1,720,981 research outputs found
Compromised metabolic function and dysregulated induction of type 1 interferon promote susceptibility in a model for tuberculosis infection
Get PDFTuberculosis (TB) is a critical infectious disease world-wide, and the increasing development of antibiotic resistance drives the search for effective host-directed therapies. One molecular target of potential host-directed therapy is Type 1 Interferon, (IFN-I or IFNβ), an excess of which correlates with TB progression. The mechanisms underlying IFNβ overproduction are still unclear. In this dissertation we review cellular mechanisms, including mitochondrial function and metabolism, oxidative stress, and the Integrated Stress Response, which are involved in IFNβ production and macrophage function. We also describe an experimental model of human-like TB, the B6J.C3-Sst1C3HeB/Fej Krmn (B6.Sst1S) mouse, which provides a unique and convenient system for studying mechanisms of necrosis in TB granulomas.
We use primary macrophages from the B6.Sst1S mouse to establish a mechanism that links the B6.Sst1S genotype to a cascade of dysregulation that drives IFNβ superinduction and susceptibility to TB infection. TNF is necessary for granuloma formation in vivo, but in the context of transcriptional dysregulation and excess free iron, it drives oxidative stress, which amplifies IFNβ induction to pathologic levels. This induction is maintained by positive feedback through the double stranded RNA-dependent Protein Kinase (PKR). We demonstrate that interruption of this cascade by iron chelation or inhibition of lipid peroxidation attenuates IFNβ induction and improves subsequent infection outcomes. We conclude by comparing the in vitro model system to an in vivo necrotic TB granuloma, describing similarities between our system and human TB, and discussing the connections between IFN-I and autoimmune and degenerative disease and the broader application of the B6.Sst1S model system to studies of human immunity
Mycobacteria-Host Interactions: Genetics, Immunity, Pathology
No full textThis eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contac
Identification of disease susceptibility regions in a mouse model of spondyloarthritis
Get PDFBACKGROUND: Spondyloarthritis is a family of related inflammatory diseases including psoriatic arthritis and ankylosing spondylitis. The cytokine IL-23 is known to play an important role in spondyloarthritis development. Overexpression of IL-23 using IL-23 minicircle DNA in B10.RIII mice results in the development of a spondyloarthritis-like disease. B10.RIII is a major histocompatibility complex (MHC) congenic mouse strain that is susceptible to a number of autoimmune and autoinflammatory diseases. Contaminating regions outside the congenic interval from the donor strain, RIII, have been previously detected. While B10.RIII mice develop collagen-induced arthritis (CIA) and collagen antibody induced arthritis (CAIA), the background strain, C57BL/10 (B10) does not. The MHC region is known to play a role in the susceptibility of B10.RIII mice to CIA, but not in CAIA development, so other regions must be involved in arthritis development as well. These contaminating RIII-derived regions may control susceptibility to IL-23 minicircle induced arthritis in B10.RIII mice.
OBJECTIVE: This study aimed to identify RIII-derived regions in the genome of B10.RIII mice and begin to interrogate their effects on IL-23 minicircle induced arthritis.
METHODS: A systematic literature review was conducted using Pubmed and Web of Science. Articles using B10.RIII mice to study inflammatory disease models were included and data about year of publication, inbred mouse strains used, disease model, and inbred strain notation were extracted. Genome sequences of B10.RIII(71NS)/Sn, C57BL/10SnJ, and C57BL/10J were compared to identify RIII-derived clusters of variation in the B10.RIII genome. B10.RIII mice were crossed with B10 mice and subsequently backcrossed to B10.RIII mice to introduce the B10 allele at chromosome 15. Chr15b/b, Chr15b/r, and Chr15r/r B10.RIII mice were hydrodynamically injected with IL-23 minicircles, and arthritis development was monitored every other day for two weeks.
RESULTS: The systematic literature review yielded 8 studies that compared arthritis development in B10.RIII to RIII or B10. These studies identified three arthritis susceptibility regions: Cia5/Eae3 on chromosome 3, Eae2 on chromosome 15, and Eae39 on chromosome 5. Eae2 is further split into four sub-regions: Cia30, Cia31, Cia32, and Cia26. Genome sequence comparison identified RIII-derived clusters in B10.RIII mice on chromosomes 10, 14, 15, and 17. The chromosome 15 region overlaps with the Eae2 susceptibility region for approximately 17 Mbp and includes the arthritis susceptibility loci Cia26 and Cia32. When this region was interrogated in vivo, Chr15r/r and Chr15b/r B10.RIII mice developed IL-23 minicircle arthritis, while Chr15b/b mice did not.
CONCLUSION: The B10.RIII(71NS)/Sn strain contains several large RIII/WySn-derived regions outside the congenic MHC region. One of these clusters on chromosome 15 includes the arthritis susceptibility loci Cia26 and Cia32 and appears to determine susceptibility to IL-23 minicircle induced arthritis. Future studies will interrogate the role of the chromosome 15 RIII-derived region in arthritis development in more detail and aim to identify the specific gene variants that control arthritis susceptibility.2023-01-28T00:00:00
Multiplex immunohistochemical analysis of granulomatous inflammation in lung tissue sections using a mouse model of M. avium infection
Get PDFINTRODUCTION: Investigating mechanisms of how intracellular bacterial pathogens such as Mycobacterium. avium (M. avium) evade the host immune response and replicate within macrophages is crucial to devising rational targets for host-directed therapies (HDT) against these associated diseases. This studied utilized the congenic mouse strain B6.Sst1S, which contains the super-susceptibility to tuberculosis (TB) allele. Among murine models of TB, this strain uniquely replicates human disease because mice develop granulomas with central caseous necrosis. Utilizing a susceptible model for M. avium infection, this study investigated the effect of mycobacterial pathogenesis on altering macrophage phenotypes and T cells distribution in areas of pulmonary granulomatous inflammation.
METHODS:12 formalin fixed paraffin embedded (FFPE) lung sections from M. avium infected B6.Sst1S and B6 mice were examined microscopically (12 weeks post infection (wpi) n=5, 16 wpi=7). A targeted histology approach was initiated by using MRI coordinates to dictate the depths at which formalin fixed paraffin embedded (FFPE) lung
samples were sectioned. Since interpretation of MRI images displayed no evidence of 2
discrete necrotizing granulomas, lungs were cut at sections representative of diffuse pathology at 2 mm into FFPE blocks. Using the Opal MethodTM (Akoya Biosciences), 6- plex immunohistochemical staining was performed with Arginase-1 (Arg1), inducible nitric oxide synthase (iNOS), CD68, CD3, M. tuberculosis antigen (cross-reacts with M. avium) and DAPI to segment nuclei. Slides were digitized by a Vectra PolarisTM fluorescent whole slide scanner. Autofluorescence was removed by InFormTM, and image analysis (IA) was conducted using HaloTM IA software. Statistical analysis was conducted using GraphPad PrismTM 8.0.
RESULTS: Sst1 mediated susceptibility was statistically evident at 16 wpi but not at 12 wpi. B6.Sst1S mice showed a statistically significant (P <0.05) increase in M. avium+ cell expression in the non-inoculated lung lobes, but not the inoculated lung lobes. Pulmonary lesions within the inoculated and non-inoculated lung lobes contain different immune signatures. The predominately primary lesions of the inoculated lung lobes were associated with increased CD3+, M. avium+, and iNOS+ cell levels. When controlling for level of infection, there was lower levels of CD3+ cells within granulomatous lesions of B6.Sst1S mice, especially in the non-inoculated lung lobe. Controlling for level of infection also revealed elevated iNOS+ M. avium- cell expression in B6 mice. We observed elevated Arg1+ cell expression near iNOS+ M. avium+ cells, and, qualitatively, around larger lesions. T cell proximity analysis was contradictory and offers lessons for future the development of future IA modules.
CONCLUSIONS: Sst1 mediated susceptibility was evident at 16 wpi and predominately
mediated through secondary, metastatic lesions. Sst1 mediated susceptibility was also associated with fewer supportive cells (T cells and iNOS+ M. avium- cells) within granulomatous lesions. Future studies are necessary to evaluate to what degree granulomatous lesion Arg1+ cell expression and CD3+ proximity correlate to susceptibility
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
