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proteomic analysis of purified turkey adenovirus 3 virions.turkey adenovirus 3 (tadv-3) causes high mortality and significant economic losses to the turkey industry. however, little is known about the molecular determinants required for viral replication and pathogenesis. moreover, tadv-3 does not grow well in cell culture, thus detailed structural studies of the infectious particle is particularly challenging. to develop a better understanding of virus-host interactions, we performed a comprehensive proteomic analysis of proteinase k treated purified t ...201526159706
a genome-wide rnai screening method to discover novel genes involved in virus infection.systematic and comprehensive analysis of host cell proteins involved in virus infection has been difficult in large part due to the lack of robust unbiased methods for their identification. recent technological breakthroughs allowing development of cell-based genetic screens have greatly facilitated our understanding of virus-host interactions. these include instrumentation for processing in microtiter plates (e.g., 384 well), coupled with sensitive readers and off-the-shelf analysis and informa ...201526164699
hunting viral receptors using haploid cells.viruses have evolved intricate mechanisms to gain entry into the host cell. identification of host proteins that serve as viral receptors has enabled insights into virus particle internalization, host and tissue tropism, and viral pathogenesis. in this review we discuss the most commonly employed methods for virus receptor discovery, specifically highlighting the use of forward genetic screens in human haploid cells. the ability to generate true knockout alleles at high saturation provides a sen ...201526958914
ebola virus entry into host cells: identifying therapeutic strategies.filoviruses cause severe hemorrhagic fever in humans. the archetypal virus of this group, ebola virus, is responsible for the current filovirus epidemic in west africa. filoviruses infect most mammalian cells, resulting in broad species tropism and likely contributing to rapid spread of virus throughout the body. a thorough understanding of filovirus entry events will facilitate the development of therapeutics against these critical steps in the viral life cycle. this review summarizes the curre ...201526509109
double-stranded rna is detected by immunofluorescence analysis in rna and dna virus infections, including those by negative-stranded rna viruses.early biochemical studies of viral replication suggested that most viruses produce double-stranded rna (dsrna), which is essential for the induction of the host immune response. however, it was reported in 2006 that dsrna could be detected by immunofluorescence antibody staining in double-stranded dna and positive-strand rna virus infections but not in negative-strand rna virus infections. other reports in the literature seemed to support these observations. this suggested that negative-strand r ...201526136565
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
neuroanatomy goes viral!the nervous system is complex not simply because of the enormous number of neurons it contains but by virtue of the specificity with which they are connected. unraveling this specificity is the task of neuroanatomy. in this endeavor, neuroanatomists have traditionally exploited an impressive array of tools ranging from the golgi method to electron microscopy. an ideal method for studying anatomy would label neurons that are interconnected, and, in addition, allow expression of foreign genes in t ...201526190977
interleukin-10 is a critical regulator of white matter lesion containment following viral induced demyelination.neurotropic coronavirus induces an acute encephalomyelitis accompanied by focal areas of demyelination distributed randomly along the spinal column. the initial areas of demyelination increase only slightly after the control of infection. these circumscribed focal lesions are characterized by axonal sparing, myelin ingestion by macrophage/microglia, and glial scars associated with hypertrophic astrocytes, which proliferate at the lesion border. accelerated virus control in mice lacking the anti- ...201526132901
viroporins, examples of the two-stage membrane protein folding model.viroporins are small, α-helical, hydrophobic virus encoded proteins, engineered to form homo-oligomeric hydrophilic pores in the host membrane. viroporins participate in multiple steps of the viral life cycle, from entry to budding. as any other membrane protein, viroporins have to find the way to bury their hydrophobic regions into the lipid bilayer. once within the membrane, the hydrophobic helices of viroporins interact with each other to form higher ordered structures required to correctly p ...201526131957
viral membrane channels: role and function in the virus life cycle.viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. these proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating to viral release. in addition, the ion channel activity of viroporin causes disruption in the cellular ion homeostasis, in particular the calcium ion. fluctuation in the calcium level triggers the activation of t ...201526110585
isolation and full-length genome analysis of mosquito-borne manzanilla virus from yunnan province, china.there have been four strains on manzanilla virus (manv) identified to date. here, we identify a novel manv strain (dhl10m107) isolated from culex tritaeniorhynchus giles mosquitoes from ruili city, dehong prefecture, yunnan province, in the people's republic of china.201526100251
impact of vesicular stomatitis virus m proteins on different cellular functions.three different matrix (m) proteins termed m1, m2 and m3 have been described in cells infected with vesicular stomatitis virus (vsv). individual expression of vsv m proteins induces an evident cytopathic effect including cell rounding and detachment, in addition to a partial inhibition of cellular protein synthesis, likely mediated by an indirect mechanism. analogous to viroporins, m1 promotes the budding of new virus particles; however, this process does not produce an increase in plasma membra ...201526091335
calcium flux-independent nmda receptor activity is required for aβ oligomer-induced synaptic loss.synaptic loss is one of the major features of alzheimer's disease (ad) and correlates with the degree of dementia. n-methyl-d-aspartate receptors (nmdars) have been shown to mediate downstream effects of the β-amyloid peptide (aβ) in ad models. nmdars can trigger intracellular cascades via ca(2+) entry, however, also ca(2+)-independent (metabotropic) functions of nmdars have been described. we aimed to determine whether ionotropic or metabotropic nmdar signaling is required for the induction of ...201526086964
the effect of oral administration of dsrna on viral replication and mortality in bombus terrestris.israeli acute paralysis virus (iapv), a single-stranded rna virus, has a worldwide distribution and affects honeybees as well as other important pollinators. iapv infection in honeybees has been successfully repressed by exploiting the rna interference (rnai) pathway of the insect's innate immune response with virus-specific double stranded rna (dsrna). here we investigated the effect of iapv infection in the bumblebee bombus terrestris and its tissue tropism. b. terrestris is a common pollinato ...201526110584
lentiviral protein transfer vectors are an efficient vaccine platform and induce a strong antigen-specific cytotoxic t cell response.to induce and trigger innate and adaptive immune responses, antigen-presenting cells (apcs) take up and process antigens. retroviral particles are capable of transferring not only genetic information but also foreign cargo proteins when they are genetically fused to viral structural proteins. here, we demonstrate the capacity of lentiviral protein transfer vectors (ptvs) for targeted antigen transfer directly into apcs and thereby induction of cytotoxic t cell responses. targeting of lentiviral ...201526085166
circumsporozoite protein as a potential target for antimalarials.since the discovery of circumsporozoite protein (csp), a major sporozoite surface antigen, by ruth nussenzweig and victor nussenzweig in the early 1980s, the role of csp in protection against malaria has been extensively investigated. several monoclonal antibodies against csp have been generated to date, with some of them mediating antimalarial protection upon passive transfer into animals. genetically engineered transgenic mosquitoes producing the anti-csp antibody have recently been generated ...201526081442
important role of the il-32 inflammatory network in the host response against viral infection.the pro-inflammatory cytokine interleukin (il)-32 has gained much attention recently because of its important role in the inflammatory network. since the discovery of il-32 in 2005, our appreciation for its diverse roles continues to grow. recent studies have discovered the antiviral effects induced by il-32 and its associated regulatory mechanisms. the interactions between il-32 and various cytokines including cyclooxygenase 2 (cox-2), inducible nitric oxide synthase (inos), interferon (ifn)-λ1 ...201526087456
antiviral activity of silymarin against chikungunya virus.the mosquito-borne chikungunya virus (chikv) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. although there are several studies to evaluate the efficacy of drugs against chikv, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. here, we investigated the antiviral activity of three t ...201526078201
amino-terminal arginylation targets endoplasmic reticulum chaperone bip for autophagy through p62 binding.we show that ate1-encoded arg-transfer rna transferase (r-transferase) of the n-end rule pathway mediates n-terminal arginylation of multiple endoplasmic reticulum (er)-residing chaperones, leading to their cytosolic relocalization and turnover. n-terminal arginylation of bip (also known as grp78), protein disulphide isomerase and calreticulin is co-induced with autophagy during innate immune responses to cytosolic foreign dna or proteasomal inhibition, associated with increased ubiquitylation. ...201526075355
electron tomography analysis of tick-borne encephalitis virus infection in human neurons.tick-borne encephalitis virus (tbev) causes serious, potentially fatal neurological infections that affect humans in endemic regions of europe and asia. neurons are the primary target for tbev infection in the central nervous system. however, knowledge about this viral infection and virus-induced neuronal injury is fragmental. here, we directly examined the pathology that occurs after tbev infection in human primary neurons. we exploited the advantages of advanced high-pressure freezing and free ...201526073783
spinoculation enhances hbv infection in ntcp-reconstituted hepatocytes.hepatitis b virus (hbv) infection and its sequelae remain a major public health burden, but both hbv basic research and the development of antiviral therapeutics have been hindered by the lack of an efficient in vitro infection system. recently, sodium taurocholate cotransporting polypeptide (ntcp) has been identified as the hbv receptor. we herein report that we established a ntcp-complemented hepg2 cell line (hepg2-ntcp12) that supports hbv infection, albeit at a low infectivity level followin ...201526070202
rnasek is required for internalization of diverse acid-dependent viruses.viruses must gain entry into cells to establish infection. in general, viruses enter either at the plasma membrane or from intracellular endosomal compartments. viruses that use endosomal pathways are dependent on the cellular factors that control this process; however, these genes have proven to be essential for endogenous cargo uptake, and thus are of limited value for therapeutic intervention. the identification of genes that are selectively required for viral uptake would make appealing drug ...201526056282
fragile x proteins fmrp and fxr2p control synaptic glua1 expression and neuronal maturation via distinct mechanisms.fragile x mental retardation protein (fmrp) and its autosomal paralog fxr2p are selective neuronal rna-binding proteins, and mice that lack either protein exhibit cognitive deficits. although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. in the present study, we discovered that fxr2p (also known as fxr2) is important for neuronal dendritic development. fmrp and fxr2p additively promote the maturation of new neur ...201526051932
distinct immune responses in resistant and susceptible strains of mice during neurovirulent alphavirus encephalomyelitis.susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. neuroadapted sindbis virus (nsv) causes uniformly fatal disease in adult c57bl/6 (b6) mice, but adult balb/c (bc) mice recover from infection. in b6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. to identify the immunological determinants of host susceptibility to fatal nsv-induced encephalomyelitis, we compared virus ...201526041298
new insights into the understanding of hepatitis c virus entry and cell-to-cell transmission by using the ionophore monensin a.in our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular ph, on the hepatitis c virus (hcv) life cycle. we showed that monensin inhibits hcv entry in a pangenotypic and dose-dependent manner. monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. interestingly, we demonstrated that hcv cell-to-cell transmission is dependent on the vesicular ph. using the se ...201526041282
sequence-independent characterization of viruses based on the pattern of viral small rnas produced by the host.virus surveillance in vector insects is potentially of great benefit to public health. large-scale sequencing of small and long rnas has previously been used to detect viruses, but without any formal comparison of different strategies. furthermore, the identification of viral sequences largely depends on similarity searches against reference databases. here, we developed a sequence-independent strategy based on virus-derived small rnas produced by the host response, such as the rna interference ...201526040701
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
cross-species comparative analysis of dicer proteins during sindbis virus infection.in plants and invertebrates rna silencing is a major defense mechanism against virus infections. the first event in rna silencing is dicing of long double stranded rnas into small interfering rnas (sirnas). the dicer proteins involved in this process are phylogenetically conserved and have the same domain organization. accordingly, the production of viral derived sirnas has also been observed in the mouse, but only in restricted cell types. to gain insight on this restriction, we compare the dic ...201526024431
elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. a number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to t ...201526025608
the baculovirus antiapoptotic p35 protein functions as an inhibitor of the host rna interference antiviral response.rna interference (rnai) is considered an ancient antiviral defense in diverse organisms, including insects. virus infections generate double-strand rnas (dsrnas) that trigger the rnai machinery to process dsrnas into virus-derived short interfering rnas (vsirnas), which target virus genomes, mrnas, or replication intermediates. viruses, in turn, have evolved viral suppressors of rnai (vsrs) to counter host antiviral rnai. following recent discoveries that insects mount an rnai response against d ...201526018163
astaxanthin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ros/mapk pathway in mice.hepatic ischemia reperfusion (ir) is an important issue in complex liver resection and liver transplantation. the aim of the present study was to determine the protective effect of astaxanthin (asx), an antioxidant, on hepatic ir injury via the reactive oxygen species/mitogen-activated protein kinase (ros/mapk) pathway.201526023842
full length and protease domain activity of chikungunya virus nsp2 differ from other alphavirus nsp2 proteases in recognition of small peptide substrates.alphavirus nsp2 proteins are multifunctional and essential for viral replication. the protease role of nsp2 is critical for virus replication as only the virus protease activity is used for processing of the viral non-structural polypeptide. chikungunya virus is an emerging disease problem that is becoming a world-wide health issue. we have generated purified recombinant chikungunya virus nsp2 proteins, both full length and a truncated protease domain from the c-terminus of the nsp2 protein. enz ...201526182358
virus-induced translational arrest through 4ebp1/2-dependent decay of 5'-top mrnas restricts viral infection.the mosquito-transmitted bunyavirus, rift valley fever virus (rvfv), is a highly successful pathogen for which there are no vaccines or therapeutics. translational arrest is a common antiviral strategy used by hosts. in response, rvfv inhibits two well-known antiviral pathways that attenuate translation during infection, pkr and type i ifn signaling. despite this, translational arrest occurs during rvfv infection by unknown mechanisms. here, we find that rvfv infection triggers the decay of core ...201526038567
development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors.it is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (rcl) in lentiviral vector products prior to use in clinical trials. immune design previously described an hiv-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (vp02). vp02 is enveloped with e1001, a modified sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (dc-sign) expressed on dendrit ...201526029728
murine herc6 plays a critical role in protein isgylation in vivo and has an isgylation-independent function in seminal vesicles.isg15 conjugation (isgylation) to proteins is a multistep process involving interferon (ifn)-inducible ube1l (e1), ubch8 (e2), and isg15 e3 ligases (e3s). studies performed over the past several years have shown that isgylation plays a pivotal role in the host antiviral response against certain viruses. recent in vitro studies revealed that human herc5 and mouse herc6 are major isg15 e3 ligases, respectively. however, the global function of herc5/6 proteins in vivo still remains unclear. here, w ...201425406959
recovery of recombinant crimean congo hemorrhagic fever virus reveals a function for non-structural glycoproteins cleavage by furin.crimean congo hemorrhagic fever virus (cchfv) is a negative-strand rna virus of the family bunyaviridae (genus: nairovirus). in humans, cchfv causes fever, hemorrhage, severe thrombocytopenia, and high fatality. a major impediment in precisely determining the basis of cchfv's high pathogenicity has been the lack of methodology to produce recombinant cchfv. we developed a reverse genetics system based on transfecting plasmids into bsr-t7/5 and huh7 cells. in our system, bacteriophage t7 rna polym ...201525933376
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
inhibition of cav3.2 t-type calcium channels by its intracellular i-ii loop.voltage-dependent calcium channels (cav) of the t-type family (cav3.1, cav3.2, and cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. enhanced t-type channel activity, especially cav3.2, contributes to disease states, including absence epilepsy. interestingly, the intracellular loop connecting domains i and ii (i-ii loop) of cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating t ...201525931121
comparison of α-glucosyl hesperidin of citrus fruits and epigallocatechin gallate of green tea on the loss of rotavirus infectivity in cell culture.a number of secondary plant metabolites (e.g., flavonoids) possess antiviral/antimicrobial activity. most flavonoids, however, are difficult to study, as they are immiscible in water-based systems. the relatively new semisynthetic α-glucosyl hesperitin (gh), and the natural plant product epigallocatechin gallate (egcg) are unique among most flavonoids, as these flavonoids are highly soluble. the antiviral activity of these plant metabolites were investigated using the rotavirus as a model enteri ...201525972850
a neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes.mosquitoes are natural vectors for many etiologic agents of human viral diseases. mosquito-borne flaviviruses can persistently infect the mosquito central nervous system without causing dramatic pathology or influencing the mosquito behavior and lifespan. the mechanism by which the mosquito nervous system resists flaviviral infection is still largely unknown. here we report that an aedes aegypti homologue of the neural factor hikaru genki (aahig) efficiently restricts flavivirus infection of the ...201525915054
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
a small antigenic determinant of the chikungunya virus e2 protein is sufficient to induce neutralizing antibodies which are partially protective in mice.the mosquito-borne chikungunya virus (chikv) causes high fever and severe joint pain in humans. it is expected to spread in the future to europe and has recently reached the usa due to globalization, climate change and vector switch. despite this, little is known about the virus life cycle and, so far, there is no specific treatment or vaccination against chikungunya infections. we aimed here to identify small antigenic determinants of the chikv e2 protein able to induce neutralizing immune resp ...201525905779
the brainstem oscillator for whisking and the case for breathing as the master clock for orofacial motor actions.whisking and sniffing are predominant aspects of exploratory behavior in rodents. we review evidence that these motor rhythms are coordinated by the respiratory patterning circuitry in the ventral medulla. a recently described region in the intermediate reticular zone of the medulla functions as an autonomous whisking oscillator, whose neuronal output is reset upon each breath by input from the pre-bötzinger complex. based on similarities between this neuronal circuit architecture and that of ot ...201525876629
endogenous sirnas and pirnas derived from transposable elements and genes in the malaria vector mosquito anopheles gambiae.the sirna and pirna pathways have been shown in insects to be essential for regulation of gene expression and defence against exogenous and endogenous genetic elements (viruses and transposable elements). the vast majority of endogenous small rnas produced by the sirna and pirna pathways originate from repetitive or transposable elements (te). in d. melanogaster, te-derived endogenous sirnas and pirnas are involved in genome surveillance and maintenance of genome integrity. in the medically rele ...201525879960
discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3a.there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. to discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (ev71) to screen an fda-approved drug library. itraconazole (itz), a triazole antifungal agent, was identified as an effective inhi ...201525691649
understanding west nile virus ecology in europe: culex pipiens host feeding preference in a hotspot of virus emergence.understanding wildlife disease ecology is becoming an urgent need due to the continuous emergence and spread of several wildlife zoonotic diseases. west nile virus (wnv) is the most widespread arthropod-borne virus in the world, and in recent decades there has been an increase both in geographic range, and in the frequency of symptomatic infections in humans and wildlife. the principal vector for wnv in europe is the common house culex pipiens mosquito, which feeds on a wide variety of vertebrat ...201525888754
structural basis of arc binding to synaptic proteins: implications for cognitive disease.arc is a cellular immediate-early gene (ieg) that functions at excitatory synapses and is required for learning and memory. we report crystal structures of arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (hiv) gag protein. analysis indicates arc originated from the ty3/gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. the arc n-terminal lobe evolved a unique hydrophobic pocket ...201525864631
the transcription factor foxk participates with nup98 to regulate antiviral gene expression.upon infection, pathogen recognition leads to a rapidly activated gene expression program that induces antimicrobial effectors to clear the invader. we recently found that nup98 regulates the expression of a subset of rapidly activated antiviral genes to restrict disparate rna virus infections in drosophila by promoting rna polymerase occupancy at the promoters of these antiviral genes. how nup98 specifically targets these loci was unclear; however, it is known that nup98 participates with trans ...201525852164
generation of a safe and effective live viral vaccine by virus self-attenuation using species-specific artificial microrna.vaccination with live attenuated vaccines (lavs) is an effective way for prevention of infectious disease. while several methods are employed to create them, efficacy and safety are still a challenge. in this study, we evaluated the feasibility of creating a self-attenuated rna virus expressing a functional species-specific artificial microrna. using influenza virus as a model, we produced an attenuated virus carrying a mammalian-specific mir-93 expression cassette that expresses a viral nucleop ...201525858415
emerging role of natural killer cells in oncolytic virotherapy.natural killer (nk) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. the ability of nk cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. therapies with nk cells involve activation of endogenous nk cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. to exploit the diverse functional abil ...201527471713
virus-induced dormancy in the archaeon sulfolobus islandicus.we investigated the interaction between sulfolobus spindle-shaped virus (ssv9) and its native archaeal host sulfolobus islandicus. we show that upon exposure to ssv9, s. islandicus strain rjw002 has a significant growth delay where the majority of cells are dormant (viable but not growing) for 24 to 48 hours postinfection (hpi) compared to the growth of controls without virus. we demonstrate that in this system, dormancy (i) is induced by both active and inactive virus particles at a low multipl ...201525827422
autophagy mediates tolerance to staphylococcus aureus alpha-toxin.resistance and tolerance are two defense strategies employed by the host against microbial threats. autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant staphylococcus aureus usa300 is to mediate tolerance rather than resistance. atg16l1 hypomorphic mice (atg16l1(hm)), which have reduced autophagy, were ...201525816775
parallel epigenomic and transcriptomic responses to viral infection in honey bees (apis mellifera).populations of honey bees are declining throughout the world, with us beekeepers losing 30% of their colonies each winter. though multiple factors are driving these colony losses, it is increasingly clear that viruses play a major role. however, information about the molecular mechanisms mediating antiviral immunity in honey bees is surprisingly limited. here, we examined the transcriptional and epigenetic (dna methylation) responses to viral infection in honey bee workers. one-day old worker ho ...201525811620
catch me if you can: the link between autophagy and viruses. 201525811485
dissection of amino-terminal functional domains of murine coronavirus nonstructural protein 3.coronaviruses, the largest rna viruses, have a complex program of rna synthesis that entails genome replication and transcription of subgenomic mrnas. rna synthesis by the prototype coronavirus mouse hepatitis virus (mhv) is carried out by a replicase-transcriptase composed of 16 nonstructural protein (nsp) subunits. among these, nsp3 is the largest and the first to be inserted into the endoplasmic reticulum. nsp3 comprises multiple structural domains, including two papain-like proteases (plps) ...201525810552
in vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin.we have described a novel antidepressant peptide, spadin, that acts by blocking the twik-related-potassium channel, type 1 (trek-1). here, we examined possible mechanisms of action of spadin at both molecular and cellular levels.201525598009
antiviral and immunoregulatory effects of indoleamine-2,3-dioxygenase in hepatitis c virus infection.in patients with hepatitis c virus (hcv) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (ido) has been reported. ido - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. the molecular mechanism of ido induction in hcv infection and its role in the antiviral immune response remain unknown. using primary human hepatocytes, we show that hcv infection stimulates ido expression. ido gene inductio ...201525792183
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
ltp-triggered cholesterol redistribution activates cdc42 and drives ampa receptor synaptic delivery.neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. however, little is known about the contribution of lipid metabolism during these processes. in this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (ltp). we found that n-methyl-d-aspartate-type glutamate receptor (nmdar) activation during ltp induction leads to a rapid and ...201525753037
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
the hub protein loquacious connects the microrna and short interfering rna pathways in mosquitoes.aedes aegypti mosquitoes vector several arboviruses of global health significance, including dengue viruses and chikungunya virus. rna interference (rnai) plays an important role in antiviral immunity, gene regulation and protection from transposable elements. double-stranded rna binding proteins (dsrbps) are important for efficient rnai; in drosophila functional specialization of the mirna, endo-sirna and exo-sirna pathway is aided by the dsrbps loquacious (loqs-pb, loqs-pd) and r2d2, respectiv ...201525765650
simultaneous recording of fluorescence and electrical signals by photometric patch electrode in deep brain regions in vivo.despite its widespread use, high-resolution imaging with multiphoton microscopy to record neuronal signals in vivo is limited to the surface of brain tissue because of limited light penetration. moreover, most imaging studies do not simultaneously record electrical neural activity, which is, however, crucial to understanding brain function. accordingly, we developed a photometric patch electrode (pme) to overcome the depth limitation of optical measurements and also enable the simultaneous recor ...201525761950
activation of tomato bushy stunt virus rna-dependent rna polymerase by cellular heat shock protein 70 is enhanced by phospholipids in vitro.similar to other positive-strand rna viruses, tombusviruses are replicated by the membrane-bound viral replicase complex (vrc). the vrc consists of the p92 virus-coded rna-dependent rna polymerase (rdrp), the viral p33 rna chaperone, and several co-opted host proteins. in order to become a functional rdrp after its translation, the p92 replication protein should be incorporated into the vrc, followed by its activation. we have previously shown in a cell-free yeast extract-based assay that the ac ...201525762742
role of zinc-finger anti-viral protein in host defense against sindbis virus.accumulating evidence indicates that type i interferon (ifn) mediates the host protective response to rna viruses. however, the anti-viral effector molecules involved in this response have not been fully identified. here, we show that zinc-finger anti-viral protein (zap), an ifn-inducible gene, plays a critical role in the elimination of sindbis virus (sinv) in vitro and in vivo. the loss of zap greatly enhances the replication of sinv but does not inhibit type i ifn production in primary mouse ...201525758257
mechanisms of innate immune evasion in re-emerging rna viruses.recent outbreaks of ebola, west nile, chikungunya, middle eastern respiratory and other emerging/re-emerging rna viruses continue to highlight the need to further understand the virus-host interactions that govern disease severity and infection outcome. as part of the early host antiviral defense, the innate immune system mediates pathogen recognition and initiation of potent antiviral programs that serve to limit virus replication, limit virus spread and activate adaptive immune responses. conc ...201525765605
the role of misshapen nck-related kinase (mink), a novel ste20 family kinase, in the ires-mediated protein translation of human enterovirus 71.human enterovirus 71 (ev71) commonly causes hand, foot and mouth disease in young children, and occasional occurrences of neurological complications can be fatal. in this study, a high-throughput cell-based screening on the serine/threonine kinase sirna library was performed to identify potential antiviral agents against ev71 replication. among the hits, misshapen/niks-related kinase (mink) was selected for detailed analysis due to its strong inhibitory profile and novelty. in the investigation ...201525747578
xrn1 stalling in the 5' utr of hepatitis c virus and bovine viral diarrhea virus is associated with dysregulated host mrna stability.we demonstrate that both hepatitis c virus (hcv) and bovine viral diarrhea virus (bvdv) contain regions in their 5' utrs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease xrn1, resulting in dramatic changes in the stability of cellular mrnas. we used biochemical assays, virus infections, and transfection of the hcv and bvdv 5' untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-v ...201525747802
to translate, or not to translate: viral and host mrna regulation by interferon-stimulated genes.type i interferon (ifn) is one of the first lines of cellular defense against viral pathogens. as a result of ifn signaling, a wide array of ifn-stimulated gene (isg) products is upregulated to target different stages of the viral life cycle. we review recent findings implicating a subset of isgs in translational regulation of viral and host mrnas. translation inhibition is mediated either by binding to viral rna or by disrupting physiological interactions or levels of the translation complex co ...201525748385
impacts of the creation, expansion and management of english wetlands on mosquito presence and abundance - developing strategies for future disease mitigation.the incidence of mosquito-borne diseases is increasing in europe, partly due to the incursion of a number of invasive species known to be vectors of dengue and chikungunya viruses, but also due to the involvement of native species in the transmission of west nile virus and malaria. for some of these pathogens, there is a risk of the re-emergence of vector-borne diseases that were once widespread in europe, but declined partly due to large-scale land-drainage projects. some mosquito species explo ...201525889666
forced complementation between subgenomic rnas: does human immunodeficiency type 1 virus reverse transcription occur in viral core, cytoplasm, or early endosome?although the process of reverse transcription is well elucidated, it remains unclear if viral core disruption provides a more cellular or viral milieu for hiv-1 reverse transcription. we have devised a method to require mixing of viral cores or core constituents to produce infectious progeny virus by a bipartite subgenomic rna (sgrna) system, in which hiv-1 cplt_r/u5/gag/δpol and nfl sgrnas are complementary to each other and when together can complete viral reverse transcription. only the heter ...201527239643
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
description and utilization of the united states department of defense serum repository: a review of published studies, 1985-2012.specimens in the united states department of defense (dod) serum repository have accumulated in frozen storage since 1985 when the dod began universal screening for human immunodeficiency virus. use of the stored serum for health research has been carefully controlled, but the resulting publications have never been systematically identified or described. the armed forces health surveillance center (afhsc) information systems and open (online) sites were used as data sources. through 2012, the re ...201525723497
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
rapid selection against arbovirus-induced apoptosis during infection of a mosquito vector.millions of people are infected each year by arboviruses (arthropod-borne viruses) such as chikungunya, dengue, and west nile viruses, yet for reasons that are largely unknown, only a relatively small number of mosquito species are able to transmit arboviruses. understanding the complex factors that determine vector competence could facilitate strategies for controlling arbovirus infections. apoptosis is a potential antiviral defense response that has been shown to be important in other virus-ho ...201525713358
the α2,3-sialyltransferase encoded by myxoma virus is a virulence factor that contributes to immunosuppression.myxoma virus (myxv) induces a lethal disease called myxomatosis in european rabbits. myxv is one of the rare viruses that encodes an α2,3-sialyltransferase through its m138l gene. in this study, we showed that although the absence of the enzyme was not associated with any in vitro deficit, the m138l deficient strains are highly attenuated in vivo. indeed, while all rabbits infected with the parental and the revertant strains died within 9 days post-infection from severe myxomatosis, all but one ...201525705900
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
the laminin receptor is a cellular attachment receptor for classical swine fever virus.classical swine fever virus (csfv) is the causative agent of classical swine fever (csf), a highly contagious, economically important viral disease in many countries. the e(rns) and e2 envelope glycoproteins are responsible for the binding to and entry into the host cell by csfv. to date, only one cellular receptor, heparan sulfate (hs), has been identified as being involved in csfv attachment. hs is also present on the surface of various cells that are nonpermissive to csfv. hence, there must b ...201525694590
a basic cluster in the n terminus of yellow fever virus ns2a contributes to infectious particle production.the flavivirus ns2a protein is involved in the assembly of infectious particles. to further understand its role in this process, a charged-to-alanine scanning analysis was performed on ns2a encoded by an infectious cdna clone of yellow fever virus (yfv). fifteen mutants containing single, double, or triple charged-to-alanine changes were tested. five of them did not produce infectious particles, whereas efficient rna replication was detectable for two of the five ns2a mutants (r22a-k23a-r24a and ...201525694595
functional analysis of the short isoform of orf virus protein ov20.0.orf virus (orfv) ov20.0l is an ortholog of vaccinia virus (vacv) gene e3l. the function of vacv e3 protein as a virulence factor is well studied, but ov20.0 has received less attention. here we show that like vacv e3l, ov20.0l encodes two proteins, a full-length protein and a shorter form (sh20). the shorter sh20 is an n-terminally truncated ov20.0 isoform generated when a downstream aug codon is used for initiating translation. these isoforms differed in cellular localization, with full-length ...201525694596
dendritic geometry shapes neuronal camp signalling to the nucleus.neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. yet the rules of molecular signal propagation from dendrites to nuclei are unknown. darpp-32 is a phosphorylation-regulated signalling hub in striatal output neurons. we combine diffusion-reaction modelling and live imaging to investigate camp-activated darpp-32 signalling to the nucleus. the model predicts maximal effects on the nucleus of camp production in secondary dendrites, due to segme ...201525692798
de novo assembly and transcriptome analysis of atlantic salmon macrophage/dendritic-like to cells following type i ifn treatment and salmonid alphavirus subtype-3 infection.interferons (ifn) are cytokines secreted by vertebrate cells involved in activation of signaling pathways that direct the synthesis of antiviral genes. to gain a global understanding of antiviral genes induced by type i ifns in salmonids, we used rna-seq to characterize the transcriptomic changes induced by type i ifn treatment and salmon alphavirus subtype 3 (sav-3) infection in to-cells, a macrophage/dendritic like cell-line derived from atlantic salmon (salmo salar l) head kidney leukocytes.201525765343
tnbp⁄triton x-45 treatment of plasma for transfusion efficiently inactivates hepatitis c virus.risk of transmission of hepatitis c virus (hcv) by clinical plasma remains high in countries with a high prevalence of hepatitis c, justifying the implementation of viral inactivation treatments. in this study, we assessed the extent of inactivation of hcv during minipool solvent/detergent (sd; 1% tnbp / 1% triton x-45) treatment of human plasma. luciferase-tagged infectious cell culture-derived hcv (hcvcc) particles were used to spike human plasma prior to treatment by sd at 31 ± 0.5°c for 30 m ...201525658612
eukaryote-specific extensions in ribosomal proteins of the small subunit: structure and function.high-resolution structures of yeast ribosomes have improved our understanding of the architecture and organization of eukaryotic rrna and proteins, as well as eukaryote-specific extensions present in some conserved ribosomal proteins. despite this progress, assignment of specific functions to individual proteins and/or eukaryote-specific protein extensions remains challenging. it has been suggested that eukaryote-specific extensions of conserved proteins from the small ribosomal subunit may faci ...201526779416
neurological sequelae induced by alphavirus infection of the cns are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine.recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. infection of mice with the prototypic alphavirus, sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. infectious virus is cleared from the brain within a week after infection, but viral rna is cleared slowly and persists for the life of the animal. however, no studies hav ...201525645378
residue-level resolution of alphavirus envelope protein interactions in ph-dependent fusion.alphavirus envelope proteins, organized as trimers of e2-e1 heterodimers on the surface of the pathogenic alphavirus, mediate the low ph-triggered fusion of viral and endosomal membranes in human cells. the lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. in this work, we performed constant ph molecular dynamics based on an atomic model of the alphav ...201525646410
adp-ribosylation factor 6 (arf6) bidirectionally regulates dendritic spine formation depending on neuronal maturation and activity.recent studies have reported conflicting results regarding the role of arf6 in dendritic spine development, but no clear answer for the controversy has been suggested. we found that adp-ribosylation factor 6 (arf6) either positively or negatively regulates dendritic spine formation depending on neuronal maturation and activity. arf6 activation increased the spine formation in developing neurons, whereas it decreased spine density in mature neurons. genome-wide microarray analysis revealed that a ...201525605715
selective inactivation of usp18 isopeptidase activity in vivo enhances isg15 conjugation and viral resistance.protein modification by the ubiquitin-like protein isg15 is an interferon (ifn) effector system, which plays a major role in antiviral defense. isg15 modification is counteracted by the isopeptidase usp18, a major negative regulator of ifn signaling, which was also shown to exert its regulatory function in an isopeptidase-independent manner. to dissect enzymatic and nonenzymatic functions of usp18 in vivo, we generated knock-in mice (usp18(c61a/c61a)) expressing enzymatically inactive usp18. usp ...201525605921
a polyprotein-expressing salmonid alphavirus replicon induces modest protection in atlantic salmon (salmo salar) against infectious pancreatic necrosis.vaccination is an important strategy for the control and prevention of infectious pancreatic necrosis (ipn) in farmed atlantic salmon (salmo salar) in the post-smolt stage in sea-water. in this study, a heterologous gene expression system, based on a replicon construct of salmonid alphavirus (sav), was used for in vitro and in vivo expression of ipn virus proteins. the large open reading frame of segment a, encoding the polyprotein nh2-pvp2-vp4-vp3-cooh, as well as pvp2, were cloned and expresse ...201525606973
relationships among dissemination of primary parainfluenza virus infection in the respiratory tract, mucosal and peripheral immune responses, and protection from reinfection: a noninvasive bioluminescence-imaging study.respiratory paramyxoviruses such as respiratory syncytial virus (rsv) and human parainfluenza virus type 1 (hpiv1) to hpiv4 infect virtually all children by the age of 2 to 5 years, leading to partial but incomplete protection from reinfection. here, we used luciferase-expressing reporter sendai viruses (the murine counterpart of hpiv1) to noninvasively measure primary infection, immune responses, and protection from reinfection by either a lethal challenge or natural transmission in living mice ...201525589649
teaching the basics of autophagy and mitophagy to redox biologists--mechanisms and experimental approaches.autophagy is a lysosomal mediated degradation activity providing an essential mechanism for recycling cellular constituents, and clearance of excess or damaged lipids, proteins and organelles. autophagy involves more than 30 proteins and is regulated by nutrient availability, and various stress sensing signaling pathways. this article provides an overview of the mechanisms and regulation of autophagy, its role in health and diseases, and methods for its measurement. hopefully this teaching revie ...201525618581
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
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
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
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
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
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
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
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