RESUMO
Metagenomics was used to characterize viral genomes in clinical specimens of horses with various organ-specific diseases of unknown aetiology. A novel parvovirus as well as a previously described hepacivirus closely related to human hepatitis C virus and equid herpesvirus 2 were identified in the cerebrospinal fluid of horses with neurological signs. Four co-infecting picobirnaviruses, including an unusual genome with fused RNA segments, and a divergent anellovirus were found in the plasma of two febrile horses. A novel cyclovirus genome was characterized from the nasal secretion of another febrile animal. Lastly, a small circular DNA genome with a Rep gene, from a virus we called kirkovirus, was identified in the liver and spleen of a horse with fatal idiopathic hepatopathy. This study expands the number of viruses found in horses, and characterizes their genomes to assist future epidemiological studies of their transmission and potential association with various equine diseases.
Assuntos
Doenças dos Cavalos/virologia , Viroses/veterinária , Viroses/virologia , Vírus/isolamento & purificação , Animais , Genoma Viral , Cavalos , Humanos , Metagenômica , Dados de Sequência Molecular , Filogenia , Vírus/classificação , Vírus/genéticaRESUMO
Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of human TFRC knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.
Assuntos
Antígenos CD , Encéfalo , Capsídeo , Técnicas de Transferência de Genes , Vetores Genéticos , Glucosilceramidase , Receptores da Transferrina , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos CD/genética , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Dependovirus , Células Endoteliais/metabolismo , Técnicas de Introdução de Genes , Terapia Genética , Receptores da Transferrina/metabolismo , Receptores da Transferrina/genética , Glucosilceramidase/genética , Doença de Gaucher/genética , Doença de Gaucher/terapia , Doença de Parkinson/genética , Doença de Parkinson/terapiaRESUMO
Freedom House is our national EMS legacy. It was a revolutionary idea born out of the convergence of political forces. It's our EMS history, but it isn't found in our textbooks. Today we labor over the need to build workforce diversity, create community paramedicine and increase physician interaction during paramedic training. Freedom House had all of those things, yet we have collectively forgotten. Freedom House isn't about being the first. It's about believing in the power of each individual to achieve success. It's about building a system of clinical excellence and responsibility to the public. The original Freedom House paramedics became known for their advanced medical care, but to those they treated, they were known for their compassion and commitment to public service.
Assuntos
Ambulâncias , Serviços Médicos de Emergência/organização & administração , Humanos , Minnesota , Objetivos Organizacionais , PennsylvaniaRESUMO
Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, that binds human Transferrin Receptor (TfR1), a protein expressed on the blood-brain barrier (BBB). BI-hTFR1 was actively transported across a human brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in the CNS of human TFRC knock-in mice. The enhanced tropism was CNS-specific and absent in wild type mice. When used to deliver GBA1, mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared to AAV9. These findings establish BI-hTFR1 as a promising vector for human CNS gene therapy.