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Lercher A, Cheong JG, Bale MJ, Jiang CY, Hoffmann HH, Ashbrook AW, Lewy T, Yi...
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Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 i...

IMMUNITY 2024 NOV 12; 57(11):?
Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.
Barbelanne M, Lu Y, Kumar K, Zhang XX, Li CM, Park K, Warner A, Xu XZS, Shaha...
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C. elegans PPEF-type phosphatase (Retinal degeneration C ortholog) fun...

SCIENTIFIC REPORTS 2024 NOV 16; 14(1):? Article 28347
Primary (non-motile) cilia represent structurally and functionally diverse organelles whose roles as specialized cellular antenna are central to animal cell signaling pathways, sensory physiology and development. An ever-growing number of ciliary proteins, including those found in vertebrate photoreceptors, have been uncovered and linked to human disorders termed ciliopathies. Here, we demonstrate that an evolutionarily-conserved PPEF-family serine-threonine phosphatase, not functionally linked to cilia in any organism but associated with rhabdomeric (non-ciliary) photoreceptor degeneration in the Drosophila rdgC (retinal degeneration C) mutant, is a bona fide ciliary protein in C. elegans. The nematode protein, PEF-1, depends on transition zone proteins, which make up a 'ciliary gate' in the proximal-most region of the cilium, for its compartmentalization within cilia. Animals lacking PEF-1 protein function display structural defects to several types of cilia, including potential degeneration of microtubules. They also exhibit anomalies to cilium-dependent behaviors, including impaired responses to chemical, temperature, light, and noxious CO2 stimuli. Lastly, we demonstrate that PEF-1 function depends on conserved myristoylation and palmitoylation signals. Collectively, our findings broaden the role of PPEF proteins to include cilia, and suggest that the poorly-characterized mammalian PPEF1 and PPEF2 orthologs may also have ciliary functions and thus represent ciliopathy candidates.
Engel JL, Zhang X, Wu MM, Wang Y, Valle-Inclán JE, Hu Q, Woldehawariat KS, Sa...
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The Fanconi anemia pathway induces chromothripsis and ecDNA-driven cancer dru...

CELL 2024 OCT 17; 187(21):?
Chromothripsis describes the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei. Although micronuclei accumulate DNA double-strand breaks and replication defects throughout interphase, how chromosomes undergo shattering remains unresolved. Using CRISPRCas9 screens, we identify a non-canonical role of the Fanconi anemia (FA) pathway as a driver of chromothripsis. Inactivation of the FA pathway suppresses chromosome shattering during mitosis without impacting interphase-associated defects within micronuclei. Mono-ubiquitination of FANCIFANCD2 by the FA core complex promotes its mitotic engagement with under-replicated micronuclear chromosomes. The structure-selective SLX4-XPF-ERCC1 endonuclease subsequently induces largescale nucleolytic cleavage of persistent DNA replication intermediates, which stimulates POLD3-dependent mitotic DNA synthesis to prime shattered fragments for reassembly in the ensuing cell cycle. Notably, FA-pathway-induced chromothripsis generates complex genomic rearrangements and extra- chromosomal DNA that confer acquired resistance to anti-cancer therapies. Our findings demonstrate how pathological activation of a central DNA repair mechanism paradoxically triggers cancer genome evolution through chromothripsis.
Leung G, Diaz LL, Monette S, Jiang CS, Tolwani R, Peneyra S
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Effectiveness, Safety, and Pharmacokinetics of Meloxicam Formulations in Afri...

COMPARATIVE MEDICINE 2024 OCT; 74(5):336-343
Pain management in amphibians is an emerging field of veterinary medicine with only a limited number of analgesics studied for their efficacy. The African-clawed frog, Xenopus laevis, is a popular animal model in research due to its oocyte morphology and embryonic development. We investigated analgesic effects of 2 formulations of meloxicam (standard and extended release [ER]) along with their pharmacokinetics and potential toxicity in this species. Adult female African-clawed frogs (n = 6/group) received either standard (0.2, 0.4, 1, or 5 mg/kg) or ER meloxicam (0.6, 1.2, 3, or 15 mg/kg) injected into the dorsal lymph sac. The acetic acid test (AAT) was performed at -1, 1, 6, 12, 24, 48, and 72 h postadministration to evaluate pain response. In addition, a subset of frogs (n = 2/group) were euthanized 72 h postinjection and submitted for necropsy. There were no significant differences in AAT with both formulations compared with saline control. No signs of meloxicam-induced toxicity with either formulation was present in histology. A pharmacokinetic study was conducted for both the standard and ER formulation of meloxicam at 5 and 15 mg/kg, respectively. Results were consistent with the fact that both formulations of meloxicam were readily absorbed with the standard plasma concentrations peaking at 20.40 mu g/mL at 2 h and ER plasma concentration at 30.4 mu g/mL at 12 h. The elimination half-life was only determinable for standard formulation (7.74 h). According to the AAT, both formulations of meloxicam did not provide effective analgesia in adult female Xenopus laevis despite reaching high plasma concentrations.
Jacobs RV, Wang CX, Nguyen L, Pruitt TJ, Wang PX, Lozada-Perdomo F, Deere JU,...
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Overlap and divergence of neural circuits mediating distinct behavioral respo...

CELL REPORTS 2024 OCT 22; 43(10):? Article 114782
How do neural circuits coordinate multiple behavioral responses to a single sensory cue? Here, we investigate how sweet taste drives appetitive behaviors in Drosophila, , including feeding, locomotor suppression, spatial preference, and associative learning. We find that neural circuits mediating different innate responses to sugar are partially overlapping and diverge at the second and third layers. Connectomic analyses reveal distinct subcircuits that mediate different behaviors. Connectome-based simulations of neuronal activity predict that second-order sugar neurons act synergistically to promote downstream activity and that bitter input overrides the sugar circuit through multiple pathways acting at third- and fourth-order neurons. Consistent with the latter prediction, optogenetic experiments suggest that bitter input inhibits third- and fourth-order sugar neurons to override the sugar pathway, whereas hunger and diet act earlier in the circuit to modulate behavior. Together, these studies provide insight into how circuits are organized to drive diverse behavioral responses to a single stimulus.
Gervais A, Le Floc'h C, Le Voyer T, Bizien L, Bohlen J, Celmeli F, Al Quresha...
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A sensitive assay for measuring whole- blood responses to type I IFNs

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024 OCT 1; 121(40):? Article e2402983121
Human inborn errors of the type I IFN response pathway and auto-Abs neutralizing IFN-alpha,-beta, and/or-omega can underlie severe viral illnesses. We report a simple assay for the detection of both types of condition. We stimulate whole blood from healthy individuals and patients with either inborn errors of type I IFN immunity or auto-Abs against type I IFNs with glycosylated human IFN-alpha 2,-beta, or-omega. As controls, we add a monoclonal antibody (mAb) blocking the type I IFN receptors and stimulate blood with IFN-gamma (type II IFN). Of the molecules we test, IP-10 (encoded by the interferon- stimulated gene (ISG) CXCL10) is the molecule most strongly induced by type I and type II IFNs in the whole blood of healthy donors in an ELISA-like assay. In patients with inherited IFNAR1, IFNAR2, TYK2, or IRF9 deficiency, IP-10 is induced only by IFN-gamma, whereas, in those with auto-Abs neutralizing specific type I IFNs, IP-10 is also induced by the type I IFNs not neutralized by the auto-Abs. The measurement of type I and type II IFN- dependent IP-10 induction therefore constitutes a simple procedure for detecting rare inborn errors of the type I IFN response pathway and more common auto-Abs neutralizing type I IFNs.
Bonilla SL, Jang K
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Challenges, advances, and opportunities in RNA structural biology by Cryo-EM

CURRENT OPINION IN STRUCTURAL BIOLOGY 2024 OCT; 88(?):? Article 102894
RNAs are remarkably versatile molecules that can fold into intricate three-dimensional (3D) structures to perform diverse cellular and viral functions. Despite their biological importance, relatively few RNA 3D structures have been solved, and our understanding of RNA structure-function relationships remains in its infancy. This limitation partly arises from challenges posed by RNA's complex conformational landscape, characterized by structural flexibility, formation of multiple states, and a propensity to misfold. Recently, cryoelectron microscopy (cryo-EM) has emerged as a powerful tool for the visualization of conformationally dynamic RNA- only 3D structures. However, RNA's characteristics continue to pose challenges. We discuss experimental methods developed to overcome these hurdles, including the engineering of modular modifications that facilitate the visualization of small RNAs, improve particle alignment, and validate structural models.
Tumasyan A, Adam W, Andrejkovic JW, Bergauer T, Chatterjee S, Damanakis K, Dr...
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KS0 and Λ((Λ)over-bar) two-particle femtoscopic correla...

PHYSICS LETTERS B 2024 OCT; 857(?):? Article 138936
Two-particle correlations are presented for K-S(0), Lambda, and (Lambda) over bar strange hadrons as a function of relative momentum in lead-lead collisions at a nucleon-nucleon center-of-mass energy of 5.02 TeV. The dataset corresponds to an integrated luminosity of 0.607 nb(-1) and was collected using the CMS detector at the CERN LHC. These correlations are sensitive to quantum statistics and to final-state interactions between the particles. The source size extracted from the (KSKS0)-K-0 correlations is found to decrease from 4.6 to 1.6 fm in going from central to peripheral collisions. Strong interaction scattering parameters (i.e., scattering length and effective range) are determined from the Lambda K-S(0) and Lambda Lambda (including their charge conjugates) correlations using the Lednicky-Lyuboshitz model and are compared to theoretical and other experimental results.
Ryder EL, Nasir N, Durgan AEO, Jenkyn-Bedford M, Tye S, Zhang XD, Wu Q
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Structural mechanisms of SLF1 interactions with Histone H4 and RAD18 at the s...

NUCLEIC ACIDS RESEARCH 2024 OCT 3; 52(20):12405-12421
DNA damage that obstructs the replication machinery poses a significant threat to genome stability. Replication-coupled repair mechanisms safeguard stalled replication forks by coordinating proteins involved in the DNA damage response (DDR) and replication. SLF1 (SMC5-SMC6 complex localization factor 1) is crucial for facilitating the recruitment of the SMC5/6 complex to damage sites through interactions with SLF2, RAD18, and nucleosomes. However, the structural mechanisms of SLF1's interactions are unclear. In this study, we determined the crystal structure of SLF1's ankyrin repeat domain bound to an unmethylated histone H4 tail, illustrating how SLF1 reads nascent nucleosomes. Using structure-based mutagenesis, we confirmed a phosphorylation-dependent interaction necessary for a stable complex between SLF1's tandem BRCA1 C-Terminal domain (tBRCT) and the phosphorylated C-terminal region (S442 and S444) of RAD18. We validated a functional role of conserved phosphate-binding residues in SLF1, and hydrophobic residues in RAD18 that are adjacent to phosphorylation sites, both of which contribute to the strong interaction. Interestingly, we discovered a DNA-binding property of this RAD18-binding interface, providing an additional domain of SLF1 to enhance binding to nucleosomes. Our results provide critical structural insights into SLF1's interactions with post-replicative chromatin and phosphorylation-dependent DDR signalling, enhancing our understanding of SMC5/6 recruitment and/or activity during replication-coupled DNA repair. Graphical Abstract
Chudnovskiy A, Castro TBR, Nakandakari-Higa S, Cui A, Lin CH, Sade-Feldman M,...
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Proximity-dependent labeling identifies dendritic cells that drive the tumor-...

SCIENCE IMMUNOLOGY 2024 OCT 4; 9(100):? Article eadq8843
Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4(+) T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4(+) and CD8(+) tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.