Browse Articles

Cryoelectron tomography reveals an age-related decline in mitoribosomes that contributes to T cell dysfunction in older individuals

Mitochondrial dysfunction drives T cell aging in mice. Yet, due to fundamental differences in T cell aging mechanisms between species, whether human T cells exhibit similar mitochondrial alterations remains unclear, with existing evidence often conflicting. Using cryoelectron tomography, we resolved the structure and spatial organization of mitochondrial ribosomes in primary human CD8 + T cells under physiological conditions. Comparative analysis with human aging models revealed an age-related reduction in mitoribosome abundance and in higher-order mitoribosome organization, which is necessary for cooperative translation. Defective mitochondrial translation suppressed cytosolic ribosomal protein expression, thereby limiting mitochondrial biogenesis. The consequent reduction in mitochondrial mass induced an aged T cell phenotype characterized by compromised memory phenotypes and proliferative capacity. Enhancing mitochondrial translation via overexpression of the mitoribosomal component Mrps5 reversed aged T cell phenotypes in a mouse model of viral infection or tumor. Together, our findings provide nanoscale-resolution views of internal mitochondrial structures in situ, revealing an age-related loss of mitoribosomes. This loss contributes to mitochondrial dysfunction and the subsequent decline in T cell function observed in older individuals. Restoring mitochondrial translation may therefore represent a strategy for mitigating T cell dysfunction in the aging population.

A fungal effector inhibits plant MAPK signaling by acting as a decoy substrate of MKK5

Plant immune responses rely on mitogen-activated protein kinase (MAPK) cascade that integrates pattern-triggered immunity and effector-triggered immunity. How fungal pathogens suppress this central signaling hub remains poorly understood. Here, we identify a secreted effector from phytopathogenic fungus Verticillium dahliae , VdHCE1, that is required for full virulence and directly targets host MAPK signaling. VdHCE1 interacts with the MAPK kinase MKK5 and is phosphorylated at threonine 166 in planta. Biochemical analyses demonstrated that VdHCE1 competes with MPK3 and MPK6 as a substrate of MKK5, thereby attenuating downstream MAPK activation. Consistently, VdHCE1 suppresses elicitor- and NLR-triggered immune responses, while deletion of VdHCE1 compromises fungal virulence in Arabidopsis and cotton. Genetic disruption of MKK5 restores the virulence of VdHCE1-deficient strains, establishing MKK5 as the functional target of VdHCE1. These findings reveal a strategy by which a filamentous fungal pathogen suppresses plant immunity by acting as a decoy substrate within the MAPK cascade and provide a molecular framework for engineering resistance to vascular wilt disease.

ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis

Abstract Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development.

Effective mass of a migrating interface

Interfaces are ubiquitous in materials and play a central role in microstructural evolution and material properties. Although interface migration has been studied for more than a century and remains an active field, several foundational assumptions of interface kinetics remain largely untested. In particular, interfaces are commonly treated as massless objects governed by overdamped dynamics. In this study, we show that grain boundaries exhibit measurable inertial behavior under high-frequency oscillatory driving. We introduce a quantitative method to extract an effective interface mass from the phase lag between the applied force and the interface velocity and find that this mass scales with the atoms participating in boundary migration. Using this framework, we identify regimes in which inertial effects significantly modify interfacial kinetics, especially at frequencies relevant to thermal fluctuations. These results challenge the conventional overdamped description and establish effective interface mass as a key ingredient in a physically complete theory of interface migration.

A potassium-based single-atom catalyst enables acute lung injury immunotherapy in mice by inhibiting macrophage pyroptosis

Abstract Acute lung injury (ALI), which can have a mortality rate approaching 40%, lacks effective therapies. Macrophage pyroptosis represents a pro-inflammatory event and a potential therapeutic target. Here, we report a single-atom immunomodulator, a potassium-based single-atom catalyst (K-SAC) with K–N 4 sites, that suppresses macrophage pyroptosis for ALI therapy through antioxidant catalysis. Constructed from biocompatible potassium, the most abundant intracellular metal in humans, K-SAC displays potent superoxide dismutase- and catalase-like activities, with the underlying mechanisms revealed by density functional theory simulations. Following preferential macrophage uptake, K-SAC scavenges reactive oxygen species, downregulates gasdermin D and its N-terminal fragment, activates endosomal sorting complexes required for transport-mediated membrane repair, and promotes membrane phospholipid remodeling, thereby effectively inhibiting macrophage pyroptosis. Notably, this catalytic membrane repair mechanism offers a versatile strategy for restoring membrane integrity. Such catalytic inhibition of pyroptosis preserves pulmonary immune homeostasis and ameliorates lipopolysaccharide- or cecal ligation and puncture-induced ALI, establishing a catalytic immunotherapeutic approach using a physiologically abundant element for therapeutic applications.

A posttranslational modification of fimbriae drives pathogenicity in <i> <i>Klebsiella pneumoniae</i> </i>

Antimicrobial resistance is a severe public health burden. Especially concerning are multidrug resistant (MDR) infections, which restrict treatment options and significantly increase mortality risk. A major cause of MDR infections worldwide is carbapenem-resistant Klebsiella pneumoniae (CR Kp ). The predominant CR Kp sequence type worldwide is ST258. However, the factors underlying ST258’s epidemic success are not well defined. Genomic analyses of clinical isolates of CR Kp have found that the two-component regulatory system CrrAB is a genomic feature of ST258, suggesting that it may contribute to its global dominance. Despite this, the molecular details underpinning CrrAB’s contribution to ST258 Kp biology and pathogenicity are poorly understood. We used RNA-sequencing to identify the regulon of CrrA and found that CrrAB induces the expression of a gene, encoding Crr-regulated fimbriae modifying protein (CfmP), that is essential for pathogenesis driven by this two-component system. We performed mass spectrometry analyses of fimbriae purified from Kp expressing or lacking cfmP and found that CfmP induces a novel oxidation to a histidine residue in the major pilin subunit of fimbriae, FimA. We demonstrate that this oxidation significantly increases host cell adhesion and high bacterial loads within the host. CrrAB also drives high antibiotic resistance in CR Kp . Thus, our results place CrrAB at the intersection of pathogenicity and antibiotic resistance supporting its function as an important regulatory system driving the global dominance of ST258.

Multi-omics integration unravels four molecular subgroups of corticotroph pituitary neuroendocrine tumours with distinct clinicopathological features

Abstract Corticotroph pituitary neuroendocrine tumours (PitNETs)/adenomas are heterogeneous sellar neoplasms. Currently established histopathological classification approaches are often considered limited in fully capturing the clinical and biological complexity of these tumours. Thus far, a molecular-based classification has not been established in corticotroph PitNETs. We compile molecular data of 270 corticotroph PitNETs (111 internal, 159 external), encompassing epigenome, transcriptome, and proteome profiles. Comprehensive integrative analyses are performed to identify, validate and characterise definitive molecular subgroups. Corticotroph PitNETs separate into four robust and clinicopathologically distinct molecular subgroups, which are broadly distinguishable by microscopy using SSTR1, GATA3 and SSTR5 immunohistochemistry. An integrated stratification model incorporating these molecular subgroups demonstrates significant prognostic utility. Our findings support the establishment of a refined molecular-based corticotroph PitNET classification, the full clinical value of which will require validation in prospective studies. To facilitate future research, we provide an easy-to-use epigenomic classifier for corticotroph PitNETs.

Sediment accumulation rate predicts the temporal resolution of marine fossil assemblages

Time averaging (TA), the mixing of noncontemporaneous organisms in fossil assemblages, governs the resolution of paleontological data and determines which biological and environmental processes are recorded in the geological record. To assess variation in TA and its dependence on external drivers, we used amino acid and radiocarbon methods to individually date 7,593 specimens across 384 samples from late Quaternary marine assemblages of calcifying organisms. Bivalve mollusks dominated the data, but 65 samples represented other taxa. Estimates of TA, measured by dispersion of specimen ages within samples, ranged from decades to millennia and scaled proportionally ( r 2 = 0.77) with sediment accumulation time (SAT), an inverse of sediment accumulation rate (SAR) that accounts for the stratigraphic span of samples. In agreement with numerical modeling, the observed TA estimates were an order-of-magnitude higher than SAT and modulated by SAT-dependent effects of vertical mixing and skeletal disintegration. When SAT is short, effective disintegration rates are too slow to suppress the amplifying role of mixing but increase in importance when SAT is long. The strong dependency of TA on SAT points to the overriding role of SAR in controlling the temporal resolution of fossil assemblages, notwithstanding other interacting drivers known to influence TA. These results demonstrate a long-suspected paleontological rule: The temporal resolution of fossil assemblages scales predictably with SAR. This straightforward relationship provides a quantitative guideline for determining the temporal adequacy of sedimentary records as archives of Earth system processes.

Pregnancy promotes tumor metastasis through adenosine-induced immunosuppressive neutrophils in pre-metastatic microenvironment

AI will reorganize science. Will research remain a human enterprise?

Identification of carnivory in the flowering plant Saxifraga via multidisciplinary evidence

Abstract The transformation from prey to predator is a striking adaptive innovation shared by all carnivorous plants, which capture and digest diverse animal prey for nutrients (nitrogen, N). Here, we report carnivory in the alpine flowering plant Saxifraga candelabrum (Saxifragaceae; Saxifragales). Field experiments and herbarium surveys reveal that this plant actively attracts and captures insect prey via glandular hairs. Enzymatic analyses further confirm the ability of plants to digest prey, and isotope labelling experiments using ¹⁵N-labelled insects demonstrate the transfer of nitrogen from prey to plant tissues, thus verifying the presence of carnivory. Genomic comparisons reveal a significant genome-wide convergence in genes related to carnivory (e.g., leaf morphogenesis, digestion and nutrition) across six independent origins of carnivory in diverse flowering plant lineages. Our findings provide definitive evidence of carnivory in Saxifraga , addressing Charles Darwin’s long-standing hypothesis that some Saxifraga species may be capable of carnivory, and further suggest that carnivory may be more widespread among angiosperms than previously recognized.

RelB NF-κB tunes Notch2 signaling to promote IL-23-secreting solitary isolated lymphoid tissue–resident DCs critical for gut immunity

While preserving tolerance toward commensals, dendritic cells (DCs) also orchestrate response against pathogens. The noncanonical RelB NF-κB pathway in DCs curbs tolerogenic Tregs in the intestine. Whether RelB-dependent DC regulations also impact intestinal immunity remains less clear. Here, we show that genetic ablation of RelB in DCs compromises IL-23-dependent immune response in the intestine, imparting vulnerability in Relb ΔCD11c mice to infection with Citrobacter rodentium , an enteropathogen. Our mechanistic studies revealed that RelB supported the expression of RBP-J from a κB site-driven promoter, tuning Notch2 response in DCs. This RelB-mediated Notch2 control specified a solitary isolated lymphoid tissue–resident DC subset, which served as a dominant source of IL-23 in infected mice. Indeed, we found that IL-23 supplementation readily rescued the immune deficiency of Relb ΔCD11c mice, improving bacterial clearance. In sum, we illustrate a previously unrecognized crosstalk between RelB and Notch2 underpinning IL-23-secreting DCs critical for gut immunity.

Translational control by RPL22L1-specific ribosomes enhances DNA repair and chemoresistance

Profile of Morris Moscovitch

Morris Moscovitch’s five-decade career has reshaped scientists’ understanding of how the brain stores and retrieves memories. His Multiple Trace Theory challenged the view that the hippocampus serves only as temporary storage, showing instead that richly detailed episodic memories remain dependent on the hippocampus indefinitely. Moscovitch demonstrated that the hippocampus contributes not just to remembering but to imagination, problem-solving, and social cognition. His recent work reveals that people detect episodic richness in others’ memories and use this signal to guide social preferences. Through collaborative research spanning hemispheric specialization and face recognition, Moscovitch has revealed memory as central to human cognition.

Biomimetic diffusion metamaterials enabled by physical-geometric duality

Comparative archaeology reveals recurrent but nondeterministic pathways through complexification

The amount of variation observed among early complex societies has challenged efforts to understand their social dynamics. We advocate for a comparative approach that directly investigates the forces producing this variation. By holistically ranking 63 trajectories of societal change along five axes of differentiation, we characterize their development from a multidimensional perspective. Our analysis reveals that the majority of these trajectories align with one of six recurrent pathways through “complexification,” identified from broadly similar courses of development shared across multiple trajectories. These patterns provide a framework for understanding the conditions under which different forms of complexity emerged—or failed to do so. Particular attention is paid to the ways in which social and demographic forces interact along these pathways. Crucially, these forces interact probabilistically rather than deterministically, producing widespread tendencies rather than inevitable outcomes. Focusing future research on mediating and confounding variables, expanding the sample of trajectories available for analysis, identifying additional complexification pathways and the social forces at work in them, and leveraging the explanatory potential of trajectories that do not align well with any developmental pattern, will further enrich our understanding of the complexification process.

Coupled air–sea interactions drove and sustained the 2013–2016 North Pacific marine heatwave

Abstract The 2013–2016 marine heatwave (MHW) in the Northeastern Pacific ranks among the most intense extratropical ocean warming events on record. Its intricate evolution has complicated efforts to understand the underlying dynamics crucial for predicting future MHWs. Here, we track the MHW using a closed, three-dimensional Lagrangian heat budget that quantifies the processes driving its evolution. Three-dimensional particle trajectories separate the MHW into northern and southern components and reveal that they are of distinct kinematic origin. We quantitatively demonstrate through a closed budget that advection, rather than surface forcing, plays the dominant role in sustaining the MHW’s heat content. The northern component was maintained by a weakening of Ekman heat transport across the North Pacific Current, combined with reduced wintertime surface heat loss. The southern component was driven by weakened Ekman upwelling caused by reduced alongshore winds over the California Current. We further identify a persistent low sea-level pressure anomaly over the central Pacific that altered wind patterns, redistributing heat and moisture poleward to ultimately force both parts of the MHW. Elevated surface temperatures, in turn, amplified this pressure anomaly, completing a positive feedback loop that sustained the event across multiple years.

An expanded apolipoprotein D family provides spider mites with dual-layer protection against dietary oxidative stress

Plant defense has driven the evolution of species-dependent adaptive strategies in many herbivores, but the molecular mechanisms of adaptation in most arthropods remain largely unknown. The two-spotted spider mite ( Tetranychus urticae ) is a generalist herbivore that feeds by sucking the contents of mesophyll cells, a feeding strategy distinct from that of phloem-feeding insects. Here, we show the unexpected differential expression of apolipoprotein D ( ApoD ) genes during feeding when mites are transferred to different host plant species, as well as extreme gene family expansion (64 ApoD paralogs, the largest reported in any organism). We find that ApoD proteins protect mites against reactive oxygen species (ROS) during feeding, and we identify a dual-layer mechanism by which ApoD proteins counteract plant ROS defenses during ingestion and digestion. First, the salivary protein TuApoD2 is secreted during the ingestion of mesophyll cell contents, where it interacts with glycolate oxidase 2 (GOX2) to inhibit H 2 O 2 generation. After ingestion, TuApoD33 in the gut cells also interacts with GOX2 to maintain the inhibition of H 2 O 2 generation. These findings suggest that the evolutionary expansion of the ApoD gene family is a key component of the molecular arms race between herbivorous mites and host plants.

In vivo CRISPR screening identifies metastasis suppressors in triple-negative breast cancer

Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission

Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.