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syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance.arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. therefore, arbovirus infections are often neglected by travel diagnostics. here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers.201526372010
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
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
mosquito rasputin interacts with chikungunya virus nsp3 and determines the infection rate in aedes albopictus.chikungunya virus (chikv) is an arthritogenic alphavirus (family togaviridae), transmitted by aedes species mosquitoes. chikv re-emerged in 2004 with multiple outbreaks worldwide and recently reached the americas where it has infected over a million individuals in a rapidly expanding epidemic. while alphavirus replication is well understood in general, the specific function (s) of non-structural protein nsp3 remain elusive. chikv nsp3 modulates the mammalian stress response by preventing stress ...201526384002
colorimetric detection of dengue by single tube reverse-transcription-loop-mediated isothermal amplification.dengue is usually diagnosed by isolation of the virus, serology or molecular diagnostic methods. several commercial kits for the diagnosis of dengue are existing, but concerns have arisen regarding to the affordability and performance characteristics of these kits. hence, the loop-mediated isothermal amplification (lamp) is potentially ideal to be used especially in resource limited environments. serum was collected from healthy donors and patients diagnosed with dengue infection. rna extracted ...201526384248
stress granules and virus replication.viruses are dependent on the cellular translation machinery for protein synthesis. part of the innate immune response to infection is activation of the stress kinase pkr which phosphorylates the alpha subunit of the initiation factor eif2. this results in inhibition of translation and is intended to block virus replication. a downstream effect of translational shutoff involves the formation of cytoplasmic granules, termed stress granules (sgs), that contain mrnas, initiation factors, ribosomal s ...026388931
infectious bronchitis coronavirus inhibits stat1 signaling and requires accessory proteins for resistance to type i interferon activity.the innate immune response is the first line of defense against viruses, and type i interferon (ifn) is a critical component of this response. similar to other viruses, the gammacoronavirus infectious bronchitis virus (ibv) has evolved under evolutionary pressure to evade and counteract the ifn response to enable its survival. previously, we reported that ibv induces a delayed activation of the ifn response. in the present work, we describe the resistance of ibv to ifn and the potential role of ...201526401035
genetic dissection of the host tropism of human-tropic pathogens.infectious diseases are the second leading cause of death worldwide. although the host multitropism of some pathogens has rendered their manipulation possible in animal models, the human-restricted tropism of numerous viruses, bacteria, fungi, and parasites has seriously hampered our understanding of these pathogens. hence, uncovering the genetic basis underlying the narrow tropism of such pathogens is critical for understanding their mechanisms of infection and pathogenesis. moreover, such gene ...201526407032
eastern equine encephalitis virus in mice ii: pathogenesis is dependent on route of exposure.eastern equine encephalitis virus (eeev) is an alphavirus with a case fatality rate estimated to be as high as 75 % in humans and 90 % in horses. surviving patients often have long-lasting and severe neurological sequelae. at present, there is no licensed vaccine or therapeutic for eeev infection. this study completes the clinical and pathological analysis of mice infected with a north american strain of eeev by three different routes: aerosol, intranasal, and subcutaneous. such an understanding ...201526423229
intracellular mono-adp-ribosylation in signaling and disease.a key process in the regulation of protein activities and thus cellular signaling pathways is the modification of proteins by post-translational mechanisms. knowledge about the enzymes (writers and erasers) that attach and remove post-translational modifications, the targets that are modified and the functional consequences elicited by specific modifications, is crucial for understanding cell biological processes. moreover detailed knowledge about these mechanisms and pathways helps to elucidate ...201526426055
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
immune surveillance of the cns following infection and injury.the central nervous system (cns) contains a sophisticated neural network that must be constantly surveyed in order to detect and mitigate a diverse array of challenges. the innate and adaptive immune systems actively participate in this surveillance, which is critical for the maintenance of cns homeostasis and can facilitate the resolution of infections, degeneration, and tissue damage. infections and sterile injuries represent two common challenges imposed on the cns that require a prompt immun ...026431941
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
interactions involved in ph protection of the alphavirus fusion protein.the alphavirus membrane protein e1 mediates low ph-triggered fusion of the viral and endosome membranes during virus entry. during virus biogenesis e1 associates as a heterodimer with the transmembrane protein p62. late in the secretory pathway, cellular furin cleaves p62 to the mature e2 protein and a peripheral protein e3. e3 remains bound to e2 at low ph, stabilizing the heterodimer and thus protecting e1 from the acidic ph of the secretory pathway. release of e3 at neutral ph then primes the ...201526433749
myeloid cell arg1 inhibits control of arthritogenic alphavirus infection by suppressing antiviral t cells.arthritogenic alphaviruses, including ross river virus (rrv) and chikungunya virus (chikv), are responsible for explosive epidemics involving millions of cases. these mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. we previously showed that arginase 1 (arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of rrv- and chikv-infected mice, and specific deletion of arg1 from ...201526436766
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
immunoproteomic profiling of antiviral antibodies in new-onset type 1 diabetes using protein arrays.the rapid rise in the incidence of type 1 diabetes (t1d) suggests the involvement of environmental factors including viral infections. we evaluated the association between viral infections and t1d by profiling antiviral antibodies using a high-throughput immunoproteomics approach in patients with new-onset t1d. we constructed a viral protein array comprising the complete proteomes of seven viruses associated with t1d and open reading frames from other common viruses. antibody responses to 646 vi ...201526450993
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
a fast cross-validation method for alignment of electron tomography images based on beer-lambert law.in electron tomography, accurate alignment of tilt series is an essential step in attaining high-resolution 3d reconstructions. nevertheless, quantitative assessment of alignment quality has remained a challenging issue, even though many alignment methods have been reported. here, we report a fast and accurate method, tomoaligneval, based on the beer-lambert law, for the evaluation of alignment quality. our method is able to globally estimate the alignment accuracy by measuring the goodness of l ...201526455556
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
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
fighting arbovirus transmission: natural and engineered control of vector competence in aedes mosquitoes.control of aedine mosquito vectors, either by mosquito population reduction or replacement with refractory mosquitoes, may play an essential role in the fight against arboviral diseases. in this review, we will focus on the development and application of biological approaches, both natural or engineered, to limit mosquito vector competence for arboviruses. the study of mosquito antiviral immunity has led to the identification of a number of host response mechanisms and proteins that are required ...201526463078
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
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
new insights into control of arbovirus replication and spread by insect rna interference pathways.arthropod-borne (arbo) viruses are transmitted by vectors, such as mosquitoes, to susceptible vertebrates. recent research has shown that arbovirus replication and spread in mosquitoes is not passively tolerated but induces host responses to control these pathogens. small rna-mediated host responses are key players among these antiviral immune strategies. studies into one such small rna-mediated antiviral response, the exogenous rna interference (rnai) pathway, have generated a wealth of informa ...201226466541
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
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
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
antiviral potential of algae polysaccharides isolated from marine sources: a review.from food to fertilizer, algal derived products are largely employed in assorted industries, including agricultural, biomedical, food, and pharmaceutical industries. among different chemical compositions isolated from algae, polysaccharides are the most well-established compounds, which were subjected to a variety of studies due to extensive bioactivities. over the past few decades, the promising results for antiviral potential of algae-derived polysaccharides have advocated them as inordinate c ...201526484353
loss of glycosaminoglycan receptor binding after mosquito cell passage reduces chikungunya virus infectivity.chikungunya virus (chikv) is a mosquito-transmitted alphavirus that can cause fever and chronic arthritis in humans. chikv that is generated in mosquito or mammalian cells differs in glycosylation patterns of viral proteins, which may affect its replication and virulence. herein, we compare replication, pathogenicity, and receptor binding of chikv generated in vero cells (mammal) or c6/36 cells (mosquito) through a single passage. we demonstrate that mosquito cell-derived chikv (chikv mos) has s ...201526484530
cryo-em structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity.chikungunya virus (chikv) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. although highly inhibitory murine and human monoclonal antibodies (mabs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. here, we determined the cryo-em structures of chikungunya virus-like particles complexed with antibody fragments (fab) of two highly protective human mabs, 4j21 and 5m16, that block virus fusion with host ...201526504196
battle between influenza a virus and a newly identified antiviral activity of the parp-containing zapl protein.previous studies showed that zapl (parp-13.1) exerts its antiviral activity via its n-terminal zinc fingers that bind the mrnas of some viruses, leading to mrna degradation. here we identify a different antiviral activity of zapl that is directed against influenza a virus. this zapl antiviral activity involves its c-terminal parp domain, which binds the viral pb2 and pa polymerase proteins, leading to their proteasomal degradation. after the pb2 and pa proteins are poly(adp-ribosylated), they ar ...201526504237
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
dendritic cell targeted vaccines: recent progresses and challenges.dendritic cells (dcs) are known to be a set of morphology, structure and function of heterogeneous professional antigen presenting cells (apcs), as well as the strongest functional antigen presenting cells, which can absorb, process and present antigens. as the key regulators of innate and adaptive immune responses, dcs are at the center of the immune system and capable of interacting with both b cells and t cells, thereby manipulating the humoral and cellular immune responses. dcs provide an es ...026513200
structural studies of chikungunya virus-like particles complexed with human antibodies: neutralization and cell-to-cell transmission.chikungunya virus is a positive-stranded rna alphavirus. structures of chikungunya virus-like particles in complex with strongly neutralizing antibody fab fragments (8b10 and 5f10) were determined using cryo-electron microscopy and x-ray crystallography. by fitting the crystallographically determined structures of these fab fragments into the cryo-electron density maps, we show that fab fragments of antibody 8b10 extend radially from the viral surface and block receptor binding on the e2 glycopr ...201526537684
trisubstituted thieno[3,2-b]pyrrole 5-carboxamides as potent inhibitors of alphaviruses.chikungunya virus (chikv) is a re-emerging vector-borne alphavirus and is transmitted to humans by aedes mosquitoes. despite the re-emergence of chikv as an epidemic threat, there is no approved effective antiviral treatment currently available for chikv. herein, we report the synthesis and structure-activity relationship studies of a class of thieno[3,2-b]pyrroles and the discovery of a trisubstituted thieno[3,2-b]pyrrole 5-carboxamide 15c that exhibits potent inhibitory activity against in vit ...201526540338
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
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
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
trehalose, an mtor-independent inducer of autophagy, inhibits human cytomegalovirus infection in multiple cell types.human cytomegalovirus (hcmv) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. previous studies have shown that the induction of autophagy can inhibit the replication of several different types of dna and rna viruses. the goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of hcmv. most prior studies have used agents that induce autop ...201526559848
microbiota-dependent priming of antiviral intestinal immunity in drosophila.enteric pathogens must overcome intestinal defenses to establish infection. in drosophila, the erk signaling pathway inhibits enteric virus infection. the intestinal microflora also impacts immunity but its role in enteric viral infection is unknown. here we show that two signals are required to activate antiviral erk signaling in the intestinal epithelium. one signal depends on recognition of peptidoglycan from the microbiota, particularly from the commensal acetobacter pomorum, which primes th ...026567510
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
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
sphingosine kinase 2 is a chikungunya virus host factor co-localized with the viral replication complex.chikungunya virus (chikv) is a re-emerging alphavirus which causes severe and prolonged arthralgic febrile illness. the recent global spread of the virus and lack of approved therapeutic options makes it imperative to gain greater insight into the molecular mechanisms underlying chikv pathogenesis, in particular host factors recruited by the virus. in the current study, we identify sphingosine kinase 2 (sk2) as a chikv host factor co-localized with the viral replication complex (vrc) during infe ...201526576339
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
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
sindbis and middelburg old world alphaviruses associated with neurologic disease in horses, south africa.old world alphaviruses were identified in 52 of 623 horses with febrile or neurologic disease in south africa. five of 8 sindbis virus infections were mild; 2 of 3 fatal cases involved co-infections. of 44 middelburg virus infections, 28 caused neurologic disease; 12 were fatal. middelburg virus likely has zoonotic potential.026583836
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
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
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
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
arbovirus-mosquito interactions: rnai pathway.arthropod-borne (arbo) viruses infect hematophagous arthropods (vectors) to maintain virus transmission between vertebrate hosts. the mosquito vector actively controls arbovirus infection to minimize its fitness costs. the rna interference (rnai) pathway is the major antiviral response vectors use to restrict arbovirus infections. we know this because depleting rnai gene products profoundly impacts arbovirus replication, the antiviral rnai pathway genes undergo positive, diversifying selection a ...201526629932
fluorescent protein-tagged sindbis virus e2 glycoprotein allows single particle analysis of virus budding from live cells.sindbis virus (sinv) is an enveloped, mosquito-borne alphavirus. here we generated and characterized a fluorescent protein-tagged (fp-tagged) sinv and found that the presence of the fp-tag (mcherry) affected glycoprotein transport to the plasma membrane whereas the specific infectivity of the virus was not affected. we examined the virions by transmission electron cryo-microscopy and determined the arrangement of the fp-tag on the surface of the virion. the fluorescent proteins are arranged icos ...201526633461
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
the sd1 subdomain of venezuelan equine encephalitis virus capsid protein plays a critical role in nucleocapsid and particle assembly.venezuelan equine encephalitis virus (veev) is an important human and animal pathogen, for which no safe and efficient vaccines or therapeutic means have been developed. viral particle assembly and budding processes represent potential targets for therapeutic intervention. however, our understanding of the mechanistic process of veev assembly, rna encapsidation, and the roles of different capsid-specific domains in these events remain to be described. the results of this new study demonstrate th ...201526656680
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
dissecting the role of e2 protein domains in alphavirus pathogenicity.alphaviruses represent a diverse set of arboviruses, many of which are important pathogens. chikungunya virus (chikv), an arthritis-inducing alphavirus, is the cause of a massive ongoing outbreak in the caribbean and south america. in contrast to chikv, other related alphaviruses, such as venezuelan equine encephalitis virus (veev) and semliki forest virus (sfv), can cause encephalitic disease. e2, the receptor binding protein, has been implicated as a determinant in cell tropism, host range, pa ...201526676771
low-fidelity polymerases of alphaviruses recombine at higher rates to overproduce defective interfering particles.low-fidelity rna-dependent rna polymerases for many rna virus mutators have been shown to confer attenuated phenotypes, presumably due to increased mutation rates. additionally, for many rna viruses, replication to high titers results in the production of defective interfering particles (dis) that also attenuate infection. we hypothesized that fidelity, recombination, and di production are tightly linked. we show that a sindbis virus mutator replicating at a high multiplicity of infection manife ...201526676773
global emergence of alphaviruses that cause arthritis in humans.arthropod-borne viruses (arboviruses) may cause severe emerging and re-emerging infectious diseases, which pose a significant threat to human and animal health in the world today. these infectious diseases range from mild febrile illnesses, arthritis, and encephalitis to haemorrhagic fevers. it is postulated that certain environmental factors, vector competence, and host susceptibility have a major impact on the ecology of arboviral diseases. presently, there is a great interest in the emergence ...201526689654
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
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
synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones.a novel series of indolylthiosemicarbazides (6a-6g) and their cyclization products, 4-thiazolidinones (7a-7g), have been designed, synthesized and evaluated, in vitro, for their antiviral activity against a wide range of dna and rna viruses. compounds 6a, 6b, 6c and 6d exhibited notable antiviral activity against coxsackie b4 virus, at ec50 values ranging from 0.4 to 2.1 μg/ml. the selectivity index (ratio of cytotoxic to antivirally effective concentration) values of these compounds were betwee ...201626707844
enhancing and initiating phage-based therapies.drug development has typically been a primary foundation of strategy for systematic, long-range management of pathogenic cells. however, drug development is limited in speed and flexibility when response is needed to changes in pathogenic cells, especially changes that produce drug-resistance. the high replication speed and high diversity of phages are potentially useful for increasing both response speed and response flexibility when changes occur in either drug resistance or other aspects of p ...201426713220
an odyssey in antiviral drug development-50 years at the rega institute: 1964-2014. 201526713268
characterization of ryden (c19orf66) as an interferon-stimulated cellular inhibitor against dengue virus replication.dengue virus (denv) is one of the most important arthropod-borne pathogens that cause life-threatening diseases in humans. however, no vaccine or specific antiviral is available for dengue. as seen in other rna viruses, the innate immune system plays a key role in controlling denv infection and disease outcome. although the interferon (ifn) response, which is central to host protective immunity, has been reported to limit denv replication, the molecular details of how denv infection is modulated ...201626735137
cytokine diedel and a viral homologue suppress the imd pathway in drosophila.viruses are obligatory intracellular parasites that suffer strong evolutionary pressure from the host immune system. rapidly evolving viral genomes can adapt to this pressure by acquiring genes that counteract host defense mechanisms. for example, many vertebrate dna viruses have hijacked cellular genes encoding cytokines or cytokine receptors to disrupt host cell communication. insect viruses express suppressors of rna interference or apoptosis, highlighting the importance of these cell intrins ...201626739560
rainbow trout (oncorhynchus mykiss) muscle satellite cells are targets of salmonid alphavirus infection.sleeping disease in rainbow trout is characterized by an abnormal swimming behaviour of the fish which stay on their side at the bottom of the tanks. this sign is due to extensive necrosis and atrophy of red skeletal muscle induced by the sleeping disease virus (sdv), also called salmonid alphavirus 2. infections of humans with arthritogenic alphaviruses, such as chikungunya virus (chikv), are global causes of debilitating musculoskeletal diseases. the mechanisms by which the virus causes these ...201626743565
activation of the dna damage response by rna viruses.rna viruses are a genetically diverse group of pathogens that are responsible for some of the most prevalent and lethal human diseases. numerous viruses introduce dna damage and genetic instability in host cells during their lifecycles and some species also manipulate components of the dna damage response (ddr), a complex and sophisticated series of cellular pathways that have evolved to detect and repair dna lesions. activation and manipulation of the ddr by dna viruses has been extensively stu ...201626751489
discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses.chikungunya virus (chikv) is an arthritogenic arbovirus of the alphavirus genus, which has infected millions of people after its re-emergence in the last decade. in this study, a bhk cell line containing a stable chikv replicon with a luciferase reporter was used in a high-throughput platform to screen approximately 3000 compounds. following initial validation, 25 compounds were chosen as primary hits for secondary validation with wild type and reporter chikv infection, which identified three pr ...201626752081
a viral mrna motif at the 3'-untranslated region that confers translatability in a cell-specific manner. implications for virus evolution.sindbis virus (sinv) mrnas contain several motifs that participate in the regulation of their translation. we have discovered a motif at the 3' untranslated region (utr) of viral mrnas, constituted by three repeated sequences, which is involved in the translation of both sinv genomic and subgenomic mrnas in insect, but not in mammalian cells. these data illustrate for the first time that an element present at the 3'-utr confers translatability to mrnas from an animal virus in a cell-specific man ...201626755446
autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation.host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. murine gammaherpesvirus 68 (mhv68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (ifn-γ). using a lysozyme-m-cre (lysmcre) expression system, we show that deletion of autophagy-related (atg) genes fip200, beclin 1, atg14, atg16l1, atg7, atg3, and atg5, in the myeloid compartment, inhibited mhv68 reactivation in macrophages. atg5 deficiency ...026764599
eukaryote-specific extensions in ribosomal proteins of the small subunit: structure and function.high-resolution structures of yeast ribosomes have improved our understanding of the architecture and organization of eukaryotic rrna and proteins, as well as eukaryote-specific extensions present in some conserved ribosomal proteins. despite this progress, assignment of specific functions to individual proteins and/or eukaryote-specific protein extensions remains challenging. it has been suggested that eukaryote-specific extensions of conserved proteins from the small ribosomal subunit may faci ...201526779416
apoptosis, autophagy and unfolded protein response pathways in arbovirus replication and pathogenesis.arboviruses are pathogens that widely affect the health of people in different communities around the world. recently, a few successful approaches toward production of effective vaccines against some of these pathogens have been developed, but treatment and prevention of the resulting diseases remain a major health and research concern. the arbovirus infection and replication processes are complex, and many factors are involved in their regulation. apoptosis, autophagy and the unfolded protein r ...201626781343
2-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-1-yl)-n-(4-phenoxyphenyl)-acetamides as a novel class of cytomegalovirus replication inhibitors.a series of novel uracil derivatives, bearing n-(4-phenoxyphenyl)acetamide moiety at n3 of a pyrimidine ring, has been synthesized. their antiviral activity has been evaluated. it has been found that the novel compounds possess high inhibitory activity against replication of human cytomegalovirus (ad-169 and davis strains) in hel cell cultures. in addition, some of the derivatives proved to be inhibitory against varicella zoster virus.026798502
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
serial femtosecond x-ray diffraction of enveloped virus microcrystals.serial femtosecond crystallography (sfx) using x-ray free-electron lasers has produced high-resolution, room temperature, time-resolved protein structures. we report preliminary sfx of sindbis virus, an enveloped icosahedral rna virus with ∼700 å diameter. microcrystals delivered in viscous agarose medium diffracted to ∼40 å resolution. small-angle diffuse x-ray scattering overlaid bragg peaks and analysis suggests this results from molecular transforms of individual particles. viral proteins un ...201526798819
overexpression of trim14 promotes tongue squamous cell carcinoma aggressiveness by activating the nf-κb signaling pathway.tongue squamous cells carcinoma (tscc) is one of the most lethal malignancies of oral cancers and its prognosis remains dismal due to the paucity of effective therapeutic targets. herein, we showed that tripartite motif containing 14(trim14) is markedly up-regulated in tscc cell lines and clinical tissues. immunohistochemical (ihc) analysis of 116 clinical tscc specimens revealed that trim14 expression was significantly correlated with the tnm classification (t: p = 0.01; n: p < 0.001; m: p < 0. ...026799420
surveillance for western equine encephalitis, st. louis encephalitis, and west nile viruses using reverse transcription loop-mediated isothermal amplification.collection of mosquitoes and testing for vector-borne viruses is a key surveillance activity that directly influences the vector control efforts of public health agencies, including determining when and where to apply insecticides. vector control districts in california routinely monitor for three human pathogenic viruses including west nile virus (wnv), western equine encephalitis virus (weev), and st. louis encephalitis virus (slev). reverse transcription quantitative polymerase chain reaction ...201626807734
assessment of productivity of culex spp. larvae (diptera: culicidae) in urban storm water catch basin system in wrocław (sw poland).in urban environments, catch basins serve as major developmental and resting sites for anthropophilic and zoophilic mosquitoes. however, the use of this habitat is inconsistent, with abundance of larvae varying significantly across catch basins at a fine spatial scale. during seasonal summer investigations on mosquito species composition, their spatial and temporal distribution and the environmental characteristic of the breeding sites in the underground storm drain systems of the wrocław urban ...201626809340
status of hepatitis c virus vaccination: recent update.hepatitis c virus (hcv) infection is still a major public health problem worldwide since its first identification in 1989. at the start, hcv infection was post-transfusion viral infection, particularly in developing countries. recently, due to iv drug abuse, hcv infection became number one health problem in well-developed countries as well. following acute hcv infection, the innate immune response is triggered in the form of activated coordinated interaction of nk cells, dendritic cells and inte ...026811632
proteomic approaches to uncovering virus-host protein interactions during the progression of viral infection.the integration of proteomic methods to virology has facilitated a significant breadth of biological insight into mechanisms of virus replication, antiviral host responses and viral subversion of host defenses. throughout the course of infection, these cellular mechanisms rely heavily on the formation of temporally and spatially regulated virus-host protein-protein interactions. reviewed here are proteomic-based approaches that have been used to characterize this dynamic virus-host interplay. sp ...026817613
lncrna oip5-as1/cyrano sponges rna-binding protein hur.the function of the vast majority of mammalian long noncoding (lnc) rnas remains unknown. here, analysis of a highly abundant mammalian lncrna, oip5-as1, known as cyrano in zebrafish, revealed that oip5-as1 reduces cell proliferation. in human cervical carcinoma hela cells, the rna-binding protein hur, which enhances cell proliferation, associated with oip5-as1 and stabilized it. tagging oip5-as1 with ms2 hairpins to identify associated micrornas revealed that mir-424 interacted with oip5-as1 an ...201626819413
inhibition of chikungunya virus replication by 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea(mbzm-n-ibt).chikungunya virus (chikv) infection is one of the most challenging human arboviral infections with global significance and without any specific antiviral. in this investigation, 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene] amino] thiourea (mbzm-n-ibt) was synthesised as a molecular hybrid of 2-methyl benzimidazole and isatin-β-thiosemicarbazone and its anti-chikv property was evaluated. the release of infectious virus particles was calculated by plaque assay, expression profil ...201626843462
aβ-induced synaptic alterations require the e3 ubiquitin ligase nedd4-1.alzheimer's disease (ad) is a neurodegenerative disease in which patients experience progressive cognitive decline. a wealth of evidence suggests that this cognitive impairment results from synaptic dysfunction in affected brain regions caused by cleavage of amyloid precursor protein into the pathogenic peptide amyloid-β (aβ). specifically, it has been shown that aβ decreases surface ampars, dendritic spine density, and synaptic strength, and also alters synaptic plasticity. the precise molecula ...026843640
activation of rnase l is dependent on oas3 expression during infection with diverse human viruses.the 2',5'-oligoadenylate (2-5a) synthetase (oas)-rnase l system is an ifn-induced antiviral pathway. rnase l activity depends on 2-5a, synthesized by oas. although all three enzymatically active oas proteins in humans--oas1, oas2, and oas3--synthesize 2-5a upon binding dsrna, it is unclear which are responsible for rnase l activation during viral infection. we used clustered regularly interspaced short palindromic repeats (crispr)-crispr-associated protein-9 nuclease (cas9) technology to enginee ...201626858407
seropositivity for west nile virus antibodies in patients affected by myasthenia gravis.myasthenia gravis (mg) is an autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal muscles. specific auto-antibodies against acetylcholine receptor (achr) are present in the majority of mg patients, although the main cause behind its development still remains unclear. recently mg development following west nile virus (wnv) infection has been described in patients without any earlier evidence of mg. it is known that infectious agents trigger immune response ...201626858791
big data offers novel insights for oncolytic virus immunotherapy.large-scale assays, such as microarrays, next-generation sequencing and various "omics" technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (ovit) in the cancer setting. tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and function ...201626861383
identification of a nucleotide in 5' untranslated region contributing to virus replication and virulence of coxsackievirus a16.coxsackievirus a16 (ca16) and enterovirus 71 (ev71) are two main causative pathogens of hand, foot and mouth disease (hfmd). unlike ev71, virulence determinants of ca16, particularly within 5' untranslated region (5'utr), have not been investigated until now. here, a series of nucleotides present in 5'utr of lethal but not in non-lethal ca16 strains were screened by aligning nucleotide sequences of lethal circulating changchun ca16 and the prototype g10 as well as non-lethal shzh05 strains. a re ...201626861413
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
role of tspan9 in alphavirus entry and early endosomes.alphaviruses are small enveloped rna viruses that infect cells via clathrin-mediated endocytosis and low-ph-triggered fusion in the early endosome. using a small interfering rna (sirna) screen in human cells, we previously identified tspan9 as a host factor that promotes infection by the alphaviruses sindbis virus (sinv), semliki forest virus (sfv), and chikungunya virus (chikv). depletion of tspan9 specifically decreases sfv membrane fusion in endosomes. tspan9 is a member of the tetraspanin fa ...201626865714
effects of an in-frame deletion of the 6k gene locus from the genome of ross river virus.the alphaviral6kgene region encodes the two structural proteins 6k protein and, due to a ribosomal frameshift event, the transframe protein (tf). here, we characterized the role of the6kproteins in the arthritogenic alphavirus ross river virus (rrv) in infected cells and in mice, using a novel6kin-frame deletion mutant. comprehensive microscopic analysis revealed that the6kproteins were predominantly localized at the endoplasmic reticulum of rrv-infected cells. rrv virions that lack the6kprotein ...201626865723
interferon-inducible protein scotin interferes with hcv replication through the autolysosomal degradation of ns5a.hepatitis c virus (hcv) utilizes autophagy to promote its propagation. here we show the autophagy-mediated suppression of hcv replication via the endoplasmic reticulum (er) protein scotin. scotin overexpression inhibits hcv replication and infectious virion production in cells infected with cell culture-derived hcv. hcv nonstructural 5a (ns5a) protein, which is a critical factor for hcv rna replication, interacts with the ifn-β-inducible protein scotin, which transports ns5a to autophagosomes fo ...201626868272
transstadial effects of bti on traits of aedes aegypti and infection with dengue virus.most mosquito control efforts are primarily focused on reducing the adult population size mediated by reductions in the larval population, which should lower risk of disease transmission. although the aim of larviciding is to reduce larval abundance and thus recruitment of adults, nonlethal effects on adults are possible, including transstadial effects on phenotypes of adults such as survival and pathogen infection and transmission. in addition, the mortality induced by control efforts may act i ...201626871951
computational virology: from the inside out.viruses typically pack their genetic material within a protein capsid. enveloped viruses also have an outer membrane made up of a lipid bilayer and membrane-spanning glycoproteins. x-ray diffraction and cryoelectron microscopy provide high resolution static views of viral structure. molecular dynamics (md) simulations may be used to provide dynamic insights into the structures of viruses and their components. there have been a number of simulations of viral capsids and (in some cases) of the inn ...201626874202
concentration of sindbis virus with optimized gradient insulator-based dielectrophoresis.biotechnology, separation science, and clinical research are impacted by microfluidic devices. separation and manipulation of bioparticles such as dna, protein and viruses are performed on these platforms. microfluidic systems provide many attractive features, including small sample size, rapid detection, high sensitivity and short processing time. dielectrophoresis (dep) and electrophoresis are especially well suited to microscale bioparticle control and have been demonstrated in many formats. ...201626878279
the presence and seroprevalence of arthropod-borne viruses in nasiriyah governorate, southern iraq: a cross-sectional study.the knowledge on the presence and seroprevalence of arboviruses in iraq is fragmental. to assess the exposure of the population to arbovirus infections in southern iraq, we conducted a serological screening of the most common arbovirus groups using immunofluorescence, hemagglutination inhibition and neutralization tests. serum samples of 399 adult volunteers were collected in nasiriyah, iraq. antibodies were detected against west nile virus (wnv) (11.6%), sandfly-borne sicilian virus serocomplex ...201626880770
hippocampal dendritic spines are segregated depending on their actin polymerization.dendritic spines are mushroom-shaped protrusions of the postsynaptic membrane. spines receive the majority of glutamatergic synaptic inputs. their morphology, dynamics, and density have been related to synaptic plasticity and learning. the main determinant of spine shape is filamentous actin. using frap, we have reexamined the actin dynamics of individual spines from pyramidal hippocampal neurons, both in cultures and in hippocampal organotypic slices. our results indicate that, in cultures, the ...201626881098
emerging role of lipid droplets in aedes aegypti immune response against bacteria and dengue virus.in mammals, lipid droplets (lds) are ubiquitous organelles that modulate immune and inflammatory responses through the production of lipid mediators. in insects, it is unknown whether lds play any role during the development of immune responses. we show that aedes aegypti aag2 cells - an immune responsive cell lineage - accumulates lds when challenged with enterobacter cloacae, sindbis, and dengue viruses. microarray analysis of aag2 challenged with e.cloacae or infected with dengue virus reveal ...201626887863
presynaptic serotonin 2a receptors modulate thalamocortical plasticity and associative learning.higher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (pfc). alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. prefrontal serotonin (5-ht)2a receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. here, we show that ...201626903620
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