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sumoylation and phosphorylation of gluk2 regulate kainate receptor trafficking and synaptic plasticity.phosphorylation or sumoylation of the kainate receptor (kar) subunit gluk2 have both individually been shown to regulate kar surface expression. however, it is unknown whether phosphorylation and sumoylation of gluk2 are important for activity-dependent kar synaptic plasticity. we found that protein kinase c–mediated phosphorylation of gluk2 at serine 868 promotes gluk2 sumoylation at lysine 886 and that both of these events are necessary for the internalization of gluk2-containing kars that occ ...022522402
insights into the roles of local translation from the axonal transcriptome.much of our knowledge on the roles of intra-axonal translation derives from the characterization of a small number of individual mrnas that were found to be localized in axons. however, two recent studies, using large-scale approaches to provide a more comprehensive characterization of the axonal transcriptome, have led to the discovery of thousands of axonal mrnas. the apparent abundance of mrnas in axons raises the possibility that local translation has many more functions than previously thou ...022773949
beneficial effects of fucoidan in patients with chronic hepatitis c virus infection.to evaluate the effects of fucoidan, a complex sulfated polysaccharide extract from marine seaweed, on hepatitis c virus (hcv) rna load both in vitro and in vivo.022611316
phosphorylation of rpt6 regulates synaptic strength in hippocampal neurons.it has become increasingly evident that protein degradation via the ubiquitin proteasome system plays a fundamental role in the development, maintenance and remodeling of synaptic connections in the cns. we and others have recently described the activity-dependent regulation of proteasome activity and recruitment of proteasomes into spine compartments involving the phosphorylation of the 19s atpase subunit, rpt6, by the plasticity kinase ca(2+)/calmodulin-dependent protein kinase ii α (camkiiα) ...022496558
cell death pathways and autophagy in the central nervous system and its involvement in neurodegeneration, immunity and central nervous system infection: to die or not to die--that is the question.death rules our lives. in this short paper, we summarize new insights into molecular mechanisms of neurodegeneration. here we review the most important processes of cell death: apoptosis and oncosis. we focus on autophagy, which is pivotal for neuronal homeostasis, in the context of neurodegeneration, infection and immunity. its dysfunction has been linked to several neurodegenerative diseases such as parkinson's, huntington's and alzheimer's diseases. our understanding is still incomplete, but ...022385237
palmitoylation by dhhc5/8 targets grip1 to dendritic endosomes to regulate ampa-r trafficking.palmitoylation, a key regulatory mechanism controlling protein targeting, is catalyzed by dhhc-family palmitoyl acyltransferases (pats). impaired pat activity is linked to neurodevelopmental and neuropsychiatric disorders, suggesting critical roles for palmitoylation in neuronal function. however, few substrates for specific pats are known, and functional consequences of palmitoylation events are frequently uncharacterized. here, we identify the closely related pats dhhc5 and dhhc8 as specific r ...022325201
risk for emergence of dengue and chikungunya virus in israel. 022305194
s-scam/magi-2 is an essential synaptic scaffolding molecule for the glua2-containing maintenance pool of ampa receptors.synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of ampa receptors (ampars) into and out of synapses. one of the remaining key unanswered aspects of ampar trafficking is the mechanism by which synaptic strength is preserved despite protein turnover. in particular, the identity of ampar scaffolding molecule(s) involved in the maintenance of glua2-containing ampars is completely unknown. here we report that the synaptic scaffolding molecule (s-scam; ...022593065
viral polymerases.viral polymerases play a central role in viral genome replication and transcription. based on the genome type and the specific needs of particular virus, rna-dependent rna polymerase, rna-dependent dna polymerase, dna-dependent rna polymerase, and dna-dependent rna polymerases are found in various viruses. viral polymerases are generally active as a single protein capable of carrying out multiple functions related to viral genome synthesis. specifically, viral polymerases use variety of mechanis ...022297518
principles of virus structural organization.viruses, the molecular nanomachines infecting hosts ranging from prokaryotes to eukaryotes, come in different sizes, shapes, and symmetries. questions such as what principles govern their structural organization, what factors guide their assembly, how these viruses integrate multifarious functions into one unique structure have enamored researchers for years. in the last five decades, following caspar and klug's elegant conceptualization of how viruses are constructed, high-resolution structural ...022297509
oncolytic virus therapy for glioblastoma multiforme: concepts and candidates.twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. with the field constantly expanding-more than 20 viruses have been recognized as potential oncolytic viruses-new virus candidates continue to emerge even as established viruses reach clinical trials. they all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. m ...022290260
a virological view of innate immune recognition.the innate immune system uses multiple strategies to detect viral infections. because all viruses rely on host cells for their synthesis and propagation, the molecular features used to detect viral infections must be unique to viruses and absent from host cells. research in the past decade has advanced our understanding of various cell-intrinsic and cell-extrinsic modes of virus recognition. this review examines the innate recognition from the point of view of virus invasion and replication stra ...022994491
clonal propagation of phyllanthus amarus: a hepatoprotector.the micropropagation protocol for phyllanthus amarus, an important medicinal herb used widely for the treatment of hepatitis in ethnomedicinal systems, was standardized with shoot tip and single node explants.022438668
recent insights into the involvement of progranulin in frontotemporal dementia.progranulin is a widely expressed protein that is involved in the regulation of multiple biological processes, including embryogenesis, host defense, and wound repair. in the central nervous system, progranulin is constitutively expressed at modest levels in neurons and microglia, but shows dramatic microglial immunoreactivity in degenerative diseases that exhibit prominent neuroinflammation. in addition to the role that pgrn plays in the periphery, its expression is of critical importance in br ...022654721
virus-derived sirnas and pirnas in immunity and pathogenesis.cellular organisms have evolved related pathways for the biogenesis and function of small interfering rnas (sirnas), micrornas and piwi-interacting rnas (pirnas). these distinct classes of small rnas guide specific gene silencing at both transcriptional and posttranscriptional levels by serving as specificity determinants. small rnas of virus and host origins have been found to modulate virus–host interactions by rna interference (rnai), leading to antiviral immunity or viral pathogenesis. deep ...022180767
modulation of nucleotide sensitivity of atp-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase.atp-sensitive potassium channels (k(atp) channels) regulate cell excitability in response to metabolic changes. k(atp) channels are formed as a complex of a sulfonylurea receptor (surx), a member of the atp-binding cassette protein family, and an inward rectifier k(+) channel subunit (kir6.x). membrane phospholipids, in particular phosphatidylinositol (pi) 4,5-bisphosphate (pip(2)), activate k(atp) channels and antagonize atp inhibition of k(atp) channels when applied to inside-out membrane patc ...010639183
arf6 is required for growth factor- and rac-mediated membrane ruffling in macrophages at a stage distal to rac membrane targeting.activation of rac1, a member of the rho family of gtpases, is associated with multiple cellular responses, including membrane ruffling and focal complex formation. the mechanisms by which rac1 is coupled to these functional responses are not well understood. it was recently shown that arf6, a gtpase implicated in cytoskeletal alterations and a membrane recycling pathway, is required for rac1-dependent phagocytosis in macrophages (q. zhang et al., j. biol. chem. 273:19977-19981, 1998). to determi ...010567541
a visual screen of a gfp-fusion library identifies a new type of nuclear envelope membrane protein.the nuclear envelope (ne) is a distinct subdomain of the er, but few membrane components have been described that are specific to it. we performed a visual screen in tissue culture cells to identify proteins targeted to the ne. this approach does not require assumptions about the nature of the association with the ne or the physical separation of ne and er. we confirmed that screening a library of fusions to the green fluorescent protein can be used to identify proteins targeted to various subco ...010402458
mechanisms of arthropod transmission of plant and animal viruses.a majority of the plant-infecting viruses and many of the animal-infecting viruses are dependent upon arthropod vectors for transmission between hosts and/or as alternative hosts. the viruses have evolved specific associations with their vectors, and we are beginning to understand the underlying mechanisms that regulate the virus transmission process. a majority of plant viruses are carried on the cuticle lining of a vector's mouthparts or foregut. this initially appeared to be simple mechanical ...010066833
does nitric oxide play a critical role in viral infections? 09573217
translational readthrough in the hdc mrna generates a novel branching inhibitor in the drosophila trachea.a central question in the development of many branched tubular organs, including the drosophila trachea, concerns the mechanisms and molecules that control the number and pattern of new branches arising from preexisting vessels. we report on a branching inhibitor, fusion-6 (fus-6) produced by specialized tracheal cells to prevent neighboring cells from branching. in fus-6 mutants, cells that are normally quiescent acquire the branching fate and form an increased number of sprouts emanating from ...09531534
arf6 targets recycling vesicles to the plasma membrane: insights from an ultrastructural investigation.we have shown previously that the adp-ribosylation factor (arf)-6 gtpase localizes to the plasma membrane and intracellular endosomal compartments. expression of arf6 mutants perturbs endosomal trafficking and the morphology of the peripheral membrane system. however, another study on the distribution of arf6 in subcellular fractions of chinese hamster ovary (cho) cells suggested that arf6 did not localize to endosomes labeled after 10 min of horseradish peroxidase (hrp) uptake, but instead was ...09456320
common origins and host-dependent diversity of plant and animal viromes.many viruses infecting animals and plants share common cores of homologous genes involved in the key processes of viral replication. in contrast, genes that mediate virus–host interactions including in many cases capsid protein (cp) genes are markedly different. there are three distinct scenarios for the origin of related viruses of plants and animals: first, evolution from a common ancestral virus predating the divergence of plants and animals; second, horizontal transfer of viruses, for exampl ...022408703
positive reinforcement for viruses.virus-cell membrane fusion requires a critical transition from positive to negative membrane curvature. st. vincent et al. (2010), in pnas, designed a class of antivirals that targets this transition. these rigid amphipathic fusion inhibitors are active against an array of enveloped viruses.021035726
death and survival of heterozygous lurcher purkinje cells in vitro.the differentiation and survival of heterozygous lurcher (+/lc) purkinje cells in vitro was examined as a model system for studying how chronic ionic stress affects neuronal differentiation and survival. the lurcher mutation in the delta2 glutamate receptor (glurdelta2) converts an orphan receptor into a membrane channel that constitutively passes an inward cation current. in the glurdelta2(+/lc) mutant, purkinje cell dendritic differentiation is disrupted and the cells degenerate following the ...019294643
the role of rnai and micrornas in animal virus replication and antiviral immunity.the closely related microrna (mirna) and rnai pathways have emerged as important regulators of virus-host cell interactions. although both pathways are relatively well conserved all the way from plants to invertebrates to mammals, there are important differences between these systems. a more complete understanding of these differences will be required to fully appreciate the relationship between these diverse host organisms and the various viruses that infect them. insights derived from this res ...019451215
autophagy genes in immunity.in its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane-bound autophagosome and delivered to the lysosome for degradation. this pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type i interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. ...019381141
(in)validating experimentally derived knowledge about influenza a defective interfering particles.a defective interfering particle (dip) in the context of influenza a virus is a virion with a significantly shortened rna segment substituting one of eight full-length parent rna segments, such that it is preferentially amplified. hence, a cell co-infected with dips will produce mainly dips, suppressing infectious virus yields and affecting infection kinetics. unfortunately, the quantification of dips contained in a sample is difficult because they are indistinguishable from standard virus (stv) ...027881801
genetic dissection of flaviviridae host factors through genome-scale crispr screens.the flaviviridae are a family of viruses that cause severe human diseases. for example, dengue virus (denv) is a rapidly emerging pathogen causing an estimated 100 million symptomatic infections annually worldwide. no approved antivirals are available to date and clinical trials with a tetravalent dengue vaccine showed disappointingly low protection rates. hepatitis c virus (hcv) also remains a major medical problem, with 160 million chronically infected patients worldwide and only expensive tre ...027383987
inflammatory and oxidative stress in rotavirus infection.rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. the entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. it appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotav ...027175349
a conserved virus-induced cytoplasmic tramp-like complex recruits the exosome to target viral rna for degradation.rna degradation is tightly regulated to selectively target aberrant rnas, including viral rna, but this regulation is incompletely understood. through rnai screening in drosophila cells, we identified the 3'-to-5' rna exosome and two components of the exosome cofactor tramp (trf4/5-air1/2-mtr4 polyadenylation) complex, dmtr4 and dzcchc7, as antiviral against a panel of rna viruses. we extended our studies to human orthologs and found that the exosome as well as tramp components hmtr4 and hzcchc7 ...027474443
larval food quantity affects the capacity of adult mosquitoes to transmit human malaria.adult traits of holometabolous insects are shaped by conditions experienced during larval development, which might impact interactions between adult insect hosts and parasites. however, the ecology of larval insects that vector disease remains poorly understood. here, we used anopheles stephensi mosquitoes and the human malaria parasite plasmodium falciparum, to investigate whether larval conditions affect the capacity of adult mosquitoes to transmit malaria. we reared larvae in two groups; one ...027412284
the proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugates.differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. however, the full nature of the local events governing presynaptic assembly remains unknown. herein, we investigated the involvement of the ubiquitin-proteasome system (ups), the major degradative pathway, in the local modulation of presynaptic differentiation. we found that prote ...027022091
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
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
autophagy and its role in mhc-mediated antigen presentation.intracellular degradation by autophagy plays a role in the maintenance of cellular homeostasis under normal conditions and during periods of cellular stress. autophagy has also been implicated in several other cellular processes including immune recognition and responsiveness. more specifically, autophagy has been identified as a route by which cytoplasmic and nuclear ag are delivered to mhc class ii molecules for presentation to cd4(+) t cells. autophagy has also recently been implicated in mhc ...019265109
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
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
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
bagaza virus inhibits japanese encephalitis & west nile virus replication in culex tritaeniorhynchus & cx. quinquefasciatus mosquitoes.studies have shown that certain flaviviruses influence susceptibility of mosquitoes by inhibiting/enhancing replication of important flaviviruses. hence, a study was designed to determine whether bagaza virus (bagv), a flavivirus isolated from culex tritaeniorhynchus mosquitoes in india, alters susceptibility of cx. tritaeniorhynchus and cx. quinquefasciatus mosquitoes to japanese encephalitis (jev) and west nile viruses (wnv).026905241
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
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
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
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
antiviral defense mechanisms in honey bees.honey bees are significant pollinators of agricultural crops and other important plant species. high annual losses of honey bee colonies in north america and in some parts of europe have profound ecological and economic implications. colony losses have been attributed to multiple factors including rna viruses, thus understanding bee antiviral defense mechanisms may result in the development of strategies that mitigate colony losses. honey bee antiviral defense mechanisms include rna-interference ...026273564
the new vaccines: building viruses that elicit antitumor immunity.whereas cancer cells are poor immunogens, some viruses are capable of eliciting powerful and lifelong immunity. recombinant viruses and plasmid dna encoding tumor-associated antigens can elicit powerful and specific immune responses that can be enhanced by the use of cytokines and costimulatory molecules. these immune responses have destroyed growing tumor cells in experimental animal models. for the first time, immunotherapeutic strategies that employ recombinant viruses are being tested in cli ...08902391
targeting transmission pathways for emerging zoonotic disease surveillance and control.we used literature searches and a database of all reported emerging infectious diseases (eids) to analyze the most important transmission pathways (e.g., vector-borne, aerosol droplet transmitted) for emerging zoonoses. our results suggest that at the broad scale, the likelihood of transmission occurring through any one pathway is approximately equal. however, the major transmission pathways for zoonoses differ widely according to the specific underlying drivers of eid events (e.g., land-use cha ...026186515
rate of novel host invasion affects adaptability of evolving rna virus lineages.although differing rates of environmental turnover should be consequential for the dynamics of adaptive change, this idea has been rarely examined outside of theory. in particular, the importance of rna viruses in disease emergence warrants experiments testing how differing rates of novel host invasion may impact the ability of viruses to adaptively shift onto a novel host. to test whether the rate of environmental turnover influences adaptation, we experimentally evolved 144 sindbis virus linea ...026246544
neurons versus herpes simplex virus: the innate immune interactions that contribute to a host-pathogen standoff.herpes simplex virus (hsv) is a prevalent neurotropic virus, which establishes lifelong latent infections in the neurons of sensory ganglia. despite our long-standing knowledge that hsv predominately infects sensory neurons during its life cycle, little is known about the neuronal antiviral response to hsv infection. recent studies show that while sensory neurons have impaired intrinsic immunity to hsv infection, paracrine ifn signaling can potentiate a potent antiviral response. additionally, a ...026213562
sars hcov papain-like protease is a unique lys48 linkage-specific di-distributive deubiquitinating enzyme.ubiquitin (ub) and the ub-like (ubl) modifier interferon-stimulated gene 15 (isg15) participate in the host defence of viral infections. viruses, including the severe acute respiratory syndrome human coronavirus (sars hcov), have co-opted ub-isg15 conjugation pathways for their own advantage or have evolved effector proteins to counter pro-inflammatory properties of ub-isg15-conjugated host proteins. in the present study, we compare substrate specificities of the papain-like protease (plpro) fro ...025764917
modification of becn1 by isg15 plays a crucial role in autophagy regulation by type i ifn/interferon.isg15 (isg15 ubiquitin-like modifier), a ubiquitin-like protein, is one of the major type i ifn (interferon) effector systems. isg15 can be conjugated to target proteins (isgylation) via the stepwise action of e1, e2, and e3 enzymes. conjugated isg15 can be removed (deisgylated) from target proteins by usp18 (ubiquitin-specific peptidase 18). here we investigated the role of deisgylation by usp18 in regulating autophagy and egfr degradation in cells treated with type i ifns. we show that type i ...025906440
culex torrentium mosquito role as major enzootic vector defined by rate of sindbis virus infection, sweden, 2009.we isolated sindbis virus (sinv) from the enzootic mosquito vectors culex torrentium, cx. pipiens, and culiseta morsitans collected in an area of sweden where sinv disease is endemic. the infection rate in cx. torrentium mosquitoes was exceptionally high (36 infections/1,000 mosquitoes), defining cx. torrentium as the main enzootic vector of sinv in scandinavia.025898013
viral noncoding rnas: more surprises.eukaryotic cells produce several classes of long and small noncoding rna (ncrna). many dna and rna viruses synthesize their own ncrnas. like their host counterparts, viral ncrnas associate with proteins that are essential for their stability, function, or both. diverse biological roles--including the regulation of viral replication, viral persistence, host immune evasion, and cellular transformation--have been ascribed to viral ncrnas. in this review, we focus on the multitude of functions playe ...025792595
recent advances and the future of stem cell therapies in amyotrophic lateral sclerosis.amyotrophic lateral sclerosis is a progressive neurodegenerative disease of the motor neurons without a known cure. based on the possibility of cellular neuroprotection and early preclinical results, stem cells have gained widespread enthusiasm as a potential treatment strategy. preclinical models demonstrate a protective role of engrafted stem cells and provided the basis for human trials carried out using various types of stem cells, as well as a range of cell delivery methods. to date, no tri ...025776222
new tricks for old dogs: countering antibiotic resistance in tuberculosis with host-directed therapeutics.despite the availability of mycobacterium tuberculosis (mtb) drugs for over 50 years, tuberculosis (tb) remains at pandemic levels. new drugs are urgently needed for resistant strains, shortening duration of treatment, and targeting different stages of the disease, especially for treatment during human immunodeficiency virus co-infection. one solution to the conundrum that antibiotics kill the bacillus yet select for resistance is to target the host rather than the pathogen. here, we discuss rec ...025703571
autophagy plays an important role in protecting pacific oysters from oshv-1 and vibrio aestuarianus infections.recent mass mortality outbreaks around the world in pacific oysters, crassostrea gigas, have seriously affected the aquaculture economy. although the causes for these mortality outbreaks appear complex, infectious agents are involved. two pathogens are associated with mass mortality outbreaks, the virus ostreid herpesvirus 1 (oshv-1) and the bacterium vibrio aestuarianus. here we describe the interactions between these 2 pathogens and autophagy, a conserved intracellular pathway playing a key ro ...025714877
binding of the pathogen receptor hsp90aa1 to avibirnavirus vp2 induces autophagy by inactivating the akt-mtor pathway.autophagy is an essential component of host innate and adaptive immunity. viruses have developed diverse strategies for evading or utilizing autophagy for survival. the response of the autophagy pathways to virus invasion is poorly documented. here, we report on the induction of autophagy initiated by the pathogen receptor hsp90aa1 (heat shock protein 90 kda α [cytosolic], class a member 1) via the akt-mtor (mechanistic target of rapamycin)-dependent pathway. transmission electron microscopy and ...025714412
virological and preclinical characterization of a dendritic cell targeting, integration-deficient lentiviral vector for cancer immunotherapy.dendritic cells (dcs) are essential antigen-presenting cells for the initiation of cytotoxic t-cell responses and therefore attractive targets for cancer immunotherapy. we have developed an integration-deficient lentiviral vector termed id-vp02 that is designed to deliver antigen-encoding nucleic acids selectively to human dcs in vivo. id-vp02 utilizes a genetically and glycobiologically engineered sindbis virus glycoprotein to target human dcs through the c-type lectin dc-sign (cd209) and also ...025658613
adp-ribosyltransferases and poly adp-ribosylation.protein adp-ribosylation is an important posttranslational modification that plays versatile roles in multiple biological processes. adp-ribosylation is catalyzed by a group of enzymes known as adp-ribosyltransferases (arts). using nicotinamide adenine dinucleotide (nad(+)) as the donor, arts covalently link single or multiple adp-ribose moieties from nad(+) to the substrates, forming mono adp-ribosylation or poly adp-ribosylation (parylation). novel functions of arts and adpribosylation have be ...025938242
parkin mutations reduce the complexity of neuronal processes in ipsc-derived human neurons.parkinson's disease (pd) is characterized by the degeneration of nigral dopaminergic (da) neurons and non-da neurons in many parts of the brain. mutations of parkin, an e3 ubiquitin ligase that strongly binds to microtubules, are the most frequent cause of recessively inherited pd. the lack of robust pd phenotype in parkin knockout mice suggests a unique vulnerability of human neurons to parkin mutations. here, we show that the complexity of neuronal processes as measured by total neurite length ...025332110
autophagy and checkpoints for intracellular pathogen defense.autophagy plays a crucial role in intracellular defense against various pathogens. xenophagy is a form of selective autophagy that targets intracellular pathogens for degradation. in addition, several related, yet distinct, intracellular defense responses depend on autophagy-related genes. this review gives an overview of these processes, pathogen strategies to subvert them, and their crosstalk with various cell death programs.025394238
ddx17: structured rna recognition drives diverse outputs. 025493410
synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of nedd4-1 and usp8.the trafficking of ampa receptors (ampars) to and from synapses is crucial for synaptic plasticity. previous work has demonstrated that ampars undergo activity-dependent ubiquitination by the e3 ubiquitin ligase nedd4-1, which promotes their internalization and degradation in lysosomes. here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of ampars. we report that nedd4-1 is rapidly redistributed to dendritic spines in response to ampar activation and not in r ...025505317
response to voinnet et al. 025437535
targeting axonal protein synthesis in neuroregeneration and degeneration.localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. during the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. in contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mrnas are recruited into axons ...025371166
cytoplasmic rna granules and viral infection.rna granules are dynamic cellular structures essential for proper gene expression and homeostasis. the two principal types of cytoplasmic rna granules are stress granules, which contain stalled translation initiation complexes, and processing bodies (p bodies), which concentrate factors involved in mrna degradation. rna granules are associated with gene silencing of transcripts; thus, viruses repress rna granule functions to favor replication. this article discusses the breadth of viral interact ...026958719
mining the human autoantibody repertoire: isolation of potent il17a-neutralizing monoclonal antibodies from a patient with thymoma.anti-cytokine autoantibodies have been widely reported to be present in human plasma, both in healthy subjects and in patients with underlying autoimmune conditions, such as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (apeced) or thymic epithelial neoplasms. while often asymptomatic, they can cause or facilitate a wide range of diseases including opportunistic infections. the potential therapeutic value of specific neutralizing anti-cytokine autoantibodies has not been thoroug ...025484038
ifitm-family proteins: the cell's first line of antiviral defense.animal cells use a wide variety of mechanisms to slow or prevent replication of viruses. these mechanisms are usually mediated by antiviral proteins whose expression and activities can be constitutive but are frequently amplified by interferon induction. among these interferon-stimulated proteins, members of the ifitm (interferon-induced transmembrane) family are unique because they prevent infection before a virus can traverse the lipid bilayer of the cell. at least three human ifitm proteins-i ...025599080
vaccines against respiratory viral pathogens for use in neonates: opportunities and challenges.the first six months of life reflect a time of high susceptibility to severe disease following respiratory virus infection. although this could be improved significantly by immunization, current vaccines are not approved for use in these very young individuals. this is the result of the combined effects of poor immune responsiveness and safety concerns regarding the use of live attenuated vaccines or potent adjuvants in this population. vaccines to effectively combat respiratory viral infection ...025411431
differential release of β-amyloid from dendrite- versus axon-targeted app.the β-amyloid precursor protein (app) plays a central role in the pathogenesis of alzheimer's disease. app is processed in neurons, but little is known about the relative contributions of presynaptic or postsynaptic compartments to the release of aβ peptides. to address this issue, we transduced primary neurons from sprague-dawley rats or app(-/-) mice (b6.129s7-app(tm1dbo)/j) with lentiviral constructs expressing app chimeras harboring targeting motifs from low-density lipoprotein receptor or n ...025209273
stem-loop recognition by ddx17 facilitates mirna processing and antiviral defense.dead-box helicases play essential roles in rna metabolism across species, but emerging data suggest that they have additional functions in immunity. through rnai screening, we identify an evolutionarily conserved and interferon-independent role for the dead-box helicase ddx17 in restricting rift valley fever virus (rvfv), a mosquito-transmitted virus in the bunyavirus family that causes severe morbidity and mortality in humans and livestock. loss of drosophila ddx17 (rm62) in cells and flies enh ...025126784
transcriptional pausing controls a rapid antiviral innate immune response in drosophila.innate immune responses are characterized by precise gene expression whereby gene subsets are temporally induced to limit infection, although the mechanisms involved are incompletely understood. we show that antiviral immunity in drosophila requires the transcriptional pausing pathway, including negative elongation factor (nelf) that pauses rna polymerase ii (pol ii) and positive elongation factor b (p-tefb), which releases paused pol ii to produce full-length transcripts. we identify a set of g ...023084920
dynamic regulation of synaptic maturation state by voltage-gated a-type k+ channels in ca1 hippocampal pyramidal neurons.neuronal activity is critical for the formation and modification of neural circuits during brain development. in hippocampal ca1 pyramidal dendrites, a-type voltage-gated k(+) currents, formed primarily by kv4.2 subunits, control excitability. here we used kv4.2 knock-out (kv4.2-ko) mice along with acute in vivo expression of kv4.2 or its dominant-negative pore mutant to examine the role of kv4.2 in the development of ca1 synapses. we found that kv4.2 expression induces synaptic maturation in ju ...023055512
gene therapy for gastric cancer: a review.gastric cancer is common in china, and its early diagnosis and treatment are difficult. in recent years great progress has been achieved in gene therapy, and a wide array of gene therapy systems for gastric cancer has been investigated. the present article deals with the general principles of gene therapy and then focuses on how these principles may be applied to gastric cancer.014606062
real-time imaging of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (ampa receptor) movements in neurons.the mechanisms that regulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (ampar) synthesis, transport, targeting and surface expression are of fundamental importance for fast excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system. it has become apparent that these control processes involve complex sets of protein-protein interactions and many of the proteins responsible have been identified. we have been working to visualize ampar movem ...012887326
nucleic acid-based immune system: the antiviral potential of mammalian rna silencing. 012805414
dna vaccines and apoptosis: to kill or not to kill? 012840054
developing baculovirus-insect cell expression systems for humanized recombinant glycoprotein production.the baculovirus-insect cell expression system is widely used to produce recombinant glycoproteins for many different biomedical applications. however, due to the fundamental nature of insect glycoprotein processing pathways, this system is typically unable to produce recombinant mammalian glycoproteins with authentic oligosaccharide side chains. this minireview summarizes our current understanding of insect protein glycosylation pathways and our recent efforts to address this problem. these effo ...012788624
orientation refinement of virus structures with unknown symmetry.structural biology, in particular the structure determination of viruses and other large macromolecular complexes leads to data- and compute-intensive problems that require resources well beyond those available on a single system. thus, there is an imperative need to develop parallel algorithms and programs for clusters and computational grids. we present one of the most challenging computational problems posed by the three-dimensional structure determination of viruses, the orientation refineme ...025580470
the 64-kilodalton capsid protein homolog of beet yellows virus is required for assembly of virion tails.the filamentous virion of the closterovirus beet yellows virus (byv) consists of a long body formed by the major capsid protein (cp) and a short tail composed of the minor capsid protein (cpm) and the virus-encoded hsp70 homolog. by using nano-liquid chromatography-tandem mass spectrometry and biochemical analyses, we show here that the byv 64-kda protein (p64) is the fourth integral component of byv virions. the n-terminal domain of p64 is exposed at the virion surface and is accessible to anti ...012551975
synapto-depressive effects of amyloid beta require pick1.amyloid beta (aβ), a key component in the pathophysiology of alzheimer's disease, is thought to target excitatory synapses early in the disease. however, the mechanism by which aβ weakens synapses is not well understood. here we showed that the pdz domain protein, protein interacting with c kinase 1 (pick1), was required for aβ to weaken synapses. in mice lacking pick1, elevations of aβ failed to depress synaptic transmission in cultured brain slices. in dissociated cultured neurons, aβ failed t ...024713001
the role of hts in drug discovery at the university of michigan.high throughput screening (hts) is an integral part of a highly collaborative approach to drug discovery at the university of michigan. the hts lab is one of four core centers that provide services to identify, produce, screen and follow-up on biomedical targets for faculty. key features of this system are: protein cloning and purification, protein crystallography, small molecule and sirna hts, medicinal chemistry and pharmacokinetics. therapeutic areas that have been targeted include anti-bacte ...024409957
potential roles of microglial cell progranulin in hiv-associated cns pathologies and neurocognitive impairment.progranulin (pgrn) is a highly unusual molecule with both neuronal and microglial expression with two seemingly unrelated functions, i.e., as a neuronal growth factor and a modulator of neuroinflammation. haploinsufficiency due to loss of function mutations lead to a fatal presenile dementing illness (frontotemporal lobar degeneration), indicating that adequate expression of pgrn is essential for successful aging. pgrn might be a particularly relevant factor in the pathogenesis of hivencephaliti ...023959579
hepatitis c virus, mitochondria and auto/mitophagy: exploiting a host defense mechanism.hepatitis c virus (hcv) is the major reason for liver transplantation and the main cause of liver-related morbidity and mortality in a great number of countries. as for the other viruses, this pathogen interferes in more than one process and in more than one way with host cell biology. a mounting body of evidence points, in particular, toward the drastic alterations of mitochondrial physiology and functions that virus is able to induce, albeit the mechanisms have partly remained elusive. role of ...024627598
hsp90 chaperone inhibitor 17-aag attenuates aβ-induced synaptic toxicity and memory impairment.the excessive accumulation of soluble amyloid peptides (aβ) plays a crucial role in the pathogenesis of alzheimer's disease (ad), particularly in synaptic dysfunction. the role of the two major chaperone proteins, hsp70 and hsp90, in clearing misfolded protein aggregates has been established. despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. here, we report that hsp90 inhibition by 17-aag elicited not only a heat shock-like response but also u ...024523537
generation of infectious virus particles from inducible transgenic genomes.arboviruses like dengue virus, yellow fever virus, and west nile virus are enveloped particles spread by mosquitoes, infecting millions of humans per year, with neither effective vaccines, nor specific antiviral therapies [1,2]. previous studies of infection and virus replication utilize either purified virus particles or deficient genomes that do not complete the viral life cycle [1,2]. here we describe transgenic drosophila strains expressing trans-complementing genomes (referred to as 'replic ...024502780
pharmacological rescue of ras signaling, glua1-dependent synaptic plasticity, and learning deficits in a fragile x model.fragile x syndrome, caused by the loss of fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. using a tractable animal model, we investigated mechanisms of action of a few fda-approved psychoactive drugs that modestly benefit the cognitive performance in fragile x patients. here we report that compounds activating serotonin (5ht) subtype 2b receptors (5ht2b-rs) or dopamine (da) subtype 1-like receptors (d1-rs) and/or those inhibiting 5ht2a-rs ...024493647
the xxiiird phage/virus assembly meeting.the xxiiird phage/virus assembly (pva) meeting returned to its birthplace in lake arrowhead, ca on september 8-13, 2013 (fig. 1). the original meeting occurred in 1968, organized by bob edgar (caltech, pasadena, ca usa), fred eiserling (university of california, los angeles, los angeles, ca usa) and bill wood (caltech, pasadena, ca usa). the organizers of the 2013 meeting were bill gelbart (university of california, los angeles, los angeles, ca usa) and jack johnson (scripps research institute, ...024498537
autophagy in the immune system.autophagy is an intracellular homeostatic mechanism important for the degradation of waste components from the cytoplasm in acidic lysosomal compartments. originally, surplus parts of the cytoplasm that acted as targets for autophagy were thought to comprise cellular organelles and proteins, but this has now extended to include a range of pathogens with particular emphasis on intracellular bacteria. the finding that autophagy can sequester intracellular bacteria and mediate their destruction has ...023991647
novel genetic and molecular tools for the investigation and control of dengue virus transmission by mosquitoes.aedes aegypti is the principal vector of dengue virus (denv) throughout the tropical world. this anthropophilic mosquito species needs to be persistently infected with denv before it can transmit the virus through its saliva to a new vertebrate host. in the mosquito, denv is confronted with several innate immune pathways, among which rna interference is considered the most important. the ae. aegypti genome project opened the doors for advanced molecular studies on pathogen-vector interactions in ...024693489
mayaro virus infection, amazon basin region, peru, 2010-2013.during 2010-2013, we recruited 16 persons with confirmed mayaro virus infection in the peruvian amazon to prospectively follow clinical symptoms and serologic response over a 12-month period. mayaro virus infection caused long-term arthralgia in more than half, similar to reports of other arthritogenic alphaviruses.024210165
ampars and synaptic plasticity: the last 25 years.the study of synaptic plasticity and specifically ltp and ltd is one of the most active areas of research in neuroscience. in the last 25 years we have come a long way in our understanding of the mechanisms underlying synaptic plasticity. in 1988, ampa and nmda receptors were not even molecularly identified and we only had a simple model of the minimal requirements for the induction of plasticity. it is now clear that the modulation of the ampa receptor function and membrane trafficking is criti ...024183021
panorama from the oncolytic virotherapy summit. 024081122
genetically engineered mice as experimental tools to dissect the critical events in breast cancer.elucidating the mechanism of pathogenesis of breast cancer has greatly benefited from breakthrough advances in both genetically engineered mouse (gem) models and xenograft transplantation technologies. the vast array of breast cancer mouse models currently available is testimony to the complexity of mammary tumorigenesis and attempts by investigators to accurately portray the heterogeneity and intricacies of this disease. distinct molecular changes that drive various aspects of tumorigenesis, su ...024889535
gene delivery in malignant b cells using the combination of lentiviruses conjugated to anti-transferrin receptor antibodies and an immunoglobulin promoter.we previously developed an antibody-avidin fusion protein (ch128.1av) specific for the human transferrin receptor 1 (tfr1; cd71) to be used as a delivery vector for cancer therapy and showed that ch128.1av delivers the biotinylated plant toxin saporin-6 into malignant b cells. however, as a result of widespread expression of tfr1, delivery of the toxin to normal cells is a concern. therefore, we explored the potential of a dual targeted lentiviral-mediated gene therapy strategy to restrict gene ...024436117
host restriction factor screening: let the virus do the work.in this issue of cell host & microbe, varble et al. (2013) engineer a library of rna viruses to express small interfering rnas and couple this with the power of virus evolution and selection to screen for host genes that when silenced resulted in greater viral infection in vivo.024034609
palladium-catalyzed aryl amination reactions of 6-bromo- and 6-chloropurine nucleosides.palladium-catalyzed c-n bond forming reactions of 6-bromo- as well as 6-chloropurine ribonucleosides and the 2'-deoxy analogues with aryl amines are described. efficient conversions were observed with pd(oac)(2)/xantphos/cs(2)co(3), in phme at 100 °c. reactions of the bromo nucleoside derivatives could be conducted at a lowered catalytic loading (5 mol % pd(oac)(2)/7.5 mol % xantphos), whereas good product yields were obtained with a higher catalyst load (10 mol % pd(oac)(2)/15 mol % xantphos) w ...021818182
intertwined pathways of programmed cell death in immunity.programmed cell death (pcd) occurs widely in species from every kingdom of life. it has been shown to be an integral aspect of development in multicellular organisms, and it is an essential component of the immune response to infectious agents. an analysis of the phylogenetic origin of pcd now shows that it evolved independently several times, and it is fundamental to basic cellular physiology. undoubtedly, pcd pervades all life at every scale of analysis. these considerations provide a backdrop ...020636807
ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond?ribavirin was discovered nearly 40 years ago as a broad-spectrum antiviral drug. recent data suggest that ribavirin may also be an effective cancer therapy. in this case, ribavirin targets an oncogene, the eukaryotic translation initiation factor eif4e, elevated in approximately 30% of cancers including many leukemias and lymphomas. specifically, ribavirin impedes eif4e mediated oncogenic transformation by acting as an inhibitor of eif4e. in a phase ii clinical trial, ribavirin treatment led to ...020629523
the prion protein as a receptor for amyloid-beta.increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (app), is believed to be critical in the aetiology of alzheimer's disease. increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (ltp), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. ...020703260
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