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important role of the il-32 inflammatory network in the host response against viral infection.the pro-inflammatory cytokine interleukin (il)-32 has gained much attention recently because of its important role in the inflammatory network. since the discovery of il-32 in 2005, our appreciation for its diverse roles continues to grow. recent studies have discovered the antiviral effects induced by il-32 and its associated regulatory mechanisms. the interactions between il-32 and various cytokines including cyclooxygenase 2 (cox-2), inducible nitric oxide synthase (inos), interferon (ifn)-λ1 ...201526087456
antiviral activity of silymarin against chikungunya virus.the mosquito-borne chikungunya virus (chikv) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. although there are several studies to evaluate the efficacy of drugs against chikv, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. here, we investigated the antiviral activity of three t ...201526078201
amino-terminal arginylation targets endoplasmic reticulum chaperone bip for autophagy through p62 binding.we show that ate1-encoded arg-transfer rna transferase (r-transferase) of the n-end rule pathway mediates n-terminal arginylation of multiple endoplasmic reticulum (er)-residing chaperones, leading to their cytosolic relocalization and turnover. n-terminal arginylation of bip (also known as grp78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses to cytosolic foreign dna or proteasomal inhibition, associated with increased ubiquitylation. ...201526075355
electron tomography analysis of tick-borne encephalitis virus infection in human neurons.tick-borne encephalitis virus (tbev) causes serious, potentially fatal neurological infections that affect humans in endemic regions of europe and asia. neurons are the primary target for tbev infection in the central nervous system. however, knowledge about this viral infection and virus-induced neuronal injury is fragmental. here, we directly examined the pathology that occurs after tbev infection in human primary neurons. we exploited the advantages of advanced high-pressure freezing and free ...201526073783
spinoculation enhances hbv infection in ntcp-reconstituted hepatocytes.hepatitis b virus (hbv) infection and its sequelae remain a major public health burden, but both hbv basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. recently, sodium taurocholate cotransporting polypeptide (ntcp) has been identified as the hbv receptor. we herein report that we established a ntcp-complemented hepg2 cell line (hepg2-ntcp12) that supports hbv infection, albeit at a low infectivity level followin ...201526070202
rnasek is required for internalization of diverse acid-dependent viruses.viruses must gain entry into cells to establish infection. in general, viruses enter either at the plasma membrane or from intracellular endosomal compartments. viruses that use endosomal pathways are dependent on the cellular factors that control this process; however, these genes have proven to be essential for endogenous cargo uptake, and thus are of limited value for therapeutic intervention. the identification of genes that are selectively required for viral uptake would make appealing drug ...201526056282
fragile x proteins fmrp and fxr2p control synaptic glua1 expression and neuronal maturation via distinct mechanisms.fragile x mental retardation protein (fmrp) and its autosomal paralog fxr2p are selective neuronal rna-binding proteins, and mice that lack either protein exhibit cognitive deficits. although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. in the present study, we discovered that fxr2p (also known as fxr2) is important for neuronal dendritic development. fmrp and fxr2p additively promote the maturation of new neur ...201526051932
distinct immune responses in resistant and susceptible strains of mice during neurovirulent alphavirus encephalomyelitis.susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. neuroadapted sindbis virus (nsv) causes uniformly fatal disease in adult c57bl/6 (b6) mice, but adult balb/c (bc) mice recover from infection. in b6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. to identify the immunological determinants of host susceptibility to fatal nsv-induced encephalomyelitis, we compared virus ...201526041298
new insights into the understanding of hepatitis c virus entry and cell-to-cell transmission by using the ionophore monensin a.in our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular ph, on the hepatitis c virus (hcv) life cycle. we showed that monensin inhibits hcv entry in a pangenotypic and dose-dependent manner. monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. interestingly, we demonstrated that hcv cell-to-cell transmission is dependent on the vesicular ph. using the se ...201526041282
sequence-independent characterization of viruses based on the pattern of viral small rnas produced by the host.virus surveillance in vector insects is potentially of great benefit to public health. large-scale sequencing of small and long rnas has previously been used to detect viruses, but without any formal comparison of different strategies. furthermore, the identification of viral sequences largely depends on similarity searches against reference databases. here, we developed a sequence-independent strategy based on virus-derived small rnas produced by the host response, such as the rna interference ...201526040701
rnai and antiviral defense in the honey bee.honey bees play an important agricultural and ecological role as pollinators of numerous agricultural crops and other plant species. therefore, investigating the factors associated with high annual losses of honey bee colonies in the us is an important and active area of research. pathogen incidence and abundance correlate with colony collapse disorder- (ccd-) affected colonies in the us and colony losses in the us and in some european countries. honey bees are readily infected by single-strande ...201526798663
the phosphatidylserine and phosphatidylethanolamine receptor cd300a binds dengue virus and enhances infection.dengue virus (denv) is the etiological agent of the major human arboviral disease. we previously demonstrated that the tim and tam families of phosphatidylserine (ptdser) receptors involved in the phagocytosis of apoptotic cells mediate denv entry into target cells. we show here that human cd300a, a recently identified phospholipid receptor, also binds directly denv particles and enhances viral entry. cd300a facilitates infection of the four denv serotypes, as well as of other mosquito-borne vir ...201526468529
aberrant regulation of synchronous network activity by the attention-deficit/hyperactivity disorder-associated human dopamine d4 receptor variant d4.7 in the prefrontal cortex.the hd4.7 variant has been linked to attention-deficit/hyperactivity disorder (adhd); however, the underlying mechanism is unknown. we found that activation of hd4.7 induced over-suppression of glutamatergic excitatory network bursts and under-suppression of gabaergic inhibitory network bursts in the prefrontal cortex (pfc) circuitry. methylphenidate, a psychostimulant drug used to treat adhd, normalized the effects of hd4.7 on synchronous network bursts in pfc pyramidal neurons. the findings of ...201526541360
direct pcr of indigenous and invasive mosquito species: a time- and cost-effective technique of mosquito barcoding.millions of people die each year as a result of pathogens transmitted by mosquitoes. however, the morphological identification of mosquito species can be difficult even for experts. the identification of morphologically indistinguishable species, such as members of the anopheles maculipennis complex (diptera: culicidae), and possible hybrids, such as culex pipiens pipiens/culex pipiens molestus (diptera: culicidae), presents a major problem. in addition, the detection and discrimination of newly ...201526663040
characterization of a novel human-specific sting agonist that elicits antiviral activity against emerging alphaviruses.pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. in light of this we sought to identify small molecules capable of activating the type i interferon (ifn) response by way of the transcription factor ifn regulatory factor 3 (irf3). a high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-n-(furan-2- ...201526646986
detection of persistent chikungunya virus rna but not infectious virus in experimental vertical transmission in aedes aegypti from malaysia.vertical transmission may contribute to the maintenance of arthropod-borne viruses, but its existence in chikungunya virus (chikv) is unclear. experimental vertical transmission of infectious clones of chikv in aedes aegypti mosquitoes from malaysia was investigated. eggs and adult progeny from the second gonotrophic cycles of infected parental mosquitoes were tested. using polymerase chain reaction (pcr), 56.3% of pooled eggs and 10% of adult progeny had detectable chikv rna, but no samples had ...201526598564
mtor is essential for corticosteroid effects on hippocampal ampa receptor function and fear memory.glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. we examined how corticosterone regulates ampa receptors (ampars), which are crucial for synaptic plasticity and memory formation. combining a live imaging fluorescent recovery after photobleaching approach with the use of the ph-sensitive gfp-ampar tagging revealed that corticosterone enhances the ampar mobile fraction and increases synaptic trapping of am ...201526572647
self-assembling protein nanoparticles in the design of vaccines.for over 100 years, vaccines have been one of the most effective medical interventions for reducing infectious disease, and are estimated to save millions of lives globally each year. nevertheless, many diseases are not yet preventable by vaccination. this large unmet medical need demands further research and the development of novel vaccines with high efficacy and safety. compared to the 19th and early 20th century vaccines that were made of killed, inactivated, or live-attenuated pathogens, mo ...201526862374
chikungunya nsp2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine.chikungunya virus is the pathogenic alphavirus that causes chikungunya fever in humans. in the last decade millions of cases have been reported around the world from africa to asia to the americas. the alphavirus nsp2 protein is multifunctional and is considered to be pivotal to viral replication, as the nsp2 protease activity is critical for proteolytic processing of the viral polyprotein during replication. classically the alphavirus nsp2 protease is thought to be papain-like with the enzyme r ...201526597768
conformational ensemble of the poliovirus 3cd precursor observed by md simulations and confirmed by saxs: a strategy to expand the viral proteome?the genomes of rna viruses are relatively small. to overcome the small-size limitation, rna viruses assign distinct functions to the processed viral proteins and their precursors. this is exemplified by poliovirus 3cd protein. 3c protein is a protease and rna-binding protein. 3d protein is an rna-dependent rna polymerase (rdrp). 3cd exhibits unique protease and rna-binding activities relative to 3c and is devoid of rdrp activity. the origin of these differences is unclear, since crystal structur ...201526610545
design, synthesis, and antiviral activity of novel ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates.a novel series of ribonucleosides of 1,2,3-triazolylbenzyl-aminophosphonates was synthesized through the kabachnik-fields reaction using i2 as catalyst followed by copper-catalyzed cycloaddition of the azide-alkyne reaction (cuaac). all structures of the newly prepared compounds were characterized by (1) h nmr, (13) c nmr, and hrms spectra. the structures of 2e, 2f, 3d, and 3g were further confirmed by x-ray diffraction analysis. these compounds were tested against various strains of dna and rna ...201526575425
chikungunya virus replication in salivary glands of the mosquito aedes albopictus.chikungunya virus (chikv) is an emerging arbovirus transmitted to humans by mosquitoes such as aedes albopictus. to be transmitted, chikv must replicate in the mosquito midgut, then disseminate in the hemocele and infect the salivary glands before being released in saliva. we have developed a standardized protocol to visualize viral particles in the mosquito salivary glands using transmission electron microscopy. here we provide direct evidence for chikv replication and storage in ae. albopictus ...201526593936
both rig-i and mda5 detect alphavirus replication in concentration-dependent mode.alphaviruses are a family of positive-strand rna viruses that circulate on all continents between mosquito vectors and vertebrate hosts. despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus-host interaction are insufficiently understood. in this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating alphaviruses. our new da ...201526550947
region-specific dendritic simplification induced by aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.dendritic simplification, a key feature of the neurodegenerative triad of alzheimer's disease (ad) in addition to spine changes and neuron loss, occurs in a region-specific manner. however, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.201526541821
beclin 1-vps34 complex architecture: understanding the nuts and bolts of therapeutic targets.autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. dysregulation of autophagy is linked to a growing number of human diseases. the beclin 1-vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. manipulation of autophagy, in particular via modulation of the action of the beclin 1-vps34 complexes, is considered a ...201526692106
an odyssey in antiviral drug development-50 years at the rega institute: 1964-2014. 201526713268
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
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
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
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
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
rapid antidepressants stimulate the decoupling of gaba(b) receptors from girk/kir3 channels through increased protein stability of 14-3-3η.a single injection of n-methyl-d-aspartate receptor (nmdar) antagonists produces a rapid antidepressant response. lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. we recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (gababr) signaling pathway, such that gababr activation shifts from opening inwardly rectifiying potassium channels (kir/girk) to increasing resting dendritic calcium signal and mammalia ...201525560757
conserved motifs in a tombusvirus polymerase modulate genome replication, subgenomic transcription, and amplification of defective interfering rnas.the replication of plus-strand rna virus genomes is mediated by virally encoded rna-dependent rna polymerases (rdrps). we have investigated the role of the c-proximal region in the rdrp of tomato bushy stunt virus (tbsv) in mediating viral rna synthesis. tbsv is the prototype species in the genus tombusvirus, family tombusviridae, and its rdrp is responsible for replicating the viral genome, transcribing two subgenomic mrnas, and supporting replication of defective interfering rnas. comparative ...201525568204
early detection of dengue virus by use of reverse transcription-recombinase polymerase amplification.a method for the rapid diagnosis of early dengue virus (denv) infection is highly needed. here, a prototype reverse transcription-recombinase polymerase amplification (rt-rpa) assay was developed. the assay detected denv rna in <20 min without the need for thermocycling amplification. the assay enabled the detection of as few as 10 copies of denv rna. the designed rt-rpa primers and exo probe detected the denv genome of at least 12 genotypes of denv circulating globally without cross-reacting wi ...201525568438
identification of hnrnpk as regulator of hepatitis c virus particle production.hepatitis c virus (hcv) is a major cause of chronic liver disease affecting around 130 million people worldwide. while great progress has been made to define the principle steps of the viral life cycle, detailed knowledge how hcv interacts with its host cells is still limited. to overcome this limitation we conducted a comprehensive whole-virus rna interference-based screen and identified 40 host dependency and 16 host restriction factors involved in hcv entry/replication or assembly/release. of ...201525569684
vpx-containing dendritic cell vaccine induces ctls and reactivates latent hiv-1 in vitro.eradication of human immunodeficiency virus-1 (hiv-1) from an infected individual requires a means of inducing production of virus from latently infected cells and stimulating an immune response against the infected cells. we report the development of lentiviral vectors that transduce dendritic cells (dcs) to both induce production of virus from latently infected cells and stimulate antigen-specific cytotoxic t lymphocytes (ctls). the vectors package vpx, a lentiviral accessory protein that coun ...201525567537
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
suramin inhibits chikungunya virus replication through multiple mechanisms.chikungunya virus (chikv) is a mosquito-borne alphavirus that causes severe and often persistent arthritis. in recent years, millions of people have been infected with this virus for which registered antivirals are still lacking. using our recently established in vitro assay, we discovered that the approved anti-parasitic drug suramin inhibits chikv rna synthesis (ic50 of ∼5μm). the compound inhibited replication of various chikv isolates in cell culture with an ec50 of ∼80μm (cc50>5mm) and was ...201526112648
antiviral activity of flexibilane and tigliane diterpenoids from stillingia lineata.in an effort to identify new potent and selective inhibitors of chikungunya virus and hiv-1 and hiv-2 virus replication, the endemic mascarene species stillingia lineata was investigated. lc/ms and bioassay-guided purification of the etoac leaf extract using a chikungunya virus-cell-based assay led to the isolation of six new (4-9) and three known (1-3) tonantzitlolones possessing the rare c20-flexibilane skeleton, along with tonantzitloic acid (10), a new linear diterpenoid, and three new (11, ...201525946116
antiviral activities of whey proteins.milk contains an array of proteins with useful bioactivities. many milk proteins encompassing native or chemically modified casein, lactoferrin, alpha-lactalbumin, and beta-lactoglobulin demonstrated antiviral activities. casein and alpha-lactalbumin gained anti-hiv activity after modification with 3-hydroxyphthalic anhydride. many milk proteins inhibited hiv reverse transcriptase. bovine glycolactin, angiogenin-1, lactogenin, casein, alpha-lactalbumin, beta-lactoglobulin, bovine lactoferrampin, ...201526198883
sphingolipids in viral infection.viruses exploit membranes and their components such as sphingolipids in all steps of their life cycle including attachment and membrane fusion, intracellular transport, replication, protein sorting and budding. examples for sphingolipid-dependent virus entry are found for: human immunodeficiency virus (hiv), which besides its protein receptors also interacts with glycosphingolipids (gsls); rhinovirus, which promotes the formation of ceramide-enriched platforms and endocytosis; or measles virus ( ...201525525752
enveloped virus flocculation and removal in osmolyte solutions.our ability to reduce infectious disease burden throughout the world has been greatly improved by the creation of vaccines. however, worldwide immunization rates are low. the two most likely reasons are the lack of sufficient distribution in underdeveloped countries and the high cost of vaccine products. the high costs are due to the difficulties of manufacturing individual vaccine products with specialized purification trains. in this study, we propose to use virus flocculation in osmolytes, fo ...201525865274
semliki forest virus and sindbis virus, but not vaccinia virus, require glycolysis for optimal replication.viruses are obligate intracellular pathogens which rely on the cell's machinery to produce the energy and macromolecules required for replication. infection is associated with a modified metabolic profile and one pathway which can be modified is glycolysis. in this study, we investigated if the glycolysis pathway is required for alphavirus replication. pre-treatment of vero cells with three different glycolysis inhibitors (2-deoxyglucose, lonidamine and oxamate) resulted in a significant reducti ...201526297236
inactivation of viruses in platelet and plasma products using a riboflavin-and-uv-based photochemical treatment.multilayered blood safety programs reduce the risk of transfusion-transmitted diseases; however, there remains a risk of window period transmission of screened viruses and transmission of unscreened and emerging viruses from asymptomatic donors. to reduce this risk, a riboflavin-and-uv-light-based pathogen reduction process was evaluated against eight viral agents.201525731607
virus adsorption of water-stable quaternized chitosan nanofibers.the burden of unsafe drinking water is responsible for millions of deaths each year. to relieve this burden, we are in search of an inexpensive material that can adsorb pathogens from drinking water. in this pursuit, we have studied the natural carbohydrate, chitosan. to impart virus removal features, chitosan has been functionalized with a quaternary amine to form quaternized chitosan n-[(2-hydroxyl-3-trimethylammonium) propyl] chitosan (htcc). htcc can be electrospun into nanofibers with the n ...201424561959
antiviral activity of lanatoside c against dengue virus infection.dengue infection poses a serious threat globally due to its recent rapid spread and rise in incidence. currently, there is no approved vaccine or effective antiviral drug for dengue virus infection. in response to the urgent need for the development of an effective antiviral for dengue virus, the us drug collection library was screened in this study to identify compounds with anti-dengue activities. lanatoside c, an fda approved cardiac glycoside was identified as a candidate anti-dengue compoun ...201425251726
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
jatrophane diterpenes as inhibitors of chikungunya virus replication: structure-activity relationship and discovery of a potent lead.bioassay-guided purification of an etoac extract of the whole plant of euphorbia amygdaloides ssp. semiperfoliata using a chikungunya virus-cell-based assay led to the isolation of six new (1-4, 9, and 10) and six known (5-7, 8, 11, and 12) jatrophane esters. their planar structures and relative configurations were determined by extensive spectroscopic analysis, and their absolute configurations by x-ray analysis. these compounds were investigated for selective antiviral activity against chikung ...201424926807
[complete genome characterization of the kyzylagach virus (kyzv) (togaviridae, alphavirus, sindbis serogroup) isolated from mosquitoes culex modestus ficalbi, 1889 (culicinae) collected in a colony of herons (ardeidae leach, 1820) in azerbaijan].complete genome sequencing of the kyzylagach virus (kyzv) leiv-65a strain isolated from the culex modestus ficalbi, 1889 (culicinae), which was collected in the colony of the ardeidae leach, 1820 birds on the coast of caspian sea, kyzyl-agach bay, in the southern part of azerbaijan, was carried out. kyzv has high homology (about 99%) with the chinese xj-160 strain of the sindbis virus (sinv) isolated from anopheles sp. in xinjiang uyghur autonomic region (north-eastern china). homologies of kyzv ...201425895208
effect of mixed infections of sindbis and la crosse viruses on replication of each virus in vitro.mixed viral infections are ubiquitous in natural populations and may have significant but unpredictable biological and epidemiological consequences. these infections may be acquired simultaneously (coinfection) or result from two single infections at different time intervals (superinfection). this study investigated the effect of mixed infections of two mosquito-borne viruses, sindbis (sinv) and la crosse (lacv), on the replication of each virus in vertebrate baby hamster kidney (bhk) and invert ...201424463260
design, synthesis, antiviral and cytotoxic evaluation of novel acyclic phosphonate nucleotide analogues with a 5,6-dihydro-1h-[1,2,3]triazolo[4,5-d]pyridazine-4,7-dione system.a series of diethyl 2-(4,5-dimethoxycarbonyl-1h-1,2,3-triazol-1-yl)alkylphosphonates was synthesised from ω-azidoalkylphosphonates and dimethyl acetylenedicarboxylate and was further transformed into the respective diamides, dihydrazides, and 5,6-dihydro-1h-[1,2,3]triazolo[4,5-d]pyridazine-4,7-diones as phosphonate analogues of acyclic nucleosides having nucleobases replaced with substituted 1,2,3-triazoles. all compounds containing p-c-c-triazole or p-c-c-ch2-triazole moieties exist in single c ...201426166892
distinctive effects of the cellular inhibitor of apoptosis protein c-iap2 through stabilization by xiap in glioblastoma multiforme cells.inhibitor of apoptosis proteins (iaps) are extensively involved in nfκb signaling pathways. regulation of c-iap2 turnover by other proteins was investigated in glioblastoma multiforme (gbm) cells in the present study. when overexpressed, x-linked iap (xiap) enhanced expression of ectopic c-iap2, but not c-iap1, and endogenous c-iap2 levels were reduced once xiap expression was silenced. tnfα stimulation substantially increased c-iap2 expression, and this upregulation was impaired by suppression ...201424552816
targeting γ-herpesvirus 68 bcl-2-mediated down-regulation of autophagy.γ-herpesviruses (γhvs) are common human pathogens that encode homologs of the anti-apoptotic cellular bcl-2 proteins, which are critical to viral reactivation and oncogenic transformation. the murine γhv68 provides a tractable in vivo model for understanding general features of these important human pathogens. bcl-xl, a cellular bcl-2 homolog, and the murine γhv68 bcl-2 homolog, m11, both bind to a bh3 domain within the key autophagy effector beclin 1 with comparable affinities, resulting in the ...201424443581
alphavirus mutator variants present host-specific defects and attenuation in mammalian and insect models.arboviruses cycle through both vertebrates and invertebrates, which requires them to adapt to disparate hosts while maintaining genetic integrity during genome replication. to study the genetic mechanisms and determinants of these processes, we use chikungunya virus (chikv), a re-emerging human pathogen transmitted by the aedes mosquito. we previously isolated a high fidelity (or antimutator) polymerase variant, c483y, which had decreased fitness in both mammalian and mosquito hosts, suggesting ...201424453971
from scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer.tumour mutations corrupt cellular pathways, and accumulate to disrupt, dysregulate, and ultimately avoid mechanisms of cellular control. yet the very changes that tumour cells undergo to secure their own growth success also render them susceptible to viral infection. enhanced availability of surface receptors, disruption of antiviral sensing, elevated metabolic activity, disengagement of cell cycle controls, hyperactivation of mitogenic pathways, and apoptotic avoidance all render the malignant ...201424453963
differential regulation of gabab receptor trafficking by different modes of n-methyl-d-aspartate (nmda) receptor signaling.inhibitory gabab receptors (gababrs) can down-regulate most excitatory synapses in the cns by reducing postsynaptic excitability. functional gababrs are heterodimers of gabab1 and gabab2 subunits and here we show that the trafficking and surface expression of gababrs is differentially regulated by synaptic or pathophysiological activation of nmda receptors (nmdars). activation of synaptic nmdars using a chemltp protocol increases gababr recycling and surface expression. in contrast, excitotoxic ...201424425870
the role of viral genomic rna and nucleocapsid protein in the autophagic clearance of hantavirus glycoprotein gn.hantaviruses have tri-segmented negative sense rna genome. the viral m-segment rna encodes a glycoprotein precursor (gpc), which is cleaved into two glycoprotein molecules gn and gc that form spikes on the viral envelope. we previously reported that gn is degraded shortly after synthesis by the host autophagy machinery. however, gn being an important integral component of the virion, must escape degradation during the packaging and assembly stage of virus replication cycle. the mechanism regulat ...201424412713
sorting through the roles of beclin 1 in microglia and neurodegeneration.beclin 1 has a well-established role in regulating autophagy, a cellular degradation pathway. although the yeast ortholog of beclin 1 (atg6/vps30) was discovered to also regulate vacuolar protein sorting nearly 30 years ago, the varied functions of beclin 1 in mammalian cells are only beginning to be sorted out. we recently described a role for beclin 1 in regulating recycling of phagocytic receptors in microglia, a function analogous to that of its yeast ortholog. microglia lacking beclin 1 hav ...201424385262
chemical derivatives of a small molecule deubiquitinase inhibitor have antiviral activity against several rna viruses.most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. a good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. the small molecule wp1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other rna viruses ...201424722666
prevention of contamination by xenotropic murine leukemia virus-related virus: susceptibility to alcohol-based disinfectants and environmental stability.xenotropic murine leukemia virus-related virus (xmrv) represents a novel γ-retrovirus that is capable of infecting human cells and has been classified as a biosafety level 2 (bsl-2) organism. hence, xmrv represents a potential risk for personnel in laboratories worldwide. here, we measured the stability of xmrv and its susceptibility to alcohol-based disinfectants. to this end, we exposed an infectious xmrv reporter virus encoding a secretable luciferase to different temperatures, ph values, and ...201424532072
interferon-stimulated genes: a complex web of host defenses.interferon-stimulated gene (isg) products take on a number of diverse roles. collectively, they are highly effective at resisting and controlling pathogens. in this review, we begin by introducing interferon (ifn) and the jak-stat signaling pathway to highlight features that impact isg production. next, we describe ways in which isgs both enhance innate pathogen-sensing capabilities and negatively regulate signaling through the jak-stat pathway. several isgs that directly inhibit virus infection ...201424555472
the role of ikkβ in venezuelan equine encephalitis virus infection.venezuelan equine encephalitis virus (veev) belongs to the genus alphavirus, family togaviridae. veev infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the nf-κb cascade in the in vivo pathology. initial studies indicated that at early time points of veev infection, the nf-κb complex was activated in cells infected with the tc-83 strain of veev. one upstream kinase that contributes to the phosphorylation of p65 is the ikkβ compo ...201424586253
genome-wide rnai screen identifies broadly-acting host factors that inhibit arbovirus infection.vector-borne viruses are an important class of emerging and re-emerging pathogens; thus, an improved understanding of the cellular factors that modulate infection in their respective vertebrate and insect hosts may aid control efforts. in particular, cell-intrinsic antiviral pathways restrict vector-borne viruses including the type i interferon response in vertebrates and the rna interference (rnai) pathway in insects. however, it is likely that additional cell-intrinsic mechanisms exist to limi ...201424550726
pick1 links ampa receptor stimulation to cdc42.rho-family gtpases control numerous cell biological processes via effects on actin dynamics, such as cell migration, cell adhesion, morphogenesis and vesicle traffic. in neurons, they are involved in dendritic spine morphogenesis and other aspects of neuronal morphology via regulation of the actin cytoskeleton. the rho-family member cdc42 regulates dendritic spine morphology via its effector n-wasp, which activates the actin-nucleating arp2/3 complex. excitatory synaptic transmission is known to ...201425475687
upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon beta producers that protect from lethal encephalitis.previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (vsv) type i interferon receptor (ifnar) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. to address whether locally active ifn-β was induced proximally, we studied spatiotemporal conditions of vsv-mediated ifn-β induction. to this end, we performed infection studies with ifn-β reporter mice. one day after intravenous (i.v.) vsv infection, ...201425540366
deficiency in either 4e-bp1 or 4e-bp2 augments innate antiviral immune responses.genetic deletion of both 4e-bp1 and 4e-bp2 was found to protect cells against viral infections. here we demonstrate that the individual loss of either 4e-bp1 or 4e-bp2 in mouse embryonic fibroblasts (mefs) is sufficient to confer viral resistance. shrna-mediated silencing of 4e-bp1 or 4e-bp2 renders mefs resistant to viruses, and compared to wild type cells, mefs knockout for either 4e-bp1 or 4e-bp2 exhibit enhanced translation of irf-7 and consequently increased innate immune response to viruse ...201425531441
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
capacity of mosquitoes to transmit malaria depends on larval environment.adult traits of holometabolous insects such as reproduction and survival can be shaped by conditions experienced during larval development. these "carry-over" effects influence not only individual life history and fitness, but can also impact interactions between insect hosts and parasites. despite this, the implications of larval conditions for the transmission of human, wildlife and plant diseases that are vectored by insects remain poorly understood.201425496502
oxidative stress influences positive strand rna virus genome synthesis and capping.flaviviruses are 5' capped positive-stranded rna viruses that replicate their genomes within endoplasmic reticulum-derived vesicles. flaviviruses are well known to induce oxidative stress late in infection but it is unknown if oxidative stress plays a positive role in the viral rna replication cycle. we therefore examined how oxidation affects flavivirus rna replication. we found that antioxidant treatment reduced virus production, reduced the viral positive-to-negative strand rna ratio, and res ...201425514423
the nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis.all coronaviruses encode a macrodomain containing adp-ribose-1"-phosphatase (adrp) activity within the n terminus of nonstructural protein 3 (nsp3). previous work showed that mouse hepatitis virus strain a59 (mhv-a59) with a mutated catalytic site (n1348a) replicated similarly to wild-type virus but was unable to cause acute hepatitis in mice. to determine whether this attenuated phenotype is applicable to multiple disease models, we mutated the catalytic residue in the jhm strain of mhv (jhmv), ...201425428866
going viral and the fatal vulnerability of neurons from immunity, not from infection. 201425422437
detection of chikungunya virus antigen by a novel rapid immunochromatographic test.chikungunya fever is a mosquito-borne disease of key public health importance in tropical and subtropical countries. although severe joint pain is the most distinguishing feature of chikungunya fever, diagnosis remains difficult because the symptoms of chikungunya fever are shared by many pathogens, including dengue fever. the present study aimed to develop a new immunochromatographic diagnosis test for the detection of chikungunya virus antigen in serum. mice were immunized with isolates from p ...201425411170
mosquito immunity against arboviruses.arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. the recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundament ...201425415198
emerging biomedical applications of nano-chitins and nano-chitosans obtained via advanced eco-friendly technologies from marine resources.the present review article is intended to direct attention to the technological advances made in the 2010-2014 quinquennium for the isolation and manufacture of nanofibrillar chitin and chitosan. otherwise called nanocrystals or whiskers, n-chitin and n-chitosan are obtained either by mechanical chitin disassembly and fibrillation optionally assisted by sonication, or by e-spinning of solutions of polysaccharides often accompanied by poly(ethylene oxide) or poly(caprolactone). the biomedical are ...201425415349
enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication.redox homeostasis is an important host factor determining the outcome of infectious disease. enterovirus 71 (ev71) infection has become an important endemic disease in southeast asia and china. we have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. the detailed mechanism for reactive oxygen species (ros) generation in infected cells remains elusive. in the current study, we demonstrate that mitochondria were a major ro ...201425401329
immune responses to non-tumor antigens in the central nervous system.the central nervous system (cns), once viewed as an immune-privileged site protected by the blood-brain barrier (bbb), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. during these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate bbb permeability and recruit additional circulating immune cells. her ...201425431758
the toll-dorsal pathway is required for resistance to viral oral infection in drosophila.pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. here we investigate the role of the toll pathway in resistance to oral viral infection in d. melanogaster. we show that several toll pathway components, including spätzle, toll, pelle and the nf-kb-like transcription factor dorsal, are required to resist oral ...201425473839
mosquitoes (diptera: culicidae) and their relevance as disease vectors in the city of vienna, austria.mosquitoes (diptera: culicidae) are important vectors for a wide range of pathogenic organisms. as large parts of the human population in developed countries live in cities, the occurrence of vector-borne diseases in urban areas is of particular interest for epidemiologists and public health authorities. in this study, we investigated the mosquito occurrence in the city of vienna, austria, in order to estimate the risk of transmission of mosquito-borne diseases. mosquitoes were captured using di ...201425468380
drosophila c virus systemic infection leads to intestinal obstruction.drosophila c virus (dcv) is a positive-sense rna virus belonging to the dicistroviridae family. this natural pathogen of the model organism drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both rna interference and inducible responses. although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. here, we characterize the ...201425253354
viruses and rna interference: issues and controversies.the question of whether any mammalian cells are able to mount an effective rna interference-mediated antiviral innate immune response has remained highly controversial. in this gem, i review recent data addressing this important issue and propose a testable hypothesis that can explain many of the apparently contradictory results published in this area of research.201425210170
interleukin 10 modulation of pathogenic th17 cells during fatal alphavirus encephalomyelitis.mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. we show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine il-10, and in the absence of il-10, paralytic disease occurred earlier and mice died faster. to determine the reason for accelerated disease in ...201425362048
regulation of autophagic activation by rta of epstein-barr virus via the extracellular signal-regulated kinase pathway.autophagy is an intracellular degradation pathway that provides a host defense mechanism against intracellular pathogens. however, many viruses exploit this mechanism to promote their replication. this study shows that lytic induction of epstein-barr virus (ebv) increases the membrane-bound form of lc3 (lc3-ii) and lc3-containing punctate structures in ebv-positive cells. transfecting 293t cells with a plasmid that expresses rta also induces autophagy, revealing that rta is responsible for autop ...201425122800
a chimeric virus-mouse model system for evaluating the function and inhibition of papain-like proteases of emerging coronaviruses.to combat emerging coronaviruses, developing safe and efficient platforms to evaluate viral protease activities and the efficacy of protease inhibitors is a high priority. here, we exploit a biosafety level 2 (bsl-2) chimeric sindbis virus system to evaluate protease activities and the efficacy of inhibitors directed against the papain-like protease (plpro) of severe acute respiratory syndrome coronavirus (sars-cov), a biosafety level 3 (bsl-3) pathogen. we engineered sindbis virus to coexpress ...201425100850
putative novel lineage of west nile virus in uranotaenia unguiculata mosquito, hungary.west nile virus (wnv) is an increasing public health concern in europe with numerous human cases. a total of 23,029 female mosquitoes were tested for a variety of mosquito-borne flaviviruses and orthobunyaviruses supposedly endemic in southern transdanubia, hungary, in the frames of a large-scale surveillance between 2011 and 2013. wnv nucleic acid was detected in a single pool containing uranotaenia unguiculata mosquitoes. sequence- and phylogenetic analyses for two different regions (ns5 and e ...201425674630
arboviral bottlenecks and challenges to maintaining diversity and fitness during mosquito transmission.the term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. the infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing the virus is processed, to the salivary glands, in order to transmit the virus to the next host. during this process the virus is subject to numerous bottlenecks, stochastic events that significantly reduce the ...201425341663
ribosomal readthrough at a short uga stop codon context triggers dual localization of metabolic enzymes in fungi and animals.translation of mrna into a polypeptide chain is a highly accurate process. many prokaryotic and eukaryotic viruses, however, use leaky termination of translation to optimize their coding capacity. although growing evidence indicates the occurrence of ribosomal readthrough also in higher organisms, a biological function for the resulting extended proteins has been elucidated only in very few cases. here, we report that in human cells programmed stop codon readthrough is used to generate peroxisom ...201425340584
autophagy restricts hiv-1 infection by selectively degrading tat in cd4+ t lymphocytes.autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. upon human immunodeficiency virus type 1 (hiv-1) infection, viral envelope (env) glycoproteins induce a ...201425339774
the ubiquitin c-terminal hydrolase l1 (uch-l1) c terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons.ubiquitin c-terminal hydrolase l1 (uch-l1) is a deubiquitinating enzyme that is highly expressed in neurons. a possible role for uch-l1 in neurodegeneration has been highlighted because of its presence in lewy bodies associated with parkinson disease and neurofibrillary tangles observed in alzheimer disease. uch-l1 exists in two forms in neurons, a soluble cytoplasmic form (uch-l1(c)) and a membrane-associated form (uch-l1(m)). alzheimer brains show reduced levels of soluble uch-l1(c) correlatin ...201425326379
engineering recombinant orsay virus directly in the metazoan host caenorhabditis elegans.the recent identification of orsay virus, the first virus that is capable of naturally infecting caenorhabditis elegans, provides a unique opportunity to explore host-virus interaction studies in this invaluable model organism. a key feature of this system is the robust genetic tractability of the host, c. elegans, which would ideally be complemented by the ability to genetically manipulate orsay virus in parallel. to this end, we developed a plasmid-based reverse genetics system for orsay virus ...201425078701
phosphatidylserine receptors: enhancers of enveloped virus entry and infection.a variety of both rna and dna viruses envelop their capsids in a lipid bilayer. one of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (ptdser). surface exposure of ptdser disguises viruses as apoptotic bodies; tricking cells into engulfing virions. this mechanism is termed apoptotic mimicry. several ptdser receptors have been identified to enhance virus entry and we have termed this group of proteins ptdser-mediated virus entry enhancing receptors or ...201425277499
potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying rna vaccine expressing hiv type 1 envelope with a cationic nanoemulsion.self-amplifying messenger rna (mrna) of positive-strand rna viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. the sam vaccine platform is based on a synthetic, self-amplifying mrna delivered by a nonviral delivery system. the safety and immunogenicity of an hiv sam vaccine encoding a clade c envelope glycoprotein formulated with a cationic nanoemulsion (cne) delivery system ...201425234719
sponging of cellular proteins by viral rnas.viral rnas accumulate to high levels during infection and interact with a variety of cellular factors including mirnas and rna-binding proteins. although many of these interactions exist to directly modulate replication, translation and decay of viral transcripts, evidence is emerging that abundant viral rnas may in certain cases serve as a sponge to sequester host non-coding rnas and proteins. by effectively reducing the ability of cellular rna binding proteins to regulate host cell gene expres ...201425233339
virus-mediated compartmentalization of the host translational machinery.viruses require the host translational apparatus to synthesize viral proteins. host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (vf). vf are the sites of reovirus replication and assembly but were thought not to contain ribosomes. it was assumed viral ...201425227463
venezuelan equine encephalitis virus variants lacking transcription inhibitory functions demonstrate highly attenuated phenotype.alphaviruses represent a significant public health threat worldwide. they are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. to date, no efficient and safe vaccines have been developed against any alphavirus infection. however, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. these data have provided the possibility for the developmen ...201425320296
differentiation of neurons restricts arbovirus replication and increases expression of the alpha isoform of irf-7.susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. to identify factors associated with maturation-dependent restriction of virus replication, we studied ap-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses sindbis virus and venezuelan equine encephalitis virus, as well as la ...201425320290
variations in ph sensitivity, acid stability, and fusogenicity of three influenza virus h3 subtypes.influenza a virus strains adapt to achieve successful entry into host species. entry is mediated by the viral membrane protein hemagglutinin (ha), which triggers membrane fusion and genome release under acidic conditions in the endosome. in addition to changes in the receptor binding domain, the acid stability of ha has been linked to the successful transmission of virus between avian and human hosts. however, to fully understand the connection between changes in ha and host tropism, additional ...201425320308
novel mode of isg15-mediated protection against influenza a virus and sendai virus in mice.isg15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type i interferon stimulation. hundreds of host proteins and a number of viral proteins have been shown to be isgylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. isg15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza b virus and vaccinia virus, isg15 conjugation has been shown to res ...201425320315
alginate hydrogel protects encapsulated hepatic huh-7 cells against hepatitis c virus and other viral infections.cell microencapsulation in alginate hydrogel has shown interesting applications in regenerative medicine and the biomedical field through implantation of encapsulated tissue or for bioartificial organ development. although alginate solution is known to have low antiviral activity, the same property regarding alginate gel has not yet been studied. the aim of this work is to investigate the potential protective effect of alginate encapsulation against hepatitis c virus (hcv) infection for a hepati ...201425310111
age-dependent myeloid dendritic cell responses mediate resistance to la crosse virus-induced neurological disease.la crosse virus (lacv) is the major cause of pediatric viral encephalitis in the united states; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. our current studies in a mouse model of lacv infection indicated that differences in myeloid dendritic cell (mdc) responses between weanling and adult mice accounted for susceptibility to lacv-induced neurological disease. we found that type i interferon (ifn) responses were signific ...201425008929
short self-interacting n-terminal region of rubella virus capsid protein is essential for cooperative actions of capsid and nonstructural p150 proteins.nucleocapsid formation is a primary function of the rubella virus capsid protein, which also promotes viral rna synthesis via an unknown mechanism. the present study demonstrates that in infected cells, the capsid protein is associated with the nonstructural p150 protein via the short self-interacting n-terminal region of the capsid protein. mutational analyses indicated that hydrophobic amino acids in this n-terminal region are essential for its n-terminal self-interaction, which is critical fo ...201425056903
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