Reactive oxygen species induce virus-independent MAVS-oligomerization in systemic lupus erythematosus

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)–like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress–induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome

Instructional Strategies to Enhance Dermoscopic Image Interpretation Education: a Review of the Literature

Introduction: In image interpretation education, many educators have shifted away from traditional methods that involve passive instruction and fragmented learning to interactive ones that promote active engagement and integrated knowledge. By training pattern recognition skills in an effective manner, these interactive approaches provide a promising direction for dermoscopy education. Objectives: A narrative review of the literature was performed to probe emerging directions in medical image interpretation education that may support dermoscopy education. This article represents the second of a two-part review series. Methods: To promote innovation in dermoscopy education, the International Skin Imaging Collaboration (ISIC) assembled an Education Working Group that comprises international dermoscopy experts and educational scientists. Based on a preliminary literature review and their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. For each approach, literature searches were performed for relevant articles. Results: Through a consensus-based approach, the group identified a number of theory-based approaches, as discussed in the first part of this series. The group also acknowledged the role of motivation, metacognition, and early failures in optimizing the learning process. Other promising teaching tools included gamification, social media, and perceptual and adaptive learning modules (PALMs). Conclusions: Over the years, many dermoscopy educators may have intuitively adopted these instructional strategies in response to learner feedback, personal observations, and changes in the learning environment. For dermoscopy training, PALMs may be especially valuable in that they provide immediate feedback and adapt the training schedule to the individual’s performance

Theory-Based Approaches to Support Dermoscopic Image Interpretation Education: A Review of the Literature

Introduction: Efficient interpretation of dermoscopic images relies on pattern recognition, and the development of expert-level proficiency typically requires extensive training and years of practice. While traditional methods of transferring knowledge have proven effective, technological advances may significantly improve upon these strategies and better equip dermoscopy learners with the pattern recognition skills required for real-world practice. Objectives: A narrative review of the literature was performed to explore emerging directions in medical image interpretation education that may enhance dermoscopy education. This article represents the first of a two-part review series on this topic. Methods: To promote innovation in dermoscopy education, the International Skin Imaging Collaboration (ISIC)assembled a 12-member Education Working Group that comprises international dermoscopy experts and educational scientists. Based on a preliminary literature review and their experiences as educators, the group developed and refined a list of innovative approaches through multiple rounds of discussion and feedback. For each approach, literature searches were performed for relevant articles. Results: Through a consensus-based approach, the group identified a number of emerging directions in image interpretation education. The following theory-based approaches will be discussed in this first part: whole-task learning, microlearning, perceptual learning, and adaptive learning. Conclusions: Compared to traditional methods, these theory-based approaches may enhance dermoscopy education by making learning more engaging and interactive and reducing the amount of time required to develop expert-level pattern recognition skills. Further exploration is needed to determine how these approaches can be seamlessly and successfully integrated to optimize dermoscopy education

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance

© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world's most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.This work was supported by NIH R01AI143723 (R.M. and D.F.W.), NIH R01AI152533 (M.R.L. and E.A.W.), 5F31AI129412 (L.F.), and the Bill & Melinda Gates Foundation (OPP1054480, E.A.W. and D.F.W.), LEAN program of the Leducq Foundation (U.O.), Arthritis Research UK 20522 (U.O.), Cancer Research UK A23900 (U.O.). N.C.P. was supported by a National Science Foundation Graduate Research Fellowship (DGE1745303). M.R.L. was supported in part by a Ruth L. Kirschstein Institutional National Research Award from the National Institute for General Medical Sciences (T32 GM008666). This publication includes data generated at the University of California, San Diego IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).info:eu-repo/semantics/publishedVersio

Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease