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Highly sensitive chemiluminescence imaging of misfolded proteins in neurodegenerative models

Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.

A self-wrapping, bioresorbable neural interface for wireless multimodal therapy of localized peripheral nerve injury

High-precision in vivo therapeutic technologies that establish three-dimensional (3D), multimodal neural interfaces with targeted biotissues offer significant clinical potential for the timely treatments of localized peripheral nerve injury (PNI). Current approaches for this purpose such as implantable devices face challenges in terms of percutaneous wires and/or nondegradable designs, and support only single-mode operation that lack microscale spatial resolution. Here, we develop a miniaturized, self-wrapping system that yields wireless, multimodal neural interfaces with 3D adaptation across localized peripheral nerves at scales ranging from tens of micrometers (15 μm) to millimeters. Such platform integrates multilayer architectures that include SiN x layers as the mechanically triggered substrate for 3D wrapping, with multimodal treatments via MXene and drug-loaded layers for photothermal stimulation and pharmacological release. Experimental and computational studies establish operational principle as the basis for the combination of long-term photothermal therapy and transient drug delivery at high spatiotemporal resolution. In vivo tests on living rat models demonstrate that the implantable neural interface can roll up across the localized, dynamic surface of injured nerves, providing sustained treatments over 1 mo in a fully bioresorbable design after the healing process. These findings create future opportunities of such wireless, multimodal system with 3D self-wrapping techniques for precise PNI therapeutic strategies.

Reactive oxygen species drove red lineage phytoplankton to displace green lineage phytoplankton during the Mesozoic

The great phytoplanktonic shift from green to red plastid lineage dominance in the early Mesozoic marks a primary producer revolution in marine ecosystems, facilitating the rise of modern ecosystems and impacting global carbon cycling and energy flows. The causes driving this evolutionary transition have been attributed to the changes in essential nutrients and the environmental crises of the Permian–Triassic mass extinction. Nonetheless, the underlying mechanisms driving this transition remain poorly understood. Here, we integrated culture experiments, molecular and physiological analyses, big data analysis, and phylogenomic dating analyses to uncover how environmental stresses influence algal physiology, thereby altering their evolutionary trajectories. We find that environmental and endogenous reactive oxygen species (ROS) collaboratively shape phytoplanktonic responses. The structural characteristics of red lineage phytoplankton enhance resistance to environmental ROS, facilitating physiological strategies that minimize endogenous ROS accumulation, thereby driving more adaptive evolutionary trajectories under environmental stresses in the early Mesozoic. The alignment of the turnover in diversification dynamics between the two lineages with paleoenvironmental shifts that triggered increased ROS production supports the role of ROS in driving this evolutionary transition. Our findings highlight ROS as a key underlying factor driving phytoplankton evolution, providing predictive insights into major biota–environment coevolutions throughout Earth’s history.

Neural substrate of conditioned stimulus for associative learning in the hippocampus

Associative learning allows animals to learn the predictive relationships between events. Presentation of a conditioned stimulus (CS) preceding an unconditioned stimulus (US) within a short interval associates these events. However, little is known about the neural substrates that represent CSs. By combining in vivo calcium imaging with retrospective identification of dorsal hippocampal CA1 neurons, in which c-fos is induced during contextual fear conditioning in mice, we found that prospective c-fos (+) neurons were activated upon novel environmental exposure. Importantly, a part of them was transiently reactivated 1 to 2 s before the shock US as well as during memory retrieval, and these activities were correlated with memory expressions. Optogenetic silencing demonstrated that timing-dependent neuronal activity is crucial for memory formation. Our study identifies a cellular substrate for the CS that underlies the CS–US temporal contiguity rule under physiological conditions and suggests how the internal representation of context serves as a CS, demonstrating the role of prospective engram cells at the moment of conditioned learning.

Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation

Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging—increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.

Primate-informed neural network for visual decision-making

The human brain excels at complex tasks with remarkable efficiency, adaptability, and resilience, making it a powerful source of inspiration for AI. Here, we present a neural dynamics model inspired by the primate dorsal visual pathway, a circuit crucial for motion and spatial processing. Incorporating key neuronal and synaptic dynamics, the model reproduces human-like decision-making behaviors and neural activity patterns without the need for extensive training. Compared with conventional artificial networks, it exhibits superior robustness to perturbations such as noise and damage. To further enhance its performance, we introduce a neuroimaging-guided fine-tuning strategy. Correlations between MRI features and behavioral performance are mapped onto critical model parameters, guiding the optimization toward more biologically plausible operational regimes. This approach improves performance and adaptability while preserving biological plausibility and reducing the parameter search space. This is a demonstration of directly integrating human neuroimaging evidence into AI model optimization, establishing a methodology for brain-inspired modeling. By combining insights from primate electrophysiology, human neuroimaging, and biologically grounded modeling, our work narrows the gap between neuroscience and AI. It demonstrates how brain-inspired approaches can advance the development of adaptive, resilient, and interpretable AI systems, offering a paradigm for biologically grounded intelligence.

Hyperglycemia promotes SIRT3-mediated deacetylation of SARM1 to exacerbate diabetic peripheral neuropathy in mice

Diabetic peripheral neuropathy (DPN), the most common complication of diabetes, lacks effective treatments and is characterized by early axonal degeneration mediated by sterile alpha and Toll/interleukin receptor motif-containing protein 1 (SARM1). Here, we identify a regulatory mechanism of SARM1’s NAD + -cleaving activity via acetylation at lysine 641 (K641). In high-glucose conditions, SIRT3 deacetylates SARM1 at K641, enhancing its NAD + cleavage activity and exacerbating axonal damage. In type 2 diabetic (T2DM) mice, acetylation of SARM1 at K641 (K641Ac) or Sirt3 knockout mitigates hypoalgesia, intraepidermal nerve fiber loss in footpad skin, and axonal growth retardation in dorsal root ganglia. These interventions also attenuate ROS accumulation, ATP depletion, and NAD + decline, conferring protection against DPN pathology. Notably, wild-type SARM1 expression reverses the protective effects of Sirt3 ablation in T2DM mice, whereas SARM1 K641Q does not. Our findings establish that SIRT3-mediated deacetylation of SARM1 at K641 drives axonal degeneration in DPN, and enhancing K641 acetylation mitigates disease progression. This study uncovers a critical posttranslational regulation of SARM1 and suggests that targeting the SIRT3–SARM1 axis may offer therapeutic potential for DPN and related neurodegenerative conditions.

M cell–dependent commensal uptake confers encephalitogenic phenotypes on γδT17 cells in Peyer’s patches

Interleukin-17-producing γδT cells (γδT17 cells) play a dual role in immune regulation, serving as both protectors in various tissues and orchestrators of inflammatory responses in autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis. However, the ontology and repertoires of encephalitogenic γδT17 cells remain unclear. In this study, we demonstrate that the encephalitogenicity of γδT17 cells is conferred through microfold cell (M cell)-dependent uptake of commensal bacteria in Peyer’s patches. Specifically, CXCR6 hi Vγ6 + Vδ1 + invariant γδT17 cells are activated by specific commensal bacteria such as Lactobacillus spp., which stimulate TCR of CXCR6 hi Vγ6 + Vδ1 + invariant γδT17 cells. During the early stages of EAE, γδT17 cells infiltrate the central nervous system (CNS), initiating a type 17 inflammatory response. Our findings illustrate that Peyer’s patch M cells serve as a critical bridge, linking the pathological association between commensal bacteria and the onset of CNS inflammation.

Pathogen-inspired engineering of plant protease enhances late blight resistance

The apoplast is an important battlefield in plant–pathogen interactions. The late blight oomycete pathogen Phytophthora infestans, for instance, secretes cystatin-like protease inhibitors EpiC1 and EpiC2B to suppress C14, a papain-like immune protease secreted by tomato. Here, we found that P. infestans also secretes two distinct papain-like proteases termed Pain1 and Pain2, which are transcriptionally induced during infection. Both Pains promote P. infestans infection, but not when their catalytic residues are mutated. Strikingly, EpiC1 and EpiC2B preferentially inhibit tomato C14 rather than self-produced Pains, suggesting that they coevolved with Pains to avoid self-inhibition. To mimic the avoidance of inhibition by EpiCs, we engineered C14 (eC14) with seven Pain1 residues that potentially disturb the EpiCs–C14 interface. This eC14 is less sensitive to inhibition by EpiCs and enhances resistance to P. infestans infection. This strategy demonstrates that a pathogen-inspired protein engineering approach can increase crop resistance to plant pathogens.

Nonsense-mediated decay controls a negative feedback loop in innate immune sensing

Nonsense-mediated decay (NMD) is an mRNA decay pathway which degrades potential harmful transcripts that contain premature termination codons. However, NMD’s importance also extends to the control of isoform abundance under physiological conditions. During viral infection, NMD is inhibited through numerous mechanisms; however, NMD has been shown to have both antiviral as well as proviral activities, raising further questions into the role and control of NMD during viral infection. These observations have led us to investigate the potential involvement of NMD in dsRNA sensing as a mechanism that might explain these discrepancies. Using EIF4A2 exon 10B inclusion as an example of AS-NMD isoform accumulating during viral infection, we show that dsRNA sensing inhibits NMD. This effect is correlated with translational blockade and is driven primarily by RNaseL activation, and by PKR in the absence of RNaseL activation. Surprisingly, NMD inhibition limits the induction of IFN-β as well as interferon-stimulated genes, and this effect is upstream of IRF3 phosphorylation and translocation to the nucleus. NMD inhibition also decreases PKR and RNaseL activation as well as PIC-mediated cell death by decreasing the dsRNA content, suggesting NMD directly controls dsRNA sensing by controlling the dsRNA load. Therefore, inhibition of NMD upon dsRNA sensing provides a negative feedback loop that contributes to shaping the innate immune sensing pathways.

Correction to: Long-Term Outcomes of Early Surgery Versus Conventional Treatment for Asymptomatic Severe Mitral Regurgitation: A Propensity Analysis

The major ion chemistry of seawater was closely coupled to the long-term carbon cycle during the Cenozoic

A ~fivefold decrease in the atmospheric concentration of CO 2 took place during the Cenozoic. This has often been viewed within the context of silicate weathering changes, although the specific contributions of the potential drivers remain poorly understood. Indeed, it has been alternatively argued that changes in the sea floor spreading rate contributed to the Cenozoic p CO 2 decline, although the magnitude of the decrease means that this is unlikely to account for the entirety of the p CO 2 change. One previously overlooked factor is the concomitant change in the major element composition of seawater, especially the concentration of calcium ([Ca 2+ sw ]), which is typically viewed as responding to processes such as weathering, rather than representing a driver in and of itself. Here, we present the first detailed record of the Cenozoic major ion chemistry of seawater and show that [Ca 2+ sw ] has the potential to control key processes that impact the carbon cycle. Although our record cannot determine whether CO 2 is causally driven by [Ca 2+ sw ], carbon cycle box modeling identifies that this may have been the case. Whether or not [Ca 2+ sw ] indeed directly drove p CO 2 during the Cenozoic principally depends on the strength of the silicate weathering feedback and the magnitude of any possible changes in organic carbon burial, both of which could overwhelm a [Ca 2+ sw ]-driven impact on the carbon cycle. As such, determining the sensitivity of the weathering–climate relationship on million-year timescales is key to resolving whether factors such as seawater major ion composition are important carbon cycle drivers.

Profiling Immune-Independent Response to Immune Checkpoint Inhibitors on Stem Cell–Derived Cardiomyocytes, Organoids, and Mouse Models

Cell numbers contribute to cell fate during Ciona cardiopharyngeal mesoderm specification

The Ciona heart cell lineage can be accurately traced back to a pair of blastomeres, the B7.5 cells, that form at the 64-cell stage. In addition to the adult heart, the B7.5 cells also contribute to two tail muscle cells in the larva, as well as the muscles that form the siphons for pumping water for feeding. Because of the simplicity of this system, we have a good understanding of how the B7.5 derivatives are specified during development. However, we know less about how the Ciona embryo precisely regulates cell numbers, as well as what effects altering cell numbers will have on development. We found that cell numbers in the B7.5 lineage are controlled by a pulse of transcription of the cell cycle inhibitor Cdkn1.b . Cdkn1.b can be repressed by the paralogs Prdm1-r.a and Prdm1-r.b that are exclusively transcribed in the B7.5 cells at the 112-cell stage. We unexpectedly found that precocious arrest of cell division in the B7.5 cell lineage resulted in a reversion to tail muscle fate, even in cells that can migrate. Our work demonstrates an unexpected connection between the control of cell numbers and cell fate in development.

When Less Is More: Is It Time for a New Gold Standard?

Elucidating cooperative genetic events in DCIS progression in mutant <i>p53</i> –driven breast cancer

Ductal carcinoma in situ (DCIS) is a precursor mammary lesion characterized by abnormal epithelial cells in mammary ducts that remain confined to the luminal space. Not all DCIS becomes invasive, and no strategy currently exists in patients to stratify indolent DCIS from DCIS at risk of progression. Several studies of human DCIS and breast cancer suggest that TP53 mutations occur early in DCIS. However, TP53 mutation alone is insufficient for DCIS formation or transformation to invasive disease. Using an autochthonous somatic mouse model of Trp53 R245W induced breast cancer (equivalent to the TP53 R248W hotspot mutation in humans), we identified DCIS lesions. Through exome sequencing and low-pass whole-genome sequencing, we identified additional genomic changes shared between DCIS and invasive tumors. This comparison nominated seven murine candidate genes, with eight human orthologs. We assessed the cooperativity of these genes with mutant TP53 in human breast cells using acinar morphogenesis and migration assays. Overexpression of TMEM267 , which encodes a transmembrane protein overexpressed in 22% of TP53 missense mutant breast cancer cases, in cells with mutant TP53 caused a significant increase in the filled duct, DCIS-like phenotype. We nominate TMEM267 as a cooperating event with mutant TP53 in DCIS progression.

Correction to: Contemporary Burden of Cardiovascular Disease in Pregnancy: Insights From a Real-World Pregnancy Electronic Health Record Cohort

Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) tract in the huntingtin protein (HTT), leading to its misfolding and aggregation. The subcellular localization of mutant HTT (mHTT) aggregates critically influences their neuronal toxicity, with nuclear aggregates contributing more significantly to neurodegeneration than those in the neuropil. Our previous findings demonstrated that site-specific ubiquitination of lysine residues at the positions of K6 and K9 in HTT significantly affect the aggregation properties of mHTT and influence cell viability. However, the in vivo functional relevance of this modification remains elusive. To address this, we generated two HD knock-in (KI) mouse models in which the mouse Htt exon 1 was replaced by human mutant HTT exon 1 containing 134 pure cytosine–adenine–guanine (CAG) repeats. In addition, one of these KI lines carries lysine-to-arginine (K &gt; R) substitutions at residues 6 and 9 to block site-specific ubiquitination (Q134 RR line). Compared to Q134 KK control mice, Q134 RR mice showed a more pronounced accumulation of both soluble and aggregated forms of mHTT. Notably, the K &gt; R substitutions accelerated mHTT aggregation kinetics, resulting in the formation of large inclusion bodies and their exclusive nuclear localization. Furthermore, Q134 RR mice exhibited earlier onset and accelerated progression of motor impairments, brain atrophy, and neuropathological features. Collectively, our findings provide strong in vivo evidence for the crucial role of site-specific ubiquitination at K6 and K9 in modulating mHTT aggregation and HD pathology. These results reinforce the therapeutic potential of targeting these specific ubiquitination sites for clinical translation.

Correction to: Transcatheter Closure of Patent Foramen Ovale with a Novel Biodegradable Device: A Prospective, Multicenter, Randomized Controlled Clinical Trial

SARS-CoV-2 peptide fragments selectively dysregulate specific immune cell populations via Gaussian curvature targeting

Immune cell populations are dysregulated in COVID-19 for currently unknown reasons: Plasmacytoid dendritic cell (pDC) populations are reduced, thus hampering antiviral responses. CD8 + T cell populations are reduced, the level of which has emerged as an index of disease severity. Recent work has shown that the proteome of SARS-CoV-2 is a rich reservoir of antimicrobial peptide-like sequence motifs (xenoAMPs) which can chaperone and organize dsRNA for amplified Toll-Like Receptor 3 (TLR3)-mediated inflammation in vitro and in vivo. Here, we demonstrate that proteolytic digestion of the SARS-CoV-2 spike protein by host trypsin-like serine proteases directly produces xenoAMPs. Synchrotron Small Angle X-ray Scattering, mass spectrometry, and a theoretical analysis based on continuum membrane elasticity show that proteolytically generated xenoAMPs from SARS-CoV-2 proteins in vitro and machine learning-predicted high-scoring xenoAMPs all induce negative Gaussian curvature (NGC) necessary for pore formation in membranes. We find that xenoAMPs alone as well as xenoAMPs synergistically with endogenous AMP LL-37 can induce NGC in membranes. A computational analysis of immune cells with morphologically complex shapes (e.g., pDC, CD8 + , and CD4 + T cells) suggests that surfaces with high local NGC can concentrate AMP-like sequences and promote selective membrane disruption. Consistent with this hypothesis, experiments with freshly isolated human peripheral blood mononuclear cells confirm that viable pDCs, DCs, and T cells are significantly depleted after xenoAMP exposure, in contrast to monocytes and neutrophils, the immune cell subsets with spheroidal morphology. Structural data from Omicron variant xenoAMP homologs indicate reduced pore formation, consistent with clinical observations of reduced T cell cytopenia in Omicron variant infections.