CORD-19:02a009e42054081b441d0f4b203679c4b0cae38d JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-106 Sentence denotes Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses
T93306 0-106 Sentence denotes Three asymptomatic animal infection models of hemorrhagic fever with renal syndrome caused by hantaviruses
TextSentencer_T2 108-116 Sentence denotes Abstract
T23232 108-116 Sentence denotes Abstract
TextSentencer_T3 117-288 Sentence denotes Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia.
T77055 117-288 Sentence denotes Hantaan virus (HTNV) and Puumala virus (PUUV) are rodent-borne hantaviruses that are the primary causes of hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia.
TextSentencer_T4 289-461 Sentence denotes The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics.
T76096 289-461 Sentence denotes The development of well characterized animal models of HTNV and PUUV infection is critical for the evaluation and the potential licensure of HFRS vaccines and therapeutics.
TextSentencer_T5 462-615 Sentence denotes In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret).
T98768 462-615 Sentence denotes In this study we present three animal models of HTNV infection (hamster, ferret and marmoset), and two animal models of PUUV infection (hamster, ferret).
TextSentencer_T6 616-901 Sentence denotes Infection of hamsters with a~3 times the infectious dose 99% (ID 99 ) of HTNV by the intramuscular and~1 ID 99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney.
T61250 616-901 Sentence denotes Infection of hamsters with a~3 times the infectious dose 99% (ID 99 ) of HTNV by the intramuscular and~1 ID 99 of HTNV by the intranasal route leads to a persistent asymptomatic infection, characterized by sporadic viremia and high levels of viral genome in the lung, brain and kidney.
TextSentencer_T7 902-1116 Sentence denotes In contrast, infection of hamsters with~2 ID 99 of PUUV by the intramuscular or~1 ID 99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome.
T6943 902-1116 Sentence denotes In contrast, infection of hamsters with~2 ID 99 of PUUV by the intramuscular or~1 ID 99 of PUUV by the intranasal route leads to seroconversion with no detectable viremia, and a transient detection of viral genome.
TextSentencer_T8 1117-1366 Sentence denotes Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected.
T67680 1117-1366 Sentence denotes Infection of ferrets with a high dose of either HTNV or PUUV by the intramuscular route leads to seroconversion and gradual weight loss, though kidney function remained unimpaired and serum viremia and viral dissemination to organs was not detected.
TextSentencer_T9 1367-1487 Sentence denotes In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production.
T60961 1367-1487 Sentence denotes In marmosets a 1,000 PFU HTNV intramuscular challenge led to robust seroconversion and neutralizing antibody production.
TextSentencer_T10 1488-1631 Sentence denotes Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets.
T10249 1488-1631 Sentence denotes Similarly to the ferret model of HTNV infection, no renal impairment, serum viremia or viral dissemination to organs was detected in marmosets.
TextSentencer_T11 1632-1706 Sentence denotes This is the first report of hantavirus infection in ferrets and marmosets.
T96567 1632-1706 Sentence denotes This is the first report of hantavirus infection in ferrets and marmosets.
TextSentencer_T12 1708-1798 Sentence denotes Hantaviruses are negative-sense RNA viruses transmitted to humans from small animal hosts.
T82130 1708-1798 Sentence denotes Hantaviruses are negative-sense RNA viruses transmitted to humans from small animal hosts.
TextSentencer_T13 1799-1963 Sentence denotes Different viral species are associated with one of two disease syndromes: hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS) [1] .
T53923 1799-1963 Sentence denotes Different viral species are associated with one of two disease syndromes: hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS) [1] .
TextSentencer_T14 1964-2173 Sentence denotes Hantaan virus a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 (HTNV), primarily found in Asia, is among the most prevalent HFRS-causing hantaviruses with a case fatality rate of between 1-15% [2] .
T32493 1964-2173 Sentence denotes Hantaan virus a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 (HTNV), primarily found in Asia, is among the most prevalent HFRS-causing hantaviruses with a case fatality rate of between 1-15% [2] .
TextSentencer_T15 2174-2283 Sentence denotes Puumala virus (PUUV) causes most HFRS cases in Europe, though its case fatality rate is lower at <1% [3, 4] .
T56812 2174-2283 Sentence denotes Puumala virus (PUUV) causes most HFRS cases in Europe, though its case fatality rate is lower at <1% [3, 4] .
TextSentencer_T16 2284-2373 Sentence denotes There are currently no FDA licensed vaccines or therapeutics for either HFRS or HPS [5] .
T63427 2284-2373 Sentence denotes There are currently no FDA licensed vaccines or therapeutics for either HFRS or HPS [5] .
TextSentencer_T17 2374-2485 Sentence denotes The Syrian hamster (Mesocricetus auratus) is the typical animal used to model hantavirus infection and disease.
T5320 2374-2485 Sentence denotes The Syrian hamster (Mesocricetus auratus) is the typical animal used to model hantavirus infection and disease.
TextSentencer_T18 2486-2783 Sentence denotes Andes virus (ANDV), an HPS-causing hantavirus, causes lethal disease in immunocompetent hamsters [6] , while numerous other HPS-causing hantaviruses including Sin Nombre Virus (SNV) and Choclo virus cause lethal disease in hamsters immunosuppressed with dexamethasone and cyclophosphamide [7, 8] .
T93256 2486-2783 Sentence denotes Andes virus (ANDV), an HPS-causing hantavirus, causes lethal disease in immunocompetent hamsters [6] , while numerous other HPS-causing hantaviruses including Sin Nombre Virus (SNV) and Choclo virus cause lethal disease in hamsters immunosuppressed with dexamethasone and cyclophosphamide [7, 8] .
TextSentencer_T19 2784-3066 Sentence denotes In contrast to HPS-causing hantaviruses, exposure of hamsters to HFRS-causing hantaviruses such as HTNV, PUUV, Dobrava (DOBV) and Seoul (SEOV) leads to asymptomatic infection, despite viral dissemination, even when immunosuppressed (Hooper Lab, unpublished data) [8] [9] [10] [11] .
T22030 2784-3066 Sentence denotes In contrast to HPS-causing hantaviruses, exposure of hamsters to HFRS-causing hantaviruses such as HTNV, PUUV, Dobrava (DOBV) and Seoul (SEOV) leads to asymptomatic infection, despite viral dissemination, even when immunosuppressed (Hooper Lab, unpublished data) [8] [9] [10] [11] .
TextSentencer_T20 3067-3199 Sentence denotes In these studies hamsters were exposed to high doses of HTNV and PUUV, far exceeding the infectious dose 99% (ID 99 ) for the virus.
T29803 3067-3199 Sentence denotes In these studies hamsters were exposed to high doses of HTNV and PUUV, far exceeding the infectious dose 99% (ID 99 ) for the virus.
TextSentencer_T21 3200-3360 Sentence denotes Development and characterization of a uniformly infective, low-dose challenge model, enhances the hamster model's usefulness in vaccine and therapeutic testing.
T92505 3200-3360 Sentence denotes Development and characterization of a uniformly infective, low-dose challenge model, enhances the hamster model's usefulness in vaccine and therapeutic testing.
TextSentencer_T22 3361-3462 Sentence denotes In this report we present a low-dose hamster infection model for both HTNV and PUUV infected animals.
T6217 3361-3462 Sentence denotes In this report we present a low-dose hamster infection model for both HTNV and PUUV infected animals.
TextSentencer_T23 3463-3709 Sentence denotes Ferrets (Mustela putorius furo) have become a popular animal model for a number of respiratory pathogens including influenza [12] , coronavirus [13] , Nipah virus [14] , and morbillivirus [15] , due to the similarity in lung physiology to humans.
T75074 3463-3709 Sentence denotes Ferrets (Mustela putorius furo) have become a popular animal model for a number of respiratory pathogens including influenza [12] , coronavirus [13] , Nipah virus [14] , and morbillivirus [15] , due to the similarity in lung physiology to humans.
TextSentencer_T24 3710-3908 Sentence denotes In addition, they have recently been described as a disease model of two hemorrhagic fever viruses, Bundibugyo virus and Ebola virus [16, 17] , supporting viral replication without prior adaptation.
T5461 3710-3908 Sentence denotes In addition, they have recently been described as a disease model of two hemorrhagic fever viruses, Bundibugyo virus and Ebola virus [16, 17] , supporting viral replication without prior adaptation.
TextSentencer_T25 3909-4116 Sentence denotes Most hantavirusrelated human disease occurs by aerosolized transmission of the virus from the excreta or secreta of infected rodents [18, 19] , a model of viral infection for which the ferret is well suited.
T80457 3909-4116 Sentence denotes Most hantavirusrelated human disease occurs by aerosolized transmission of the virus from the excreta or secreta of infected rodents [18, 19] , a model of viral infection for which the ferret is well suited.
TextSentencer_T26 4117-4333 Sentence denotes In this study we demonstrate that ferrets are capable of being infected by high titers of HTNV and PUUV, though aside from gradual weight loss infected animals exhibit no clinical symptoms or impaired renal function.
T41405 4117-4333 Sentence denotes In this study we demonstrate that ferrets are capable of being infected by high titers of HTNV and PUUV, though aside from gradual weight loss infected animals exhibit no clinical symptoms or impaired renal function.
TextSentencer_T27 4334-4738 Sentence denotes It has been established that infection of rhesus macaques (Macaca mulatta) with HFRScausing hantaviruses (DOBV, SEOV, HTNV, and PUUV) leads to asymptomatic infection and seroconversion [9] , while infection of cynomolgus macaques (Macaca fascicularis) with PUUV leads to a mild disease characterized by lethargy, mild proteinuria and hematuria, and kidney pathology, similar to mild HFRS in humans [20] .
T13552 4334-4738 Sentence denotes It has been established that infection of rhesus macaques (Macaca mulatta) with HFRScausing hantaviruses (DOBV, SEOV, HTNV, and PUUV) leads to asymptomatic infection and seroconversion [9] , while infection of cynomolgus macaques (Macaca fascicularis) with PUUV leads to a mild disease characterized by lethargy, mild proteinuria and hematuria, and kidney pathology, similar to mild HFRS in humans [20] .
TextSentencer_T28 4739-4933 Sentence denotes However, the macaques' large size and cost limits their usefulness in therapeutic studies, especially when test article availability is limited, as is often the case in passive transfer studies.
T72194 4739-4933 Sentence denotes However, the macaques' large size and cost limits their usefulness in therapeutic studies, especially when test article availability is limited, as is often the case in passive transfer studies.
TextSentencer_T29 4934-5031 Sentence denotes The common marmoset (Callithrix jacchus) is becoming more popular for infectious disease studies.
T92336 4934-5031 Sentence denotes The common marmoset (Callithrix jacchus) is becoming more popular for infectious disease studies.
TextSentencer_T30 5032-5185 Sentence denotes Its genetic similarity to humans, cost, relative safety, and small size make it an attractive alternative to traditional non-human primate species [21] .
T41590 5032-5185 Sentence denotes Its genetic similarity to humans, cost, relative safety, and small size make it an attractive alternative to traditional non-human primate species [21] .
TextSentencer_T31 5186-5484 Sentence denotes Marmosets have been used as a disease model for other viral agents including Dengue virus [22] , Hepatitis C virus [23] , influenza virus [24] , Lassa fever virus [25] , orthopox viruses [26] [27] [28] , Rift Valley Fever virus [29] , Eastern Equine Encephalitis virus [30] , and filoviruses [31] .
T58449 5186-5484 Sentence denotes Marmosets have been used as a disease model for other viral agents including Dengue virus [22] , Hepatitis C virus [23] , influenza virus [24] , Lassa fever virus [25] , orthopox viruses [26] [27] [28] , Rift Valley Fever virus [29] , Eastern Equine Encephalitis virus [30] , and filoviruses [31] .
TextSentencer_T32 5485-5637 Sentence denotes In this study we demonstrate that exposure of marmosets to HTNV leads to asymptomatic infection characterized by high levels of neutralizing antibodies.
T68718 5485-5637 Sentence denotes In this study we demonstrate that exposure of marmosets to HTNV leads to asymptomatic infection characterized by high levels of neutralizing antibodies.
TextSentencer_T33 5638-5700 Sentence denotes This is the first report of hantavirus infection in marmosets.
T88370 5638-5700 Sentence denotes This is the first report of hantavirus infection in marmosets.
TextSentencer_T34 5701-5882 Sentence denotes Medical countermeasures are products including biologics (e.g., vaccines and antibodies) and small molecule drugs that can be used to prevent or combat infectious disease outbreaks.
T3091 5701-5882 Sentence denotes Medical countermeasures are products including biologics (e.g., vaccines and antibodies) and small molecule drugs that can be used to prevent or combat infectious disease outbreaks.
TextSentencer_T35 5883-6166 Sentence denotes This study presents three animal models of HTNV infection, and two models of PUUV infection that can be used to evaluate the efficacy of medical countermeasure that are intended to prevent or mitigate infection (e.g., vaccines) by these viruses through induction of sterile immunity.
T30828 5883-6166 Sentence denotes This study presents three animal models of HTNV infection, and two models of PUUV infection that can be used to evaluate the efficacy of medical countermeasure that are intended to prevent or mitigate infection (e.g., vaccines) by these viruses through induction of sterile immunity.
TextSentencer_T36 6167-6668 Sentence denotes HTNV strain 76-118 [32] , PUUV strain K27 [33] , and PUUV strains Beaumont, and Seloignes (gifts of Piet Maes, Leuven, Beligium) were propagated in Vero E6 cells (Vero C1008, ATCC CRL 1586) in T-150 flasks and cEMEM media (Eagle 0 s minimal essential medium with Earle 0 s salts (EMEM) containing 10% heat inactivated fetal bovine serum, 200 μM glutamine, 1% non-essential amino acids, 10 mM HEPES pH 7.4; and antibiotics [penicillin (100 U/ml), amphotericin B (250 μg/ml), and gentamicin (50 mg/ml)].
T22027 6167-6668 Sentence denotes HTNV strain 76-118 [32] , PUUV strain K27 [33] , and PUUV strains Beaumont, and Seloignes (gifts of Piet Maes, Leuven, Beligium) were propagated in Vero E6 cells (Vero C1008, ATCC CRL 1586) in T-150 flasks and cEMEM media (Eagle 0 s minimal essential medium with Earle 0 s salts (EMEM) containing 10% heat inactivated fetal bovine serum, 200 μM glutamine, 1% non-essential amino acids, 10 mM HEPES pH 7.4; and antibiotics [penicillin (100 U/ml), amphotericin B (250 μg/ml), and gentamicin (50 mg/ml)].
TextSentencer_T37 6669-6725 Sentence denotes Virus was collected from infectedmonolayer supernatants.
T10172 6669-6725 Sentence denotes Virus was collected from infectedmonolayer supernatants.
TextSentencer_T38 6726-6815 Sentence denotes Cell debris was removed by low speed centrifugation (2500 rpm in a table top centrifuge).
T68561 6726-6815 Sentence denotes Cell debris was removed by low speed centrifugation (2500 rpm in a table top centrifuge).
TextSentencer_T39 6816-6904 Sentence denotes HTNV and PUUV strain K27 were twice plaque purified according to published methods [6] .
T88323 6816-6904 Sentence denotes HTNV and PUUV strain K27 were twice plaque purified according to published methods [6] .
TextSentencer_T40 6905-6963 Sentence denotes Virus stocks were aliquoted and stored at -60˚C or colder.
T38472 6905-6963 Sentence denotes Virus stocks were aliquoted and stored at -60˚C or colder.
TextSentencer_T41 6964-7026 Sentence denotes Virus identity has been confirmed by sequencing of the stocks.
T62302 6964-7026 Sentence denotes Virus identity has been confirmed by sequencing of the stocks.
TextSentencer_T42 7028-7196 Sentence denotes Female Syrian hamsters 6-8 wks of age (Envigo, Indianapolis, IN) were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine.
T20395 7028-7196 Sentence denotes Female Syrian hamsters 6-8 wks of age (Envigo, Indianapolis, IN) were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine.
TextSentencer_T43 7197-7295 Sentence denotes Once anesthetized, animals were injected with the indicated concentration of virus diluted in PBS.
T69679 7197-7295 Sentence denotes Once anesthetized, animals were injected with the indicated concentration of virus diluted in PBS.
TextSentencer_T44 7296-7430 Sentence denotes Intramuscular (i.m.) injections (in the caudal thigh) consisted of 0.2 ml delivered with a 1ml syringe with a 25-gauge, 5/8 in needle.
T83872 7296-7430 Sentence denotes Intramuscular (i.m.) injections (in the caudal thigh) consisted of 0.2 ml delivered with a 1ml syringe with a 25-gauge, 5/8 in needle.
TextSentencer_T45 7431-7549 Sentence denotes Intranasal (i.n.) instillation consisted of 50 μl total volume delivered as 25 μl per nare with a plastic pipette tip.
T34422 7431-7549 Sentence denotes Intranasal (i.n.) instillation consisted of 50 μl total volume delivered as 25 μl per nare with a plastic pipette tip.
TextSentencer_T46 7550-7705 Sentence denotes Blood sampling from the vena cava occurred under previously stated methods of anesthesia, and was limited to 7% of a hamster's total blood volume per week.
T89690 7550-7705 Sentence denotes Blood sampling from the vena cava occurred under previously stated methods of anesthesia, and was limited to 7% of a hamster's total blood volume per week.
TextSentencer_T47 7706-7774 Sentence denotes At time of arrival animals were randomized into experimental groups.
T71502 7706-7774 Sentence denotes At time of arrival animals were randomized into experimental groups.
TextSentencer_T48 7775-7957 Sentence denotes Animals were housed in small animal pans, not exceeding four animals to a pan, in a climate and humidity controlled animal biosafety level 3 (ABSL-3) with a 12-hour light/dark cycle.
T56936 7775-7957 Sentence denotes Animals were housed in small animal pans, not exceeding four animals to a pan, in a climate and humidity controlled animal biosafety level 3 (ABSL-3) with a 12-hour light/dark cycle.
TextSentencer_T49 7958-8014 Sentence denotes Animals had pelleted food and water provided ad libitum.
T20627 7958-8014 Sentence denotes Animals had pelleted food and water provided ad libitum.
TextSentencer_T50 8015-8101 Sentence denotes Enrichment in the form of toys, nesting material and supplemental treats was provided.
T40380 8015-8101 Sentence denotes Enrichment in the form of toys, nesting material and supplemental treats was provided.
TextSentencer_T51 8102-8297 Sentence denotes Humane endpoint conditions were established as decreased mobility (inability to obtain food and water) and subdued response to stimulation, and animals were monitored daily during the experiment.
T5270 8102-8297 Sentence denotes Humane endpoint conditions were established as decreased mobility (inability to obtain food and water) and subdued response to stimulation, and animals were monitored daily during the experiment.
TextSentencer_T52 8298-8623 Sentence denotes As infected animals did not become ill, these criteria were not met and animals were euthanized by terminal blood collection from the heart after administration of Ketamine-acepromazine-xylazine (KAX)(USAMRIID, Fort Detrick MD) and prior to intracardiac injection with pentobarbital sodium (USAMRIID) at the end of the study.
T91082 8298-8623 Sentence denotes As infected animals did not become ill, these criteria were not met and animals were euthanized by terminal blood collection from the heart after administration of Ketamine-acepromazine-xylazine (KAX)(USAMRIID, Fort Detrick MD) and prior to intracardiac injection with pentobarbital sodium (USAMRIID) at the end of the study.
TextSentencer_T53 8624-8717 Sentence denotes Due to lack of illness no pain relief, aside from anesthesia during procedures, was required.
T74116 8624-8717 Sentence denotes Due to lack of illness no pain relief, aside from anesthesia during procedures, was required.
TextSentencer_T54 8718-8859 Sentence denotes confidence intervals reaching out to 0.7log 10 (approximately 5-fold) under monotome assumptions of response profiles for intermediate doses.
T94458 8718-8859 Sentence denotes confidence intervals reaching out to 0.7log 10 (approximately 5-fold) under monotome assumptions of response profiles for intermediate doses.
TextSentencer_T55 8860-9008 Sentence denotes As our initial selection of dosages did not meet the desired infection rate span, some dosage groups were repeated leading to 20 hamsters per group.
T35059 8860-9008 Sentence denotes As our initial selection of dosages did not meet the desired infection rate span, some dosage groups were repeated leading to 20 hamsters per group.
TextSentencer_T56 9009-9075 Sentence denotes In the serial euthanasia study three hamsters per group were used.
T53100 9009-9075 Sentence denotes In the serial euthanasia study three hamsters per group were used.
TextSentencer_T57 9076-9214 Sentence denotes This is the minimum number required to provide collection of sufficient samples for detection of antibodies and viral kinetics in tissues.
T61060 9076-9214 Sentence denotes This is the minimum number required to provide collection of sufficient samples for detection of antibodies and viral kinetics in tissues.
TextSentencer_T58 9215-9284 Sentence denotes For each experiment pre-sera from animals served as negative control.
T84462 9215-9284 Sentence denotes For each experiment pre-sera from animals served as negative control.
TextSentencer_T59 9285-9522 Sentence denotes Adult, female neutered and descented ferrets (Marshall Farms, North Rose, NY), were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine, or i.m. injection of Telazol (Zoetis, Parsippany, NJ).
T26211 9285-9522 Sentence denotes Adult, female neutered and descented ferrets (Marshall Farms, North Rose, NY), were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine, or i.m. injection of Telazol (Zoetis, Parsippany, NJ).
TextSentencer_T60 9523-9621 Sentence denotes Injections (i.m. and i.n.) and blood sampling were conducted under the same condition as hamsters.
T382 9523-9621 Sentence denotes Injections (i.m. and i.n.) and blood sampling were conducted under the same condition as hamsters.
TextSentencer_T61 9622-9726 Sentence denotes Intraperitoneal (i.p.) injections consisted of 1 ml delivered with a 3 mL syringe and a 23-guage needle.
T93168 9622-9726 Sentence denotes Intraperitoneal (i.p.) injections consisted of 1 ml delivered with a 3 mL syringe and a 23-guage needle.
TextSentencer_T62 9727-9832 Sentence denotes Microchips (BMDS, Seaford, DE) were used to identify and ascertain temperature during ferret experiments.
T15209 9727-9832 Sentence denotes Microchips (BMDS, Seaford, DE) were used to identify and ascertain temperature during ferret experiments.
TextSentencer_T63 9833-9969 Sentence denotes In the first ferret challenge study faulty chips lead to inaccurate temperature readings and were only used for identification purposes.
T63505 9833-9969 Sentence denotes In the first ferret challenge study faulty chips lead to inaccurate temperature readings and were only used for identification purposes.
TextSentencer_T64 9970-10032 Sentence denotes Animals were randomized upon receipt into experimental groups.
T13453 9970-10032 Sentence denotes Animals were randomized upon receipt into experimental groups.
TextSentencer_T65 10033-10226 Sentence denotes Ferrets were socially housed in metal caging, two to a cage, with sight lines to additional animals in the study, in a climate and humidity controlled ABSL-3 with 12/hour light and dark cycles.
T96484 10033-10226 Sentence denotes Ferrets were socially housed in metal caging, two to a cage, with sight lines to additional animals in the study, in a climate and humidity controlled ABSL-3 with 12/hour light and dark cycles.
TextSentencer_T66 10227-10317 Sentence denotes Each cage had a nesting box with bedding material, and numerous tubes and shelfs for play.
T43548 10227-10317 Sentence denotes Each cage had a nesting box with bedding material, and numerous tubes and shelfs for play.
TextSentencer_T67 10318-10435 Sentence denotes Ferrets had access to pelleted food supplemented with treats and potable water, through an automated watering system.
T32868 10318-10435 Sentence denotes Ferrets had access to pelleted food supplemented with treats and potable water, through an automated watering system.
TextSentencer_T68 10436-10519 Sentence denotes Enrichment in the form of manipulada (tubes, balls, mirrors) and food was provided.
T26608 10436-10519 Sentence denotes Enrichment in the form of manipulada (tubes, balls, mirrors) and food was provided.
TextSentencer_T69 10520-10614 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
T58099 10520-10614 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
TextSentencer_T70 10615-10733 Sentence denotes Humane euthanasia criteria, defined as both dyspnea, loss of mobility (to obtain food and water) and >20% weight loss.
T23659 10615-10733 Sentence denotes Humane euthanasia criteria, defined as both dyspnea, loss of mobility (to obtain food and water) and >20% weight loss.
TextSentencer_T71 10734-10907 Sentence denotes At the end of the experiment, terminal blood samples were collected from the heart after administration of KAX and prior to intracardiac injection with pentobarbital sodium.
T70725 10734-10907 Sentence denotes At the end of the experiment, terminal blood samples were collected from the heart after administration of KAX and prior to intracardiac injection with pentobarbital sodium.
TextSentencer_T72 10908-10974 Sentence denotes No pain relief, aside from anesthesia during procedures, was used.
T11111 10908-10974 Sentence denotes No pain relief, aside from anesthesia during procedures, was used.
TextSentencer_T73 10975-11146 Sentence denotes When disease occurs independently in each of four ferrets with 50% probability, the experiment will have odds about 9:1 in favor of producing at least one diseased ferret.
T40590 10975-11146 Sentence denotes When disease occurs independently in each of four ferrets with 50% probability, the experiment will have odds about 9:1 in favor of producing at least one diseased ferret.
TextSentencer_T74 11147-11274 Sentence denotes Conversely failure to observe any diseased ferret in a group of four will yield a 95% confidence interval extending from 0-50%.
T93055 11147-11274 Sentence denotes Conversely failure to observe any diseased ferret in a group of four will yield a 95% confidence interval extending from 0-50%.
TextSentencer_T75 11275-11370 Sentence denotes That is, with 95% confidence it will be admitted that the true disease rate may be 50% or less.
T16259 11275-11370 Sentence denotes That is, with 95% confidence it will be admitted that the true disease rate may be 50% or less.
TextSentencer_T76 11371-11440 Sentence denotes For this reason groups of four ferrets were used for the experiments.
T11383 11371-11440 Sentence denotes For this reason groups of four ferrets were used for the experiments.
TextSentencer_T77 11441-11512 Sentence denotes For each experiment pre-sera from animals served as a negative control.
T90736 11441-11512 Sentence denotes For each experiment pre-sera from animals served as a negative control.
TextSentencer_T78 11513-11651 Sentence denotes Adult marmosets weighing over 300g were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine.
T92730 11513-11651 Sentence denotes Adult marmosets weighing over 300g were anesthetized by inhalation of vaporized isoflurane using an IMPAC 6 veterinary anesthesia machine.
TextSentencer_T79 11652-11750 Sentence denotes Once anesthetized, animals were injected with the indicated concentration of virus diluted in PBS.
T13491 11652-11750 Sentence denotes Once anesthetized, animals were injected with the indicated concentration of virus diluted in PBS.
TextSentencer_T80 11751-11869 Sentence denotes I.m. injections (in the caudal thigh) consisted of 0.2 ml delivered with a 1ml syringe with a 25-gauge, 5/8 in needle.
T36200 11751-11869 Sentence denotes I.m. injections (in the caudal thigh) consisted of 0.2 ml delivered with a 1ml syringe with a 25-gauge, 5/8 in needle.
TextSentencer_T81 11870-12031 Sentence denotes Blood sampling from a femoral vein occurred under previously stated methods of anesthesia, and were limited to 7% of each marmoset's total blood volume per week.
T35587 11870-12031 Sentence denotes Blood sampling from a femoral vein occurred under previously stated methods of anesthesia, and were limited to 7% of each marmoset's total blood volume per week.
TextSentencer_T82 12032-12224 Sentence denotes At time of euthanasia, terminal blood samples were collected from the heart after anesthetization by i.m. injection of Telazol and prior to intracardiac administration of pentobarbital sodium.
T15804 12032-12224 Sentence denotes At time of euthanasia, terminal blood samples were collected from the heart after anesthetization by i.m. injection of Telazol and prior to intracardiac administration of pentobarbital sodium.
TextSentencer_T83 12225-12290 Sentence denotes Animals were housed in containment as previously described [26] .
T82195 12225-12290 Sentence denotes Animals were housed in containment as previously described [26] .
TextSentencer_T84 12291-12411 Sentence denotes In brief, animals were singly housed in metal cages meeting current standards in a climate and humidity controlled room.
T74542 12291-12411 Sentence denotes In brief, animals were singly housed in metal cages meeting current standards in a climate and humidity controlled room.
TextSentencer_T85 12412-12566 Sentence denotes Animals were fed pelleted food supplemented with fruits and treats daily, and were provided potable water through an automatic watering system ad libitum.
T32118 12412-12566 Sentence denotes Animals were fed pelleted food supplemented with fruits and treats daily, and were provided potable water through an automatic watering system ad libitum.
TextSentencer_T86 12567-12688 Sentence denotes Enrichment in the form of manipulada (i.e. toys, metal mirrors), foraging devices, treats, and fruit were provided daily.
T30341 12567-12688 Sentence denotes Enrichment in the form of manipulada (i.e. toys, metal mirrors), foraging devices, treats, and fruit were provided daily.
TextSentencer_T87 12689-12783 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
T1951 12689-12783 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
TextSentencer_T88 12784-12878 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
T10396 12784-12878 Sentence denotes Animals were observed daily by trained personnel in addition to general husbandry assessments.
TextSentencer_T89 12879-13149 Sentence denotes Animals found moribund (defined as labored breathing, decreased food consumption, persistent prostration and moderate unresponsiveness) would be euthanized under humane endpoint criteria, however, as animals did not become ill during the study this criteria was not met.
T36021 12879-13149 Sentence denotes Animals found moribund (defined as labored breathing, decreased food consumption, persistent prostration and moderate unresponsiveness) would be euthanized under humane endpoint criteria, however, as animals did not become ill during the study this criteria was not met.
TextSentencer_T90 13150-13232 Sentence denotes No additional pain relief, aside from anesthesia during procedures, was necessary.
T85365 13150-13232 Sentence denotes No additional pain relief, aside from anesthesia during procedures, was necessary.
TextSentencer_T91 13233-13280 Sentence denotes All work was performed in an ABSL-3 laboratory.
T46521 13233-13280 Sentence denotes All work was performed in an ABSL-3 laboratory.
TextSentencer_T92 13281-13472 Sentence denotes The marmoset study requires a sample size of 3 for adequate power to determine if the incidence of seroconversion is significantly greater than that which would be expected in the population.
T32685 13281-13472 Sentence denotes The marmoset study requires a sample size of 3 for adequate power to determine if the incidence of seroconversion is significantly greater than that which would be expected in the population.
TextSentencer_T93 13473-13698 Sentence denotes This sample size will allow the experimenter to detect seroconversion in at least 2 of 3 animals (66%) versus the expected population constant of <1% at a 95% confidence level using a one-tailed binomial test for proportions.
T75220 13473-13698 Sentence denotes This sample size will allow the experimenter to detect seroconversion in at least 2 of 3 animals (66%) versus the expected population constant of <1% at a 95% confidence level using a one-tailed binomial test for proportions.
TextSentencer_T94 13699-13846 Sentence denotes The enzyme-linked immunosorbent assay (ELISA) used to detect nucleocapsid protein (N) specific antibodies (N-ELISA) was described previously [34] .
T33712 13699-13846 Sentence denotes The enzyme-linked immunosorbent assay (ELISA) used to detect nucleocapsid protein (N) specific antibodies (N-ELISA) was described previously [34] .
TextSentencer_T95 13847-14161 Sentence denotes Species-specific secondary antibodies were used at the following concentrations: peroxide-labeled anti-hamster (1:10,000) (Sera Care, Gaithersburg, MD), peroxide-labeled anti-ferret (1:5,000) (Sigma Aldrich, St. Louis, MO), and alkaline phosphatase conjugated anti-monkey (1:1,000) (MilliporeSigma, St. Louis, MO).
T82278 13847-14161 Sentence denotes Species-specific secondary antibodies were used at the following concentrations: peroxide-labeled anti-hamster (1:10,000) (Sera Care, Gaithersburg, MD), peroxide-labeled anti-ferret (1:5,000) (Sigma Aldrich, St. Louis, MO), and alkaline phosphatase conjugated anti-monkey (1:1,000) (MilliporeSigma, St. Louis, MO).
TextSentencer_T96 14162-14454 Sentence denotes Assays using peroxide labeled antibodies were developed with TMB microwell peroxidase substrate (Sera Care) at an absorbance of 450 nm; assays using alkaline phosphatase conjugated antibodies were developed with p-nitrophenyl phosphate (PNPP) (ThermoFisher Scientific, Waltham, MA) at 405 nm.
T70536 14162-14454 Sentence denotes Assays using peroxide labeled antibodies were developed with TMB microwell peroxidase substrate (Sera Care) at an absorbance of 450 nm; assays using alkaline phosphatase conjugated antibodies were developed with p-nitrophenyl phosphate (PNPP) (ThermoFisher Scientific, Waltham, MA) at 405 nm.
TextSentencer_T97 14455-14679 Sentence denotes A sample was considered positive if its peak optical density (OD) value was greater than either 0.025 or the background value (the average of three negative controls + 3 times their standard deviation), whichever was higher.
T57920 14455-14679 Sentence denotes A sample was considered positive if its peak optical density (OD) value was greater than either 0.025 or the background value (the average of three negative controls + 3 times their standard deviation), whichever was higher.
TextSentencer_T98 14680-14801 Sentence denotes The specific OD sum is the summation of all values greater than background and represents the area under the titer curve.
T33111 14680-14801 Sentence denotes The specific OD sum is the summation of all values greater than background and represents the area under the titer curve.
TextSentencer_T99 14802-14886 Sentence denotes PRNT assays were performed as previously described with minor modifications [35-37].
T10132 14802-14886 Sentence denotes PRNT assays were performed as previously described with minor modifications [35-37].
TextSentencer_T100 14887-15044 Sentence denotes HTNV-infected monolayers were fixed 7 days post-infection, while PUUV-infected monolayers were fixed 10 days post infection by 2 mL of 10% formalin per well.
T29487 14887-15044 Sentence denotes HTNV-infected monolayers were fixed 7 days post-infection, while PUUV-infected monolayers were fixed 10 days post infection by 2 mL of 10% formalin per well.
TextSentencer_T101 15045-15104 Sentence denotes Immunostaining was performed as previously described [38] .
T51028 15045-15104 Sentence denotes Immunostaining was performed as previously described [38] .
TextSentencer_T102 15105-15183 Sentence denotes All sera samples were assayed in duplicate beginning at a 1:20 final dilution.
T120 15105-15183 Sentence denotes All sera samples were assayed in duplicate beginning at a 1:20 final dilution.
TextSentencer_T103 15184-15281 Sentence denotes PRNT 50 values represent the reciprocal dilution at which the serum neutralizes 50% of the virus.
T96576 15184-15281 Sentence denotes PRNT 50 values represent the reciprocal dilution at which the serum neutralizes 50% of the virus.
TextSentencer_T104 15282-15491 Sentence denotes Approximately 200 mg of organ tissue was homogenized in 1.0 mL of TRIzol (ThermoFisher, Waltham, MA) reagent using M tubes on the gentleMACS (Miltenyi Biotec,Auburn, CA) dissociation system on the RNA setting.
T74974 15282-15491 Sentence denotes Approximately 200 mg of organ tissue was homogenized in 1.0 mL of TRIzol (ThermoFisher, Waltham, MA) reagent using M tubes on the gentleMACS (Miltenyi Biotec,Auburn, CA) dissociation system on the RNA setting.
TextSentencer_T105 15492-15550 Sentence denotes RNA was extracted from TRIzol per manufacturer's protocol.
T49844 15492-15550 Sentence denotes RNA was extracted from TRIzol per manufacturer's protocol.
TextSentencer_T106 15551-15710 Sentence denotes A Nanodrop 8000 was used to determined RNA concentration, which was then raised to either 100 ng/μL or 1,000 ng/μL in UltraPure distilled water (Thermofisher).
T87053 15551-15710 Sentence denotes A Nanodrop 8000 was used to determined RNA concentration, which was then raised to either 100 ng/μL or 1,000 ng/μL in UltraPure distilled water (Thermofisher).
TextSentencer_T107 15711-15964 Sentence denotes Real-time PCR was conducted on a BioRad CFX thermal cycler using either an Invitrogen Power SYBR Green RNA-to-Ct one-step kit (Thermofisher) or Brilliant II QRT-PCR 1 -Step Master Mix (Agilent, Santa Clara, CA) according to the manufacturer's protocols.
T68415 15711-15964 Sentence denotes Real-time PCR was conducted on a BioRad CFX thermal cycler using either an Invitrogen Power SYBR Green RNA-to-Ct one-step kit (Thermofisher) or Brilliant II QRT-PCR 1 -Step Master Mix (Agilent, Santa Clara, CA) according to the manufacturer's protocols.
TextSentencer_T108 15965-16077 Sentence denotes For spiked assays the master mix was spiked with either HTNV or PUUV viral RNA prior to addition to the samples.
T13931 15965-16077 Sentence denotes For spiked assays the master mix was spiked with either HTNV or PUUV viral RNA prior to addition to the samples.
TextSentencer_T109 16078-16153 Sentence denotes For HTNV, primer sequences were 594F 5'-AAG CAT GAA GGC AGA AGA GAT -3' and
T88573 16078-16153 Sentence denotes For HTNV, primer sequences were 594F 5'-AAG CAT GAA GGC AGA AGA GAT -3' and
TextSentencer_T110 16155-16272 Sentence denotes T-25 flasks of one week old Vero E6 cells were infected with 50 μL of urine plus an additional 450 μL of cEMEM media.
T11870 16155-16272 Sentence denotes T-25 flasks of one week old Vero E6 cells were infected with 50 μL of urine plus an additional 450 μL of cEMEM media.
TextSentencer_T111 16273-16352 Sentence denotes After a 1 hr adsorption at 37˚C with 5% CO 2 , the volume was raised to 3.5 mL.
T18054 16273-16352 Sentence denotes After a 1 hr adsorption at 37˚C with 5% CO 2 , the volume was raised to 3.5 mL.
TextSentencer_T112 16353-16499 Sentence denotes On Day 4 post infection supernatant was collected and frozen down, 500 μL of which was used to infected fresh Vero E6 cells at a later time point.
T59223 16353-16499 Sentence denotes On Day 4 post infection supernatant was collected and frozen down, 500 μL of which was used to infected fresh Vero E6 cells at a later time point.
TextSentencer_T113 16500-16579 Sentence denotes After a 1 hr adsorption at 37˚C with 5% CO 2 , the volume was raised to 3.5 mL.
T32791 16500-16579 Sentence denotes After a 1 hr adsorption at 37˚C with 5% CO 2 , the volume was raised to 3.5 mL.
TextSentencer_T114 16580-16673 Sentence denotes On days 7, 11, 14, 17, 21 and 28 1.2 mL of culture supernatant was collected and frozen down.
T18537 16580-16673 Sentence denotes On days 7, 11, 14, 17, 21 and 28 1.2 mL of culture supernatant was collected and frozen down.
TextSentencer_T115 16674-16745 Sentence denotes The volume of cEMEM in the flask was raised to 3.5 mL with fresh media.
T16217 16674-16745 Sentence denotes The volume of cEMEM in the flask was raised to 3.5 mL with fresh media.
TextSentencer_T116 16746-16894 Sentence denotes Approximately 200 μg of organ tissue were homogenized in 1 mL of cEMEM media using M tubes on the gentleMACS dissociation system on the RNA setting.
T93122 16746-16894 Sentence denotes Approximately 200 μg of organ tissue were homogenized in 1 mL of cEMEM media using M tubes on the gentleMACS dissociation system on the RNA setting.
TextSentencer_T117 16895-17048 Sentence denotes Plaque assays using urine, sera, or organ homogenate were then performed beginning at the 1:10 dilution as described in [6, 41] with minor modifications.
T25903 16895-17048 Sentence denotes Plaque assays using urine, sera, or organ homogenate were then performed beginning at the 1:10 dilution as described in [6, 41] with minor modifications.
TextSentencer_T118 17049-17237 Sentence denotes For spiked plaque assays the protocol was identical except for equivalent amounts of virus being spiked into either media alone (control), or the 1:10-1:1,000 dilution of organ homogenate.
T31522 17049-17237 Sentence denotes For spiked plaque assays the protocol was identical except for equivalent amounts of virus being spiked into either media alone (control), or the 1:10-1:1,000 dilution of organ homogenate.
TextSentencer_T119 17238-17394 Sentence denotes HTNV-infected monolayers were fixed 7 days postinfection, while PUUV-infected monolayers were fixed 10 days post infection by 2 mL of 10% formalin per well.
T63662 17238-17394 Sentence denotes HTNV-infected monolayers were fixed 7 days postinfection, while PUUV-infected monolayers were fixed 10 days post infection by 2 mL of 10% formalin per well.
TextSentencer_T120 17395-17454 Sentence denotes Immunostaining was performed as previously described [38] .
T78731 17395-17454 Sentence denotes Immunostaining was performed as previously described [38] .
TextSentencer_T121 17455-17503 Sentence denotes Following euthanasia, necropsies were performed.
T64851 17455-17503 Sentence denotes Following euthanasia, necropsies were performed.
TextSentencer_T122 17504-17580 Sentence denotes Samples were collected aseptically for the virology studies described above.
T38411 17504-17580 Sentence denotes Samples were collected aseptically for the virology studies described above.
TextSentencer_T123 17581-17705 Sentence denotes For the hamsters and ferrets, samples of the following were collected: heart, lung, liver, spleen, kidney, brain, and urine.
T26172 17581-17705 Sentence denotes For the hamsters and ferrets, samples of the following were collected: heart, lung, liver, spleen, kidney, brain, and urine.
TextSentencer_T124 17706-17808 Sentence denotes In addition, ferrets had samples of intestine, adrenal gland, pituitary gland, and eye were collected.
T88080 17706-17808 Sentence denotes In addition, ferrets had samples of intestine, adrenal gland, pituitary gland, and eye were collected.
TextSentencer_T125 17809-17926 Sentence denotes Samples of the following were collected from the marmosets: heart, lung, liver, spleen, kidney, intestine, and brain.
T31980 17809-17926 Sentence denotes Samples of the following were collected from the marmosets: heart, lung, liver, spleen, kidney, intestine, and brain.
TextSentencer_T126 17927-18047 Sentence denotes After the virology samples had been collected, all major internal organs in each animal were also sampled for histology.
T21080 17927-18047 Sentence denotes After the virology samples had been collected, all major internal organs in each animal were also sampled for histology.
TextSentencer_T127 18048-18113 Sentence denotes Tissues were fixed in 10% neutral-buffered formalin for �21 days.
T23633 18048-18113 Sentence denotes Tissues were fixed in 10% neutral-buffered formalin for �21 days.
TextSentencer_T128 18114-18236 Sentence denotes Tissues were then trimmed, processed under vacuum through increasing concentrations of alcohols, and embedded in paraffin.
T52092 18114-18236 Sentence denotes Tissues were then trimmed, processed under vacuum through increasing concentrations of alcohols, and embedded in paraffin.
TextSentencer_T129 18237-18431 Sentence denotes Paraffin embedded tissue sections of 5-6 μm were cut and mounted on glass slides, stained with hematoxylin and eosin (H&E), and mounted under a glass coverslip for routine histologic evaluation.
T91229 18237-18431 Sentence denotes Paraffin embedded tissue sections of 5-6 μm were cut and mounted on glass slides, stained with hematoxylin and eosin (H&E), and mounted under a glass coverslip for routine histologic evaluation.
TextSentencer_T130 18432-18588 Sentence denotes The paraffin-embedded tissues used for producing the H&E-stained histology slides were also utilized for immunohistochemistry (IHC) studies in the hamsters.
T58433 18432-18588 Sentence denotes The paraffin-embedded tissues used for producing the H&E-stained histology slides were also utilized for immunohistochemistry (IHC) studies in the hamsters.
TextSentencer_T131 18589-18766 Sentence denotes Immunolocalization of HTNV in tissues was performed with an immunoperoxidase procedure (horseradish peroxidase EnVision system; Dako) according to the manufacturer's directions.
T36022 18589-18766 Sentence denotes Immunolocalization of HTNV in tissues was performed with an immunoperoxidase procedure (horseradish peroxidase EnVision system; Dako) according to the manufacturer's directions.
TextSentencer_T132 18767-18921 Sentence denotes The primary antibody was an anti-HTNV nucleocapsid rabbit polyclonal antibody diluted 1:3,500 (ferret) or 1:5,000 (hamster) (BEI Resources, Manassas, VA).
T24143 18767-18921 Sentence denotes The primary antibody was an anti-HTNV nucleocapsid rabbit polyclonal antibody diluted 1:3,500 (ferret) or 1:5,000 (hamster) (BEI Resources, Manassas, VA).
TextSentencer_T133 18922-19144 Sentence denotes After deparaffinization and peroxidase blocking, tissue sections were pretreated with proteinase K for 6 min at room temperature, rinsed, and then covered with primary antibody and incubated at room temperature for 30 min.
T91044 18922-19144 Sentence denotes After deparaffinization and peroxidase blocking, tissue sections were pretreated with proteinase K for 6 min at room temperature, rinsed, and then covered with primary antibody and incubated at room temperature for 30 min.
TextSentencer_T134 19145-19247 Sentence denotes They were rinsed, and then the peroxidase-labeled polymer (secondary antibody) was applied for 30 min.
T28368 19145-19247 Sentence denotes They were rinsed, and then the peroxidase-labeled polymer (secondary antibody) was applied for 30 min.
TextSentencer_T135 19248-19372 Sentence denotes Slides were rinsed, and a substrate-chromogen solution (3,3'-diaminobenzidine; Dako, Santa Clara, CA) was applied for 5 min.
T55164 19248-19372 Sentence denotes Slides were rinsed, and a substrate-chromogen solution (3,3'-diaminobenzidine; Dako, Santa Clara, CA) was applied for 5 min.
TextSentencer_T136 19373-19489 Sentence denotes The substrate-chromogen solution was rinsed off the slides, and the slides were stained with hematoxylin and rinsed.
T91403 19373-19489 Sentence denotes The substrate-chromogen solution was rinsed off the slides, and the slides were stained with hematoxylin and rinsed.
TextSentencer_T137 19490-19576 Sentence denotes The sections were dehydrated and cleared with xyless, and then a coverslip was placed.
T51051 19490-19576 Sentence denotes The sections were dehydrated and cleared with xyless, and then a coverslip was placed.
TextSentencer_T138 19577-19821 Sentence denotes On the indicated days, anesthetized ferrets were injected i.p. with water soluble Cyp (Baxter Health Care Corporation, Deerfield, IL) with the indicated dosages per body weight of drug diluted in sterile phosphate-buffered saline (PBS), pH 7.4.
T2609 19577-19821 Sentence denotes On the indicated days, anesthetized ferrets were injected i.p. with water soluble Cyp (Baxter Health Care Corporation, Deerfield, IL) with the indicated dosages per body weight of drug diluted in sterile phosphate-buffered saline (PBS), pH 7.4.
TextSentencer_T139 19822-20006 Sentence denotes In the first experiment ferrets were administered a loading dose of 30 mg/kg on Day 41 post infection, with maintenance doses of 30 mg/kg administered every other day until euthanasia.
T26999 19822-20006 Sentence denotes In the first experiment ferrets were administered a loading dose of 30 mg/kg on Day 41 post infection, with maintenance doses of 30 mg/kg administered every other day until euthanasia.
TextSentencer_T140 20007-20156 Sentence denotes In the second experiment, ferrets were administered a loading dose of 30 mg/kg on Day -1, and a maintenance dose of 10 mg/kg on Day 1, 3, 11, and 13.
T68539 20007-20156 Sentence denotes In the second experiment, ferrets were administered a loading dose of 30 mg/kg on Day -1, and a maintenance dose of 10 mg/kg on Day 1, 3, 11, and 13.
TextSentencer_T141 20157-20245 Sentence denotes Administration of Cyp was discontinued between days 3 and 11 due to secondary infection.
T75989 20157-20245 Sentence denotes Administration of Cyp was discontinued between days 3 and 11 due to secondary infection.
TextSentencer_T142 20246-20463 Sentence denotes To combat the infection (rapid onset of fever and weight loss), ferrets were treated with 5mg/kg i.m. enrofloxicin(Norbrook Laboratories, Overland Park, KS) twice daily per veterinarian instructions starting on Day 4.
T96197 20246-20463 Sentence denotes To combat the infection (rapid onset of fever and weight loss), ferrets were treated with 5mg/kg i.m. enrofloxicin(Norbrook Laboratories, Overland Park, KS) twice daily per veterinarian instructions starting on Day 4.
TextSentencer_T143 20464-20607 Sentence denotes Beginning on Day 11 with the resumption of immunosuppression ferrets were treated prophylactically with 10 mg/kg i.m. enrofloxicin once daily).
T16969 20464-20607 Sentence denotes Beginning on Day 11 with the resumption of immunosuppression ferrets were treated prophylactically with 10 mg/kg i.m. enrofloxicin once daily).
TextSentencer_T144 20608-20781 Sentence denotes Blood samples of 0.5 mL were collected in lithium heparin capillary blood collection tubes and analyzed using an Advia 120 hematology analyzer (Software version 3.1.8.0-MS).
T46299 20608-20781 Sentence denotes Blood samples of 0.5 mL were collected in lithium heparin capillary blood collection tubes and analyzed using an Advia 120 hematology analyzer (Software version 3.1.8.0-MS).
TextSentencer_T145 20782-20969 Sentence denotes Per manufacturer's recommendation, the dog setting was used for the complete blood count (CBC) and the guinea pig setting was used for the white blood cell differential (WBC) in hamsters.
T36395 20782-20969 Sentence denotes Per manufacturer's recommendation, the dog setting was used for the complete blood count (CBC) and the guinea pig setting was used for the white blood cell differential (WBC) in hamsters.
TextSentencer_T146 20970-21033 Sentence denotes For ferrets, the dog setting was used for both the CBC and WBC.
T74441 20970-21033 Sentence denotes For ferrets, the dog setting was used for both the CBC and WBC.
TextSentencer_T147 21034-21126 Sentence denotes The PsVNA used to detect neutralizing antibodies in sera was described previously [42, 43] .
T50365 21034-21126 Sentence denotes The PsVNA used to detect neutralizing antibodies in sera was described previously [42, 43] .
TextSentencer_T148 21127-21286 Sentence denotes This is a replication-restricted, recombinant vesicular stomatitis virus (rVSV � ΔG) expressing luciferase, which is pseudotyped with the Hantaan glycoprotein.
T3766 21127-21286 Sentence denotes This is a replication-restricted, recombinant vesicular stomatitis virus (rVSV � ΔG) expressing luciferase, which is pseudotyped with the Hantaan glycoprotein.
TextSentencer_T149 21287-21560 Sentence denotes First, heat-inactivated sera was diluted 1:10, followed by five-fold serial dilutions that were mixed with an equal volume of Eagle 0 s minimum essential medium with Earle 0 s salts and 10% fetal bovine sera containing 4000 fluorescent focus units of Hantaan pseudovirions.
T67482 21287-21560 Sentence denotes First, heat-inactivated sera was diluted 1:10, followed by five-fold serial dilutions that were mixed with an equal volume of Eagle 0 s minimum essential medium with Earle 0 s salts and 10% fetal bovine sera containing 4000 fluorescent focus units of Hantaan pseudovirions.
TextSentencer_T150 21561-21605 Sentence denotes This mixture was incubated overnight at 4˚C.
T62528 21561-21605 Sentence denotes This mixture was incubated overnight at 4˚C.
TextSentencer_T151 21606-21739 Sentence denotes Following this incubation, 50 μl was inoculated onto Vero cell monolayers in a clear bottom, black-walled 96-well plate in duplicate.
T26527 21606-21739 Sentence denotes Following this incubation, 50 μl was inoculated onto Vero cell monolayers in a clear bottom, black-walled 96-well plate in duplicate.
TextSentencer_T152 21740-21783 Sentence denotes Plates were incubated at 37˚C for 18-24 hr.
T47348 21740-21783 Sentence denotes Plates were incubated at 37˚C for 18-24 hr.
TextSentencer_T153 21784-21893 Sentence denotes The media was discarded and cells were lysed according to the luciferase kit protocol (Promega, Madison, WI).
T58369 21784-21893 Sentence denotes The media was discarded and cells were lysed according to the luciferase kit protocol (Promega, Madison, WI).
TextSentencer_T154 21894-21947 Sentence denotes A Tecan M200 Pro was used to acquire luciferase data.
T42496 21894-21947 Sentence denotes A Tecan M200 Pro was used to acquire luciferase data.
TextSentencer_T155 21948-22153 Sentence denotes The values were graphed using GraphPad Prism (version 7) and used to calculate the percent neutralization normalized to cells alone and pseudovirions alone as the minimum and maximum signals, respectively.
T86197 21948-22153 Sentence denotes The values were graphed using GraphPad Prism (version 7) and used to calculate the percent neutralization normalized to cells alone and pseudovirions alone as the minimum and maximum signals, respectively.
TextSentencer_T156 22154-22232 Sentence denotes The percent neutralization values for duplicate serial dilutions were plotted.
T85024 22154-22232 Sentence denotes The percent neutralization values for duplicate serial dilutions were plotted.
TextSentencer_T157 22233-22357 Sentence denotes Fifty percent PsVNA (PsVNA 50 ) titers were interpolated from 4-parameter curves, and geometric mean titers were calculated.
T60575 22233-22357 Sentence denotes Fifty percent PsVNA (PsVNA 50 ) titers were interpolated from 4-parameter curves, and geometric mean titers were calculated.
TextSentencer_T158 22358-22438 Sentence denotes Blood was collected in serum separator tube, and spun at 500x g to isolate sera.
T21930 22358-22438 Sentence denotes Blood was collected in serum separator tube, and spun at 500x g to isolate sera.
TextSentencer_T159 22439-22659 Sentence denotes Ferret sera was analyzed on the Piccolo comprehensive metabolic panel, and marmoset sera was analyzed on the Piccolo general chemistry 13 panel per manufacturer's instructions (Abaxis Global Diagnostics, Union City, CA).
T10514 22439-22659 Sentence denotes Ferret sera was analyzed on the Piccolo comprehensive metabolic panel, and marmoset sera was analyzed on the Piccolo general chemistry 13 panel per manufacturer's instructions (Abaxis Global Diagnostics, Union City, CA).
TextSentencer_T160 22660-22765 Sentence denotes Urine was expressed from anesthetized ferrets and analyzed by urinalysis regent strips (VWR, Radnor, PA).
T44596 22660-22765 Sentence denotes Urine was expressed from anesthetized ferrets and analyzed by urinalysis regent strips (VWR, Radnor, PA).
TextSentencer_T161 22766-22897 Sentence denotes A Bayesian probit model was used to estimate 95% highest posterior density intervals for a 50% and 95% infectious dose calculation.
T5430 22766-22897 Sentence denotes A Bayesian probit model was used to estimate 95% highest posterior density intervals for a 50% and 95% infectious dose calculation.
TextSentencer_T162 22898-23015 Sentence denotes Student's t-test and Mann-Whitney tests were used to compare white blood cell levels pre-and post-Cyp administration.
T59845 22898-23015 Sentence denotes Student's t-test and Mann-Whitney tests were used to compare white blood cell levels pre-and post-Cyp administration.
TextSentencer_T163 23016-23062 Sentence denotes P-values of <0.05 were considered significant.
T41780 23016-23062 Sentence denotes P-values of <0.05 were considered significant.
TextSentencer_T164 23063-23176 Sentence denotes Standard deviation of data was assessed to ensure data was normally distributed prior to use of Student's t-test.
T52463 23063-23176 Sentence denotes Standard deviation of data was assessed to ensure data was normally distributed prior to use of Student's t-test.
TextSentencer_T165 23177-23278 Sentence denotes Analyses were conducted using GraphPad Prism (version 7); Bayesian analyses were performed using SAS.
T61522 23177-23278 Sentence denotes Analyses were conducted using GraphPad Prism (version 7); Bayesian analyses were performed using SAS.
TextSentencer_T166 23279-23450 Sentence denotes We have previously demonstrated that Syrian hamsters are capable of being infected by HFRScausing hantaviruses, but they do not develop any signs of clinical disease [9] .
T81450 23279-23450 Sentence denotes We have previously demonstrated that Syrian hamsters are capable of being infected by HFRScausing hantaviruses, but they do not develop any signs of clinical disease [9] .
TextSentencer_T167 23451-23751 Sentence denotes To develop standard models of HTNV and PUUV infection for future evaluation of vaccines and medical countermeasures, groups of between 10 and 20 hamsters were exposed to serial ten-fold dilutions of either HTNV or PUUV by either the i.m. or i.n. route (from 2-20,000 PFU HTNV or 0.2-20,000 PFU PUUV).
T64743 23451-23751 Sentence denotes To develop standard models of HTNV and PUUV infection for future evaluation of vaccines and medical countermeasures, groups of between 10 and 20 hamsters were exposed to serial ten-fold dilutions of either HTNV or PUUV by either the i.m. or i.n. route (from 2-20,000 PFU HTNV or 0.2-20,000 PFU PUUV).
TextSentencer_T168 23752-23876 Sentence denotes Between 28-35 days post infection, hamsters were terminally bled with infection status monitored by N-ELISA titers (Fig 1) .
T94960 23752-23876 Sentence denotes Between 28-35 days post infection, hamsters were terminally bled with infection status monitored by N-ELISA titers (Fig 1) .
TextSentencer_T169 23877-23980 Sentence denotes From these data the doses required to infect 50% (ID 50 ) and 99% (ID 99 ) were calculated ( Table 1 ).
T91317 23877-23980 Sentence denotes From these data the doses required to infect 50% (ID 50 ) and 99% (ID 99 ) were calculated ( Table 1 ).
TextSentencer_T170 23981-24126 Sentence denotes To further characterize a low-dose standard hamster infection model for HFRS-causing hantaviruses a hamster serial sacrifice study was performed.
T26859 23981-24126 Sentence denotes To further characterize a low-dose standard hamster infection model for HFRS-causing hantaviruses a hamster serial sacrifice study was performed.
TextSentencer_T171 24127-24296 Sentence denotes Hamsters were challenged with either 10 PFU (~3 ID 99 ) HTNV i.m., 500 PFU (~1.5 ID 99 ) HTNV i.n., 1,000 PFU (~1 ID 99 ) PUUV i.m., or 1,000 PFU (~1.5 ID 99 ) PUUV i.n.
T54567 24127-24296 Sentence denotes Hamsters were challenged with either 10 PFU (~3 ID 99 ) HTNV i.m., 500 PFU (~1.5 ID 99 ) HTNV i.n., 1,000 PFU (~1 ID 99 ) PUUV i.m., or 1,000 PFU (~1.5 ID 99 ) PUUV i.n.
TextSentencer_T172 24297-24414 Sentence denotes On various days post infection, groups of three hamsters were euthanized to monitor viral and serological parameters.
T30571 24297-24414 Sentence denotes On various days post infection, groups of three hamsters were euthanized to monitor viral and serological parameters.
TextSentencer_T173 24415-24521 Sentence denotes Seroconversion occurred, at least partially, by Day 17 post HTNV infection and Day 24 post PUUV infection.
T79000 24415-24521 Sentence denotes Seroconversion occurred, at least partially, by Day 17 post HTNV infection and Day 24 post PUUV infection.
TextSentencer_T174 24522-24717 Sentence denotes Seroconversion on Day 28 post HTNV i.m. infection was incomplete, though viral genome was recovered from all hamsters euthanized that day indicating a productive HTNV infection occurred (Fig 2) .
T66632 24522-24717 Sentence denotes Seroconversion on Day 28 post HTNV i.m. infection was incomplete, though viral genome was recovered from all hamsters euthanized that day indicating a productive HTNV infection occurred (Fig 2) .
TextSentencer_T175 24718-24885 Sentence denotes To confirm seroconversion, all hamsters euthanized on days 17, 24, and 28 were assayed for neutralizing antibodies by PRNT regardless of N-ELISA seroconversion status.
T40420 24718-24885 Sentence denotes To confirm seroconversion, all hamsters euthanized on days 17, 24, and 28 were assayed for neutralizing antibodies by PRNT regardless of N-ELISA seroconversion status.
TextSentencer_T176 24886-25086 Sentence denotes All HTNV infected hamsters with N-ELISA titers had neutralizing antibodies as measured by PRNT 50 , with all but one having full neutralization of virus at a 1:20 dilution of sera. (S1A and S1B Fig) .
T16389 24886-25086 Sentence denotes All HTNV infected hamsters with N-ELISA titers had neutralizing antibodies as measured by PRNT 50 , with all but one having full neutralization of virus at a 1:20 dilution of sera. (S1A and S1B Fig) .
TextSentencer_T177 25087-25340 Sentence denotes Similarly, all PUUV hamsters with N-ELISA titers had neutralizing antibodies as measured by PRNT 50 , though three of the five PUUV i.n. challenged hamsters did not have complete neutralization of the virus at a 1:20 dilution of sera (S1C and S1D Fig) .
T78873 25087-25340 Sentence denotes Similarly, all PUUV hamsters with N-ELISA titers had neutralizing antibodies as measured by PRNT 50 , though three of the five PUUV i.n. challenged hamsters did not have complete neutralization of the virus at a 1:20 dilution of sera (S1C and S1D Fig) .
TextSentencer_T178 25341-25589 Sentence denotes Two of three PUUV i.m. challenged hamsters that had not seroconverted on Day 17 post infection had low levels of neutralizing antibodies, while none of the PUUV i.n. challenged hamsters that were seronegative by N-ELISA had neutralizing antibodies.
T32702 25341-25589 Sentence denotes Two of three PUUV i.m. challenged hamsters that had not seroconverted on Day 17 post infection had low levels of neutralizing antibodies, while none of the PUUV i.n. challenged hamsters that were seronegative by N-ELISA had neutralizing antibodies.
TextSentencer_T179 25590-25734 Sentence denotes For both HTNV and PUUV infected hamsters, infection via the i.m. route lead to a more robust neutralizing antibody response than then i.n.route.
T1243 25590-25734 Sentence denotes For both HTNV and PUUV infected hamsters, infection via the i.m. route lead to a more robust neutralizing antibody response than then i.n.route.
TextSentencer_T180 25735-25891 Sentence denotes The kinetics of HTNV and PUUV infection in the heart, lung, liver, spleen, kidney, and brain were monitored by both RT-PCR and plaque assay (Figs 3 and 4) .
T38836 25735-25891 Sentence denotes The kinetics of HTNV and PUUV infection in the heart, lung, liver, spleen, kidney, and brain were monitored by both RT-PCR and plaque assay (Figs 3 and 4) .
TextSentencer_T181 25892-25974 Sentence denotes HTNV infected by either the i.m. or i.n. route resulted in a persistent infection.
T26236 25892-25974 Sentence denotes HTNV infected by either the i.m. or i.n. route resulted in a persistent infection.
TextSentencer_T182 25975-26153 Sentence denotes High levels of viral genome were detected in the heart, lung, kidney and brain of HTNV infected hamsters beginning on either Day 11 or 17 post infection (Fig 3A, 3B , 3E and 3F).
T24478 25975-26153 Sentence denotes High levels of viral genome were detected in the heart, lung, kidney and brain of HTNV infected hamsters beginning on either Day 11 or 17 post infection (Fig 3A, 3B , 3E and 3F).
TextSentencer_T183 26154-26401 Sentence denotes Infection of the kidney and brain was found in all examined hamsters beginning on either Day 17 or 24 post infection, while the high titers of viral genome detected in the heart and lung were present in only one or two hamsters at each time point.
T24501 26154-26401 Sentence denotes Infection of the kidney and brain was found in all examined hamsters beginning on either Day 17 or 24 post infection, while the high titers of viral genome detected in the heart and lung were present in only one or two hamsters at each time point.
TextSentencer_T184 26402-26548 Sentence denotes Low levels of viral genome were detected between days 11 and 24 post infection in the liver of HTNV i.m. but not i.n. infected hamsters (Fig 3C) .
T23505 26402-26548 Sentence denotes Low levels of viral genome were detected between days 11 and 24 post infection in the liver of HTNV i.m. but not i.n. infected hamsters (Fig 3C) .
TextSentencer_T185 26549-26610 Sentence denotes Hardly any viral genome was detected in the spleen (Fig 3D) .
T13066 26549-26610 Sentence denotes Hardly any viral genome was detected in the spleen (Fig 3D) .
TextSentencer_T186 26611-26797 Sentence denotes To confirm the lack of viral genome in the spleen was not due to the presence of inhibitors all spleen samples from i.m. and i.n. infected hamsters were spiked with HTNV prior to RT-PCR.
T86480 26611-26797 Sentence denotes To confirm the lack of viral genome in the spleen was not due to the presence of inhibitors all spleen samples from i.m. and i.n. infected hamsters were spiked with HTNV prior to RT-PCR.
TextSentencer_T187 26798-26956 Sentence denotes No significant inhibition of the spiked RNA was noted, indicating that HTNV infection does not result in virus dissemination to the spleen (S2A and S2B Fig) .
T6640 26798-26956 Sentence denotes No significant inhibition of the spiked RNA was noted, indicating that HTNV infection does not result in virus dissemination to the spleen (S2A and S2B Fig) .
TextSentencer_T188 26957-27155 Sentence denotes The detection of PUUV in organs was transient after i.m. infection, occurring between Day 11-17 for the heart, liver, kidney and brain, with no virus detected in the spleen (Fig 3A, 3C , 3E and 3F).
T21810 26957-27155 Sentence denotes The detection of PUUV in organs was transient after i.m. infection, occurring between Day 11-17 for the heart, liver, kidney and brain, with no virus detected in the spleen (Fig 3A, 3C , 3E and 3F).
TextSentencer_T189 27156-27298 Sentence denotes Viral genome was more persistent in the lung where it was detected in at least one of three hamsters on/after Day 11 post infection (Fig 3B) .
T96930 27156-27298 Sentence denotes Viral genome was more persistent in the lung where it was detected in at least one of three hamsters on/after Day 11 post infection (Fig 3B) .
TextSentencer_T190 27299-27509 Sentence denotes A small amount of viral genome detected in the brain of a PUUV i.n. infected hamster, 28 days post challenge, is the only viral genome detected in any organ at any time point post PUUV i.n. infection (Fig 3F) .
T90460 27299-27509 Sentence denotes A small amount of viral genome detected in the brain of a PUUV i.n. infected hamster, 28 days post challenge, is the only viral genome detected in any organ at any time point post PUUV i.n. infection (Fig 3F) .
TextSentencer_T191 27510-27674 Sentence denotes Serum viremia was detected in hamsters challenged with HTNV i.m. between 11 and 28 days post infection, though the presence of virus was sporadic except for Day 24.
T37320 27510-27674 Sentence denotes Serum viremia was detected in hamsters challenged with HTNV i.m. between 11 and 28 days post infection, though the presence of virus was sporadic except for Day 24.
TextSentencer_T192 27675-27782 Sentence denotes Serum viremia was only detected in two hamsters challenged with HTNV i.n., one on Day 11 and one on Day 17.
T42942 27675-27782 Sentence denotes Serum viremia was only detected in two hamsters challenged with HTNV i.n., one on Day 11 and one on Day 17.
TextSentencer_T193 27783-27872 Sentence denotes No serum viremia was detected in hamsters challenged with PUUV by either route (Fig 3G) .
T64625 27783-27872 Sentence denotes No serum viremia was detected in hamsters challenged with PUUV by either route (Fig 3G) .
TextSentencer_T194 27873-28108 Sentence denotes Similarly, the presence of viral genome was sporadically detected in the urine of Three HFRS-associated hantavirus infection models HTNV infected hamsters between days 17-28, but was not detected in PUUV challenged hamsters ( Fig 3H) .
T33515 27873-28108 Sentence denotes Similarly, the presence of viral genome was sporadically detected in the urine of Three HFRS-associated hantavirus infection models HTNV infected hamsters between days 17-28, but was not detected in PUUV challenged hamsters ( Fig 3H) .
TextSentencer_T195 28109-28303 Sentence denotes In HTNV i.m. infected hamsters, infectious virus was first detected in the liver beginning at Day 11, and in the lung, liver, spleen, and kidney at Day 17 post infection (Fig 4B, 4C, 4D and 4E).
T76003 28109-28303 Sentence denotes In HTNV i.m. infected hamsters, infectious virus was first detected in the liver beginning at Day 11, and in the lung, liver, spleen, and kidney at Day 17 post infection (Fig 4B, 4C, 4D and 4E).
TextSentencer_T196 28304-28546 Sentence denotes With the exception of the kidney, in which infectious virus was recovered from every hamster after 17 days post infection, infectious virus was recovered from the lung, liver, brain and spleen in only a portion of hamsters at each time point.
T87414 28304-28546 Sentence denotes With the exception of the kidney, in which infectious virus was recovered from every hamster after 17 days post infection, infectious virus was recovered from the lung, liver, brain and spleen in only a portion of hamsters at each time point.
TextSentencer_T197 28547-28621 Sentence denotes No infectious virus was detected in the heart at any time point (Fig 4A) .
T42592 28547-28621 Sentence denotes No infectious virus was detected in the heart at any time point (Fig 4A) .
TextSentencer_T198 28622-28837 Sentence denotes Virus recovery from HTNV i.n. infected hamsters was markedly lower, with infectious virus being detected only in the kidney on Day17 and 28 post Three HFRS-associated hantavirus infection models infection (Fig 4E) .
T8649 28622-28837 Sentence denotes Virus recovery from HTNV i.n. infected hamsters was markedly lower, with infectious virus being detected only in the kidney on Day17 and 28 post Three HFRS-associated hantavirus infection models infection (Fig 4E) .
TextSentencer_T199 28838-28925 Sentence denotes No infectious virus was recovered from the organ of any PUUV infected hamster (Fig 4) .
T37450 28838-28925 Sentence denotes No infectious virus was recovered from the organ of any PUUV infected hamster (Fig 4) .
TextSentencer_T200 28926-29094 Sentence denotes To confirm that the lack of infectious virus in the spleen was not due to the presence of inhibitors select samples were spiked with HTNV virus prior to a plaque assay.
T27948 28926-29094 Sentence denotes To confirm that the lack of infectious virus in the spleen was not due to the presence of inhibitors select samples were spiked with HTNV virus prior to a plaque assay.
TextSentencer_T201 29095-29277 Sentence denotes No significant inhibition of the spiked RNA was noted, confirming the RT-PCR results that that HTNV infection does not result in viral dissemination to the spleen (S2C and S2D Fig) .
T25228 29095-29277 Sentence denotes No significant inhibition of the spiked RNA was noted, confirming the RT-PCR results that that HTNV infection does not result in viral dissemination to the spleen (S2C and S2D Fig) .
TextSentencer_T202 29278-29407 Sentence denotes No infectious virus was detected in the urine for any hamster tested, even those that were RT-PCR positive for HTNV viral genome.
T72556 29278-29407 Sentence denotes No infectious virus was detected in the urine for any hamster tested, even those that were RT-PCR positive for HTNV viral genome.
TextSentencer_T203 29408-29599 Sentence denotes In human ANDV infected patients with ANDV antigen positive urine, samples had to be cultured in Vero E6 cells for between 16-22 days post infection before infectious virus was detected [44] .
T46451 29408-29599 Sentence denotes In human ANDV infected patients with ANDV antigen positive urine, samples had to be cultured in Vero E6 cells for between 16-22 days post infection before infectious virus was detected [44] .
TextSentencer_T204 29600-29710 Sentence denotes Patients infected with HFRS hantaviruses exhibit leukocytosis and thrombocytopenia during infection [45, 46] .
T97652 29600-29710 Sentence denotes Patients infected with HFRS hantaviruses exhibit leukocytosis and thrombocytopenia during infection [45, 46] .
TextSentencer_T205 29711-29894 Sentence denotes At every time point post infection, EDTA-treated whole blood from HTNV and PUUV exposed hamsters was evaluated to determine if changes in white blood cell count or platelets occurred.
T75040 29711-29894 Sentence denotes At every time point post infection, EDTA-treated whole blood from HTNV and PUUV exposed hamsters was evaluated to determine if changes in white blood cell count or platelets occurred.
TextSentencer_T206 29895-29929 Sentence denotes No changes were observed (S4 Fig).
T91786 29895-29929 Sentence denotes No changes were observed (S4 Fig).
TextSentencer_T207 29930-30106 Sentence denotes To further characterize disease, tissue sections from HTNV i.m. infected hamsters were analyzed by IHC and H&E to assess viral localization and any pathologic changes (S5 Fig).
T16672 29930-30106 Sentence denotes To further characterize disease, tissue sections from HTNV i.m. infected hamsters were analyzed by IHC and H&E to assess viral localization and any pathologic changes (S5 Fig).
TextSentencer_T208 30107-30183 Sentence denotes No significant histopathological findings were noted in the kidney or brain.
T72662 30107-30183 Sentence denotes No significant histopathological findings were noted in the kidney or brain.
TextSentencer_T209 30184-30312 Sentence denotes Splenic follicular lymphoid hyperplasia and hepatic extramedullary hematopoiesis in the liver were each noted in three hamsters.
T44213 30184-30312 Sentence denotes Splenic follicular lymphoid hyperplasia and hepatic extramedullary hematopoiesis in the liver were each noted in three hamsters.
TextSentencer_T210 30313-30502 Sentence denotes Both are seen in animals from later time points in the study (days 17-28) and likely represent a reaction to HTNV infection, though other unidentified antigenic stimuli cannot be ruled out.
T8830 30313-30502 Sentence denotes Both are seen in animals from later time points in the study (days 17-28) and likely represent a reaction to HTNV infection, though other unidentified antigenic stimuli cannot be ruled out.
TextSentencer_T211 30503-30698 Sentence denotes Five hamsters between days 4 and 17 post infection exhibited a minimal to mild inflammation of the pericardium, characterized by a mixed lymphoplasmacytic histiocytic and neutrophilic infiltrate.
T19748 30503-30698 Sentence denotes Five hamsters between days 4 and 17 post infection exhibited a minimal to mild inflammation of the pericardium, characterized by a mixed lymphoplasmacytic histiocytic and neutrophilic infiltrate.
TextSentencer_T212 30699-30934 Sentence denotes Occasional macrophages in the inflammatory infiltrate within the pericardium are immunopositive suggesting a possible association with HTNV; however, no evidence of cardiac tissue injury is associated with the presence of HTNV antigen.
T48006 30699-30934 Sentence denotes Occasional macrophages in the inflammatory infiltrate within the pericardium are immunopositive suggesting a possible association with HTNV; however, no evidence of cardiac tissue injury is associated with the presence of HTNV antigen.
TextSentencer_T213 30935-31195 Sentence denotes Beginning on Day 4 post infection 66% (12/18) hamsters exhibit minimal (likely subclinical) respiratory lesions consisting of interstitial neutrophilic and histiocytic infiltrates in the lungs, with 44% (8/18) also exhibiting minimal amounts of alveolar edema.
T2152 30935-31195 Sentence denotes Beginning on Day 4 post infection 66% (12/18) hamsters exhibit minimal (likely subclinical) respiratory lesions consisting of interstitial neutrophilic and histiocytic infiltrates in the lungs, with 44% (8/18) also exhibiting minimal amounts of alveolar edema.
TextSentencer_T214 31196-31275 Sentence denotes An additional hamster had minimal alveolar edema but not pulmonary infiltrates.
T69979 31196-31275 Sentence denotes An additional hamster had minimal alveolar edema but not pulmonary infiltrates.
TextSentencer_T215 31276-31459 Sentence denotes Such findings suggest a response to antigenic stimulus and the presence of immunopositive endothelial cells, pneumocytes and alveolar macrophages suggest a response to HTNV infection.
T2122 31276-31459 Sentence denotes Such findings suggest a response to antigenic stimulus and the presence of immunopositive endothelial cells, pneumocytes and alveolar macrophages suggest a response to HTNV infection.
TextSentencer_T216 31460-31552 Sentence denotes Immunohistochemistry staining was uniformly negative in all tissues on Day 1 post challenge.
T51217 31460-31552 Sentence denotes Immunohistochemistry staining was uniformly negative in all tissues on Day 1 post challenge.
TextSentencer_T217 31553-31681 Sentence denotes Between Day 4 and 11 post challenge minimal antigen was sporadically detected in macrophages, pneumocytes and endothelial cells.
T93060 31553-31681 Sentence denotes Between Day 4 and 11 post challenge minimal antigen was sporadically detected in macrophages, pneumocytes and endothelial cells.
TextSentencer_T218 31682-31918 Sentence denotes By Day 17 post challenge mild to moderate levels of antigen were observed in endothelial cells and choroid ependymal cells in the brain, in endothelial cells, macrophages and pneumocytes in the lung, and endothelial cells in the kidney.
T14149 31682-31918 Sentence denotes By Day 17 post challenge mild to moderate levels of antigen were observed in endothelial cells and choroid ependymal cells in the brain, in endothelial cells, macrophages and pneumocytes in the lung, and endothelial cells in the kidney.
TextSentencer_T219 31919-32093 Sentence denotes Minimal to mild levels of immunopositivity were found in endothelial cells and macrophages in the heart, and in endothelial cells, hepatocytes and Kupffer cells in the liver.
T30309 31919-32093 Sentence denotes Minimal to mild levels of immunopositivity were found in endothelial cells and macrophages in the heart, and in endothelial cells, hepatocytes and Kupffer cells in the liver.
TextSentencer_T220 32094-32296 Sentence denotes Surprisingly, given the lack of viral genome and infectious virus recovered, mild to moderate amounts of immunopositive macrophages, lymphocytes and endothelial cells were found in the spleen ( Table 2,
T9416 32094-32296 Sentence denotes Surprisingly, given the lack of viral genome and infectious virus recovered, mild to moderate amounts of immunopositive macrophages, lymphocytes and endothelial cells were found in the spleen ( Table 2,
TextSentencer_T221 32298-32377 Sentence denotes No published studies detail if ferrets are susceptible to hantavirus infection.
T42745 32298-32377 Sentence denotes No published studies detail if ferrets are susceptible to hantavirus infection.
TextSentencer_T222 32378-32462 Sentence denotes To examine this, four ferrets were exposed to either 2,000 PFU HTNV or PUUV K27 i.n.
T45105 32378-32462 Sentence denotes To examine this, four ferrets were exposed to either 2,000 PFU HTNV or PUUV K27 i.n.
TextSentencer_T223 32463-32520 Sentence denotes No seroconversion occurred within 35 days post infection.
T29076 32463-32520 Sentence denotes No seroconversion occurred within 35 days post infection.
TextSentencer_T224 32521-32689 Sentence denotes The same animals were re-exposed to either 200,000 PFU HTNV, 94,000 PFU PUUV Beaumont (a human PUUV isolate) or 164,000 PFU PUUV Seloignes (a vole PUUV isolate) by i.m.
T92249 32521-32689 Sentence denotes The same animals were re-exposed to either 200,000 PFU HTNV, 94,000 PFU PUUV Beaumont (a human PUUV isolate) or 164,000 PFU PUUV Seloignes (a vole PUUV isolate) by i.m.
TextSentencer_T225 32690-32950 Sentence denotes Prior to the re-exposure one of the seronegative ferrets in the HTNV group was removed for health concerns (rapid weight loss) unrelated to the study, and it's cage mate was subsequently removed for behavioral health reasons before the completion of the study.
T84568 32690-32950 Sentence denotes Prior to the re-exposure one of the seronegative ferrets in the HTNV group was removed for health concerns (rapid weight loss) unrelated to the study, and it's cage mate was subsequently removed for behavioral health reasons before the completion of the study.
TextSentencer_T226 32951-32993 Sentence denotes Data from those two ferrets are not shown.
T71534 32951-32993 Sentence denotes Data from those two ferrets are not shown.
TextSentencer_T227 32994-33170 Sentence denotes As soon as three days post infection ferrets began to lose weight with HTNV infected ferrets losing between 5-12% of peak body weight as did PUUV infected ferrets (Fig 5A-5C ).
T34454 32994-33170 Sentence denotes As soon as three days post infection ferrets began to lose weight with HTNV infected ferrets losing between 5-12% of peak body weight as did PUUV infected ferrets (Fig 5A-5C ).
TextSentencer_T228 33171-33308 Sentence denotes By Day 35 post infection all animals had developed antibodies against all strains of the virus as measured by N-ELISA assay (Fig 5D-5F ).
T78171 33171-33308 Sentence denotes By Day 35 post infection all animals had developed antibodies against all strains of the virus as measured by N-ELISA assay (Fig 5D-5F ).
TextSentencer_T229 33309-33471 Sentence denotes Neutralizing antibody development began as early as Day 14 post infection and all ferrets developed neutralizing antibodies by Day 28 post infection (Fig 5G-5L) .
T70835 33309-33471 Sentence denotes Neutralizing antibody development began as early as Day 14 post infection and all ferrets developed neutralizing antibodies by Day 28 post infection (Fig 5G-5L) .
TextSentencer_T230 33472-33604 Sentence denotes EDTA The organs of infected ferrets were analyzed for viral load by RT-PCR and for the presence of infectious virus by plaque assay.
T22966 33472-33604 Sentence denotes EDTA The organs of infected ferrets were analyzed for viral load by RT-PCR and for the presence of infectious virus by plaque assay.
TextSentencer_T231 33605-33801 Sentence denotes The lung, liver, spleen, intestine and urine of HTNV infected ferrets were negative for viral genome, with small amounts (<2 log 10 ) detected in the heart and spleen of a single animal (S7B Fig).
T48676 33605-33801 Sentence denotes The lung, liver, spleen, intestine and urine of HTNV infected ferrets were negative for viral genome, with small amounts (<2 log 10 ) detected in the heart and spleen of a single animal (S7B Fig).
TextSentencer_T232 33802-34019 Sentence denotes The heart, lung, kidney, intestine and urine of PUUV infected ferrets were negative for viral genome, though small amounts were detected in the liver (2/4) and spleen (1/4) of PUUV infected ferrets (S7C and S7D Fig) .
T93004 33802-34019 Sentence denotes The heart, lung, kidney, intestine and urine of PUUV infected ferrets were negative for viral genome, though small amounts were detected in the liver (2/4) and spleen (1/4) of PUUV infected ferrets (S7C and S7D Fig) .
TextSentencer_T233 34020-34136 Sentence denotes Viral genome was spiked into the assay to confirm that the lack of signal was not due to the presence of inhibitors.
T17303 34020-34136 Sentence denotes Viral genome was spiked into the assay to confirm that the lack of signal was not due to the presence of inhibitors.
TextSentencer_T234 34137-34215 Sentence denotes All organs except for the intestine (4/6) had no inhibition of RT-PCR product.
T33765 34137-34215 Sentence denotes All organs except for the intestine (4/6) had no inhibition of RT-PCR product.
TextSentencer_T235 34216-34371 Sentence denotes Similarly, no infectious virus was found in the organ of any ferret by plaque assay, despite spiked-in virus exhibiting no significant inhibition (S9 Fig).
T88780 34216-34371 Sentence denotes Similarly, no infectious virus was found in the organ of any ferret by plaque assay, despite spiked-in virus exhibiting no significant inhibition (S9 Fig).
TextSentencer_T236 34372-34614 Sentence denotes To confirm that immunosuppression of uninfected ferrets did not result in rapid weight loss, four healthy ferrets were immunosuppressed with a loading dose of 30 mg/kg Cyp followed by 10 mg/kg Cyp maintenance doses every other day (S10A Fig).
T85466 34372-34614 Sentence denotes To confirm that immunosuppression of uninfected ferrets did not result in rapid weight loss, four healthy ferrets were immunosuppressed with a loading dose of 30 mg/kg Cyp followed by 10 mg/kg Cyp maintenance doses every other day (S10A Fig).
TextSentencer_T237 34615-34751 Sentence denotes Five days post immunosuppression ferrets exhibited rapid weight loss, fever, and lethargy due to secondary infection (S10B & S10C Fig) .
T99990 34615-34751 Sentence denotes Five days post immunosuppression ferrets exhibited rapid weight loss, fever, and lethargy due to secondary infection (S10B & S10C Fig) .
TextSentencer_T238 34752-34874 Sentence denotes Immunosupression was discontinued and 5 mg/kg enrofloxicin (a broad spectrum antibiotic) was given twice daily for a week.
T7841 34752-34874 Sentence denotes Immunosupression was discontinued and 5 mg/kg enrofloxicin (a broad spectrum antibiotic) was given twice daily for a week.
TextSentencer_T239 34875-34949 Sentence denotes During this time, ferrets began to gain weight and their fever diminished.
T13223 34875-34949 Sentence denotes During this time, ferrets began to gain weight and their fever diminished.
TextSentencer_T240 34950-35047 Sentence denotes On Day 11 immunosupression resumed for two doses with prophylactic enrofloxicin given once daily.
T73104 34950-35047 Sentence denotes On Day 11 immunosupression resumed for two doses with prophylactic enrofloxicin given once daily.
TextSentencer_T241 35048-35232 Sentence denotes Even with prophylactic antibiotics two ferrets spiked fevers within a few days post the second round of immunosuppressive treatment, though they did not lose weight (S10B & S10C Fig) .
T30143 35048-35232 Sentence denotes Even with prophylactic antibiotics two ferrets spiked fevers within a few days post the second round of immunosuppressive treatment, though they did not lose weight (S10B & S10C Fig) .
TextSentencer_T242 35233-35406 Sentence denotes Based on these results the rapid weight loss and clinical signs observed upon immunosuppression of HTNV and PUUV infected ferrets was most likely due to secondary infection.
T65204 35233-35406 Sentence denotes Based on these results the rapid weight loss and clinical signs observed upon immunosuppression of HTNV and PUUV infected ferrets was most likely due to secondary infection.
TextSentencer_T243 35407-35574 Sentence denotes Due to the inability to completely manage secondary infection with prophylactic antibiotic treatment, no further immunosuppression studies were carried out in ferrets.
T77184 35407-35574 Sentence denotes Due to the inability to completely manage secondary infection with prophylactic antibiotic treatment, no further immunosuppression studies were carried out in ferrets.
TextSentencer_T244 35575-35709 Sentence denotes To refine the HFRS-causing hantavirus ferret infection model four ferrets were challenged with 94,000 PFU PUUV Beaumont i.m. on Day 0.
T1124 35575-35709 Sentence denotes To refine the HFRS-causing hantavirus ferret infection model four ferrets were challenged with 94,000 PFU PUUV Beaumont i.m. on Day 0.
TextSentencer_T245 35710-35842 Sentence denotes Weight and temperature were recorded daily, while twice weekly blood draws and urine collection was used to monitor kidney function.
T70405 35710-35842 Sentence denotes Weight and temperature were recorded daily, while twice weekly blood draws and urine collection was used to monitor kidney function.
TextSentencer_T246 35843-35975 Sentence denotes As with the pilot experiment, ferrets slowly lost between 7-11% of peak body weight, recapitulating our previous findings (Fig 6A) .
T33501 35843-35975 Sentence denotes As with the pilot experiment, ferrets slowly lost between 7-11% of peak body weight, recapitulating our previous findings (Fig 6A) .
TextSentencer_T247 35976-36025 Sentence denotes No elevated temperatures were observed (Fig 6B) .
T61773 35976-36025 Sentence denotes No elevated temperatures were observed (Fig 6B) .
TextSentencer_T248 36026-36123 Sentence denotes Ferrets developed a robust antibody response beginning on Day 10 post infection (Fig 6C and 6D) .
T4231 36026-36123 Sentence denotes Ferrets developed a robust antibody response beginning on Day 10 post infection (Fig 6C and 6D) .
TextSentencer_T249 36124-36297 Sentence denotes Neutralizing antibodies developed early as Day 14 post infection, and were present in all ferrets by Day 28 post infection, as measured by PsVNA and PRNT ( Fig 6E and 6F) .
T13527 36124-36297 Sentence denotes Neutralizing antibodies developed early as Day 14 post infection, and were present in all ferrets by Day 28 post infection, as measured by PsVNA and PRNT ( Fig 6E and 6F) .
TextSentencer_T250 36298-36370 Sentence denotes Despite the slow weight loss no signs of renal impairment were observed.
T1519 36298-36370 Sentence denotes Despite the slow weight loss no signs of renal impairment were observed.
TextSentencer_T251 36371-36525 Sentence denotes Proteinuria and hematuria are hallmarks of PUUV infection occurring in between 94-100% (proteinuria) and 58-85% (hematuria) of human clinical cases [46] .
T35595 36371-36525 Sentence denotes Proteinuria and hematuria are hallmarks of PUUV infection occurring in between 94-100% (proteinuria) and 58-85% (hematuria) of human clinical cases [46] .
TextSentencer_T252 36526-36614 Sentence denotes No prolonged proteinuria or hematuria was observed (Fig 7A and 7B ) in infected ferrets.
T254 36526-36614 Sentence denotes No prolonged proteinuria or hematuria was observed (Fig 7A and 7B ) in infected ferrets.
TextSentencer_T253 36615-36822 Sentence denotes Similarly, blood urea nitrogen and creatinine levels in the sera, both of which are elevated due to kidney failure in PUUV patients [47] remained unchanged in PUUV infected ferrets (Fig 7C and 7D) [48, 49] .
T52063 36615-36822 Sentence denotes Similarly, blood urea nitrogen and creatinine levels in the sera, both of which are elevated due to kidney failure in PUUV patients [47] remained unchanged in PUUV infected ferrets (Fig 7C and 7D) [48, 49] .
TextSentencer_T254 36823-36959 Sentence denotes No infectious virus or viral genome was detected in the brain, heart, lung, liver, spleen, kidney, intestine, or eye (S11 and S12 Figs).
T89955 36823-36959 Sentence denotes No infectious virus or viral genome was detected in the brain, heart, lung, liver, spleen, kidney, intestine, or eye (S11 and S12 Figs).
TextSentencer_T255 36960-37043 Sentence denotes No changes in other serologic or urologic parameters were noted (S13 and S14 Figs).
T79030 36960-37043 Sentence denotes No changes in other serologic or urologic parameters were noted (S13 and S14 Figs).
TextSentencer_T256 37044-37164 Sentence denotes No gross pathological changes or significant lesions associated with PUUV infection were noted in the ferrets (S15 Fig).
T81614 37044-37164 Sentence denotes No gross pathological changes or significant lesions associated with PUUV infection were noted in the ferrets (S15 Fig).
TextSentencer_T257 37165-37297 Sentence denotes In the lungs, one ferret had mild neutrophilic and histiocytic inflammation centered on the bronchioles and expanded alveolar septa.
T55496 37165-37297 Sentence denotes In the lungs, one ferret had mild neutrophilic and histiocytic inflammation centered on the bronchioles and expanded alveolar septa.
TextSentencer_T258 37298-37434 Sentence denotes Given that the inflammation was centered around bronchioles and not the vasculature, it is unlikely to be in response to PUUV infection.
T88233 37298-37434 Sentence denotes Given that the inflammation was centered around bronchioles and not the vasculature, it is unlikely to be in response to PUUV infection.
TextSentencer_T259 37435-37515 Sentence denotes A number of other common or age-associated lesions were observed in the ferrets.
T3350 37435-37515 Sentence denotes A number of other common or age-associated lesions were observed in the ferrets.
TextSentencer_T260 37516-37730 Sentence denotes Two of four ferrets had proliferative cortical cells in either the adrenal capsule or adrenal cortex that were likely clinically silent as they lack clinical signs consistent with adrenal-associated endocrinopathy.
T49160 37516-37730 Sentence denotes Two of four ferrets had proliferative cortical cells in either the adrenal capsule or adrenal cortex that were likely clinically silent as they lack clinical signs consistent with adrenal-associated endocrinopathy.
TextSentencer_T261 37731-37866 Sentence denotes Additionally, alveolar mineralization was noted in all four ferrets as was eosinophilic and lymphoplasmacytic enteritis, and hepatitis.
T8360 37731-37866 Sentence denotes Additionally, alveolar mineralization was noted in all four ferrets as was eosinophilic and lymphoplasmacytic enteritis, and hepatitis.
TextSentencer_T262 37867-37942 Sentence denotes Two ferrets had fibromyxomatous degeneration of the atrioventricular valve.
T33889 37867-37942 Sentence denotes Two ferrets had fibromyxomatous degeneration of the atrioventricular valve.
TextSentencer_T263 37943-38026 Sentence denotes The spleen, brain, kidney, and pituitary gland were normal in all ferrets examined.
T54306 37943-38026 Sentence denotes The spleen, brain, kidney, and pituitary gland were normal in all ferrets examined.
TextSentencer_T264 38027-38126 Sentence denotes As with ferrets, there is no literature on the susceptibility of marmosets to hantavirus infection.
T42468 38027-38126 Sentence denotes As with ferrets, there is no literature on the susceptibility of marmosets to hantavirus infection.
TextSentencer_T265 38127-38197 Sentence denotes To test this, three male marmosets were exposed to 1,000 PFU HTNV i.m.
T56211 38127-38197 Sentence denotes To test this, three male marmosets were exposed to 1,000 PFU HTNV i.m.
TextSentencer_T266 38198-38322 Sentence denotes Blood was collected weekly to measure seroconversion, serum viremia, as well as serum parameters relating to renal function.
T29011 38198-38322 Sentence denotes Blood was collected weekly to measure seroconversion, serum viremia, as well as serum parameters relating to renal function.
TextSentencer_T267 38323-38445 Sentence denotes All three animals seroconverted by Day 21 post infection (Fig 8A and 8B ) despite displaying no clinical signs of illness.
T35269 38323-38445 Sentence denotes All three animals seroconverted by Day 21 post infection (Fig 8A and 8B ) despite displaying no clinical signs of illness.
TextSentencer_T268 38446-38616 Sentence denotes Neutralizing antibody production began around the same time, and was robust by Day 30 post infection (14, 557 by PsVNA 50 and 10,240-20,480 by PRNT 50 ) (Fig 8C and 8D ).
T72213 38446-38616 Sentence denotes Neutralizing antibody production began around the same time, and was robust by Day 30 post infection (14, 557 by PsVNA 50 and 10,240-20,480 by PRNT 50 ) (Fig 8C and 8D ).
TextSentencer_T269 38617-38828 Sentence denotes Due to low volumes of blood drawn at each time point serum viremia could not be examined for each individual animal, however a pool of sera from all three animals was evaluated at each time point post infection.
T51233 38617-38828 Sentence denotes Due to low volumes of blood drawn at each time point serum viremia could not be examined for each individual animal, however a pool of sera from all three animals was evaluated at each time point post infection.
TextSentencer_T270 38829-38930 Sentence denotes Low levels of serum viremia were detected between days 14 and 28 post infection by RT-PCR ( Fig 8G) .
T71998 38829-38930 Sentence denotes Low levels of serum viremia were detected between days 14 and 28 post infection by RT-PCR ( Fig 8G) .
TextSentencer_T271 38931-39200 Sentence denotes As with the ferret infection model of HFRS-causing hantavirus, no renal injury as measured by changes noted in blood urea nitrogen or serum creatinine were observed over the course of infection, nor were changes in any of the other serum parameters monitored (S16 Fig).
T83051 38931-39200 Sentence denotes As with the ferret infection model of HFRS-causing hantavirus, no renal injury as measured by changes noted in blood urea nitrogen or serum creatinine were observed over the course of infection, nor were changes in any of the other serum parameters monitored (S16 Fig).
TextSentencer_T272 39201-39292 Sentence denotes Animals were euthanized on Day 30 post infection to examine organs for viral dissemination.
T2287 39201-39292 Sentence denotes Animals were euthanized on Day 30 post infection to examine organs for viral dissemination.
TextSentencer_T273 39293-39423 Sentence denotes No infectious virus or viral genome was detected in the heart, lung, liver, spleen, kidney, intestine or brain (S17 and S18 Figs).
T48850 39293-39423 Sentence denotes No infectious virus or viral genome was detected in the heart, lung, liver, spleen, kidney, intestine or brain (S17 and S18 Figs).
TextSentencer_T274 39424-39606 Sentence denotes Lymphoid hyperplasia was noted in all three animals by histology, though the location and intensity varied between the spleen, various lymph nodes and gut associated lymphoid tissue.
T51693 39424-39606 Sentence denotes Lymphoid hyperplasia was noted in all three animals by histology, though the location and intensity varied between the spleen, various lymph nodes and gut associated lymphoid tissue.
TextSentencer_T275 39607-39727 Sentence denotes Such hyperplasia is indicative of a response to antigenic stimulation and was most likely caused by the viral challenge.
T5387 39607-39727 Sentence denotes Such hyperplasia is indicative of a response to antigenic stimulation and was most likely caused by the viral challenge.
TextSentencer_T276 39728-39956 Sentence denotes Mild to moderate congestion Three HFRS-associated hantavirus infection models was also seen in the lungs of each marmoset; however, this was an acute change and was most likely associated with terminal anesthesia and euthanasia.
T11908 39728-39956 Sentence denotes Mild to moderate congestion Three HFRS-associated hantavirus infection models was also seen in the lungs of each marmoset; however, this was an acute change and was most likely associated with terminal anesthesia and euthanasia.
TextSentencer_T277 39957-40048 Sentence denotes No other significant histological lesions were noted in any of the three animals (S19 Fig).
T29200 39957-40048 Sentence denotes No other significant histological lesions were noted in any of the three animals (S19 Fig).
TextSentencer_T278 40049-40206 Sentence denotes Due to the negative virology results and the lack of significant histologic changes, IHC to detect the presence of HTNV antigen in tissues was not performed.
T85418 40049-40206 Sentence denotes Due to the negative virology results and the lack of significant histologic changes, IHC to detect the presence of HTNV antigen in tissues was not performed.
TextSentencer_T279 40207-40325 Sentence denotes To date, the use of adult animal models to evaluate anti-HTNV and anti-PUUV medical counter measures has been limited.
T49275 40207-40325 Sentence denotes To date, the use of adult animal models to evaluate anti-HTNV and anti-PUUV medical counter measures has been limited.
TextSentencer_T280 40326-40455 Sentence denotes Recombinant protein, vaccinia virus-vectored, and DNA vaccines have been tested in the high dose HTNV hamster model [9, 37, 50] .
T16458 40326-40455 Sentence denotes Recombinant protein, vaccinia virus-vectored, and DNA vaccines have been tested in the high dose HTNV hamster model [9, 37, 50] .
TextSentencer_T281 40456-40657 Sentence denotes Additionally, the ability of passively administered neutralizing antibodies has been evaluated in the high-dose hamster model of HTNV and PUUV and in PUUV challenged cynomolgus macaques PUUV [50, 51] .
T60636 40456-40657 Sentence denotes Additionally, the ability of passively administered neutralizing antibodies has been evaluated in the high-dose hamster model of HTNV and PUUV and in PUUV challenged cynomolgus macaques PUUV [50, 51] .
TextSentencer_T282 40658-40947 Sentence denotes Both of these models have limitations; the size of the macaque requires large quantities of passive transfer material, and the high dose of the hamster model, with challenge doses of~650 ID 99 , could require prohibitively large volumes of test article to neutralize the high initial dose.
T9153 40658-40947 Sentence denotes Both of these models have limitations; the size of the macaque requires large quantities of passive transfer material, and the high dose of the hamster model, with challenge doses of~650 ID 99 , could require prohibitively large volumes of test article to neutralize the high initial dose.
TextSentencer_T283 40948-41104 Sentence denotes Suckling mice, which present with a disseminated disease not reminiscent of HFRS, have been used to evaluate HTNV therapeutics as well [52] [53] [54] [55] .
T33261 40948-41104 Sentence denotes Suckling mice, which present with a disseminated disease not reminiscent of HFRS, have been used to evaluate HTNV therapeutics as well [52] [53] [54] [55] .
TextSentencer_T284 41105-41272 Sentence denotes In this paper we present three adult animal models of HFRS-causing hantavirus infection than can be used for future evaluation of therapeutics, biologics and vaccines.
T92635 41105-41272 Sentence denotes In this paper we present three adult animal models of HFRS-causing hantavirus infection than can be used for future evaluation of therapeutics, biologics and vaccines.
TextSentencer_T285 41273-41441 Sentence denotes The ID 50 's for HTNV and PUUV determined in this report are similar to the lethal dose 50% (LD 50 ) calculated for SNV and ANDV, <3 PFU via the i.m. route [6, 7, 41] .
T74740 41273-41441 Sentence denotes The ID 50 's for HTNV and PUUV determined in this report are similar to the lethal dose 50% (LD 50 ) calculated for SNV and ANDV, <3 PFU via the i.m. route [6, 7, 41] .
TextSentencer_T286 41442-41591 Sentence denotes Also similar is that the challenge dose of ANDV required to infect/kill 50% of hamsters by the i.n. or intragastric route is~10-30 fold higher [56] .
T18274 41442-41591 Sentence denotes Also similar is that the challenge dose of ANDV required to infect/kill 50% of hamsters by the i.n. or intragastric route is~10-30 fold higher [56] .
TextSentencer_T287 41592-41779 Sentence denotes Previous reports also demonstrate that PUUV is capable of infecting hamsters by the intragastric route, with an ID 50 of >10,000, making it a much less effective route of infection [57] .
T80950 41592-41779 Sentence denotes Previous reports also demonstrate that PUUV is capable of infecting hamsters by the intragastric route, with an ID 50 of >10,000, making it a much less effective route of infection [57] .
TextSentencer_T288 41780-42006 Sentence denotes Despite similarities in their ID 50 's, the ID 99 's of HTNV and PUUV greatly diverge, with~200 times less HTNV required to infect hamsters via the i.m. route, and~2 fold less required to infect via the i.n. route ( Table 1 ).
T20739 41780-42006 Sentence denotes Despite similarities in their ID 50 's, the ID 99 's of HTNV and PUUV greatly diverge, with~200 times less HTNV required to infect hamsters via the i.m. route, and~2 fold less required to infect via the i.n. route ( Table 1 ).
TextSentencer_T289 42007-42188 Sentence denotes The lower ID 99 doses, coupled with viral persistence in HTNV infected animals as opposed to viral clearance (Fig 3) , suggest that HTNV is more infectious than PUUV in the hamster.
T98439 42007-42188 Sentence denotes The lower ID 99 doses, coupled with viral persistence in HTNV infected animals as opposed to viral clearance (Fig 3) , suggest that HTNV is more infectious than PUUV in the hamster.
TextSentencer_T290 42189-42282 Sentence denotes The mechanism for this difference between these closely related hantaviruses remains unknown.
T61594 42189-42282 Sentence denotes The mechanism for this difference between these closely related hantaviruses remains unknown.
TextSentencer_T291 42283-42444 Sentence denotes Lethal infection of hamsters with ANDV leads to extensive organ dissemination, with infectious virus recovered in the lung, liver, kidney, spleen and heart [6] .
T86160 42283-42444 Sentence denotes Lethal infection of hamsters with ANDV leads to extensive organ dissemination, with infectious virus recovered in the lung, liver, kidney, spleen and heart [6] .
TextSentencer_T292 42445-42565 Sentence denotes Asymptomatic infection of hamsters with SNV repeatedly passaged through hamsters has a similar organ distribution [58] .
T2223 42445-42565 Sentence denotes Asymptomatic infection of hamsters with SNV repeatedly passaged through hamsters has a similar organ distribution [58] .
TextSentencer_T293 42566-42686 Sentence denotes The organ distribution of both those viruses is similar to the low dose HTNV hamster model, with two notable exceptions.
T76385 42566-42686 Sentence denotes The organ distribution of both those viruses is similar to the low dose HTNV hamster model, with two notable exceptions.
TextSentencer_T294 42687-42808 Sentence denotes First, the HTNV model has low, transient levels of virus in the liver and hardly any virus in the spleen (Figs 3 and 4) .
T66722 42687-42808 Sentence denotes First, the HTNV model has low, transient levels of virus in the liver and hardly any virus in the spleen (Figs 3 and 4) .
TextSentencer_T295 42809-43029 Sentence denotes This dissimilarity between the models led us to confirm the lack of virus in the spleen was not due to the presence of inhibitors by spiking either infectious virus or viral RNA into samples prior to evaluation (S2 Fig).
T95750 42809-43029 Sentence denotes This dissimilarity between the models led us to confirm the lack of virus in the spleen was not due to the presence of inhibitors by spiking either infectious virus or viral RNA into samples prior to evaluation (S2 Fig).
TextSentencer_T296 43030-43173 Sentence denotes Second, in the ANDV model, the presence of virus was determined by plaque assay, indicating the virus was infectious and replication competent.
T64214 43030-43173 Sentence denotes Second, in the ANDV model, the presence of virus was determined by plaque assay, indicating the virus was infectious and replication competent.
TextSentencer_T297 43174-43473 Sentence denotes In the HTNV low dose hamster model, while there is detection of high levels of viral genome (and in the case of the HTNV i.m. model, by pathology) by RT-PCR, recovery of infectious virus is sporadic, typically occurring at low levels, in only a few hamsters per time point (Figs 3 and 4 , Table 1 ).
T15417 43174-43473 Sentence denotes In the HTNV low dose hamster model, while there is detection of high levels of viral genome (and in the case of the HTNV i.m. model, by pathology) by RT-PCR, recovery of infectious virus is sporadic, typically occurring at low levels, in only a few hamsters per time point (Figs 3 and 4 , Table 1 ).
TextSentencer_T298 43474-43543 Sentence denotes The discrepancy between RT-PCR/pathology and plaque assay is notable.
T7593 43474-43543 Sentence denotes The discrepancy between RT-PCR/pathology and plaque assay is notable.
TextSentencer_T299 43544-43784 Sentence denotes The hamsters in this study were not perfused, and given the appearance of neutralizing antibodies as early as day XX post infection, the presence of these antibodies could be impairing out ability to recover live virus via the plaque assay.
T52989 43544-43784 Sentence denotes The hamsters in this study were not perfused, and given the appearance of neutralizing antibodies as early as day XX post infection, the presence of these antibodies could be impairing out ability to recover live virus via the plaque assay.
TextSentencer_T300 43785-43947 Sentence denotes It is also possible that viral packaging is somehow impaired in the hamster, leading to a larger amounts of nucleocapsid protein and viral genome than live virus.
T75206 43785-43947 Sentence denotes It is also possible that viral packaging is somehow impaired in the hamster, leading to a larger amounts of nucleocapsid protein and viral genome than live virus.
TextSentencer_T301 43948-43999 Sentence denotes Further studies need to be undertaken to elucidate.
T45951 43948-43999 Sentence denotes Further studies need to be undertaken to elucidate.
TextSentencer_T302 44000-44288 Sentence denotes The low dose HTNV hamster model also mimics the infection pattern of the virus in its host species, the striped field mouse (Apodemus agrarius), with viral genome being detected in the lung, liver and kidney but not the spleen (the heart and brain were not examined) [32, [59] [60] [61] .
T98288 44000-44288 Sentence denotes The low dose HTNV hamster model also mimics the infection pattern of the virus in its host species, the striped field mouse (Apodemus agrarius), with viral genome being detected in the lung, liver and kidney but not the spleen (the heart and brain were not examined) [32, [59] [60] [61] .
TextSentencer_T303 44289-44401 Sentence denotes In contrast to the HTNV low dose model, the organ distribution of virus in the PUUV low dose model is transient.
T26933 44289-44401 Sentence denotes In contrast to the HTNV low dose model, the organ distribution of virus in the PUUV low dose model is transient.
TextSentencer_T304 44402-44564 Sentence denotes In PUUV i.m. infected hamsters virus is detectable by RT-PCR around Day 11 post infection, with the virus being cleared from all organs except the lung by Day 24.
T88863 44402-44564 Sentence denotes In PUUV i.m. infected hamsters virus is detectable by RT-PCR around Day 11 post infection, with the virus being cleared from all organs except the lung by Day 24.
TextSentencer_T305 44565-44626 Sentence denotes No infectious virus was recovered at any time point examined.
T40261 44565-44626 Sentence denotes No infectious virus was recovered at any time point examined.
TextSentencer_T306 44627-44753 Sentence denotes Even less virus was detected in the PUUV i.n. model; only a small amount in the brain of one hamster on Day 28 post infection.
T1569 44627-44753 Sentence denotes Even less virus was detected in the PUUV i.n. model; only a small amount in the brain of one hamster on Day 28 post infection.
TextSentencer_T307 44754-44813 Sentence denotes In neither case was serum viremia observed (Figs 3 and 4) .
T43972 44754-44813 Sentence denotes In neither case was serum viremia observed (Figs 3 and 4) .
TextSentencer_T308 44814-45068 Sentence denotes This is most similar to the SNV models involving low passage virus in immunocompetent hamsters: the virus is transiently detected in the lung by PCR, and then sporadically found in organs 12 to 14 days post infection using immunohistochemistry [41, 58] .
T51541 44814-45068 Sentence denotes This is most similar to the SNV models involving low passage virus in immunocompetent hamsters: the virus is transiently detected in the lung by PCR, and then sporadically found in organs 12 to 14 days post infection using immunohistochemistry [41, 58] .
TextSentencer_T309 45069-45277 Sentence denotes The distribution of PUUV in the hamster differs somewhat from its host species the bank vole, where it is found to persist in the lung, spleen and kidney, and was not detected in the heart or the brain [62] .
T27672 45069-45277 Sentence denotes The distribution of PUUV in the hamster differs somewhat from its host species the bank vole, where it is found to persist in the lung, spleen and kidney, and was not detected in the heart or the brain [62] .
TextSentencer_T310 45278-45437 Sentence denotes Seroconversion of hamsters post viral exposure remains the best way to measure infection, and should be a considered the primary endpoint for efficacy studies.
T60267 45278-45437 Sentence denotes Seroconversion of hamsters post viral exposure remains the best way to measure infection, and should be a considered the primary endpoint for efficacy studies.
TextSentencer_T311 45438-45772 Sentence denotes Though the PRNT assay was slightly more sensitive than the N-ELISA assay, detecting neutralizing antibodies in all animals with N-ELISA titers, and in two PUUV animals that did not have N-ELISA titers, the increased time, sample, and biosafety requirements necessary for a PRNT assay make the N-ELISA a better choice (Fig 2, S1 Fig) .
T20781 45438-45772 Sentence denotes Though the PRNT assay was slightly more sensitive than the N-ELISA assay, detecting neutralizing antibodies in all animals with N-ELISA titers, and in two PUUV animals that did not have N-ELISA titers, the increased time, sample, and biosafety requirements necessary for a PRNT assay make the N-ELISA a better choice (Fig 2, S1 Fig) .
TextSentencer_T312 45773-46156 Sentence denotes For a 10 PFU HTNV i.m. challenge, given lower titer and specific OD sum values as compared with higher challenge doses, and the fact that one hamster with significant viral genome in its organs at Day 28 post infection (7.1 log 10 in the brain, and 6.8 log 10 in the kidney) did not seroconvert, waiting until Day 35 post infection to monitor seroconversion is advisable (Figs 1-3 ).
T24716 45773-46156 Sentence denotes For a 10 PFU HTNV i.m. challenge, given lower titer and specific OD sum values as compared with higher challenge doses, and the fact that one hamster with significant viral genome in its organs at Day 28 post infection (7.1 log 10 in the brain, and 6.8 log 10 in the kidney) did not seroconvert, waiting until Day 35 post infection to monitor seroconversion is advisable (Figs 1-3 ).
TextSentencer_T313 46157-46330 Sentence denotes Viral load in the brain, kidney, and lungs as measured by RT-PCR need to be evaluated at Day 35 post low-dose challenge to determine their usefulness as secondary endpoints.
T25338 46157-46330 Sentence denotes Viral load in the brain, kidney, and lungs as measured by RT-PCR need to be evaluated at Day 35 post low-dose challenge to determine their usefulness as secondary endpoints.
TextSentencer_T314 46331-46443 Sentence denotes Recovery of infectious virus in any organ, and viremia are too sporadic to serve as proxy markers for infection.
T67998 46331-46443 Sentence denotes Recovery of infectious virus in any organ, and viremia are too sporadic to serve as proxy markers for infection.
TextSentencer_T315 46444-46677 Sentence denotes The ferret has been used as an experimental model for numerous hemorrhagic fever viruses, and respiratory viruses [12] [13] [14] [15] [16] [17] , though no published reports exist examining its susceptibility to hantavirus infection.
T1688 46444-46677 Sentence denotes The ferret has been used as an experimental model for numerous hemorrhagic fever viruses, and respiratory viruses [12] [13] [14] [15] [16] [17] , though no published reports exist examining its susceptibility to hantavirus infection.
TextSentencer_T316 46678-46768 Sentence denotes In comparison to the hamster, the ferret is far more resistant to HTNV and PUUV infection.
T64722 46678-46768 Sentence denotes In comparison to the hamster, the ferret is far more resistant to HTNV and PUUV infection.
TextSentencer_T317 46769-46924 Sentence denotes Exposure of ferrets to 2,000 PFU i.n. (greater than the ID 99 for both viruses in hamsters), failed to result in a productive infection and seroconversion.
T87761 46769-46924 Sentence denotes Exposure of ferrets to 2,000 PFU i.n. (greater than the ID 99 for both viruses in hamsters), failed to result in a productive infection and seroconversion.
TextSentencer_T318 46925-46998 Sentence denotes Instead i.m. challenge doses of~100,000-200,000 PFU were needed (Fig 5) .
T60229 46925-46998 Sentence denotes Instead i.m. challenge doses of~100,000-200,000 PFU were needed (Fig 5) .
TextSentencer_T319 46999-47126 Sentence denotes Initially ferrets were exposed to PUUV K27, a commonly used laboratory isolate that has been in cell culture for over 15 years.
T19515 46999-47126 Sentence denotes Initially ferrets were exposed to PUUV K27, a commonly used laboratory isolate that has been in cell culture for over 15 years.
TextSentencer_T320 47127-47204 Sentence denotes Repeated passaging of hantavirus is known to cause mutations [63] [64] [65] .
T84200 47127-47204 Sentence denotes Repeated passaging of hantavirus is known to cause mutations [63] [64] [65] .
TextSentencer_T321 47205-47337 Sentence denotes In contrast PUUV Beaumont and Seloignes are relatively recent isolates, with no more than 3 passages in cell culture post isolation.
T79800 47205-47337 Sentence denotes In contrast PUUV Beaumont and Seloignes are relatively recent isolates, with no more than 3 passages in cell culture post isolation.
TextSentencer_T322 47338-47519 Sentence denotes These strains were used for all subsequent experiments to maximize the likelihood of PUUV to cause disease by eliminating possible attenuation of the laboratory strain of the virus.
T18347 47338-47519 Sentence denotes These strains were used for all subsequent experiments to maximize the likelihood of PUUV to cause disease by eliminating possible attenuation of the laboratory strain of the virus.
TextSentencer_T323 47520-47844 Sentence denotes Despite the high challenge dose and use of recent isolates, no elevation in white blood cells was observed over the course of the experiment, no pathology or organ burden was detected at the conclusion of the experiment, and the N-ELISA specific OD sum, PRNT 50 , and PsVNA 50 titers remained low (Figs 6 and 8 and S9 Fig) .
T89077 47520-47844 Sentence denotes Despite the high challenge dose and use of recent isolates, no elevation in white blood cells was observed over the course of the experiment, no pathology or organ burden was detected at the conclusion of the experiment, and the N-ELISA specific OD sum, PRNT 50 , and PsVNA 50 titers remained low (Figs 6 and 8 and S9 Fig) .
TextSentencer_T324 47845-48047 Sentence denotes This outcome is almost identical to that of Marburg and Ravn virus infection in ferrets, where the development of neutralizing antibody titers was the only sign that productive infection occurred [66] .
T91537 47845-48047 Sentence denotes This outcome is almost identical to that of Marburg and Ravn virus infection in ferrets, where the development of neutralizing antibody titers was the only sign that productive infection occurred [66] .
TextSentencer_T325 48048-48250 Sentence denotes Previous experiments in hamsters, have demonstrated that 2x10 5 PFU of gamma-irradiated ANDV and SNV are not sufficient to cause seroconversion, and neither is 1x10 4 gamma-irradiated PFU PUUV [6, 57] .
T76373 48048-48250 Sentence denotes Previous experiments in hamsters, have demonstrated that 2x10 5 PFU of gamma-irradiated ANDV and SNV are not sufficient to cause seroconversion, and neither is 1x10 4 gamma-irradiated PFU PUUV [6, 57] .
TextSentencer_T326 48251-48423 Sentence denotes Thus the seroconversion observed in ferrets, though low, is not likely to be due to a reaction to the large quantity of antigen administered, but to a productive infection.
T14226 48251-48423 Sentence denotes Thus the seroconversion observed in ferrets, though low, is not likely to be due to a reaction to the large quantity of antigen administered, but to a productive infection.
TextSentencer_T327 48424-48740 Sentence denotes PUUV antigen, viral genome, or infectious virus has been found in the brain, pituitary gland, lung, heart, liver, kidney, spleen, cerebrospinal fluid, and gastrointestinal tract of human patients with clinical symptoms of NE, though the pattern of viral dissemination varies between individuals [67] [68] [69] [70] .
T51536 48424-48740 Sentence denotes PUUV antigen, viral genome, or infectious virus has been found in the brain, pituitary gland, lung, heart, liver, kidney, spleen, cerebrospinal fluid, and gastrointestinal tract of human patients with clinical symptoms of NE, though the pattern of viral dissemination varies between individuals [67] [68] [69] [70] .
TextSentencer_T328 48741-48995 Sentence denotes Acute kidney injury and vision disturbances including blurred vision, myopic shift, and lens thickening, while pulmonary involvement including pleural effusion and vascular congestion, and renal failure occurred less frequently [47, [71] [72] [73] [74] .
T24631 48741-48995 Sentence denotes Acute kidney injury and vision disturbances including blurred vision, myopic shift, and lens thickening, while pulmonary involvement including pleural effusion and vascular congestion, and renal failure occurred less frequently [47, [71] [72] [73] [74] .
TextSentencer_T329 48996-49202 Sentence denotes Given the lack of high neutralizing antibody titers, which could have aided in viral clearance, the lack of viral genome in any of the ferret organs examined is rather surprising (S6, S7, S11 and S12 Figs).
T86683 48996-49202 Sentence denotes Given the lack of high neutralizing antibody titers, which could have aided in viral clearance, the lack of viral genome in any of the ferret organs examined is rather surprising (S6, S7, S11 and S12 Figs).
TextSentencer_T330 49203-49468 Sentence denotes Furthermore, the lack of viral antigen and pathology in the organs tested suggest either a transient infection cleared prior to Day 35 post infection, levels of virus so low as to be undetectable by the tests used, or a viral reservoir outside of the organs tested.
T17039 49203-49468 Sentence denotes Furthermore, the lack of viral antigen and pathology in the organs tested suggest either a transient infection cleared prior to Day 35 post infection, levels of virus so low as to be undetectable by the tests used, or a viral reservoir outside of the organs tested.
TextSentencer_T331 49469-49588 Sentence denotes The lack of detectable virus is most surprising given the gradual weight loss infected animals exhibit (Figs 5 and 6 ).
T55699 49469-49588 Sentence denotes The lack of detectable virus is most surprising given the gradual weight loss infected animals exhibit (Figs 5 and 6 ).
TextSentencer_T332 49589-49743 Sentence denotes The animals gained weight until~3 days post challenge, at which point a gradual weight loss occurs, regardless of if HTNV or PUUV was the challenge virus.
T25630 49589-49743 Sentence denotes The animals gained weight until~3 days post challenge, at which point a gradual weight loss occurs, regardless of if HTNV or PUUV was the challenge virus.
TextSentencer_T333 49744-50122 Sentence denotes While weight loss is a feature of other ferret models of infectious diseases, the pattern we observed was unique: ferrets infected with morbillivirus, avian influenza and filoviruses rapidly lose weight during the first week to two weeks post infection, while infection with severe acute respiratory syndrome virus results in no significant weight loss [16, 17, [75] [76] [77] .
T35343 49744-50122 Sentence denotes While weight loss is a feature of other ferret models of infectious diseases, the pattern we observed was unique: ferrets infected with morbillivirus, avian influenza and filoviruses rapidly lose weight during the first week to two weeks post infection, while infection with severe acute respiratory syndrome virus results in no significant weight loss [16, 17, [75] [76] [77] .
TextSentencer_T334 50123-50213 Sentence denotes In the hamster, infection with SNV is asymptomatic unless the hamster is immunosuppressed.
T92866 50123-50213 Sentence denotes In the hamster, infection with SNV is asymptomatic unless the hamster is immunosuppressed.
TextSentencer_T335 50214-50323 Sentence denotes When ferrets were immunosuppressed on Day 42 post infection, rapid weight loss and lethargy ensured (Fig 5) .
T87327 50214-50323 Sentence denotes When ferrets were immunosuppressed on Day 42 post infection, rapid weight loss and lethargy ensured (Fig 5) .
TextSentencer_T336 50324-50493 Sentence denotes Given that these clinical signs were also observed in unchallenged control animals (S10 Fig) , this could likely be the result of a secondary infection or drug toxicity.
T31594 50324-50493 Sentence denotes Given that these clinical signs were also observed in unchallenged control animals (S10 Fig) , this could likely be the result of a secondary infection or drug toxicity.
TextSentencer_T337 50494-50647 Sentence denotes The use of Cyp is well documented in ferrets, primarily given at a high dose as an emetic, and no dosage for long term immunosuppression was found [78] .
T57378 50494-50647 Sentence denotes The use of Cyp is well documented in ferrets, primarily given at a high dose as an emetic, and no dosage for long term immunosuppression was found [78] .
TextSentencer_T338 50648-50904 Sentence denotes The dosages used in this study (between 10-30 mg/kg) successfully reduced white blood cell levels, in ferrets and demonstrate that Cyp can be used to induce long-term immunosuppression, if antibiotics are given to control for secondary infection (S8 Fig) .
T30454 50648-50904 Sentence denotes The dosages used in this study (between 10-30 mg/kg) successfully reduced white blood cell levels, in ferrets and demonstrate that Cyp can be used to induce long-term immunosuppression, if antibiotics are given to control for secondary infection (S8 Fig) .
TextSentencer_T339 50905-51066 Sentence denotes Despite not being able to detect infectious virus or viral genome in the kidney, we hypothesized that the weight loss we observed could be due to kidney failure.
T45829 50905-51066 Sentence denotes Despite not being able to detect infectious virus or viral genome in the kidney, we hypothesized that the weight loss we observed could be due to kidney failure.
TextSentencer_T340 51067-51175 Sentence denotes Individuals with HFRS exhibit proteinuria and hematuria, both of which can indicate kidney damage [46, 47] .
T23016 51067-51175 Sentence denotes Individuals with HFRS exhibit proteinuria and hematuria, both of which can indicate kidney damage [46, 47] .
TextSentencer_T341 51176-51339 Sentence denotes Additionally, serum blood urea nitrogen and creatinine levels are both elevated in HFRS patients and provide a second way to measure kidney function [46, 47, 73] .
T31225 51176-51339 Sentence denotes Additionally, serum blood urea nitrogen and creatinine levels are both elevated in HFRS patients and provide a second way to measure kidney function [46, 47, 73] .
TextSentencer_T342 51340-51445 Sentence denotes Decreased platelet levels also characterize clinical HFRS in humans, impairing coagulation [46, 47, 73] .
T69094 51340-51445 Sentence denotes Decreased platelet levels also characterize clinical HFRS in humans, impairing coagulation [46, 47, 73] .
TextSentencer_T343 51446-51609 Sentence denotes In a second experiment designed to monitor kidney parameters, PUUV infected ferrets exhibited the same gradual weight loss that characterized the first experiment.
T2433 51446-51609 Sentence denotes In a second experiment designed to monitor kidney parameters, PUUV infected ferrets exhibited the same gradual weight loss that characterized the first experiment.
TextSentencer_T344 51610-51784 Sentence denotes However, no prolonged signs of clinical kidney failure were observed: blood urea nitrogen and creatinine levels did not dramatically increase over the five week study period.
T45910 51610-51784 Sentence denotes However, no prolonged signs of clinical kidney failure were observed: blood urea nitrogen and creatinine levels did not dramatically increase over the five week study period.
TextSentencer_T345 51785-51904 Sentence denotes Only one animal exhibited proteinuria (day 35), and two exhibited hematuria (one on Day 4, and one on Day 21) (Fig 7) .
T95500 51785-51904 Sentence denotes Only one animal exhibited proteinuria (day 35), and two exhibited hematuria (one on Day 4, and one on Day 21) (Fig 7) .
TextSentencer_T346 51905-52027 Sentence denotes Similarly to parameters monitoring renal failure, no thrombocytopenia occurred in PUUV infected ferrets (S9 and S13 Figs).
T99155 51905-52027 Sentence denotes Similarly to parameters monitoring renal failure, no thrombocytopenia occurred in PUUV infected ferrets (S9 and S13 Figs).
TextSentencer_T347 52028-52078 Sentence denotes The cause of the weight loss remains undetermined.
T98799 52028-52078 Sentence denotes The cause of the weight loss remains undetermined.
TextSentencer_T348 52079-52217 Sentence denotes Though susceptible to both HTNV and PUUV, the ferret has limited usefulness for studies involving medical countermeasure efficacy testing.
T24881 52079-52217 Sentence denotes Though susceptible to both HTNV and PUUV, the ferret has limited usefulness for studies involving medical countermeasure efficacy testing.
TextSentencer_T349 52218-52331 Sentence denotes The ferret's large mass, even as an adolescent, makes the amount of test article needed also prohibitively large.
T10036 52218-52331 Sentence denotes The ferret's large mass, even as an adolescent, makes the amount of test article needed also prohibitively large.
TextSentencer_T350 52332-52503 Sentence denotes The large challenge dose required for infection could potentially obscure the protective effect of drugs of vaccines, due to the overwhelming amount of virus administered.
T15910 52332-52503 Sentence denotes The large challenge dose required for infection could potentially obscure the protective effect of drugs of vaccines, due to the overwhelming amount of virus administered.
TextSentencer_T351 52504-52659 Sentence denotes Moreover, although the animals are infected the resultant neutralizing antibody titers are small, resulting in potential sensitivity issues with the model.
T69068 52504-52659 Sentence denotes Moreover, although the animals are infected the resultant neutralizing antibody titers are small, resulting in potential sensitivity issues with the model.
TextSentencer_T352 52660-52844 Sentence denotes Husbandry and handling of the animals under ABSL-3 procedures is also substantially more difficult than hamsters, and they lack the genetic similarity to humans that marmosets possess.
T34477 52660-52844 Sentence denotes Husbandry and handling of the animals under ABSL-3 procedures is also substantially more difficult than hamsters, and they lack the genetic similarity to humans that marmosets possess.
TextSentencer_T353 52845-52930 Sentence denotes In this study we have demonstrated the susceptibility of marmosets to HTNV infection.
T90514 52845-52930 Sentence denotes In this study we have demonstrated the susceptibility of marmosets to HTNV infection.
TextSentencer_T354 52931-53096 Sentence denotes Marmosets represent an attractive model for testing vaccines and therapeutics against HFRS-causing hantaviruses due to genetic similarities to humans and small size.
T51388 52931-53096 Sentence denotes Marmosets represent an attractive model for testing vaccines and therapeutics against HFRS-causing hantaviruses due to genetic similarities to humans and small size.
TextSentencer_T355 53097-53311 Sentence denotes Also, the model has a simple read-out of infection, i.e. robust antibody production as measured by N-ELISA and PsVNA, making the determination of protection by vaccine or passive transfer material, straightforward.
T47217 53097-53311 Sentence denotes Also, the model has a simple read-out of infection, i.e. robust antibody production as measured by N-ELISA and PsVNA, making the determination of protection by vaccine or passive transfer material, straightforward.
TextSentencer_T356 53312-53527 Sentence denotes Further optimization of the model, namely to determine the ID 99 , could prove important as a 1,000 PFU challenge dose could be excessively high and prohibit therapeutic effects of candidate medical countermeasures.
T47743 53312-53527 Sentence denotes Further optimization of the model, namely to determine the ID 99 , could prove important as a 1,000 PFU challenge dose could be excessively high and prohibit therapeutic effects of candidate medical countermeasures.
TextSentencer_T357 53528-53676 Sentence denotes Overall the marmoset model is more similar to the ferret HFRS-causing hantavirus infection model than the hamster, though there are key differences.
T31298 53528-53676 Sentence denotes Overall the marmoset model is more similar to the ferret HFRS-causing hantavirus infection model than the hamster, though there are key differences.
TextSentencer_T358 53677-53811 Sentence denotes Like the ferret, no significant pathological abnormalities were noted, and no signs of renal failure were observed (S16 and S19 Figs).
T2728 53677-53811 Sentence denotes Like the ferret, no significant pathological abnormalities were noted, and no signs of renal failure were observed (S16 and S19 Figs).
TextSentencer_T359 53812-53931 Sentence denotes Serum chemistry values do not differ from the normal range with the exception of albumin, total bilirubin, and amylase.
T71518 53812-53931 Sentence denotes Serum chemistry values do not differ from the normal range with the exception of albumin, total bilirubin, and amylase.
TextSentencer_T360 53932-54091 Sentence denotes While these values fell outside the normal range, they did not change over the course of infection indicating the problem may lie in the reference values used.
T58209 53932-54091 Sentence denotes While these values fell outside the normal range, they did not change over the course of infection indicating the problem may lie in the reference values used.
TextSentencer_T361 54092-54288 Sentence denotes The Piccolo general chemistry panel used to evaluate the parameters is optimized for human testing, and therefore may be less than optimal for evaluating the marmoset, especially those parameters.
T75070 54092-54288 Sentence denotes The Piccolo general chemistry panel used to evaluate the parameters is optimized for human testing, and therefore may be less than optimal for evaluating the marmoset, especially those parameters.
TextSentencer_T362 54289-54403 Sentence denotes Additionally, no infectious virus or viral genome was recovered from any organ at Day 30 post infection [79, 80] .
T73168 54289-54403 Sentence denotes Additionally, no infectious virus or viral genome was recovered from any organ at Day 30 post infection [79, 80] .
TextSentencer_T363 54404-54529 Sentence denotes This is not surprising, given the high levels of neutralizing antibodies present as early as 21 days post infection (Fig 8) .
T31173 54404-54529 Sentence denotes This is not surprising, given the high levels of neutralizing antibodies present as early as 21 days post infection (Fig 8) .
TextSentencer_T364 54530-54771 Sentence denotes Unlike the ferret, however, marmosets develop exceptionally high neutralizing antibody titers (10,240-20,480 by PRNT 50 and 14,866-221,557 by PsVNA 50 ), and display low-level serum viremia between two and four weeks post infection (Fig 8) .
T38808 54530-54771 Sentence denotes Unlike the ferret, however, marmosets develop exceptionally high neutralizing antibody titers (10,240-20,480 by PRNT 50 and 14,866-221,557 by PsVNA 50 ), and display low-level serum viremia between two and four weeks post infection (Fig 8) .
TextSentencer_T365 54772-55007 Sentence denotes The serum viremia is significantly lower than in hamsters infected with HTNV, where some animals displayed RT-PCR titers of >7log 10 , and in hamsters infected with ANDV, where infectious virus titers prior to death are > 6log 10 [41].
T52627 54772-55007 Sentence denotes The serum viremia is significantly lower than in hamsters infected with HTNV, where some animals displayed RT-PCR titers of >7log 10 , and in hamsters infected with ANDV, where infectious virus titers prior to death are > 6log 10 [41].
TextSentencer_T366 55008-55220 Sentence denotes Despite not exhibiting clinical signs of disease, the model's robust antibody response (as measured by PRNT, PsVNA and N-ELISA) make it a useful tool for evaluating vaccines and pre-or post-exposure therapeutics.
T92173 55008-55220 Sentence denotes Despite not exhibiting clinical signs of disease, the model's robust antibody response (as measured by PRNT, PsVNA and N-ELISA) make it a useful tool for evaluating vaccines and pre-or post-exposure therapeutics.
TextSentencer_T367 55221-55402 Sentence denotes This paper has explored the use of three laboratory animal species as possible infection and disease models for HFRS-causing hantaviruses: the hamster, the ferret, and the marmoset.
T77378 55221-55402 Sentence denotes This paper has explored the use of three laboratory animal species as possible infection and disease models for HFRS-causing hantaviruses: the hamster, the ferret, and the marmoset.
TextSentencer_T368 55403-55566 Sentence denotes These models, especially the hamster model and marmoset model, will be useful for evaluating medical countermeasures with the potential to induce sterile immunity.
T38458 55403-55566 Sentence denotes These models, especially the hamster model and marmoset model, will be useful for evaluating medical countermeasures with the potential to induce sterile immunity.
TextSentencer_T369 55567-55911 Sentence denotes The marmosets should be particularly useful for the evaluation of passively transferred protective human antibodies because of the relative genetic similarities between species in the Order Primates, and the small size of marmosets, allowing testing with smaller volumes of material than would be required for larger species such as macaques. .
T34074 55567-55911 Sentence denotes The marmosets should be particularly useful for the evaluation of passively transferred protective human antibodies because of the relative genetic similarities between species in the Order Primates, and the small size of marmosets, allowing testing with smaller volumes of material than would be required for larger species such as macaques. .
TextSentencer_T370 55912-56046 Sentence denotes Heart, lung, liver, spleen, kidney, and intestine were collected and assayed by plaque assay for the presence of infectious virus (A).
T33629 55912-56046 Sentence denotes Heart, lung, liver, spleen, kidney, and intestine were collected and assayed by plaque assay for the presence of infectious virus (A).
TextSentencer_T371 56047-56208 Sentence denotes To confirm lack of virus recovered was not due to inhibitors, virus was spiked into serial dilutions of organ homogenate to confirm no inhibitor was present (B).
T64262 56047-56208 Sentence denotes To confirm lack of virus recovered was not due to inhibitors, virus was spiked into serial dilutions of organ homogenate to confirm no inhibitor was present (B).
TextSentencer_T372 56209-56310 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
T58211 56209-56310 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
TextSentencer_T373 56311-56538 Sentence denotes In (B) the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate. (TIF) S10 Fig. Immunosuppression of uninfected ferrets leads to rapid weight loss and secondary bacterial infection.
T88417 56311-56538 Sentence denotes In (B) the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate. (TIF) S10 Fig. Immunosuppression of uninfected ferrets leads to rapid weight loss and secondary bacterial infection.
TextSentencer_T374 56539-56655 Sentence denotes Uninfected ferrets were administered 10mg/kg Cyp, and the antibiotic enrofloxicin, according to the schedule in (A).
T92961 56539-56655 Sentence denotes Uninfected ferrets were administered 10mg/kg Cyp, and the antibiotic enrofloxicin, according to the schedule in (A).
TextSentencer_T375 56656-56881 Sentence denotes Weight (B) and temperature (C) are shown. b.i.d indicates antibody was administered twice daily, and q.d indicates antibiotic was administered daily. (TIF) S11 Fig. PUUV infected ferrets had no infectious virus in the organs.
T90344 56656-56881 Sentence denotes Weight (B) and temperature (C) are shown. b.i.d indicates antibody was administered twice daily, and q.d indicates antibiotic was administered daily. (TIF) S11 Fig. PUUV infected ferrets had no infectious virus in the organs.
TextSentencer_T376 56882-56938 Sentence denotes Ferrets were infected with 94,000 PFU PUUV Beaumont i.m.
T26087 56882-56938 Sentence denotes Ferrets were infected with 94,000 PFU PUUV Beaumont i.m.
TextSentencer_T377 56939-57109 Sentence denotes Heart, lung, liver, spleen, kidney, intestine, brain, eye, and adrenal gland were collected on day 35 post infection and assayed for infectious virus by plaque assay (A).
T43553 56939-57109 Sentence denotes Heart, lung, liver, spleen, kidney, intestine, brain, eye, and adrenal gland were collected on day 35 post infection and assayed for infectious virus by plaque assay (A).
TextSentencer_T378 57110-57171 Sentence denotes Virus was spiked in to confirm no inhi bitor was present (B).
T21673 57110-57171 Sentence denotes Virus was spiked in to confirm no inhi bitor was present (B).
TextSentencer_T379 57172-57273 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
T96989 57172-57273 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
TextSentencer_T380 57274-57436 Sentence denotes In (B) the mean ± SEM is depicted in all spiked groups and the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate.
T84024 57274-57436 Sentence denotes In (B) the mean ± SEM is depicted in all spiked groups and the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate.
TextSentencer_T381 57437-57510 Sentence denotes To confirm no inhibitors were present, virus was spiked into samples (B).
T94480 57437-57510 Sentence denotes To confirm no inhibitors were present, virus was spiked into samples (B).
TextSentencer_T382 57511-57612 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
T53142 57511-57612 Sentence denotes For a standard plaque assay the limit of detection, 1.7 log 10 , is depicted as a dashed line in (A).
TextSentencer_T383 57613-57784 Sentence denotes In (B) the mean ± SEM is displayed for all spiked groups, and the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate. (TIF)
T75044 57613-57784 Sentence denotes In (B) the mean ± SEM is displayed for all spiked groups, and the dashed line is amount of HTNV plaques obtained when spiked into media rather than organ homogenate. (TIF)
TextSentencer_T384 57785-57839 Sentence denotes Three marmosets were infected with 1,000 PFU HTNV i.m.
T34145 57785-57839 Sentence denotes Three marmosets were infected with 1,000 PFU HTNV i.m.
TextSentencer_T385 57840-57931 Sentence denotes On Day 30 organs were harvested, and the presence of viral genome was determined by RT-PCR.
T45257 57840-57931 Sentence denotes On Day 30 organs were harvested, and the presence of viral genome was determined by RT-PCR.
TextSentencer_T386 57932-58008 Sentence denotes To confirm no inhibitors were present, viral genome was spiked into samples.
T39013 57932-58008 Sentence denotes To confirm no inhibitors were present, viral genome was spiked into samples.
TextSentencer_T387 58009-58109 Sentence denotes Heart (A), lung (B), liver (C), spleen (D), kidney (E), intestine (F), and brain (G) were collected.
T60415 58009-58109 Sentence denotes Heart (A), lung (B), liver (C), spleen (D), kidney (E), intestine (F), and brain (G) were collected.
TextSentencer_T388 58110-58248 Sentence denotes The mean ± SEM is shown for the not spiked (NS) and spiked (S) groups and the limit of detection, 1 log 10 , is depicted as a dashed line.
T80734 58110-58248 Sentence denotes The mean ± SEM is shown for the not spiked (NS) and spiked (S) groups and the limit of detection, 1 log 10 , is depicted as a dashed line.