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Astrocytic-OTUD7B ameliorates murine experimental autoimmune encephalomyelitis by stabilizing glial fibrillary acidic protein and preventing inflammation
Abstract Astrocytes are central to the pathogenesis of multiple sclerosis (MS); however, their regulation by post-translational ubiquitination and deubiquitination is unresolved. This study shows that the deubiquitinating enzyme OTUD7B in astrocytes protects against murine experimental autoimmune encephalomyelitis (EAE), a model of MS, by limiting neuroinflammation. RNA-sequencing of isolated astrocytes and spatial transcriptomics show that in EAE, OTUD7B downregulates chemokine expression in astrocytes of inflammatory lesions, which is associated with reduced recruitment of encephalitogenic CD4 + T cells. Furthermore, OTUD7B is necessary for glial fibrillary acidic protein (GFAP) expression of astrocytes bordering inflammatory lesions. Mechanistically, OTUD7B (i) restricts TNF-induced chemokine production of astrocytes by sequential K63- and K48-deubiquitination of RIPK1, which limits NF-κB and MAPK activation and (ii) enables GFAP protein expression by supporting GFAP mRNA expression and preventing its proteasomal degradation through K48-deubiquitination of GFAP. This dual action on TNF signaling and GFAP identifies OTUD7B as a central inhibitor of astrocyte-mediated inflammation.
Leveraging platinum-protein interactions to overcome chemoresistance
Abstract A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, enabling the removal of cytotoxic agents, such as anthracycline drugs. However, platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, we design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone. These drug conjugates retain the anticancer activity of anthracyclines and exhibit the ability to both circumvent drug efflux and delay the acquisition of drug resistance. In vivo experiments demonstrate that such drug conjugates extend survival in a preclinical organoid-based model of metastatic colon cancer in mice. Mechanistic studies indicate that these drug conjugates overcome resistance through covalent platinum-protein interactions, leading to significantly improved drug retention and alteration of subcellular drug distribution. This application of platinum offers many opportunities to confront issues related to chemoresistance and alternative pathways for augmenting conventional chemotherapeutics.
Eosinophil-derived interleukin-24 compromises epithelial integrity and aggravates airway remodeling in mouse models of allergic asthma
Mosquito salivary sialokinin reduces monocyte activation and chikungunya virus-induced inflammation via neurokinin receptors
Abstract Global warming is expanding mosquito habitats and increasing mosquito-borne diseases. In tropical and sub-tropical regions, chikungunya virus (CHIKV) transmitted by Aedes mosquitoes has become a major concern due to the debilitating chronic joint disease it causes. Mosquito saliva contains bioactive factors that enhance viral infection, with sialokinin identified as a key contributor to vascular leakage and viral spread in mice. Here, we demonstrate that sialokinin binds to neurokinin receptors and restricts the activation of human myeloid cells. Mechanistically, sialokinin facilitates early viral dissemination, as evidenced by increased viral load in the contralateral footpad at 1 day post-infection, and significantly reduces circulating CD169+ monocytes while suppressing IFN-γ-producing T-cell-driven inflammation, as reflected by reduced joint footpad swelling in female CHIKV-infected mice. Clinically, patients with severe CHIKV disease exhibited higher levels of IgG antibodies against sialokinin, which correlated with higher viral loads and systemic inflammatory markers. Our findings highlight the multifaceted role of sialokinin in facilitating early viral dissemination and modulating host immunity during CHIKV infection. Given the growing threat of mosquito-borne diseases in a warming, disease-burdened world, targeting mosquito salivary factors like sialokinin could offer a novel therapeutic strategy to mitigate viral-induced inflammation and improve clinical outcomes.
Redox and magma recharge controls on excess sulfur build-up at Mount Samalas, 1257 CE
Large protein-like leader peptides engage differently with RiPP halogenases and lanthionine synthetases
Retraction Note: Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression
Long-range moiré tuning effect via inter-layer drag interaction
The microbial metabolite desaminotyrosine protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration
Abstract Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in patients receiving allo-HSCT. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DAT´s beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DAT’s dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.
A wearable-based aging clock associates with disease and behavior
‘Ghost’ fossils of early coccolithophores point to a Triassic diversification of marine calcifying organisms
Abstract Over geologic time, biocalcification – the process by which marine organisms make calcium carbonate (CaCO3) – has reshaped climates, ocean life, and seawater chemistry. In particular, the evolution of coccolithophores, the largest group of nannoplankton and today’s most productive calcifiers, transformed ocean environments and the carbon cycle. Their origins, however, remain enigmatic. This is partly because studying coccolithophore fossils traditionally requires CaCO3 preservation. Here, we bypass this limitation, searching for their ‘ghost’ fossils –imprints on organic matter. We present coccolithophores from ~241-million-year-old (Triassic) rocks, predating previous records by ~26 million years (myrs). The >100 ghost fossils, exceptionally preserved within zooplankton faeces, show that coccolithophores, nannoplankton, ‘modern’ eukaryotic phytoplankton, and planktonic biocalcification evolved earlier than previously thought. Coccolithophores now first appear alongside stony corals and other unrelated calcifiers, suggesting a diversification of a range of marine calcifying organisms following Earth’s deadliest mass extinction, the end-Permian event. These findings indicate that coccolithophore diversity remained remarkably low for ~50 myrs, until after the end-Triassic mass extinction, showing that both Triassic-bookending extinctions were critical in their evolution. Our discoveries elucidate the evolutionary origins of coccolithophores, but also highlight the role mass extinctions have played in shaping life on Earth.
Entorhinal grid-like codes for visual space during memory formation
Abstract Eye movements, such as saccades, allow us to gather information about the environment and, in this way, can shape memory. In non-human primates, saccades are associated with the activity of grid cells in the entorhinal cortex. Grid cells are essential for spatial navigation, but whether saccade-based grid-like signals play a role in human memory formation is currently unclear. Here, human participants undergo functional magnetic resonance imaging and continuous eye gaze monitoring while studying scene images. Recognition memory is probed immediately thereafter. Results reveal saccade-based grid-like codes in the left entorhinal cortex that are specific to later remembered trials during study, a finding that we replicate with an independent data set. The grid-related effects are time-locked to activation increases in the frontal eye fields. Unexpectedly, lower saccade-based grid-like codes are associated with better subsequent recognition memory performance. Our findings suggest an entorhinal map of visual space that is timed with neural activity in oculomotor regions, and negatively associated with subsequent memory. Grid-like codes, entorhinal cortex, saccades, frontal eye fields (FEF), memory, functional magnetic resonance imaging (fMRI)
Signal-strapping as a protein-sequence search method for the discovery of metalloproteins
Abstract Metalloprotein discovery is often made post hoc , in which activity studies following protein isolation reveal a metal-ion dependence. Herein we take a different approach to finding metalloproteins, by building on the discovery of copper-containing lytic polysaccharide monooxygenases (LPMOs), which include an N-terminal histidine as part of their sequence. This residue acts as a natural chelator for transition metal ions, irrespective of the structure of the protein. We report the method of signal strapping , where sequences of N-terminal signal peptides artificially appended with a histidine residue at their C-terminus are used to bootstrap a proteomic search. These searches return sequences of proteins with an N-terminal histidine capable of coordinating a metal ion. We exemplify the approach by the discovery and characterisation of four classes of bacterial metalloproteins, including two that we denote as anglerases reflecting their potential to capture transition metal ions from the bacterial environment.
Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction
Abstract The existence of linear cholesterol-recognition motifs in transmembrane domains has long been debated. Evolutionary molecular dynamics (Evo-MD) simulations—genetic algorithms guided by (coarse-grained) molecular force-fields–reveal that thermodynamic optimal cholesterol attraction in isolated alpha-helical transmembrane domains occurs when multiple consecutive lysine/arginine residues flank a short hydrophobic segment. These findings are supported by atomistic simulations and solid-state NMR experiments. Our analyses illustrate that linear motifs in transmembrane domains exhibit weak binding affinity for cholesterol, characterized by sub-microsecond residence times, challenging the predictive value of linear CRAC/CARC motifs for cholesterol binding. Membrane protein database analyses suggest even weaker affinity for native linear motifs, whereas live cell assays demonstrate that optimizing cholesterol binding restricts transmembrane domains to the endoplasmic reticulum post-translationally. In summary, these findings contribute to our understanding of cholesterol-protein interactions and offer insight into the mechanisms of protein-mediated cholesterol regulation within membranes.
Tetrahedral DNA dendritic nanostructure-enhanced FISH for high-speed, sensitive spatial transcriptomics
Abstract Understanding where genes are active within tissues is essential to explain how cells build and maintain organs, yet many spatial RNA assays are slow and weak, limiting short-transcript detection and masking cellular diversity. Here we show that TDDN-FISH (Tetrahedral DNA Dendritic Nanostructure–Enhanced Fluorescence In Situ Hybridization), a rapid, enzyme-free method using self-assembling DNA nanostructures, accelerates and amplifies RNA detection. Per round, TDDN-FISH is ~eightfold faster than HCR-FISH and generates stronger signals than smFISH, enabling short-RNA detection and low-magnification tissue imaging with single-cell and subcellular resolution. Iterative, multiplexed hybridization produces color-coded readouts for many targets in the same specimen, supporting high-throughput spatial transcriptomics. We apply TDDN-FISH to cultured cells and tissue sections to map RNA distributions with high specificity and reveal complex expression patterns. This platform streamlines workflows and broadens access to spatial RNA profiling for studies of cellular heterogeneity, tissue organization, and disease mechanisms.