhibit reduced levels of ampar subunits. bdnf treatment acutely regulates ampa receptor expression and function, including synaptic ampar subunit trafficking, and implicates several well defined signaling molecules that are required to el ...201323460828
differential innate immune response programs in neuronal subtypes determine susceptibility to infection in the brain by positive-stranded rna viruses.although susceptibility of neurons in the brain to microbial infection is a major determinant of clinical outcome, little is known about the molecular factors governing this vulnerability. here we show that two types of neurons from distinct brain regions showed differential permissivity to replication of several positive-stranded rna viruses. granule cell neurons of the cerebellum and cortical neurons from the cerebral cortex have unique innate immune programs that confer differential susceptib ...201323455712
intracellular antibody-bound pathogens stimulate immune signaling via the fc receptor trim21.during pathogen infection, antibodies can be carried into the infected cell, where they are detected by the ubiquitously expressed cytosolic antibody receptor trim21. here we found that recognition of intracellular antibodies by trim21 activated immune signaling. trim21 catalyzed the formation of lys63 (k63)-linked ubiquitin chains and stimulated the transcription factor pathways of nf-κb, ap-1, irf3, irf5 and irf7. activation resulted in the production of proinflammatory cytokines, modulation o ...201323455675
a fully attenuated recombinant salmonid alphavirus becomes pathogenic through a single amino acid change in the e2 glycoprotein.a recombinant sleeping disease virus (rsdv) was previously shown to be totally attenuated and provide long-term protection in trout (c. moriette, m. leberre, a. lamoureux, t. l. lai, m. brémont, j. virol. 80:4088-4098, 2006). sequence comparison of the rsdv to wild-type genomes exhibited a number of nucleotide changes. in the current study, we demonstrate that the virulent phenotype of sdv was essentially associated with two amino acid changes, v8a and m136t, in the e2 glycoprotein, with the v8a ...201323449806
experimental vaccines against potentially pandemic and highly pathogenic avian influenza viruses.influenza a viruses continue to emerge and re-emerge, causing outbreaks, epidemics and occasionally pandemics. while the influenza vaccines licensed for public use are generally effective against seasonal influenza, issues arise with production, immunogenicity, and efficacy in the case of vaccines against pandemic and emerging influenza viruses, and highly pathogenic avian influenza virus in particular. thus, there is need of improved influenza vaccines and vaccination strategies. this review di ...023440999
intrathecal humoral immunity to encephalitic rna viruses.the nervous system is the target for acute encephalitic viral infections, as well as a reservoir for persisting viruses. intrathecal antibody (ab) synthesis is well documented in humans afflicted by infections associated with neurological complications, as well as the demyelinating disease, multiple sclerosis. this review focuses on the origin, recruitment, maintenance, and biological relevance of ab-secreting cells (asc) found in the central nervous system (cns) following experimental neurotrop ...201323435240
chloroquine inhibits dengue virus type 2 replication in vero cells but not in c6/36 cells.dengue viruses are the most important arthropod-borne viruses in terms of morbidity and mortality in the world. since there is no dengue vaccine available for human use, we have set out to investigate the use of chloroquine as an antiviral drug against dengue. chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal ph, was used in the in vitro treatment of vero and c6/36 cells infected with dengue virus type 2 (denv-2). real-time rt-pcr and ...201323431254
metabotropic nmda receptor function is required for β-amyloid-induced synaptic depression.the mechanisms by which β-amyloid (aβ), a peptide fragment believed to contribute to alzheimer's disease, leads to synaptic deficits are not known. here we find that elevated oligomeric aβ requires ion flux-independent function of nmda receptors (nmdars) to produce synaptic depression. aβ activates this metabotropic nmdar function on glun2b-containing nmdars but not on those containing glun2a. furthermore, oligomeric aβ leads to a selective loss of synaptic glun2b responses, effecting a switch i ...201323431156
the δ2 glutamate receptor gates long-term depression by coordinating interactions between two ampa receptor phosphorylation sites.long-term depression (ltd) commonly affects learning and memory in various brain regions. although cerebellar ltd absolutely requires the δ2 glutamate receptor (glud2) that is expressed in purkinje cells, ltd in other brain regions does not; why and how cerebellar ltd is regulated by glud2 remains unelucidated. here, we show that the activity-dependent phosphorylation of serine 880 (s880) in glua2 ampa receptor subunit, which is an essential step for ampa receptor endocytosis during ltd inductio ...201323431139
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