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1.
Hear Res ; 424: 108603, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36099806

RESUMO

For gaining insight into general principles of auditory processing, it is critical to choose model organisms whose set of natural behaviors encompasses the processes being investigated. This reasoning has led to the development of a variety of animal models for auditory neuroscience research, such as guinea pigs, gerbils, chinchillas, rabbits, and ferrets; but in recent years, the availability of cutting-edge molecular tools and other methodologies in the mouse model have led to waning interest in these unique model species. As laboratories increasingly look to include in-vivo components in their research programs, a comprehensive description of procedures and techniques for applying some of these modern neuroscience tools to a non-mouse small animal model would enable researchers to leverage unique model species that may be best suited for testing their specific hypotheses. In this manuscript, we describe in detail the methods we have developed to apply these tools to the guinea pig animal model to answer questions regarding the neural processing of complex sounds, such as vocalizations. We describe techniques for vocalization acquisition, behavioral testing, recording of auditory brainstem responses and frequency-following responses, intracranial neural signals including local field potential and single unit activity, and the expression of transgenes allowing for optogenetic manipulation of neural activity, all in awake and head-fixed guinea pigs. We demonstrate the rich datasets at the behavioral and electrophysiological levels that can be obtained using these techniques, underscoring the guinea pig as a versatile animal model for studying complex auditory processing. More generally, the methods described here are applicable to a broad range of small mammals, enabling investigators to address specific auditory processing questions in model organisms that are best suited for answering them.


Assuntos
Córtex Auditivo , Estimulação Acústica , Animais , Córtex Auditivo/fisiologia , Chinchila , Furões , Gerbillinae , Cobaias , Audição , Modelos Animais , Neurônios/fisiologia , Coelhos , Vocalização Animal/fisiologia
2.
Science ; 377(6611): eabl6422, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36074851

RESUMO

Neanderthal brains were similar in size to those of modern humans. We sought to investigate potential differences in neurogenesis during neocortex development. Modern human transketolase-like 1 (TKTL1) differs from Neanderthal TKTL1 by a lysine-to-arginine amino acid substitution. Using overexpression in developing mouse and ferret neocortex, knockout in fetal human neocortical tissue, and genome-edited cerebral organoids, we found that the modern human variant, hTKTL1, but not the Neanderthal variant, increases the abundance of basal radial glia (bRG) but not that of intermediate progenitors (bIPs). bRG generate more neocortical neurons than bIPs. The hTKTL1 effect requires the pentose phosphate pathway and fatty acid synthesis. Inhibition of these metabolic pathways reduces bRG abundance in fetal human neocortical tissue. Our data suggest that neocortical neurogenesis in modern humans differs from that in Neanderthals.


Assuntos
Homem de Neandertal , Neocórtex , Neurogênese , Transcetolase , Animais , Células Ependimogliais/citologia , Furões , Humanos , Camundongos , Homem de Neandertal/embriologia , Homem de Neandertal/genética , Neocórtex/embriologia , Neurogênese/genética , Neurogênese/fisiologia , Transcetolase/genética , Transcetolase/metabolismo
3.
Proc Natl Acad Sci U S A ; 119(38): e2206147119, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36095192

RESUMO

The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly.


Assuntos
Quinase 6 Dependente de Ciclina , Células Ependimogliais , Microcefalia , Neocórtex , Animais , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Células Ependimogliais/citologia , Células Ependimogliais/enzimologia , Furões , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Microcefalia/genética , Neocórtex/anormalidades , Neocórtex/enzimologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/enzimologia , Organoides/embriologia
4.
PLoS Pathog ; 18(9): e1010741, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36070309

RESUMO

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.


Assuntos
COVID-19 , Animais , COVID-19/complicações , Cricetinae , Furões , Humanos , Mesocricetus , Camundongos , SARS-CoV-2
5.
Front Cell Infect Microbiol ; 12: 873416, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36051240

RESUMO

Even with the COVID-19 pandemic, tuberculosis remains a leading cause of human death due to a single infectious agent. Until successfully treated, infected individuals may continue to transmit Mycobacterium tuberculosis bacilli to contacts. As with other respiratory pathogens, such as SARS-CoV-2, modeling the process of person-to-person transmission will inform efforts to develop vaccines and therapies that specifically impede disease transmission. The ferret (Mustela furo), a relatively inexpensive, small animal has been successfully employed to model transmissibility, pathogenicity, and tropism of influenza and other respiratory disease agents. Ferrets can become naturally infected with Mycobacterium bovis and are closely related to badgers, well known in Great Britain and elsewhere as a natural transmission vehicle for bovine tuberculosis. Herein, we report results of a study demonstrating that within 7 weeks of intratracheal infection with a high dose (>5 x 103 CFU) of M. tuberculosis bacilli, ferrets develop clinical signs and pathological features similar to acute disease reported in larger animals, and ferrets infected with very-high doses (>5 x 104 CFU) develop severe signs within two to four weeks, with loss of body weight as high as 30%. Natural transmission of this pathogen was also examined. Acutely-infected ferrets transmitted M. tuberculosis bacilli to co-housed naïve sentinels; most of the sentinels tested positive for M. tuberculosis in nasal washes, while several developed variable disease symptomologies similar to those reported for humans exposed to an active tuberculosis patient in a closed setting. Transmission was more efficient when the transmitting animal had a well-established acute infection. The findings support further assessment of this model system for tuberculosis transmission including the testing of prevention measures and vaccine efficacy.


Assuntos
COVID-19 , Tuberculose , Animais , Modelos Animais de Doenças , Furões , Humanos , Pandemias , SARS-CoV-2
6.
Vet Clin North Am Exot Anim Pract ; 25(3): 563-584, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36122940

RESUMO

The synthesis of bile acids occurs during the degradation of cholesterol in hepatocytes. Thus, this analyte is expected to be a sensitive indicator of hepatocellular dysfunction or alterations in portal circulation. Bile acids can be quantified via an enzymatic reaction to a highly conserved moiety across species. The evidence for the clinical utility of bile acids for the diagnosis of liver disease is strongest in birds and ferrets with equivocal evidence in rodents, rabbits, and reptiles. Current limitations to the interpretation of bile acids in exotic animal species include a paucity of species-specific reference intervals and incomplete understanding of bile acid metabolism in nonmammalian species and the diversity of bile acids synthesized by vertebrates.


Assuntos
Animais Exóticos , Hepatopatias , Animais , Ácidos e Sais Biliares , Colesterol/metabolismo , Furões , Hepatopatias/diagnóstico , Hepatopatias/veterinária , Coelhos
7.
Vet Clin North Am Exot Anim Pract ; 25(3): 631-661, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36122944

RESUMO

Endocrine disease in exotic species is less common than in small animals. Nevertheless, the diagnostic principles used in small animals can be adapted to evaluate endocrine disease in many of the exotic species although species-specific aspects need to be considered. This article covers important diseases such as thyroid dysfunction in reptiles and birds, hyperthyroidism in guinea pigs, and hyperadrenocorticism in ferrets. Glucose metabolism in neoplasms affecting normal physiology, such as insulinoma in ferrets and gastric neuroendocrine carcinoma in bearded dragons, is discussed. Calcium abnormalities, including metabolic bone disease in reptiles and hypocalcemia in birds, are also covered.


Assuntos
Animais Exóticos , Doenças do Sistema Endócrino , Animais , Aves , Cálcio , Doenças do Sistema Endócrino/veterinária , Furões , Glucose , Cobaias
8.
PLoS One ; 17(9): e0266161, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36170266

RESUMO

The introduction and expansion of an invasive non-native species could have important consequences for the genetic patterns and processes of native species, moreover if the new arrival competes strongly for resources and space. This may result in the demographic decline of the native species. Knowing the effects on the levels of genetic diversity and structure in native species is key in terms of their conservation. We analysed temporal (over 50 years) genetic variation of the population of the European polecat (Mustela putorius), a species under threat in several European countries, in the Bialowieza Primeval Forest (BPF), Poland, before and after the invasion of the American mink (Neovison vison). Using 11 microsatellite loci and a fragment of the mitochondrial control region we show that levels of diversity changed in the polecat population over 53 generations (over the period 1959-2012) and after the invasion of mink. When compared with other threatened European polecat populations, high levels of diversity are observed in the population in BPF in both periods, as well as in other areas in Poland. Our data shows that genetic structure was not present either before or after the mink invasion in BPF. This would suggest that the polecat population in Poland was not affected by invasive species and other negative factors and would be a potential good source of individuals for captive breeding or genetic rescue conservation management actions in areas where such actions are needed, for example the UK.


Assuntos
Furões , Vison , Animais , Furões/genética , Variação Genética , Humanos , Espécies Introduzidas , Repetições de Microssatélites/genética , Vison/genética
9.
Commun Biol ; 5(1): 1026, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171475

RESUMO

Influenza antivirals are important tools in our fight against annual influenza epidemics and future influenza pandemics. Combinations of antivirals may reduce the likelihood of drug resistance and improve clinical outcomes. Previously, two hospitalised immunocompromised influenza patients, who received a combination of a neuraminidase inhibitor and baloxavir marboxil, shed influenza viruses resistant to both drugs. Here-in, the replicative fitness of one of these A(H1N1)pdm09 virus isolates with dual resistance mutations (NA-H275Y and PA-I38T) was similar to wild type virus (WT) in vitro, but reduced in the upper respiratory tracts of challenged ferrets. The dual-mutant virus transmitted well between ferrets in an airborne transmission model, but was outcompeted by the WT when the two viruses were co-administered. These results indicate the dual-mutant virus had a moderate loss of viral fitness compared to the WT virus, suggesting that while person-to-person transmission of the dual-resistant virus may be possible, widespread community transmission is unlikely.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/tratamento farmacológico , Neuraminidase/genética , Replicação Viral/genética
10.
PLoS One ; 17(8): e0272419, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35939486

RESUMO

BACKGROUND: Plague, a widely distributed zoonotic disease of mammalian hosts and flea vectors, poses a significant risk to ecosystems throughout much of Earth. Conservation biologists use insecticides for flea control and plague mitigation. Here, we evaluate the use of an insecticide grain bait, laced with 0.005% fipronil (FIP) by weight, with black-tailed prairie dogs (BTPDs, Cynomys ludovicianus). We consider safety measures, flea control, BTPD body condition, BTPD survival, efficacy of plague mitigation, and the speed of FIP grain application vs. infusing BTPD burrows with insecticide dusts. We also explore conservation implications for endangered black-footed ferrets (Mustela nigripes), which are specialized predators of Cynomys. PRINCIPAL FINDINGS: During 5- and 10-day laboratory trials in Colorado, USA, 2016-2017, FIP grain had no detectable acute toxic effect on 20 BTPDs that readily consumed the grain. During field experiments in South Dakota, USA, 2016-2020, FIP grain suppressed fleas on BTPDs for at least 12 months and up to 24 months in many cases; short-term flea control on a few sites was poor for unknown reasons. In an area of South Dakota where plague circulation appeared low or absent, FIP grain had no detectable effect, positive or negative, on BTPD survival. Experimental results suggest FIP grain may have improved BTPD body condition (mass:foot) and reproduction (juveniles:adults). During a 2019 plague epizootic in Colorado, BTPDs on 238 ha habitat were protected by FIP grain, whereas BTPDs were nearly eliminated on non-treated habitat. Applications of FIP grain were 2-4 times faster than dusting BTPD burrows. SIGNIFICANCE: Deltamethrin dust is the most commonly used insecticide for plague mitigation on Cynomys colonies. Fleas on BTPD colonies exhibit the ability to evolve resistance to deltamethrin after repeated annual treatments. Thus, more tools are needed. Accumulating data show orally-delivered FIP is safe and usually effective for flea control with BTPDs, though potential acute toxic effects cannot be ruled out. With continued study and refinement, FIP might be used in rotation with, or even replace deltamethrin, and serve an important role in Cynomys and black-footed ferret conservation. More broadly, our stepwise approach to research on FIP may function as a template or guide for evaluations of insecticides in the context of wildlife conservation.


Assuntos
Infestações por Pulgas , Inseticidas , Peste , Piretrinas , Doenças dos Roedores , Sifonápteros , Yersinia pestis , Animais , Ecossistema , Furões , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Infestações por Pulgas/veterinária , Inseticidas/farmacologia , Nitrilas , Peste/prevenção & controle , Peste/veterinária , Pirazóis , Sciuridae
11.
mBio ; 13(4): e0105622, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35938724

RESUMO

Amino acid substitutions I38T and E23K in the influenza polymerase acidic (PA) protein lead to reduced susceptibility to the influenza antiviral drug baloxavir. The in vivo effectiveness of baloxavir and oseltamivir for treatment of these viruses is currently unknown. Using patient-derived influenza isolates, combination therapy was equally effective as monotherapy in reducing viral titers in the upper respiratory tract of ferrets infected with A(H1N1pdm09)-PA/E23K or A(H3N2)-PA/I38T. When treated with baloxavir plus oseltamivir, infection with a mixture of PA/I38T or PA/E23K and corresponding wild-type virus was characterized by a lower selection of viruses with reduced baloxavir susceptibility over the course of infection compared to baloxavir monotherapy. De novo emergence of the oseltamivir resistance mutation NA/H275Y occurred in ferrets treated with oseltamivir alone but not in ferrets treated with baloxavir plus oseltamivir. Our data suggest that combination therapy with influenza drugs with different mechanisms of action decreased the selection pressure for viruses with reduced drug susceptibility. IMPORTANCE Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. However, the selection of viruses with baloxavir resistance was relatively high following treatment, which may compromise the effectiveness of the drug. Here, we took two different influenza viruses that are resistant to baloxavir and tested the effectiveness alone and in combination with oseltamivir (a second influenza antiviral drug) in the ferret model. Our findings suggest that combination treatment may be a more effective method than monotherapy to reduce the selection of resistant viruses. These results may have important clinical implications for the treatment of influenza.


Assuntos
Influenza Humana , Tiepinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Morfolinas , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
12.
Proc Natl Acad Sci U S A ; 119(34): e2203919119, 2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-35969783

RESUMO

Previous studies have shown that the Eurasian avian-like H1N1 (EA H1N1) swine influenza viruses circulated widely in pigs around the world and formed multiple genotypes by acquiring non-hemagglutinin and neuraminidase segments derived from other swine influenza viruses. Swine influenza control is not a priority for the pig industry in many countries, and it is worrisome that some strains may become more pathogenic and/or transmissible during their circulation in nature. Our routine surveillance indicated that the EA H1N1 viruses obtained different internal genes from different swine influenza viruses and formed various new genotypes. In this study, we found that a naturally isolated swine influenza reassortant, A/swine/Liaoning/265/2017 (LN265), a representative strain of one of the predominant genotypes in recent years, is lethal in mice and transmissible in ferrets. LN265 contains the hemagglutinin, neuraminidase, and matrix of the EA H1N1 virus; the basic polymerase 2, basic polymerase 1, acidic polymerase (PA), and nucleoprotein of the 2009 H1N1 pandemic virus; and the nonstructural protein of the North American triple-reassortment H1N2 virus. By generating and testing a series of reassortants and mutants, we found that four gradually accumulated mutations in PA are responsible for the increased pathogenicity and transmissibility of LN265. We further revealed that these mutations increase the messenger RNA transcription of viral proteins by enhancing the endonuclease cleavage activity and viral RNA-binding ability of the PA protein. Our study demonstrates that EA H1N1 swine influenza virus became pathogenic and transmissible in ferrets by acquiring key mutations in PA and provides important insights for monitoring field strains with pandemic potential.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Infecções por Orthomyxoviridae , RNA Polimerase Dependente de RNA , Doenças dos Suínos , Animais , Furões , Genótipo , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Camundongos , Mutação , Neuraminidase/genética , Infecções por Orthomyxoviridae/veterinária , Infecções por Orthomyxoviridae/virologia , Filogenia , RNA Polimerase Dependente de RNA/genética , Vírus Reordenados/genética , Suínos , Doenças dos Suínos/virologia , Proteínas Virais/genética
13.
J Virol ; 96(16): e0055922, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35916513

RESUMO

Intracellular RIG-I receptors represent key innate sensors of RNA virus infection, and RIG-I activation results in the induction of hundreds of host effector genes, including interferon-stimulated genes (ISGs). Synthetic RNA agonists targeting RIG-I have shown promise as antivirals against a broad spectrum of viruses, including influenza A virus (IAV), in both in vitro and mouse models of infection. Herein, we demonstrate that treatment of a ferret airway epithelial (FRL) cell line with a RIG-I agonist rapidly and potently induced expression of a broad range of ISGs and resulted in potent inhibition of growth of different IAV strains. In ferrets, a single intravenous injection of RIG-I agonist was associated with upregulated ISG expression in peripheral blood mononuclear cells and lung tissue, but not in nasal tissues. In a ferret model of viral contact transmission, a single treatment of recipient animals 24 h prior to cohousing with IAV-infected donors did not reduce virus transmission and shedding but did result in reduced lung virus titers 6 days after treatment. A single treatment of the IAV-infected donor animals also resulted in reduced virus titers in the lungs 2 days later. Thus, a single intravenous treatment with RIG-I agonist prior to infection or to ferrets with an established IAV infection can reduce virus growth in the lungs. These findings support further development of RIG-I agonists as effective antiviral treatments to limit the impact of IAV infections, particularly in reducing virus replication in the lower airways. IMPORTANCE RIG-I agonists have shown potential as broad-spectrum antivirals in vitro and in mouse models of infection. However, their antiviral potential has not been reported in outbred animals such as ferrets, which are widely regarded as the gold standard small animal model for human IAV infections. Herein, we demonstrate that RIG-I agonist treatment of a ferret airway cell line resulted in ISG induction and inhibition of a broad range of human influenza viruses. A single intravenous treatment of ferrets also resulted in systemic induction of ISGs, including in lung tissue, and when delivered to animals prior to IAV exposure or to animals with established IAV infection treatment resulted in reduced virus replication in the lungs. These data demonstrate the effectiveness of single RIG-I treatment against IAV in the ferret model and highlight the importance of future studies to optimize treatment regimens and delivery routes to maximize their ability to ameliorate IAV infections.


Assuntos
Vírus da Influenza A , Influenza Humana , Animais , Antivirais/farmacologia , Furões/metabolismo , Humanos , Imunidade Inata , Vírus da Influenza A/genética , Interferons/metabolismo , Leucócitos Mononucleares/metabolismo , Pulmão , Camundongos , Replicação Viral/genética
14.
PLoS Pathog ; 18(8): e1010745, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36037230

RESUMO

In vivo bioluminescence imaging facilitates the non-invasive visualization of biological processes in living animals. This system has been used to track virus infections mostly in mice and ferrets; however, until now this approach has not been applied to pathogens in avian species. To visualize the infection of an important avian pathogen, we generated Marek's disease virus (MDV) recombinants expressing firefly luciferase during lytic replication. Upon characterization of the recombinant viruses in vitro, chickens were infected and the infection visualized in live animals over the course of 14 days. The luminescence signal was consistent with the known spatiotemporal kinetics of infection and the life cycle of MDV, and correlated well with the viral load measured by qPCR. Intriguingly, this in vivo bioimaging approach revealed two novel sites of MDV replication, the beak and the skin of the feet covered in scales. Feet skin infection was confirmed using a complementary fluorescence bioimaging approach with MDV recombinants expressing mRFP or GFP. Infection was detected in the intermediate epidermal layers of the feet skin that was also shown to produce infectious virus, regardless of the animals' age at and the route of infection. Taken together, this study highlights the value of in vivo whole body bioimaging in avian species by identifying previously overlooked sites of replication and shedding of MDV in the chicken host.


Assuntos
Herpesviridae , Herpesvirus Galináceo 2 , Doença de Marek , Animais , Galinhas , Furões , Camundongos
15.
Genes (Basel) ; 13(8)2022 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-36011357

RESUMO

Both the giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to the order Carnivora, but have changed their dietary habits to eating bamboo exclusively. The convergent evolution characteristics of their morphology, genome and gut flora have been found in the two pandas. However, the research on the convergent adaptation of their digestion and metabolism to the bamboo diet, mediated by the dietary shift of the two pandas at the gene-expression and epigenetic regulation levels, is still lacking. We therefore used RNA sequencing among five species (two pandas and three non-herbivore mammals) and bisulfite sequencing among three species (two pandas and a carnivore ferret) to sequence key digestion and metabolism tissues (stomach and small intestine). Our results provide evidence that the convergent differentially expressed genes (related to carbohydrate utilization, bile secretion, Lys and Arg metabolism, vitamin B12 utilization and cyanide detoxification) of the two pandas are adaptive responses to the bamboo diet containing low lipids, low Lys and Arg, low vitamin B12 and high cyanide. We also profiled the genome-wide methylome maps of giant panda, red panda and ferret, and the results indicated that the promoter methylation of the two pandas may regulate digestive and metabolic genes to adapt to sudden environmental changes, and then, transmit genetic information to future generations to evolve into bamboo eaters. Taken together, our study provides new insights into the molecular mechanisms of the dietary shift and the adaptation to a strict bamboo diet in both pandas using comparative transcriptomics and methylomics.


Assuntos
Ailuridae , Carnívoros , Ursidae , Ailuridae/genética , Ailuridae/metabolismo , Animais , Carnívoros/genética , Cianetos/metabolismo , Dieta , Epigênese Genética , Furões/genética , Furões/metabolismo , Transcriptoma/genética , Ursidae/genética , Vitamina B 12/metabolismo
16.
J Vis Exp ; (185)2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35969093

RESUMO

Skeletal muscle thermogenesis provides a potential avenue for better understanding metabolic homeostasis and the mechanisms underlying energy expenditure. Surprisingly little evidence is available to link the neural, myocellular, and molecular mechanisms of thermogenesis directly to measurable changes in muscle temperature. This paper describes a method in which temperature transponders are utilized to retrieve direct measurements of mouse and rat skeletal muscle temperature. Remote transponders are surgically implanted within the muscle of mice and rats, and the animals are given time to recover. Mice and rats must then be repeatedly habituated to the testing environment and procedure. Changes in muscle temperature are measured in response to pharmacological or contextual stimuli in the home cage. Muscle temperature can also be measured during prescribed physical activity (i.e., treadmill walking at a constant speed) to factor out changes in activity as contributors to the changes in muscle temperature induced by these stimuli. This method has been successfully used to elucidate mechanisms underlying muscle thermogenic control at the level of the brain, sympathetic nervous system, and skeletal muscle. Provided are demonstrations of this success using predator odor (PO; ferret odor) as a contextual stimulus and injections of oxytocin (Oxt) as a pharmacological stimulus, where predator odor induces muscle thermogenesis, and Oxt suppresses muscle temperature. Thus, these datasets display the efficacy of this method in detecting rapid changes in muscle temperature.


Assuntos
Furões , Termogênese , Tecido Adiposo Marrom/metabolismo , Animais , Metabolismo Energético/fisiologia , Músculo Esquelético/fisiologia , Ratos , Sistema Nervoso Simpático/fisiologia , Termogênese/fisiologia
17.
Vopr Virusol ; 67(3): 173-184, 2022 07 13.
Artigo em Russo | MEDLINE | ID: mdl-35831960

RESUMO

Within the last decade, a large number of viruses genetically related to human hepatitis viruses have been identified in different animal species, including monkeys. Numerous viruses related to human hepatitis A virus (HAV, Picornaviridae: Hepatovirus: Hepatovirus A) were detected in various mammalian species in 2015-2018, predominantly in bats and rodents, but also in shrews, seals and marsupials. Zoonotic hepatitis E virus (HEV, Hepeviridae: Orthohepevirus: Orthohepevirus A) genotypes have been found in wild boars, deer, camels, and rabbits, as well as in non human primates. In addition, viruses that are genetically close to HEV have been described in bats, ferrets, rodents, birds, and fish. Nevertheless, monkeys remain important laboratory animals in HAV and HEV research. The study of spontaneous and experimental infection in these animals is an invaluable source of information about the biology and pathogenesis of these viruses and continues to be an indispensable tool for vaccine and drug testing. The purpose of this literature review was to summarize and analyze published data on the circulation of HAV and HEV among wild and captive primates, as well as the results of experimental studies of HAV and HEV infections in monkeys.


Assuntos
Cervos , Vírus da Hepatite E , Hepatite E , Animais , Furões , Haplorrinos , Hepatite E/epidemiologia , Hepatite E/veterinária , Vírus da Hepatite E/genética , Primatas , Coelhos
18.
Nat Commun ; 13(1): 4416, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906230

RESUMO

SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , COVID-19/tratamento farmacológico , Cricetinae , Citidina/análogos & derivados , Furões , Humanos , Hidroxilaminas , Pulmão , Masculino
19.
Sci Transl Med ; 14(653): eabo2167, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35857640

RESUMO

Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics and from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called "universal" influenza vaccines, do not currently exist but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole-virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is composed of four ß-propiolactone-inactivated low-pathogenicity avian IAV subtypes of H1N9, H3N8, H5N1, and H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to control animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N8 , Virus da Influenza A Subtipo H5N1 , Subtipo H7N9 do Vírus da Influenza A , Vacinas contra Influenza , Infecções por Orthomyxoviridae , Animais , Anticorpos Antivirais , Furões , Cavalos , Humanos , Vírus da Influenza A Subtipo H7N3 , Camundongos , Suínos
20.
mBio ; 13(4): e0117422, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35862762

RESUMO

Past pandemic influenza viruses with sustained human-to-human transmissibility have emerged from animal influenza viruses. Employment of experimental models to assess the pandemic risk of emerging zoonotic influenza viruses provides critical information supporting public health efforts. Ferret transmission experiments have been utilized to predict the human-to-human transmission potential of novel influenza viruses. However, small sample sizes and a lack of standardized protocols can introduce interlaboratory variability, complicating interpretation of transmission experimental data. To assess the range of variation in ferret transmission experiments, a global exercise was conducted by 11 laboratories using two common stock H1N1 influenza viruses with different transmission characteristics in ferrets. Parameters known to affect transmission were standardized, including the inoculation route, dose, and volume, as well as a strict 1:1 donor/contact ratio for respiratory droplet transmission. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored and analyzed. The overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. Among environmental parameters that varied across laboratories, donor-to-contact airflow directionality was associated with increased transmissibility. To attain high confidence in identifying viruses with moderate to high transmissibility or low transmissibility under a smaller number of participating laboratories, our analyses support the notion that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment. IMPORTANCE Following detection of a novel virus, rapid characterization efforts (both in vitro and in vivo) are undertaken at numerous laboratories worldwide to evaluate the relative risk posed to human health. Aggregation of these data are critical, but the use of nonstandardized protocols can make interpretation of divergent results a challenge. For evaluation of virus transmissibility, a multifactorial trait which can only be evaluated in vivo, identifying intrinsic levels of variability between groups can improve the utility of these data, as well as ensure that experiments are performed with sufficient replication to ensure high confidence in compiled results. Using the ferret transmission model and two influenza A viruses, we conducted a multicenter standardization exercise to improve the interpretation of transmission data generated during risk assessment activities; this exercise serves as a model for future efforts employing both in vitro and in vivo models against possible pandemic pathogens.


Assuntos
Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Infecções por Orthomyxoviridae , Animais , Furões , Humanos , Laboratórios , Pulmão , Medição de Risco
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