The role of peroxisomes in skeletal muscle remains largely unexplored. Here, the authors show that peroxisomal dysfunction and disrupted crosstalk with mitochondria drive age-related muscle decline, u...

The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metaboli

Epigenetic regulation occurs over many rounds of cell division in higher organisms. However, visualisation of the regulators in vivo is limited by imaging dynamic molecules deep in tissue. We report a technology—Variable-angle Slimfield microscopy (SlimVar)—that enables tracking of single fluorescent reporters to 30 µm depth through multiple Arabidopsis thaliana root tip cell layers. SlimVar uses rapid photobleaching to resolve tracked particles to molecular steps in intensity. By modifying widefield microscopy to minimise optical aberrations and robustly post-process few-photon signals, SlimVar mitigates performance losses at depth. We use SlimVar to quantify chromatin-protein assemblies in nuclei, finding that two homologous proteins key to epigenetic switching at FLOWERING LOCUS C (FLC) —cold-induced VERNALISATION INSENSITIVE3 (VIN3) and constitutively expressed VERNALISATION 5 (VRN5)—exhibit dynamic assemblies during FLC silencing. Upon cold exposure, the number of assembly molecul

The survival of antibody-secreting plasma cells is essential for long-lasting humoral immunity. BCMA is proposed to promote APRIL-mediated survival signals. However, extensive shedding of murine BCMA raises doubts about its role as a signaling receptor. To unequivocally establish BCMA’s function in plasma cell survival, we generate two BCMA-deficient mouse lines and examine antigen-specific plasma cells post-immunization. Contrary to previous reports, both BCMA-deficient mouse lines have comparable numbers of antigen-specific long-lived plasma cells following both protein and mRNA immunizations. Transcriptome analysis reveals no reduction in survival signaling upon BCMA deletion. Interestingly, BCMA-deficient mice show increased total plasma cell numbers in the bone marrow and mesenteric lymph nodes after boost immunizations. These results indicate that BCMA has no intrinsic role in maintaining long-lived plasma cells. Instead, we propose that BCMA’s function is limited to acting as a

In the pre-synapse, vesicle fusion is a crucial process for neurotransmitter release in the nervous system. Under physiological conditions, synaptotagmin-1 (Syt1) locks synaptic vesicles in a priming state, allowing them to undergo synchronized neurotransmitter release upon Ca2+ activation. Elevation of intracellular ions during diseases or injuries may lead to uncontrolled neurotransmitter release independent on Ca2+ influx. However, its underlying molecular mechanism remains elusive. Here we show that elevation of the intracellular Zn2+ concentration leads to the increased frequency of spontaneous neurotransmitter release in hippocampal neurons. In the reconstituted system with neuronal SNAREs and Syt1, Zn2+ markedly enhances the fusion efficiency of liposomes via its binding to the interface between tandem C2 domains of Syt1. Moreover, Syt1 exhibits an elevated capacity to bind to anionic vesicles in the context of interaction with Zn2+, which leads to an augmentation in vesicles do

Type 1 diabetes (T1D) risk has been associated with enteroviral infections, particularly coxsackieviruses B (CVB). Cellular host factors contributing to virus-induced islet autoimmunity remain unclear. We show that the Hippo pathway effector Yes-associated Protein (YAP) is markedly upregulated in the exocrine and endocrine pancreas of T1D and at-risk autoantibody-positive (AAb+) donors, along with its target CTGF. YAP expression correlates with CVB RNA presence, often in or near infected cells. YAP overexpression enhances CVB replication, islet inflammation, and β-cell apoptosis, whereas its inhibition halts viral replication in primary and immortalized pancreatic cells. In exocrine-islet co-cultures, CVB triggers YAP and target gene expression. In mice, chronic β-cell YAP expression impairs glucose tolerance, abolishes insulin secretion, and promotes β-cell dedifferentiation. Mechanistically, YAP, in complex with its transcription factor TEAD, induces its own negative regulator MST1.

Children are particularly vulnerable to landscape fire sourced fine particulate matter (LFS PM2.5), yet evidence on its health effects remains limited. Here we show that short-term exposure to LFS PM2.5 is associated with increased hospital admissions for multiple diseases in children and adolescents. We analysed daily hospital admission data from 1012 communities in seven countries/territories, linked to a high-resolution LFS PM2.5 dataset. Each 10 μg/m3 increase in LFS PM2.5 was associated with elevated risks for all-cause (1.1%), respiratory (1.9%), infectious (1.5%), cardiovascular (2.9%), neurological (2.8%), diabetes (3.7%), cancer (1.5%), and digestive (0.8%) hospital admissions. Risks for respiratory, infectious, and neurological conditions increased even at low exposure, while others rose only above 15-20 μg/m3. Children aged 5-9 years and those in lower socioeconomic areas were especially affected. These findings highlight the health burden of LFS PM2.5 in young people and th

This study investigates the effects of forestation on temperature in Europe using climate model experiments. The findings indicate that conversion from coniferous to broadleaved trees in currently for...

Secretome-based therapies that target angiogenesis are promising for the treatment of ischemic heart disease (IHD). The effects of Chemokine C-C motif ligand (CCL) 28 on IHD remain unclear. In this study, we investigated the role of CCL28 in angiogenesis during IHD in male mice using the myocardial infarction (MI) and hindlimb ischemia (HI) models. The upregulated CCL28/ C-C motif receptor (CCR)10 axis has been observed in HI and MI. Additionally, CCR10 is highly expressed in endothelial cells (ECs). Compared to CCR10- ECs, CCR10+ ECs exhibited robust proangiogenic capacity, which was induced by CCL28 through CCR10/ERK/SOX5 positive feedback signaling. The deletion of CCL28 results in impaired angiogenesis, whereas the use of recombinant CCL28 protein has therapeutic potential for myocardial and hindlimb ischemia, including that in diabetes. Endothelial-specific CCR10 deficiency impairs angiogenesis and blocks the therapeutic effects of rCCL28 in ischemic models. Serum CCL28 levels hav

Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene’s optoelectronic properties and its ability to efficiently convert light into electricity. Using GraMOS in longitudinal studies, we found that repeated optical stimulation enhances the maturation of hiPSC-derived neurons and brain organoids, underscoring GraMOS’s potential for regenerative medicine and neurodevelopmental studies. To explore its potential for disease modeling, we applied short-term GraMOS to Alzheimer’s stem cell models, uncovering disease-associated alterations in neuronal activity. Finally, we demonstrated a proof-of-concept for neuroengineering applications by directing rob

In dividing cells, chromosomes are coated in a sheath of proteins and RNA called the mitotic chromosome periphery. This sheath is thought to confer biophysical properties to chromosomes, critical for successful cell division. However, the details of chromosome mechanics, and specifically, if and how the chromosome periphery contributes to them, remain poorly understood. In this study, we present a comprehensive characterisation of single-chromosome mechanics using optical tweezers and an improved broadband microrheology analysis. We extend this analysis to direct measurements of the chromosome periphery by manipulating levels of Ki-67, its chief organiser, and apply a rheological model to isolate its contribution to chromosome mechanics. We report that the chromosome periphery governs dynamic self-reorganisation of chromosomes and acts as a structural constraint, providing force-damping properties. This work provides significant insight into chromosome mechanics and will inform our und

Facial appearance, one of the most recognizable and heritable human traits, exhibits substantial variation across individuals within and between populations due to its complex genetic underpinning, which remains largely elusive. Here, we report a combined genome-wide association study (C-GWAS) of 946 facial features derived from 44 landmarks obtained from 3D digital facial images of 11,662 individuals of European descent. We identify 253 unlinked single nucleotide polymorphisms (SNPs) across 188 distinct genetic loci significantly associated with facial variation, including 64 SNPs at 62 novel loci and 33 novel SNPs within 29 previously reported face loci that are in very low LD with the previously reported top SNPs. Together, these SNPs account for up to 7.9% of the facial variation per trait, marking an average 2.25-fold increase over previous estimates. Cross-ancestry replication in 9,674 Chinese confirms the effect of 70% of these SNPs. A 382-SNPs prediction model of five nose trai

Tristetraprolin family of proteins regulate mRNA stability by binding to specific AU-rich elements in transcripts. This binding promotes the shortening of the mRNA poly(A) tail, or deadenylation, initiating mRNA degradation. The CCR4–NOT complex plays a central role in deadenylation, while the cytoplasmic poly(A)-binding protein PABPC1 typically protects mRNAs from decay. Here, we investigate how tristetraprolin interacts with CCR4–NOT and PABPC1 to control mRNA stability. Using purified proteins and in vitro assays, we find that tristetraprolin engages CCR4–NOT through multiple interaction sites and promotes its activity, emphasizing the importance of multivalent binding for efficient deadenylation. Phosphorylation of tristetraprolin does not affect its interaction with CCR4–NOT or its deadenylation activity, but is essential for tristetraprolin’s binding to PABPC1. We propose that tristetraprolin promotes the processive deadenylation activity of CCR4–NOT on mRNAs containing AU-rich e

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 workflo

As we navigate the era of big data in biological research, advanced computational techniques, such as mathematical models and machine learning algorithms, are ...

Editors' Highlights

Semantic segmentation of medical images is pivotal in applications like disease diagnosis and treatment planning. While deep learning automates this task effectively, it struggles in ultra low-data regimes for the scarcity of annotated segmentation masks. To address this, we propose a generative deep learning framework that produces high-quality image-mask pairs as auxiliary training data. Unlike traditional generative models that separate data generation from model training, ours uses multi-level optimization for end-to-end data generation. This allows segmentation performance to guide the generation process, producing data tailored to improve segmentation outcomes. Our method demonstrates strong generalization across 11 medical image segmentation tasks and 19 datasets, covering various diseases, organs, and modalities. It improves performance by 10–20% (absolute) in both same- and out-of-domain settings and requires 8–20 times less training data than existing approaches. This greatly

Genome-wide association studies (GWAS) identify numerous disease-linked genetic variants at noncoding genomic loci, yet therapeutic progress is hampered by the challenge of deciphering the regulatory roles of these loci in tissue-specific contexts. Single-cell multimodal assays that simultaneously profile chromatin accessibility and gene expression could predict tissue-specific causal links between noncoding loci and the genes they affect. However, current computational strategies either neglect the causal relationship between chromatin accessibility and transcription or lack variant-level precision, aggregating data across genomic ranges due to data sparsity. To address this, we introduce GrID-Net, a graph neural network approach that generalizes Granger causal inference to detect new causal locus–gene associations in graph-structured systems such as single-cell trajectories. Inspired by the principles of optical parallax, which reveals object depth from static snapshots, we hypothesi

2024 saw a novel outbreak of H5N1 avian influenza in US dairy cattle. Limited surveillance data has made determining the true scale of the epidemic difficult. We present a stochastic metapopulation transmission model that simulates H5N1 influenza transmission through individual dairy cows in 35,974 herds in the continental US. Transmission is enabled through the movement of cattle between herds, as indicated from Interstate Certificates of Veterinary Inspection data. We estimate the rates of under-reporting by state and present the anticipated rates of positivity for cattle tested at the point of exportation over time. We investigate the impact of intervention methods on the underlying epidemiological dynamics, demonstrating that current interventions have had insufficient impact, preventing only a mean 175.2 reported outbreaks. Our model predicts that the majority of the disease burden is, as of January 2025, concentrated within West Coast states. We quantify the uncertainty in the sc

Cellular senescence is an irreversible state of cell cycle arrest with a complex role in tissue repair, aging, and disease. However, inconsistencies in identifying cellular senescence have led to varying conclusions about their functional significance. We developed a machine learning-based approach that uses nuclear morphometrics to identify senescent cells at single-cell resolution. By applying unsupervised clustering and dimensional reduction techniques, we built a robust pipeline that distinguishes senescent cells in cultured systems, freshly isolated cell populations, and tissue sections. Here we show that this method reveals dynamic, age-associated patterns of senescence in regenerating skeletal muscle and osteoarthritic articular cartilage. Our approach offers a broadly applicable strategy to map and quantify senescent cell states in diverse biological contexts, providing a means to readily assess how this cell fate contributes to tissue remodeling and degeneration across lifespa

X chromosome inactivation (XCI) is induced by Xist long non-coding RNA and protein-coding genes. However, the role of small non-coding RNA function in XCI remains unidentified. Our genome-wide, loss-of-function CRISPR/Cas9 screen in female fibroblasts identified microRNAs (miRNAs) as regulators of XCI. A striking finding is the identification of miR106a among the top candidates from the screen. Loss of miR106a is accompanied by altered Xist interactome, leading to dissociation and destabilization of Xist. XCI interference via miR106a inhibition has therapeutic implications for Rett syndrome (RTT) girls with a defective X-linked MECP2 gene. Here, we discovered that the inhibition of miR106a significantly improves several facets of RTT pathology: it increases the life span, enhances locomotor activity and exploratory behavior, and diminishes breathing variabilities. Our results suggest that miR106a targeting offers a feasible therapeutic strategy for RTT and other monogenic X-linked neur

Wheat tillering is an important agronomic trait influencing grain yield. Here, we identify an NHL repeat-containing protein, TaNHLP1, which positively regulates tiller number in wheat. We discovered that the core components of the abscisic acid (ABA) signaling pathway, type 2C protein phosphatase TaPP2C and SNF1-related protein kinase TaSnRK2, interact with TaNHLP1 to regulate its abundance. Furthermore, TaNHLP1 interacts with the Receptor for Activated C Kinase 1 (TaRACK1A), an ABA pathway negative regulator, and influences its subcellular localization. Importantly, both the TaNHLP1 and TaRACK1A mutations promote ABA accumulation in the shoot bases and tiller buds. Notably, the NHLP1-RACK1 module is conserved across monocots and eudicots, and natural variations in the promoter of TaNHLP1-A enhance its transcriptional activity, leading to increased tiller number and yield. Collectively, these findings elucidate the genetic mechanism of NHLP1-mediated tillering regulation and highlight

Gene edited human pluripotent stem cells are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive immune responses, but have largely not addressed the innate immune cells, such as neutrophils, that mediate inflammation and rejection processes occurring early after graft transplantation. We identify the adhesion molecule ICAM-1 as a hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In our experiments, we find that ICAM-1 blocking or knockout in human pluripotent stem cell-derived cardiovascular therapies imparts significantly diminished binding of multiple immune cell types. ICAM-1 knockout results in diminished T cell proliferation and activation responses in vitro and in longer in vivo retention/protection of knockout grafts following immune cell encounter