Listeria monocytogenes (Lm) is an intracellular Gram-positive bacterium that induces expression of type I interferons (IFN-α/IFN-β) during infection. These cytokines are detrimental to the host during infection by priming leukocytes to undergo Lm-mediated apoptosis. Our previous studies showed that C5aR1−/− and C3aR−/− mice are highly susceptible to Lm infection due to elevated IFN-β–mediated apoptosis of major leukocyte cell populations, including CD4+ and CD8+ T-cells. However, the mechanisms by which C3a and C5a modulate IFN-β expression during Lm infection were not examined in these initial investigations. Accordingly, we report here that C5a and C3a suppress IFN-β production in response to Lm via c-di-AMP, a secondary messenger molecule of Lm, in both J774A.1 macrophage-like cells and in bone marrow-derived dendritic cells (BMDCs). Moreover, C5a and C3a suppress IFN-β production by acting through their respective receptors, as no inhibition was seen in C5aR1−/− or C3aR−/− BMDCs, respectively. C5a and C3a suppress IFN-β production in a manner that is dependent on Bruton’s Tyrosine Kinase (BTK), p38 MAPK, and TANK-Binding Kinase 1 (TBK1), as demonstrated by the individual use of BTK, p38 MAPK, and TBK1 inhibitors. Pre-treatment of cells with C5a and C3a reduced the expression of the IFN-β signaling molecules DDX41, STING, phosphorylated TBK1, and phosphorylated p38 MAPK in WT BMDCs following treatment with c-di-AMP. Collectively, these data demonstrate that C3a and C5a, via direct signaling through their specific receptors, suppress IFN-β expression by modulation of a distinct innate cytosolic surveillance pathway involving DDX41, STING, and other downstream molecular targets of Lm-generated c-di-AMP.
The fourth annual summer research summit organized by the Center of Excellence (COE) in Health Equity, Training and Research, Baylor College of Medicine (BCM) was held on May 20, 2021. The theme of this year’s summit was ‘Strengthening Our Commitment to Racial and Social Justice to Improve Public Health.’ Given the ongoing pandemic, the summit was conducted virtually through digital platforms. This program was intended for both BCM and external audiences interested in advancing health equity, diversity and inclusion in healthcare among healthcare providers and trainees, biomedical scientists, social workers, nurses, individuals involved in talent acquisition and development such as hiring managers (HR professionals), supervisors, college and hospital affiliate leadership and administrators, as well as diversity and inclusion excellence practitioners. We had attendees from all regions of the United States, India, Pakistan and the Demographic Republic of the Congo. The content in this Book of Abstracts encapsulates a summary of the research efforts by the BCM COE scholars (which includes post-baccalaureate students, medical students, clinical fellows and junior faculty from BCM) as well as the external summit participants. The range of topics in this year’s summit was quite diverse encompassing disparities in relation to maternal and child health (MCH), immigrant heath, cancers, vaccination uptakes and COVID-19 infections. Various solutions were ardently presented to address these disparities including community engagement and partnerships, improvement in health literacy and development of novel technologies and therapeutics. With this summit, BCM continues to build on its long history of educational outreach initiatives to promote diversity in medicine by focusing on programs aimed at increasing the number of diverse and highly qualified medical professionals ready to introduce effective and innovative approaches to reduce or eliminate health disparities. These programs will improve information resources, clinical education, curricula, research and cultural competence as they relate to minority health issues and social determinants of health. The summit received very positive response in terms of zealous participation and outstanding evaluations; and overall, it was a great success. Copyright © 2021 Lopez et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY 4.0.
Burnout is an epidemic, with deleterious effects on individuals, patient care, and healthcare systems. The Coronavirus Disease 2019 (COVID-19) pandemic may be exacerbating this problem. We aimed to explore socio-cultural and gender norms that modulate burnout development in physicians during the pandemic and analyze any disparities associated with gender, marital and immigration status and work-life balance. We conducted an online cross-sectional survey of physicians (August–November, 2021): The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) was used to measure burnout, combined with a validated survey assessing work-life balance. Demographic data was obtained for each participant. MBI-HSS subscales were measured, along with work and home related changes due to COVID-19. The association between life changes due to COVID-19 and odds of burnout was estimated by logistic regression. Complementary analysis was performed to determine factors most associated with burnout. 352 respondents were analyzed. There was a high prevalence of burnout. Over half of individuals reported a high degree of emotional exhaustion (EE) (56%). 83% of individuals reported at least one life factor changed due to COVID-19. Home-related life changes due to COVID-19 were associated with 143% higher odds of emotional burnout [adjusted odds ratio (aOR) 2.43; 95% confidence interval (CI) 1.49, 3.98] after covariate adjusted analysis. High EE was most evident when there were three or more life changes, suggesting a cumulative effect. First-generation immigrants, older physicians, and trainees were identified as protective factors. Although female gender was identified as a factor related to EE through forward selection, this was not statistically significant (aOR 1.34; 95% CI 0.80, 2.24). Burnout remains pervasive among physicians. We highlight new risk factors for EE (home-life changes due to COVID-19), and protective factors (first-generation immigrants) not previously explored. Understanding burnout and its disparities allows for improved mitigation strategies, decreasing its deleterious effects.
As the main refracting element of the eye, the cornea is necessarily transparent and appropriately shaped in order to project a focused image onto the retina. Transparency is determined by the ultrastructural organization which must be maintained and restored, if possible, in the event of injury. The unique qualities of the cornea and its importance for vision have fueled extensive research into its physical characteristics and molecular activities. The purpose of the present study was to use serial block-face sectioning and computerized 3D reconstruction to evaluate the organization of a novel filamentous structure within the corneal stroma. In most species the stroma constitutes the bulk of the total corneal thickness and is therefore critical for maintaining useful vision. The extracellular matrix (ECM) consists primarily of type I collagen, organized into tightly-spaced bundles (lamellae) of parallel fibrils laid down in cross-crossed fashion, and a lesser amount of several other types of collagen as well as proteoglycans. Uniform size and spacing of the collagen fibrils is necessary for transparency (1). Resident keratocytes form an interconnected network of flattened cells with long, slender processes interspersed between the collagen lamellae and are directly responsible for the synthesis and secretion of ECM components (2).Much of the information about the spatial organization of stromal ECM has been obtained by light microscopy (LM), standard transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM). Understanding the supramolecualr architecture of ECM is somewhat limited when using a method that provides only two dimensional ultrastructural information (TEM) or only surface information (SEM and/or AFM). Serial block-face sectioning SEM is a novel alternative approach that allows the determination of spatial distribution and organization of ECM ultrastructural components.Anesthetized mice (C57BL/6; 8-12 weeks old) received a central 2 mm corneal epithelial abrasion injury and the animals were euthanized 18h later. Excised corneas were fixed, heavy metalcontrasted and embeddd in Durcupan as previously described (3). Serial block-face images of corneal stroma (100 nm intervals between images) were obtained using a Gatan 3 View system mounted in an FEI Quanta FEG 200 SEM. Amira 5.2 software was used for 3D image reconstruction and segmentation. Figure 1 shows a volume of peripheral corneal stroma (Panel A). The segmented and reconstructed images (Panels B, C and D) reveal a novel structure composed of electron dense filaments that assemble into larger (100-200 nm in diameter) that course through the stroma. This novel fibrillar plexus appears to form a continuous network, extending from the periphery to the center of the cornea. In addition, this network appears to interface with lymphatic vessels and stromal keratocytes. In summary, we have used serial block-face sectioning SEM and 3D reconstruction to reveal the presence of a novel and extensive network o...
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