430 research outputs found

    Oropouche Virus Infection And Pathogenesis Are Restricted By Mavs, Irf-3, Irf-7, And Type I Interferon Signaling Pathways In Nonmyeloid Cells

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    Conselho Nacional de Desenvolvimento CientĂ­fico e TecnolĂłgico (CNPq)Oropouche virus (OROV) is a member of the Orthobunyavirus genus in the Bunyaviridae family and a prominent cause of insect-transmitted viral disease in Central and South America. Despite its clinical relevance, little is known about OROV pathogenesis. To define the host defense pathways that control OROV infection and disease, we evaluated OROV pathogenesis and immune responses in primary cells and mice that were deficient in the RIG-I-like receptor signaling pathway (MDA5, RIG-I, or MAVS), downstream regulatory transcription factors (IRF-3 or IRF-7), beta interferon (IFN-beta), or the receptor for type I IFN signaling (IFNAR). OROV replicated to higher levels in primary fibroblasts and dendritic cells lacking MAVS signaling, the transcription factors IRF-3 and IRF-7, or IFNAR than in wild-type (WT) cells. In mice, deletion of IFNAR, MAVS, or IRF-3 and IRF-7 resulted in uncontrolled OROV replication, hypercytokinemia, extensive liver damage, and death, whereas WT congenic animals failed to develop disease. Unexpectedly, mice with a selective deletion of IFNAR on myeloid cells (CD11c Cre(+) Ifnar(f/f) or LysM Cre(+) Ifnar(f/f)) did not sustain enhanced disease with OROV or a selective (flox/flox) deletion La Crosse virus, a closely related encephalitic orthobunyavirus. In bone marrow chimera studies, recipient irradiated Ifnar(-/-) mice reconstituted with WT hematopoietic cells sustained high levels of OROV replication and liver damage, whereas WT mice reconstituted with Ifnar(-/-) bone marrow were resistant to disease. Collectively, these results establish a dominant protective role for MAVS, IRF-3 and IRF-7, and IFNAR in restricting OROV infection and tissue injury and suggest that IFN signaling in nonmyeloid cells contributes to the host defense against orthobunyaviruses.89947204737National Institutes of Health [R01 AI104972, P30 DK52574]Conselho Nacional de Desenvolvimento CientĂ­fico e TecnolĂłgico (CNPq)University Research Committee grantConselho Nacional de Desenvolvimento CientĂ­fico e TecnolĂłgico (CNPq)CNPq [246513/2012-8

    Questioning Identity: How a Diverse Set of Respondents Answer Standard Questions About Ethnicity and Race

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    Ethnoracial identity refers to the racial and ethnic categories that people use to classify themselves and others. How it is measured in surveys has implications for understanding inequalities. Yet how people self-identify may not conform to the categories standardized survey questions use to measure ethnicity and race, leading to potential measurement error. In interviewer-administered surveys, answers to survey questions are achieved through interviewer–respondent interaction. An analysis of interviewer–respondent interaction can illuminate whether, when, how, and why respondents experience problems with questions. In this study, we examine how indicators of interviewer–respondent interactional problems vary across ethnoracial groups when respondents answer questions about ethnicity and race. Further, we explore how interviewers respond in the presence of these interactional problems. Data are provided by the 2013–2014 Voices Heard Survey, a computer-assisted telephone survey designed to measure perceptions of participating in medical research among an ethnoracially diverse sample of respondents

    Interferon-regulatory Factor 5-dependent Signaling Restricts Orthobunyavirus Dissemination To The Central Nervous System

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    Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in Irf3, Irf5, and Irf7 or in Irf5 alone. Deletion of Irf3, Irf5, and Irf7 together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of Irf5 alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected Irf5(-/-) mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in Irf5(-/-) mice had higher levels of OROV RNA in vivo yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained in vitro, since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice.90118920

    Managing suicidal ideation in a breast cancer cohort seeking reconstructive surgery

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135255/1/pon4017_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135255/2/pon4017.pd

    The maize brown midrib6 (bm6) mutation encodes a functional GTP Cyclohydrolase1

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    Brown midrib mutations in maize (Zea mays L.) and sorghum (Sorghum bicolor L.) alter lignin composition and enhance cell wall digestibility. These mutations are prime candidates for silage breeding. Six brown midrib mutants are currently known, brown midrib1 (bm1) to brown midrib6 (bm6). The bm1 and bm3 mutations are being used commercially for silage. The underlying genes responsible for five of the six bm mutations in maize (bm1, bm2, bm3, bm4, and bm5) are known. Chen and co-workers (2012) characterized the bm6 mutation, demonstratingthat bm6 increases cell wall digestibility and physically mapped bm6 within a 180 kilobase region on chromosome 2. The present investigation utilized map-based cloning to identify the candidate gene responsible for the bm6 phenotype as GTP Cyclohydrolase1 (GCH1) and validated the candidate gene through reverse genetics. Orthologs of bm6 include at least one paralogous gene in maize on chromosome 10 and various homologs in other grasses and dicots. The discovery that GCH1 is  responsible for the maize bm6 phenotype suggests that GCH1 plays a role in the tetrahydrofolate biosynthetic process

    Abiotic and Biotic Stressors Causing Equivalent Mortality Induce Highly Variable Transcriptional Responses in the Soybean Aphid

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    Environmental stress affects basic organismal functioning and can cause physiological, developmental, and reproductive impairment. However, in many nonmodel organisms, the core molecular stress response remains poorly characterized and the extent to which stress-induced transcriptional changes differ across qualitatively different stress types is largely unexplored. The current study examines the molecular stress response of the soybean aphid (Aphis glycines) using RNA sequencing and compares transcriptional responses to multiple stressors (heat, starvation, and plant defenses) at a standardized stress level (27% adult mortality). Stress-induced transcriptional changes showed remarkable variation, with starvation, heat, and plant defensive stress altering the expression of 3985, 510, and 12 genes, respectively. Molecular responses showed little overlap across all three stressors. However, a common transcriptional stress response was identified under heat and starvation, involved with up-regulation of glycogen biosynthesis and molecular chaperones and down-regulation of bacterial endosymbiont cellular and insect cuticular components. Stressor-specific responses indicated heat affected expression of heat shock proteins and cuticular components, whereas starvation altered a diverse set of genes involved in primary metabolism, oxidative reductive processes, nucleosome and histone assembly, and the regulation of DNA repair and replication. Exposure to host plant defenses elicited the weakest response, of which half of the genes were of unknown function. This study highlights the need for standardizing stress levels when comparing across stress types and provides a basis for understanding the role of general vs. stressor specific molecular responses in aphids

    Abiotic and Biotic Stressors Causing Equivalent Mortality Induce Highly Variable Transcriptional Responses in the Soybean Aphid

    Get PDF
    Environmental stress affects basic organismal functioning and can cause physiological, developmental, and reproductive impairment. However, in many nonmodel organisms, the core molecular stress response remains poorly characterized and the extent to which stress-induced transcriptional changes differ across qualitatively different stress types is largely unexplored. The current study examines the molecular stress response of the soybean aphid (Aphis glycines) using RNA sequencing and compares transcriptional responses to multiple stressors (heat, starvation, and plant defenses) at a standardized stress level (27% adult mortality). Stress-induced transcriptional changes showed remarkable variation, with starvation, heat, and plant defensive stress altering the expression of 3985, 510, and 12 genes, respectively. Molecular responses showed little overlap across all three stressors. However, a common transcriptional stress response was identified under heat and starvation, involved with up-regulation of glycogen biosynthesis and molecular chaperones and down-regulation of bacterial endosymbiont cellular and insect cuticular components. Stressor-specific responses indicated heat affected expression of heat shock proteins and cuticular components, whereas starvation altered a diverse set of genes involved in primary metabolism, oxidative reductive processes, nucleosome and histone assembly, and the regulation of DNA repair and replication. Exposure to host plant defenses elicited the weakest response, of which half of the genes were of unknown function. This study highlights the need for standardizing stress levels when comparing across stress types and provides a basis for understanding the role of general vs. stressor specific molecular responses in aphids
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