demonstration of specific antibodies in the central nervous system of horses naturally infected with borna disease virus. | from 18 horses with clinical symptoms of an affection of the central nervous system and with histopathologic alterations in the brain, four were demonstrated to have bornavirus-specific antibodies. the antibodies are monospecific, recognizing identical antigens from infected brains of different animal species as well as from persistently infected tissue culture cells. discrete immunoglobulin species (oligoclonal igg) can be demonstrated in concentrated horse cerebrospinal fluid; they carry borna ... | 1977 | 604728 |
borna disease virus infection and affective disorders in man. | borna disease virus (bdv) can persistently infect the central nervous system of a broad spectrum of animal species. the clinical course varies from slight behavioral disturbances to a fatal neurological syndrome. in-vivo diagnosis is based on the strong humoral immune response to bdv antigens. since also human infections could be confirmed by specific antibodies and increased seroprevalence was found in patients with chronic neurologic or immunologic disorders, the contribution of bdv or a bdv-l ... | 1993 | 8219801 |
borna disease virus in brains of north american and european people with schizophrenia and bipolar disorder. bornavirus study group. | | 1997 | 9269221 |
borna disease virus and neuropsychiatric disorders. the japan bornavirus study group. | | 1997 | 9284801 |
no borna disease virus-specific rna detected in blood from psychiatric patients in different regions of germany. the bornavirus study group. | | 1997 | 9329518 |
progress and controversy in bornavirus research: a meeting report. | | 1999 | 10365174 |
bornavirus immunopathogenesis in rodents: models for human neurological diseases. | although the question of human bdv infection remains to be resolved, burgeoning interest in this unique pathogen has provided tools for exploring the pharmacology and neurochemistry of neuropsychiatric disorders potentially linked to bdv infection. two animal models have been established based on bdv infection of adult or neonatal lewis rats. analysis of these models is already yielding insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature cns ... | 1999 | 10602401 |
sequence similarities between human bornavirus isolates and laboratory strains question human origin. | human bornavirus rw98, whose genome differs by 3-4% from previous isolates, is almost identical to a rat-adapted laboratory strain. other human bornaviruses are also strongly related to virus strains frequently used for experiments in the various laboratories reporting human bornavirus, questioning a human origin of isolates known to date. | 1999 | 10622306 |
bornavirus isolates of human origin. | | 2000 | 10697008 |
expression and characterization of the borna disease virus polymerase. | borna disease virus is the prototype of a new family, bornaviridae, within the order mononegavirales, that is characterized by nuclear transcription, splicing, low level replication, and neurotropism. the products of five open reading frames predicted from the genomic sequence have been confirmed; however, expression of the sixth, corresponding to the putative viral polymerase (l), has not been demonstrated. here, we describe expression and characterization of a 190-kda protein proposed to repre ... | 2000 | 10756058 |
microglial activation and neuronal apoptosis in bornavirus infected neonatal lewis rats. | lewis rats neonatally infected with borna disease virus have a behavioral syndrome characterized by hyperactivity, movement disorders, and abnormal social interactions. virus is widely distributed in brain; however, neuropathology is focused in dentate gyrus, cerebellum, and neocortex where granule cells, purkinje cells and pyramidal cells are lost through apoptosis. although a transient immune response is present, its distribution does not correlate with sites of damage. neuropathology is inste ... | 2000 | 10764045 |
isolation and characterization of a new subtype of borna disease virus. | borna disease virus (bdv), the causative agent of severe meningoencephalitis in a wide variety of animal species, has been considered to be genetically invariable and to form a single type within the genus bornavirus of the family bornaviridae. bdv infections are of particular interest, because for the first time a virus infection appears to be linked to human psychiatric disorders. we now describe a new subtype of bdv isolated from a horse which was euthanatized due to severe, incurable neurolo ... | 2000 | 10823873 |
bornavirus and psychiatric disorders -- fact or fiction? | | 2001 | 11444766 |
bornavirus tropism and targeted pathogenesis: virus-host interactions in a neurodevelopmental model. | animal models provide unique opportunities to explore interactions between host and environment. two models have been established based on bornavirus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature cns circuitry to effect complex disturbances in movement and behavior. distinct losses in da pathways in the adult infection model, and the associated dramatic movement disorder that accompanies it, make it an intrig ... | 2001 | 11450312 |
neuroprotection and reduced proliferation of microglia in ribavirin-treated bornavirus-infected rats. | in a rat model of borna disease, intracerebral ribavirin caused clinical improvement without changes in virus titer or nucleic acid. levels of microglia and infiltrating cd4 and cd8 cells were decreased, despite increases in mrnas encoding interleukin-1beta (il-1beta), il-10, and gamma interferon in the brain. intracerebral ribavirin may reduce morbidity through effects on microglia cell proliferation. | 2002 | 12069992 |
bornavirus and the brain. | borna disease virus (bdv) causes central nervous system (cns) disease that is frequently manifested by behavioral abnormalities. bdv is a nonsegmented, negative, single-stranded rna virus. on the basis of its unique genetic and biologic features, bdv is the prototypic member of a new virus family, bornaviridae, within the order mononegavirales. therefore, the investigation of the molecular and cell biology of bdv may provide new insights about virus-cell interactions in the cns. bdv is an import ... | 2002 | 12424704 |
meta-analysis of putative human bornavirus sequences fails to provide evidence implicating borna disease virus in mental illness. | all borna disease virus (bdv) sequences derived from human specimens published till date were thoroughly analysed and compared to sequences of bdv laboratory strains and to bdv sequences from animals which succumbed to classical borna disease (bd). despite high sequence conservation of the bdv genome, animal-derived bdv sequences clustered according to their geographic origin. however, in marked contrast, human-derived bdv sequences did not cluster according to their geographic origin but showed ... | 2007 | 17342788 |
hippocampal poly(adp-ribose) polymerase 1 and caspase 3 activation in neonatal bornavirus infection. | infection of neonatal rats with borna disease virus results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus, cerebellum, and cortex (neonatal borna disease [nbd]). in the nbd rat hippocampus, dentate gyrus granule cells progressively degenerate. apoptotic loss of granule cells in nbd is associated with accumulation of zinc in degenerating neurons and reduced zinc in granule cell mossy fibers. excess zinc can trigger poly(adp-ribose) polymerase 1 (pa ... | 2008 | 18057239 |
recovery of divergent avian bornaviruses from cases of proventricular dilatation disease: identification of a candidate etiologic agent. | proventricular dilatation disease (pdd) is a fatal disorder threatening domesticated and wild psittacine birds worldwide. it is characterized by lymphoplasmacytic infiltration of the ganglia of the central and peripheral nervous system, leading to central nervous system disorders as well as disordered enteric motility and associated wasting. for almost 40 years, a viral etiology for pdd has been suspected, but to date no candidate etiologic agent has been reproducibly linked to the disease. | 2008 | 18671869 |
the international berlin symposium on bornavirus infections--from animals to man--50 years of development. introduction. | | 2008 | 18771091 |
the biology of bornavirus. | | 2008 | 18771093 |
human bornavirus infection-- towards a valid diagnostic system. | | 2008 | 18771094 |
horses diagnosed clinically and by laboratory methods for bornavirus infection and treated with amantadine: "patients" of the tierärztliche klinik für pferde in meerbusch. case report. | | 2008 | 18771096 |
essentials in bornavirus virology--an epilogue. | | 2008 | 18771109 |
from animals to man--50 years of development. proceedings of the international berlin symposium on bornavirus infections. january 26-28, 2008. berlin, germany. | | 2008 | 18828206 |
broad tissue and cell tropism of avian bornavirus in parrots with proventricular dilatation disease. | avian bornaviruses (abv), representing a new genus within the family bornaviridae, were recently discovered in parrots from north america and israel with proventricular dilatation disease (pdd). we show here that closely related viruses are also present in captive european parrots of various species with pdd. the six abv strains that we identified in clinically diseased birds are new members of the previously defined abv genotypes 2 and 4. viruses of both genotypes readily established persistent ... | 2009 | 19297496 |
experimental induction of proventricular dilatation disease in cockatiels (nymphicus hollandicus) inoculated with brain homogenates containing avian bornavirus 4. | proventricular dilatation disease (pdd) is a fatal disorder of psittacine birds worldwide. the disease is characterized by lymphoplasmacytic infiltration of the central and peripheral nervous systems, leading to gastrointestinal motility and/or central nervous system dysfunction. recently, we detected a significant association between avian bornavirus (abv) infection and clinical signs of pdd in psittacines. however, it remains unclear whether abv infection actually causes pdd. to address this q ... | 2009 | 19589169 |
novel avian bornavirus in a nonpsittacine species (canary; serinus canaria) with enteric ganglioneuritis and encephalitis. | a canary bird (serinus canaria) died with nonsuppurative ganglioneuritis of the proventriculus and gizzard and encephalitis, lesions comparable to proventricular dilatation disease (pdd) of psittacine birds. recently, several genotypes of a novel avian bornavirus have been linked to pdd. in the canary, bornaviral antigen was detected by immunohistochemistry in both neural and extraneural tissues. the widespread viral dissemination was confirmed by reverse transcription-pcr. sequence analysis rev ... | 2009 | 19706702 |
proteomics computational analyses suggest that the bornavirus glycoprotein is a class iii viral fusion protein (gamma penetrene). | borna disease virus (bdv) is the type member of the bornaviridae, a family of viruses that induce often fatal neurological diseases in horses, sheep and other animals, and have been proposed to have roles in certain psychiatric diseases of humans. the bdv glycoprotein (g) is an extensively glycosylated protein that migrates with an apparent molecular mass of 84,000 to 94,000 kilodaltons (kda). bdv g is post-translationally cleaved by the cellular subtilisin-like protease furin into two subunits, ... | 2009 | 19765297 |
histopathology and the detection of avian bornavirus in the nervous system of birds diagnosed with proventricular dilatation disease. | avian bornavirus (abv) is currently considered a probable etiologic agent of proventricular dilatation disease (pdd) of psittacines. we tested 24 stored avian brain samples, processed for histopathology and retained following their submission for necropsy or histopathology to the schubot exotic bird center diagnostic laboratory in 1992. thirteen of these samples were from birds diagnosed at that time as suffering from pdd. the remaining 11 samples were diagnosed as suffering from diseases other ... | 2009 | 19937526 |
anatomical distribution of avian bornavirus in parrots, its occurrence in clinically healthy birds and abv-antibody detection. | proventricular dilatation disease (pdd) is a fatal infectious disease of birds that primarily affects psittacine birds. although a causative agent has not been formally demonstrated, the leading candidate is a novel avian bornavirus (abv) detected in post-mortem tissue samples of psittacids with pdd from the usa, israel and, recently, germany. here we describe the presence of abv in a parrot with pdd as well as in clinically normal birds exposed to birds with pdd. in two abv-positive post-mortem ... | 2009 | 19937538 |
analysis of naturally occurring avian bornavirus infection and transmission during an outbreak of proventricular dilatation disease among captive psittacine birds. | a proventricular dilatation disease (pdd) outbreak provided the opportunity to investigate the transmissibility of avian bornavirus (abv) and its linkage to pdd under natural conditions. upon exposure to a bird with a fatal case of pdd, 10 birds became symptomatic and died. abv2 rna was recovered from available tissues. further screening revealed that 12/46 exposed birds were abv2(+). three chicks boarded at this aviary developed pdd. they harbored the same abv2 isolate and transmitted it to fiv ... | 2010 | 19955301 |
virology: bornavirus enters the genome. | | 2010 | 20054386 |
endogenous non-retroviral rna virus elements in mammalian genomes. | retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements. although many other viruses, including non-retroviral rna viruses, are known to generate dna forms of their own genomes during replication, none has been found as dna in the germline of animals. bornaviruses, a genus of non-segmented, negative-sense rna virus, are unique among rna viruses in that they establish ... | 2010 | 20054395 |
presence of avian bornavirus rna and anti-avian bornavirus antibodies in apparently healthy macaws. | recently a novel avian bornavirus has been described that has been suggested to be the possible etiological agent for proventricular dilatation disease or macaw wasting disease. this article describes two macaws that shed avian bornaviral rna sequences and demonstrated anti-avian bornavirus antibodies as revealed by reverse transcriptase polymerase chain reaction (rt-pcr), enzyme-linked immunosorbent assay (elisa), and western blot, yet are free of outward clinical signs of the disease. | 2009 | 20095158 |
use of avian bornavirus isolates to induce proventricular dilatation disease in conures. | avian bornavirus (abv) is a newly discovered member of the family bornaviridae that has been associated with the development of a lethal neurologic syndrome in birds, termed proventricular dilatation disease (pdd). we successfully isolated and characterized abv from the brains of 8 birds with confirmed pdd. one isolate was passed 6 times in duck embryo fibroblasts, and the infected cells were then injected intramuscularly into 2 healthy patagonian conures (cyanoliseus patagonis). clinical pdd de ... | 2010 | 20202423 |
avian bornavirus associated with fatal disease in psittacine birds. | thanks to new technologies which enable rapid and unbiased screening for viral nucleic acids in clinical specimens, an impressive number of previously unknown viruses have recently been discovered. two research groups independently identified a novel negative-strand rna virus, now designated avian bornavirus (abv), in parrots with proventricular dilatation disease (pdd), a severe lymphoplasmacytic ganglioneuritis of the gastrointestinal tract of psittacine birds that is frequently accompanied by ... | 2010 | 20219910 |
localization of avian bornavirus rna by in situ hybridization in tissues of psittacine birds with proventricular dilatation disease. | proventricular dilatation disease (pdd) of psittacine birds is caused by a number of different genotypes of a novel viral species, avian bornavirus (abv). here we present an in situ hybridization (ish) procedure using digoxigenin-labeled rna probes for localizing viral genomic and mrna of abv-2 and abv-4 in tissues of affected birds. out of eleven immunohistochemically positive birds ish signals were only found in seven. partial sequencing of the viral genome had shown that four of them were inf ... | 2010 | 20303680 |
indirect immunofluorescence assay for intra vitam diagnosis of avian bornavirus infection in psittacine birds. | different avian bornavirus (abv) genotypes have recently been detected in psittacine birds with proventricular dilatation disease (pdd), an inflammatory fatal central and peripheral nervous system disorder. an indirect immunofluorescence assay (iifa) for intra vitam demonstration of abv-specific serum antibodies was established since reverse transcription-pcr (rt-pcr) assays may not detect all abv variants. | 2010 | 20392921 |
achalasia and viral infection: new insights from veterinary medicine. | achalasia is a serious disorder in which the movement of food and liquids through the esophagus is impaired. it is currently thought to be caused by an inflammatory process that destroys neurons in myenteric ganglia, which affect peristalsis in the esophagus. the factor(s) that precipitate this inflammatory process are unknown; possibilities include environmental agents (such as microbes or toxins) and/or cell-mediated autoimmune reactivity. recently, infection with a newly described bornavirus ... | 2010 | 20505212 |
avian bornavirus is present in many tissues of psittacine birds with histopathologic evidence of proventricular dilatation disease. | proventricular dilatation disease (pdd) is a neurologic disease of psittacine birds suspected to be caused by a recently identified avian bornavirus (abv). in the current report, data supporting the causal association of abv with pdd are presented. immunohistochemistry (ihc) with rabbit polyclonal antiserum raised against abv nucleocapsid protein was used to identify cell and organ distribution of viral antigen. the abv antigen was most consistently detected in brain, spinal cord, adrenal gland, ... | 2010 | 20622218 |
advanced diagnostic approaches and current management of proventricular dilatation disease. | proventricular dilatation disease (pdd) is a fatal inflammatory disease that affects mainly, but not exclusively, psittacine birds (order: psittaciformes). pdd has long been suspected to be a viral disease, but its causative agent, a novel bornavirus, was only identified in 2008. | 2010 | 20682431 |
the isolation, pathogenesis, diagnosis, transmission, and control of avian bornavirus and proventricular dilatation disease. | proventricular dilatation disease (pdd) is a common infectious neurologic disease of birds comprising a dilatation of the proventriculus by ingested food as a result of defects in intestinal motility, which affects more than 50 species of psittacines, and is also known as macaw wasting disease, neuropathic ganglioneuritis, or lymphoplasmacytic ganglioneuritis. definitive diagnosis of pdd has been problematic due to the inconsistent distribution of lesions. since its discovery, avian bornavirus ( ... | 2010 | 20682432 |
unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes. | vertebrate genomes contain numerous copies of retroviral sequences, acquired over the course of evolution. until recently they were thought to be the only type of rna viruses to be so represented, because integration of a dna copy of their genome is required for their replication. in this study, an extensive sequence comparison was conducted in which 5,666 viral genes from all known non-retroviral families with single-stranded rna genomes were matched against the germline genomes of 48 vertebrat ... | 2010 | 20686665 |
proventricular dilatation disease associated with avian bornavirus in a scarlet macaw (ara macao). | a case of proventricular dilatation disease is described in a scarlet macaw (ara macao) from clinical presentation to diagnosis with molecular methods. the initial clinical signs were depression progressing to head pressing over several days. a leukocytosis with toxic heterophil changes, hypoalbuminemia, and increased serum activity of aspartate aminotransferase and creatine kinase were present. lead and zinc assays were within reference ranges, and results from chlamydophila and polyomavirus te ... | 2010 | 21088184 |
proventricular dilatation disease associated with avian bornavirus infection in a citron-crested cockatoo that was born and hand-reared in japan. | a 5-month-old female citron-crested cockatoo (cacatua sulphurea citrinocristata) that was born and hand-reared in japan died with suspected proventricular dilatation disease (pdd). macroscopic and microscopic examinations of the bird revealed characteristic features of pdd, i.e., distention of the proventriculus and infiltration of lymphocytes and plasma cells in ganglia of various organs and in central and peripheral nerves. a linkage of this pdd case to infection with avian bornavirus (abv) wa ... | 2011 | 21289471 |
infectious and zoonotic disease testing in pet birds. | pet bird ownership and the veterinary diagnostic market for avian and exotic species testing have grown markedly during the past 20 years. birds present with both unique infectious diseases and other diseases that are known to the human medical community, including aspergillosis, mycobacteriosis, chlamydophilosis, and bornavirus infection, some of which have clear zoonotic implications. although diagnostic testing for these avian infectious diseases has grown considerably and includes the newer ... | 2011 | 21295723 |
unusual and severe lesions of proventricular dilatation disease in cockatiels (nymphicus hollandicus) acting as healthy carriers of avian bornavirus (abv) and subsequently infected with a virulent strain of abv. | a flock of 14 apparently healthy cockatiels, purchased from a single aviary, was tested for the presence of avian bornavirus (abv). twelve birds were found to be intermittently shedding abv, predominantly genotype 4. four of the cockatiels known to be shedding abv4 were subsequently challenged with the tissue culture derived, virulent m24 strain of abv4. the challenged birds remained in apparent good health until day 92 when one was found dead. the remaining three birds began to exhibit severe n ... | 2011 | 21331944 |
[endogenous bornavirus elements in mammalian genome]. | approximately 8% of our genome is made up of endogenous retroviral elements. endogenous retrovirus is a fossil record of ancient retrovirus infection and, therefore, gives important insights into the evolutional relationship between retroviruses and their hosts. on the other hand, until recently, it has been believed that no endogenous non-retroviral viruses exist in animal genomes. we lately discovered endogenous elements homologous to the nucleoprotein of bornaviruses, a negative-strand rna vi ... | 2010 | 21488328 |
using a pan-viral microarray assay (virochip) to screen clinical samples for viral pathogens. | the diagnosis of viral causes of many infectious diseases is difficult due to the inherent sequence diversity of viruses as well as the ongoing emergence of novel viral pathogens, such as sars coronavirus and 2009 pandemic h1n1 influenza virus, that are not detectable by traditional methods. to address these challenges, we have previously developed and validated a pan-viral microarray platform called the virochip with the capacity to detect all known viruses as well as novel variants on the basi ... | 2011 | 21559002 |
occurrence of avian bornavirus infection in captive psittacines in various european countries and its association with proventricular dilatation disease. | a total of 1442 live birds and 73 dead birds out of 215 bird collections in spain, germany, italy, the uk and denmark were tested for avian bornavirus (abv) infection by four different methods. the majority of the birds were psittacines belonging to 54 different genera of the order psittaciformes. in total, 22.8% of the birds reacted positive for abv in at least one of the tests. combined testing of swabs from the crop and cloaca, and serum for the diagnosis of abv infection in live birds reveal ... | 2011 | 21812722 |
new genotype of avian bornavirus in wild geese and trumpeter swans in canada. | | 2011 | 21784813 |
Antigen tissue distribution of Avian bornavirus (ABV) in psittacine birds with natural spontaneous proventricular dilatation disease and ABV genotype 1 infection. | Tissues of 10 psittacines from aviary 1 ("case birds") and 5 psittacines from different aviaries were investigated for the presence of Avian bornavirus (ABV) antigen by immunohistochemistry using a polyclonal serum specific for the viral nucleocapsid (N) protein. Seven of 10 case birds had clinical signs, and necropsy findings consistent with proventricular dilatation disease (PDD) while 3 case birds and the 5 birds from other aviaries did not exhibit signs and lesions of this disease. In birds ... | 2011 | 21908314 |
intracerebral borna disease virus infection of bank voles leading to peripheral spread and reverse transcription of viral rna. | bornaviruses, which chronically infect many species, can cause severe neurological diseases in some animal species; their association with human neuropsychiatric disorders is, however, debatable. the epidemiology of borna disease virus (bdv), as for other members of the family bornaviridae, is largely unknown, although evidence exists for a reservoir in small mammals, for example bank voles (myodes glareolus). in addition to the current exogenous infections and despite the fact that bornaviruses ... | 2011 | 21935357 |
Diagnosis of Avian bornavirus infection in psittaciformes by serum antibody detection and reverse transcription polymerase chain reaction assay using feather calami. | Avian bornavirus (ABV) is the causative agent of proventricular dilatation disease (PDD), a highly devastating and contagious disease of psittacines (parrots and parakeets), which has resulted in the death of many captive birds. Accurate diagnosis of bornavirus infection is therefore important for the identification and isolation of infected birds. The current study showed that nonvascular contour (chest) feather calami provide a ready and minimally invasive source of RNA for the detection of AB ... | 2011 | 21908270 |
no evidence for natural selection on endogenous borna-like nucleoprotein elements after the divergence of old world and new world monkeys. | endogenous borna-like nucleoprotein (eblns) elements were recently discovered as non-retroviral rna virus elements derived from bornavirus in the genomes of various animals. most of eblns appeared to be defective, but some of primate ebln-1 to -4, which appeared to be originated from four independent integrations of bornavirus nucleoprotein (n) gene, have retained an open reading frame (orf) for more than 40 million years. it was therefore possible that primate eblns have encoded functional prot ... | 2011 | 21912690 |
detection and characterization of a distinct bornavirus lineage from healthy canada geese (branta canadensis). | avian bornaviruses (abv), identified in 2008, infect captive parrots and macaws worldwide. the natural reservoirs of these viruses are unknown. reverse transcription-pcr (rt-pcr) was used to screen oropharyngeal/cloacal swab and brain samples from wild canada geese (branta canadensis) for abv. approximately 2.9% of swab samples were positive for bornavirus sequences. fifty-two percent of brain samples from 2 urban flocks also tested positive, and brain isolates were cultured in duck embryo fibro ... | 2011 | 21900161 |
Vertical transmission of avian bornavirus in psittacines. | TO THE EDITOR: Proventricular dilatation disease (PDD) is a fatal disease in psittacines that jeopardizes critical species conservation projects, such as that involving the Spix's macaw (Cyanopsitta spixii), the world's most endangered bird species (1). The disease is characterized by lymphoplasmacytic infiltrations in the enteric and central nervous systems (2). Consequently, gastrointestinal and neurologic disorders are the major clinical manifestations. Only recently has the cause of the dise ... | 2011 | 22172160 |
proventricular dilatation disease in cockatiels (nymphicus hollandicus) after infection with a genotype 2 avian bornavirus. | an isolate of genotype 2 avian bornavirus (abv) was recovered from a cockatiel (nymphicus hollandicus) that was euthanatized for an unrelated lesion and showing no clinical evidence of proventricular dilatation disease (pdd). on histopathologic examination, mild inflammatory lesions were present in the heart and brain, but gastrointestinal lesions characteristic of classic pdd were not observed. to investigate if this abv2 isolate had reduced virulence, the virus was propagated in duck embryo fi ... | 2011 | 22216720 |