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Single-Cell Multi-Omics Identifies Specialized Cytotoxic and Migratory CD8 ⁺ Effector T Cells in Acute Myocarditis

BACKGROUND: Acute myocarditis (AM), particularly fulminant myocarditis (FM), is an infrequent but life-threatening cardiac inflammation, with limited effective precision-targeted treatments available. This urgent clinical challenge has prompted further investigations into the mechanisms underlying this pathology to develop novel therapeutic approaches. METHODS: We enrolled 40 patients diagnosed with AM (24 mild, 16 fulminant) between December 2022 and November 2023. Using a multi-omics approach, we analyzed peripheral blood mononuclear cells and plasma, integrating single-cell RNA sequencing, single-cell T-cell receptor sequencing, cytometry by time of flight, and Olink proteomics to identify specific pathogenic immune subsets and molecular alterations. In vitro experiments validated the function and inducing signals of identified pathogenic subsets. In coxsackievirus B3–induced FM mice, cytometry by time of flight analysis was performed on peripheral blood mononuclear cells and cardiac infiltrating immune cells. Pharmacological blockade of key molecules was tested to assess potential therapeutic efficacy. RESULTS: We identified that a specialized type of CD8 + effector T cells, CD57 + CD8 + T cells with high cytotoxicity and migration potential, were substantially enriched and exhibited large clonal expansion in AM. Differential expression analysis revealed upregulation of natural killer–like receptor genes in CD57 + CD8 + effector T cells from FM compared with mild cases, which was positively associated with enhanced cytotoxicity and migration potential. In vitro experiments confirmed the existence of circulating CD57 + CD8 + effector T cells with high cytotoxic degranulation and migration potential inducing cardiomyocyte apoptosis, supporting their cardiac migration and cardiomyocyte cytotoxicity in pathogenesis. Elevated circulating interleukin (IL)–18 levels in patients with AM induced the functional differentiation of CD57 + CD8 + effector T cells. In addition, increased proinflammatory CXCL8 + CD14 + monocytes potentially contributed to increasing IL-18 levels and crosstalk with CD57 + CD8 + effector T cells. In FM mice, we observed the analogous expansions of CD57 + CD8 + effector T cells and CXCL2 + LY6C + monocytes in both blood and hearts, accompanied by elevated plasma IL-18 levels. Disrupting the pathogenic axis involving proinflammatory monocytes, IL-18 signaling, and CCR5-mediated cardiac recruitment significantly alleviated FM in mice. CONCLUSIONS: Our study provides a comprehensive immune landscape for understanding the pathogenesis of AM, especially in FM, highlighting clonal CD57 + CD8 + effector T cells with high cytotoxicity and migration potential, along with their upstream inflammatory signals, as potential therapeutic targets for mitigating immune-related cardiac damage in AM management, especially in FM.

A fixed mutation in the respiratory complex I impairs mitochondrial bioenergetics in the endangered Apennine brown bear

Effective conservation genomics of endangered species requires realistic understanding of the fitness consequences caused by the accumulation of deleterious mutations in declining populations. We experimentally investigated three mutations which have been bioinformatically predicted to be deleterious in the mitochondrial ND5 subunit of respiratory complex I and are fixed in the Apennine brown bear, an inbred population of about 50 individuals isolated in Central Italy. Functional assays in transfected cell models and fibroblasts demonstrated that the G527E substitution significantly reduces mitochondrial transmembrane potential and calcium uptake by ca. 40 and 25% of the control level, respectively, while increasing reactive oxygen species production by ca. 45%. While further confirming these findings, experiments with bear fibroblasts highlighted lower oxygen consumption and impaired mitochondrial turnover in the Apennine bear. Molecular dynamics simulations uncovered structural effects of the G527E substitution, including increased rigidity of the ND5 and associated NDUFB8 subunits and altered hydration dynamics in key aqueous channels of the complex I which are essential for proton pumping. These findings validate previous bioinformatic predictions of the negative fitness effects for one out of three mtDNA mutations, and elucidate the molecular mechanisms behind compromised bioenergetics in this endangered bear population produced by the G527E substitution. By linking genotype to phenotype via advanced molecular biology tools in a non-model species of conservation concern, this study highlights the need to fully integrate genomics and molecular experimental approaches in modern conservation biology.

Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene

Letter by Jiang et al Regarding Article, “Arterial-Lymphatic-Like Endothelial Cells Appear in Hereditary Hemorrhagic Telangiectasia 2 and Contribute to Vascular Leakage and Arteriovenous Malformations”

Engineering antibody–drug conjugates targeting an adhesion GPCR, CD97

Adhesion G protein–coupled receptors (aGPCRs) are key cell-adhesion molecules involved in many cellular functions and contribute to human diseases, including cancer. aGPCRs are characterized by large extracellular regions that could serve as readily accessible antigens. However, the potential of aGPCRs as targets for biologic therapeutics has not been extensively explored. CD97, also known as ADGRE5, is an aGPCR that is upregulated in various cancer types, including acute myeloid leukemia (AML) and glioblastoma (GBM), and their respective cancer stem cells. Here, we developed antibody–drug conjugates (ADCs) targeting CD97 and assessed their efficacy against AML and GBM cells. We generated a panel of synthetic human antibodies targeting distinct epitopes of CD97, from which we identified an antibody that was efficiently internalized. This antibody binds to all isoforms of human CD97 but not to its close homolog, EMR2. Structure determination by single-particle cryo-electron microscopy revealed that this antibody targets the CD97 GPCR autoproteolysis-inducing (GAIN) domain, whose presence is conserved in aGPCRs, through an unconventional binding mode where it extensively utilizes the light chain framework for antigen recognition. Screening of conjugation methods and payloads resulted in a stable ADC that effectively killed AML and GBM cell lines, as well as patient-derived GBM stem cells, with minimal cytotoxicity against peripheral blood mononuclear cells from healthy donors. Our study demonstrates the therapeutic potential of targeting CD97, as well as the aGPCR GAIN domain in general, and uncovers a previously unrecognized surface that an antibody can utilize for antigen recognition.

Spontaneous complexity in the dynamics of slow laboratory earthquakes

Characterization and Application of Novel Exercise Recovery Patterns That Reflect Cardiac Performance: A Substudy of the SEQUOIA-HCM Trial

BACKGROUND: Post-exercise oxygen uptake recovery (VO 2 Rec) is slow in advanced heart failure. We sought to establish easily derived VO 2 Rec measures and evaluate their cardiospecificity and prognostic relevance in patients with dyspnea on exertion. We further sought to determine VO 2 Rec modifiability proportional to changes in cardiac function with disease-specific treatment of obstructive hypertrophic cardiomyopathy. METHODS: VO 2 Rec patterns were evaluated in relation to cardiac performance and the primary outcome of heart failure hospitalization or death in a referral cohort with dyspnea on exertion undergoing cardiopulmonary exercise testing with hemodynamic monitoring (MGH-ExS [Massachusetts General Hospital Exercise Study]). We then investigated longitudinal measures of VO 2 Rec in the pivotal phase 3 randomized controlled trial SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in Hypertrophic Cardiomyopathy) of aficamten versus placebo for 24 weeks in participants with symptomatic obstructive hypertrophic cardiomyopathy. For both cohorts, VO 2 Rec was uniformly measured as time for VO 2 to decline by >0%, 12.5% (VO 2 T 12.5% ), 25%, and 50% of peak VO 2 . RESULTS: Among 814 MGH-ExS patients (58±16 years of age, 58% women), those with a longer VO 2 T 12.5% (≥35 versus <35 seconds) demonstrated elevated exercise pulmonary capillary wedge pressure to cardiac output slope ( P <0.0001) with no difference in peripheral oxygen extraction ( P =0.11). For each 15-second increase in VO 2 T 12.5% , the hazard ratio for heart failure hospitalization and all-cause death was 1.54 (95% CI, 1.35–1.76; P <0.001). In SEQUOIA-HCM participants with cardiopulmonary exercise testing at baseline and week 24 (n=263, 59.1±2.9 years of age, 41% women), baseline VO 2 T 12.5% was 45±20 seconds and improved 8 seconds (95% CI, −12 to −5 seconds; P <0.001) with aficamten treatment compared with placebo at 24 weeks. Participants treated with aficamten versus placebo were more likely to improve VO 2 T 12.5% by ≥15 seconds (odds ratio [OR], 3.7 [95% CI, 1.9–6.9]; number needed to treat=4.8). Shortening of VO 2 T 12.5% correlated with reduced NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin I, and left ventricular outflow tract gradient (all P <0.005). CONCLUSIONS: This study established VO 2 T 12.5% as a new measure that reflects cardiac performance during exercise and predicted heart failure event-free survival. Furthermore, VO 2 T 12.5% improved proportional to improvements in left ventricular outflow tract gradient and cardiac biomarkers in response to aficamten treatment, a cardiospecific therapy for obstructive hypertrophic cardiomyopathy. The simplicity and physiological relevance of VO 2 T 12.5% support its regular inclusion in cardiopulmonary exercise testing protocols evaluating cardiac function during exercise. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05186818.

Hippocampal CA2 to CA1: A metaplastic switch for memory encoding

The hippocampus is essential for spatial and episodic memory, subserved by CA1 neurons. Hippocampal area CA2, which processes social memory, also makes direct connections to CA1. However, the function of these connections is unknown. To test whether CA2-CA1 connections might facilitate the interaction of social and episodic memories, we used models of behaving mice and in vitro electrophysiology that allow prior activation of CA2 by either novel social interaction or electrical stimulation before inhibitory avoidance training or induction of activity-dependent synaptic plasticity in CA1. We show that social novelty promotes consolidation of CA1-associated memory, which was blocked by the selective chemogenetic silencing of CA1-projecting CA2 neurons. In both cases, CA2 priming was time-dependent, involved direct CA2-CA1 connections, increased expression of plasticity protein protein kinase M zeta (PKMζ), and promoted associativity via synaptic tagging and capture. Taken together, CA2-CA1 connections can significantly impact CA1 plasticity and memory consolidation. The inclusion of CA2 into hippocampal circuitry and function broadens the role of the hippocampus as an integrative memory hub.

Multilayered gradient Ti2AlC0.5N0.5 prepared by crystal/amorphous C diffusion for efficient electromagnetic absorption and thermal shielding

Mapping macaque to human cortex with natural scene responses

Neuroscience has long relied on macaque studies to infer human brain function, yet identifying functionally corresponding brain regions across species and measurement modalities remains a fundamental challenge. This is especially true for the higher-order cortex, where functional interpretations are constrained by narrow hypotheses and anatomical landmarks are often nonhomologous. We present a data-driven approach for mapping functional correspondence across species using rich, naturalistic stimuli. By directly comparing macaque electrophysiology with human fMRI responses to 700 natural scenes, we identify fine-grained alignment based on response pattern similarity, without relying on predefined tuning concepts or hand-picked stimuli. As a test case, we examine the ventral face patch system, a well-studied but contested domain in cross-species alignment. Our approach resolves a long-standing ambiguity by supporting a correspondence between macaque ML and human FFA and between AL and more anterior temporal cortex in humans. This result is consistent with full-brain anatomical warping but inconsistent with prior studies limited by narrow functional hypotheses. These findings show that natural image-evoked response patterns provide a robust foundation for cross-species functional alignment, supporting scalable comparisons as large-scale primate recordings become more widespread.

Data-driven fine-grained region discovery in the mouse brain with transformers

Abstract Spatial transcriptomics offers unique opportunities to define the spatial organization of tissues and organs, such as the mouse brain. We address a key bottleneck in the analysis of organ-scale spatial transcriptomic data by establishing a workflow for self-supervised spatial domain detection that is scalable to multimillion-cell datasets. This workflow uses a self-supervised framework for learning latent representations of tissue spatial domains or niches. We use an encoder-decoder architecture, which we named CellTransformer, to hierarchically learn higher-order tissue features from lower-level cellular and molecular statistical patterns. Coupling our representation learning workflow with minibatched GPU-accelerated clustering algorithms allows us to scale to multi-million cell MERFISH datasets where other methods cannot. CellTransformer is effective at integrating cells across tissue sections, identifying domains highly similar to ones in existing ontologies such as Allen Mouse Brain Common Coordinate Framework (CCF) while allowing discovery of hundreds of uncataloged areas with minimal loss of domain spatial coherence. CellTransformer domains recapitulate previous neuroanatomical studies of areas in the subiculum and superior colliculus and characterize putatively uncataloged subregions in subcortical areas, which currently lack subregion annotation. CellTransformer is also capable of domain discovery in whole-brain Slide-seqV2 datasets. Our workflows enable complex multi-animal analyses, achieving nearly perfect consistency of up to 100 spatial domains in a dataset of four individual mice with nine million cells across more than 200 tissue sections. CellTransformer advances the state of the art for spatial transcriptomics by providing a performant solution for the detection of fine-grained tissue domains from spatial transcriptomics data.

Protopeptide backbone affects assembly in aqueous solutions

One of the most fascinating mysteries in the field of origins of life concerns the driving force that led to the selection of today’s 20 universal L -alpha amino acids in biology. An essential aspect of life’s emergence involves the formation of compartments, which offer encapsulation for target molecules and provide protection from hydrolysis in aqueous environments. Thus, polymers capable of assembly may have had a chemical evolutionary advantage over polymers that lacked this ability. We postulated that primordial peptide assembly could be one of the driving forces that led to the chemical selection of alpha amino acids in life today. To test this hypothesis, we generated depsipeptides, oligomers composed of ester bonds and peptide bonds that form readily under mild drying conditions, as model prebiotic peptides. However, it is unknown whether depsipeptides form assemblies in an aqueous environment similarly to peptides and proteins. To test the hypothesis that depsipeptides with alpha backbones will form assemblies more readily than beta backbones, we synthesized depsipeptides using a matrix of eight alpha- and beta-hydroxy acids and six alpha-, beta-, and gamma-amino acids. The reaction products were analyzed by microscopy and a physical stability analyzer to study assembly formation as well as various analytical techniques for chemical analysis. Our results demonstrate assembly formation in depsipeptide systems containing hydrophobic hydroxy acids and indicate that depsipeptide assemblies containing alpha hydroxy acid backbones are significantly more stable than beta analogs. Overall, our results offer an assembly-driven mode of selection for the alpha backbone in present-day biology.

SafeTraffic Copilot: adapting large language models for trustworthy traffic safety assessments and decision interventions

The impact of air pollution on petcare utilization

Air pollution is one of the leading causes of morbidity and premature mortality globally. A large literature documents the adverse impacts of ambient air pollution on human health. In contrast, there is a lack of comparable research studying the effects of air pollution on animal health. We fill this gap, utilizing 5 y of data on over seven million visits to veterinary practices across the United Kingdom. Leveraging within-city variation in daily monitor-measured air pollution levels, we find that increases in fine particulate matter (i.e., PM 2.5 ) are associated with significant increases in the number of vet visits for both cats and dogs. In aggregate, these estimates suggest that reducing ambient PM 2.5 levels to a maximum of 5 μg per cubic meter as recommended by the World Health Organization would result in a 0.7 to 2.5% reduction in vet visits.

Self-powered near-infrared mechanoluminescence through MgO/MgF2 piezo-photonic heterojunctions

An extended network for regulation of heme homeostasis in cells

Iron-bound tetrapyrroles (hemes) are essential for the regulation of cellular functions and bioenergetics. The processes of heme biosynthesis, transport, and degradation are responsible for the supply of heme in mitochondria and its insertion into other downstream proteins. What remains unresolved is how these processes interconnect and the wider implications for the cell in the restoration of homeostasis when heme concentrations change. We demonstrate a wide-ranging and coordinated response to changes in intracellular heme in HEK293 cells through a network of complementary mechanisms that extend well beyond the direct regulation of heme biosynthesis and degradation. These responses connect changes in heme homeostasis to mitochondrial function, including core metabolic processes such as the tricarboxylic acid cycle and oxidative phosphorylation, as well as to enzymes involved in the control and storage of iron. Our findings demonstrate far-reaching consequences to perturbations of heme homeostasis and provide insights into the complexity of the cellular hemome.

Within-host genetic diversity of pneumococcal serotype 3 during one-year prolonged carriage in a healthy adult

Spectroscopic Supermassive Dark Star candidates

Dark Stars (DSs), i.e., early stars composed almost entirely of hydrogen and helium but powered by Dark Matter (DM), could form in zero metallicity clouds located close to the center of high redshift DM halos. In 2023, three of us identified (in a PNAS work) the first three photometric DS candidates: JADES-GS-z11-0, JADES-GS-z12-0, and JADES-GS-z13-0. We report here our results of a follow-up analysis based on available NIRSpec JWST data. We find that JADES-GS-z11-0 and JADES-GS-z13-0 are spectroscopically consistent with a DS interpretation. Moreover, we find two additional spectroscopic DS candidates: JADES-GS-z14-0 and JADES-GS-z14-1, with the former being the second most distant luminous object ever observed. We furthermore identify, in the spectrum of JADES-GS-z14-0, a tentative feature ( S / N ∼ 2 ) indicative of the smoking gun signature of DSs: the He II λ 1640 absorption line. In view of ALMA’s recent identification of a probable O III nebular emission line in the spectrum of JADES-GS-z14-0, the simple interpretation of this object as an isolated DS is unlikely. If both spectral features survive follow-up observations, it would imply a DS embedded in a metal rich environment, requiring theoretical refinements of the formation of evolution of DSs, which in previous studies were assumed to form in isolation, without any companions.

Signatures of sliding Wigner crystals in bilayer graphene at zero and finite magnetic fields

Abstract AB-stacked bilayer graphene has emerged as a fascinating yet simple platform for exploring macroscopic quantum phenomena of correlated electrons. Under large electric displacement fields and near low-density van-Hove singularities, it exhibits a phase with features consistent with Wigner crystallization, including negative dR/dT and nonlinear bias behavior. However, direct evidence for the emergence of an electron crystal at zero magnetic field remains elusive. Here, we explore low-frequency noise consistent with depinning and sliding of a Wigner crystal or solid. At large magnetic fields, we observe enhanced noise at low bias current and a frequency-dependent response characteristic of depinning and sliding, consistent with earlier scanning tunnelling microscopy studies confirming Wigner crystallization in the fractional quantum Hall regime. At zero magnetic field, we detect pronounced AC noise whose peak frequency increases linearly with applied DC current—indicative of collective electron motion. These transport signatures pave the way toward confirming an anomalous Hall crystal.

Activation of epigenetic reprogramming via crotonylation overcomes resistance to EGFR-TKI therapy in lung cancer

Posttranslational modifications (PTMs) on histones play critical roles in cellular processes, including gene expression and tumorigenesis. However, the regulatory mechanisms and functional consequences of newly identified lysine acylation modifications in cancer therapy remain to be elucidated. Here, we established diverse preclinical tumor models resistant to epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and focused on histone lysine crotonylation (Kcr), as it exhibited more pronounced alterations compared to other acylations. Next, we identified acyl-CoA synthetase short-chain family member 2 as a key regulator responsible for the resistance-associated decrease in crotonylation levels. Furthermore, integrated crotonylomic, transcriptomic, and epigenomic profiling, supplemented by gene manipulation studies, revealed that EGFR-TKI resistance resulted from transcriptional suppression of HNF1A and activation of the PI3K/AKT signaling pathway, which were regulated by reduced histone H3 lysine 56 crotonylation. Importantly, through pharmacological screening, we identified a histone decrotonylase inhibitor that enhanced EGFR-TKI sensitivity by activating epigenetic reprogramming through the selective upregulation of histone Kcr levels across multiple models in vitro and in vivo. Collectively, our findings uncover a previously unrecognized epigenetic mechanism driven by crotonylation that contributes to EGFR-TKI resistance, highlighting the potential of modulating crotonylation as a novel therapeutic strategy to enhance the efficacy of EGFR-TKIs in lung cancer.