Ding L, Du W, Zhu J
… +7 more, Zhang Y, Wang X, Li L, Liu B, Wang X, Wang Q, Pei D
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335237
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Ferroptosis has emerged as a key effector mechanism in antitumor immunity, yet the transcellular metabolic cross talk that modulates ferroptotic sensitivity in colorectal cancer (CRC) remains incompletely understood. Her...Ferroptosis has emerged as a key effector mechanism in antitumor immunity, yet the transcellular metabolic cross talk that modulates ferroptotic sensitivity in colorectal cancer (CRC) remains incompletely understood. Here, we describe an integrative regulatory axis linking immune cell-intrinsic Stimulator of Interferon Genes (STING) signaling to tumor ferroptosis through coordinated lipid metabolism and posttranslational modifications (PTMs). Mechanistically, STING activation in immune cells triggers TANK-binding kinase 1 (TBK1)-dependent phosphorylation of cytosolic phospholipase A (cPLA) at Ser505, thereby releasing arachidonic acid (AA) into the tumor microenvironment (TME). This immune-derived AA is taken up by adjacent CRC cells, where it promotes ACSL4-dependent ferroptosis by inhibiting EP300-mediated lactylation of ACSL4 at lysine 426 (K426). In vivo, pharmacological activation of STING enhances AA release and facilitates ferroptosis-mediated tumor suppression. Notably, STING agonist synergizes with PD-1 checkpoint blockade to inhibit tumor progression, which is reversed by the ferroptosis inhibitor. Collectively, our findings establish an integrative and transcellular immunometabolic framework linking innate immune sensing to tumor ferroptosis, providing a strong rationale for combinatorial therapeutic strategies in CRC.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335236
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Wetlands on the world's most fertile black soil serve as critical yet vulnerable carbon reservoirs, yet their stability is threatened by redox fluctuations intensified by climate change and human activities. However, how...Wetlands on the world's most fertile black soil serve as critical yet vulnerable carbon reservoirs, yet their stability is threatened by redox fluctuations intensified by climate change and human activities. However, how cultivation modulates this process and its temperature sensitivity remains poorly understood. Here, we integrated field surveys of 10 black soils with mechanistic experiments on three contrasting soils along a cultivation gradient, including microbial inoculation, sterilization, radical quenching, and mineral chelation, to demonstrate that rice cultivation fundamentally reshaped the coupled biotic-abiotic process governing temperature sensitivity of carbon pulses under redox fluctuations. We found that rice cultivation enhanced iron-reducing capacity and shifted microbial metabolic pathways toward catabolism, establishing a persistent anaerobic legacy that amplified the warming sensitivity of aerobic carbon pulses. Mechanistically, ferrous mineral-catalyzed oxidation through both direct catalytic oxidation and OH-mediated pathways dominated the aerobic pulse in cultivated soils (>44 to 61% of CO yields). This pathway was dependent on anaerobic legacies, including activated mineral catalytic potential and accumulated dissolved organic carbon, and was further intensified by warming. Across 10 soils, paddies exhibited stronger ferrous mineral catalytic capacity for aerobic CO pulses than natural wetlands, with warming further amplifying this divergence. These findings reveal a bio-abiotic coupling mechanism, where antecedent anaerobic microbial processes establish a functional legacy that governs subsequent abiotic mineral catalysis, that is currently underrepresented in ecosystem models.
Weinandt SA, Child ZJ, Lartey D
… +15 more, Santos A, Maxfield H, Sevigny JK, Garrett FES, Smith PD, Giersch RM, Hart SFM, Rabins L, Kaiser S, Boyar A, Newton J, Kerr J, Perez F, Dimond JL, Metzger MJ
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335235
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Bivalve transmissible neoplasias (BTNs) are transmissible cancers that have arisen in multiple bivalve species, including Eastern soft-shell clam () populations on the East Coast of North America. Two sublineages of a si...Bivalve transmissible neoplasias (BTNs) are transmissible cancers that have arisen in multiple bivalve species, including Eastern soft-shell clam () populations on the East Coast of North America. Two sublineages of a single clone (termed MarBTN) currently circulate at low enzootic levels (1 to 5%) in New England, the United States, and Prince Edward Island, Canada, but MarBTN has not previously been observed in soft-shell clams on the West Coast. In 2022, we collected soft-shell clams in Puget Sound, Washington, and unexpectedly found MarBTN in two sites. Prevalence increased in subsequent years, surpassing 75% at both sites in 2024, while remaining undetectable in other populations, suggesting the early stages of a severe disease outbreak. Based on the presence of somatic transposon insertion sites found only in the USA-sublineage, the cancer was likely recently transplanted from New England. We also found that soft-shell clams in multiple Puget Sound locations are hybridizing populations of and . may have decreased susceptibility to this cancer, though further sampling will be needed to confirm this hypothesis. We further developed a sensitive environmental DNA (eDNA) assay, targeting somatic mutations in the MarBTN mitogenome. Using this assay, we surveyed 51 sites throughout Puget Sound, detecting cancer at high levels at sites where MarBTN-positive clams were observed and in the surrounding area. These results identify a severe outbreak of transmissible cancer in a hybridizing population, due to transfer of disease from another ocean, and demonstrate the utility of eDNA methods to track BTN through the environment.
Hargrove J, Mahamat MH, Aldjibert M
… +9 more, Yoni W, Signaboubo D, Darnas J, Salou E, Tirados I, Mugenyi A, Barreaux P, Solano P, Barreaux AMG
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335234
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Every year, over 700,000 people, particularly children under five, die from vector-borne diseases worldwide. Effectively controlling endemics and preventing new outbreaks requires an integrated approach that can lead to...Every year, over 700,000 people, particularly children under five, die from vector-borne diseases worldwide. Effectively controlling endemics and preventing new outbreaks requires an integrated approach that can lead to the elimination of both vectors and diseases. In the last two decades, integrating medical interventions and vector control has significantly reduced the incidence of Gambian Human African Trypanosomiasis (g-HAT), with the World Health Organization validating eight countries as having eliminated the disease as a public health problem. However, elimination of the tsetse vector has not been confirmed, leaving the possibility of re-emergence. We developed a six-step modeling framework to assess vector elimination by calculating: i) the probability of vector capture; ii) the probability of observing a series of zero catches, even without actual elimination; iii) the probability of natural elimination; iv) the probability of failing to detect a rebound; v) the reinvasion risk; and vi) the sensitivity analysis. Our case study is g-HAT in Mandoul, Chad, and the elimination of We used vector control from 2014 to 2025 with no tsetse detected since 2018. We cannot yet conclude, with over 90% confidence, that tsetse has been eliminated from Mandoul, nor that any remnant population will be naturally eliminated. However, since vector control stopped in April 2025, we estimate that with continued sampling over the next 2 y, and no tsetse detected, elimination could be demonstrated with 99% confidence. Our multistep modeling framework can be applied to other vectors, providing policymakers with guidelines for ongoing and future efforts.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335233
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Distributed acoustic sensing (DAS) has emerged as a powerful tool for passive whale monitoring, enabling both the detection of vocalizations and the simultaneous tracking of multiple individuals. However, a fundamental l...Distributed acoustic sensing (DAS) has emerged as a powerful tool for passive whale monitoring, enabling both the detection of vocalizations and the simultaneous tracking of multiple individuals. However, a fundamental limitation of passive acoustic monitoring is that most methods rely on acoustic data, which is only available when whales vocalize. This clearly demonstrates the need for new sensing methods that can detect silent whales. In this paper, we detect hydrodynamic pressure and velocity fields in the low-frequency DAS data induced by a whale's motion and develop methods to analyze these signals. First, we use ships as proxies to demonstrate and calibrate the proposed method. Then, we show that a simple fluid mechanical model can be adapted to understand how whale swimming can be detected and analyzed using DAS. We detect multiple silent whales simultaneously, estimate their characteristics, and show that whale motion signals decay as one over distance cubed. Moreover, we demonstrate that we can observe hydrodynamic pressure and velocity signals from a cruise ship at 413 m water depth, and up to 550 m from the fiber cable. In comparison, the smaller blue whales can be observed when diving within 40 m of the fiber-optical cable. This sensing method enables an approach to monitoring one of the world's most endangered species.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335232
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How can social animals divide labor to forage effectively without a leader? Effective foraging requires balancing individual exploration costs against collective information gains, but without central coordination. This...How can social animals divide labor to forage effectively without a leader? Effective foraging requires balancing individual exploration costs against collective information gains, but without central coordination. This balance must emerge from the distributed decisions of group members. We address this challenge using a collective foraging model in which individuals share information and rewards but each must choose whether to bear the cost of exploring or to remain idle. We show that decentralized collectives can match the performance of centrally controlled groups through a division of labor with a small exploratory minority bearing the cost of foraging in lean times, continuously gathering information to enable a synchronized majority to exploit favorable conditions. This division of labor is inherently adaptive because fixed individual thresholds produce flexible collective behavior without central adjustment of roles. Information redundancy causes the optimal number of explorers to grow logarithmically with group size, so larger groups need proportionally fewer explorers. We find that the ideal level of group heterogeneity is maximized at intermediate ecological pressures, whereas optimal groups are homogeneous under extreme conditions. Collective responses to environmental changes are asymmetric and detecting improving conditions is slower than detecting deteriorating ones, as the exploratory minority needed to signal recovery is costly to maintain. We thus show how a division of labor based on simple individual threshold rules leads to optimal collective performance without central coordination, and predict when ecological pressures favor heterogeneous vs. uniform group composition.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335231
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The term "Lilliput Effect" describes a substantial decrease in the average body size of fossil assemblages during major environmental perturbations in Earth's history, which is reported in many paleontological studies. T...The term "Lilliput Effect" describes a substantial decrease in the average body size of fossil assemblages during major environmental perturbations in Earth's history, which is reported in many paleontological studies. The limited regional, temporal and taxonomic focus of most studies, however, has sparked discussions concerning its generality. Additionally, even though a negative relationship between warming and body size has been established in recent marine ectotherms, the environmental and mechanistic drivers of the Lilliput effect are still debated. We compiled close to 9,000 body size changes from fossil, historical, and modern body size studies, to show that a decrease in body size is indeed a general response of marine ectotherms to environmental crises. The magnitude and temporal variability of size changes at the species-level are significantly higher during hyperthermal than nonhyperthermal events, suggesting differing mechanisms of body size decrease depending on the environmental stressor. Our results further show that ancient environmental perturbations with a higher magnitude of warming were associated with a greater dwarfing. This implies that warming was a major driver of body size decreases during hyperthermal events throughout the Phanerozoic, and future warming will impact current trajectories of body size reduction in modern marine ectotherms.
Ye W, Ma W, Li Y
… +22 more, Guo Z, Gao S, Guo H, Yan Z, Shi S, Han S, Lou Q, Li J, Gu Y, Su R, Wang H, Nabi HG, Liu Y, Zhu H, Zhang H, Zhang Z, Sun X, Zeng Y, Chen X, Feng Y, Li Z, Li J
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335230
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Improving multistress resilience in crops is essential for sustainable agriculture, yet the genetic mechanisms coordinating abiotic and biotic stress responses remain poorly understood. This study identifies (), encodin...Improving multistress resilience in crops is essential for sustainable agriculture, yet the genetic mechanisms coordinating abiotic and biotic stress responses remain poorly understood. This study identifies (), encoding the transcription factor OsWRKY74, as a key pleiotropic regulator that mediates both cold tolerance and blast resistance in rice. Through genome-wide association study, we found that negatively regulates cold tolerance at the seedling stage. The natural allele confers greater cold tolerance than by mildly repressing the expression of , thereby maintaining sterol glycoside homeostasis and membrane stability. Furthermore, during infection, CTS1 activates the expression of and upregulates pathogenesis-related genes, thereby enhancing blast resistance. Our findings reveal a dual-function mechanism of in stress adaptation and provide valuable alleles for breeding multistress resilient rice varieties.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335229
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(Gc) pilin antigenic variation is a diversity-generating system that uses gene conversion to produce numerous PilE protein variants, the major subunit of the Type IV pilus (T4p). Pilin antigenic variation allows the bact...(Gc) pilin antigenic variation is a diversity-generating system that uses gene conversion to produce numerous PilE protein variants, the major subunit of the Type IV pilus (T4p). Pilin antigenic variation allows the bacteria to escape immune surveillance by expressing a variant but functional pilus, and can also alter T4p expression. While pilin antigenic variation requires many conserved homologous recombination and DNA repair factors, the pattern of sequence changes leading to pilin antigenic variants resembles that of an annealing reaction, rather than the expected long recombination tracts usually found in homologous recombination. We demonstrate that two paralogous restriction-modification modules cleave specific, unmodified sequences within the expressed and silent pilin loci and that cleavage is an important process for pilin antigenic variation. Moreover, expression of these restriction activities in a subset of the bacterial population affects the fitness. These findings partially explain the patchwork recombination patterns of pilin antigenic variants and show a unique mechanism for generating diversity.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335228
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Nanoscale geometries can profoundly alter chemical reactivity, yet platforms that isolate and control this regime remain limited primarily to microdroplets. Here, we introduce a simple, surfactant-free method to generate...Nanoscale geometries can profoundly alter chemical reactivity, yet platforms that isolate and control this regime remain limited primarily to microdroplets. Here, we introduce a simple, surfactant-free method to generate a floating oil nanofilm by trapping a gas bubble at the interface between immiscible aqueous and organic phases. This geometry produces a stable, suspended organic film approximately 100 nm thick with a surface-area-to-volume ratio of 10 m, mimicking a droplet with a radius of 300 nm, bounded by closely spaced gas|liquid and liquid|liquid interfaces without a solid substrate. Using electrochemistry combined with finite-element modeling, we quantitatively characterize the nanofilm thickness and show that it enables spontaneous oxidation chemistry that is greatly accelerated compared to bulk systems. Decamethylferrocene undergoes pronounced oxidation within the nanofilm within seconds, in contrast to 10 s of hours required at bulk liquid|liquid interfaces. This behavior is absent under oxygen-free conditions and can be tuned by selective ion transfer across the interface, implicating charge compensation as an important factor in enhanced interfacial chemistry. By accelerating redox processes that are otherwise slow or inaccessible in bulk systems, the floating liquid nanofilm establishes a distinct regime of interfacial reactivity and provides a versatile platform for probing chemical transformations under nanoscale confinement.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335227
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The cell wall peptidoglycan (PG) protects virtually all bacteria from osmotic lysis and specifies cell shape. Synthesis of this exoskeleton is carried out by enzymes that polymerize glycan strands and transpeptidases tha...The cell wall peptidoglycan (PG) protects virtually all bacteria from osmotic lysis and specifies cell shape. Synthesis of this exoskeleton is carried out by enzymes that polymerize glycan strands and transpeptidases that crosslink them into the existing cell wall matrix. In many bacteria, a broadly conserved cell wall synthesis complex known as the Rod complex or elongasome plays an essential role in cell growth. To investigate whether there are undiscovered Rod complex components, we combined high-throughput genetics with AlphaFold-Multimer screens. The two approaches converged on the lipoprotein ClcR (formerly, YerH or CamS). ClcR is broadly conserved among gram-positive bacteria and is predicted to interact with the Rod complex transpeptidases. We find that ClcR contributes to proper cell wall synthesis in and and is essential for proper elongation and cell shape in . We show that ClcR orthologs interact with their cognate transpeptidases and function as positive regulators of Rod complex activity in a distinct pathway from that of the known regulators MreCD. Altogether, our data define a broadly conserved component of the cell wall elongation machinery. As part of this study, we built a webtool to facilitate visualization and analysis of transposon-sequencing datasets. Our findings and accompanying resources provide a framework for uncovering biologically relevant protein-protein interactions that pairs genetic and in silico approaches.
Swaminathan A, Gonzalez DG, Matte-Martone C
… +9 more, Xu F, Simpson D, Moore JL, Lin Z, Rana U, Monedero-Alonso D, Mack JJ, Kam CY, Greco V
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335226
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Ca signaling and its regulation are important for endothelial cell (EC) function and signaling. Yet, the spatiotemporal organization of Ca activity and its regulation across a vascular plexus is poorly understood in an i...Ca signaling and its regulation are important for endothelial cell (EC) function and signaling. Yet, the spatiotemporal organization of Ca activity and its regulation across a vascular plexus is poorly understood in an in vivo mammalian context. To overcome this gap in knowledge, we developed an intravital imaging approach to resolve Ca activity with single-cell resolution in skin vasculature of adult mice via multiphoton microscopy. Here, we tracked thousands of Ca events in the skin capillary plexus during homeostasis and observed signaling heterogeneity between ECs, with just over half displaying Ca activity at any given time. Longitudinal tracking of the same mice revealed that the same capillary ECs maintain Ca activity over days to weeks. Interestingly, activity dynamics, such as frequency and event duration, are not conserved at a single-cell level but are maintained at an EC population level. Molecularly, conditional deletion of the gap junction protein Connexin 43 (Cx43cKO) in ECs leads to a subset of ECs displaying sustained Ca activity, biasing signaling dynamics of the whole network toward chronically persistent activity over time. Sustained capillary Ca activity results in vascular permeability and flow dysregulation. Last, through pharmacological targeting of known agonists/antagonists, we showed that inhibition of L-type Voltage Gated Ca channels non-cell-autonomously restores Ca activity, blood flow, and barrier function in Cx43cKO mice. Collectively, our work provides insight into the spatial and temporal characteristics, extent, and regulation of Ca activity in skin capillaries of live mice.
Alamgir A, Yaneva M, Sela M
… +15 more, Mora-Raimundo P, Kadosh H, Ghosal S, Odeh A, Richtman Y, Fibeesh N, Leichtmann-Bardoogo Y, Sade O, Hasson P, Chien RC, Ashery U, Maoz BM, Schroeder A, DeLisa MP, Alabi CA
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335225
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Antibodies are proteins prized for their ability to bind to extracellular antigens with exceptionally high affinities and specificities. These features have motivated researchers to utilize antibody-antigen binding to in...Antibodies are proteins prized for their ability to bind to extracellular antigens with exceptionally high affinities and specificities. These features have motivated researchers to utilize antibody-antigen binding to inhibit intracellular disease targets in the proteome, yet delivery of antibodies into the cytosol of cells has long been a considerable challenge. Here, we outline the development of a lipid nanoparticle (LNP) platform for delivering antibodies into cells to selectively inhibit disease-relevant cytosolic targets. This approach efficiently delivers various therapeutic antibodies into multiple cancer cell lines, inhibiting key transcription factors in inflammatory and cancer signaling pathways. We further demonstrate systemic delivery of therapeutic antibodies in disease models, including α-synuclein-specific antibodies for Parkinson's disease and RelA-specific Immunoglobulins for acute lung injury using targeted LNP formulations. This work establishes a promising method for using LNPs for the delivery of antibody and antibody-derived therapeutics intracellularly to treat numerous proteome targets.
Okie JG, Brown JH, Kodric-Brown A
… +7 more, Burger JR, Flanagan TP, Fristoe TS, Hammond ST, Mercado-Silva N, Nekola JC, Richter J
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335224
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What socioecological conditions nurture the ingenuity and collaborative interactions underlying transformative technological innovations? We compiled a dataset on more than 400 major technological inventions from 1690 to...What socioecological conditions nurture the ingenuity and collaborative interactions underlying transformative technological innovations? We compiled a dataset on more than 400 major technological inventions from 1690 to 1990 spanning seven categories (agriculture, armaments, information and communication, household, industry, medical, and transportation) and performed inductive macroecological analyses to address how attributes of inventors, teams, and their social and geographic environments contributed to the innovation of new technologies that have changed the way people live. The vast majority of inventions were attributed to single inventors of various ages. The frequency, size, and cultural diversity of teams increased in the 20th Century, as did the proportion of inventions attributed to women and immigrants. A wide variety of environments acted as innovation hubs, including rural areas as well as specialized institutions and large cities. Invention rate (number of inventions per time period) peaked during the 1800s in cities, rural areas, and most categories but continued increasing over time in institutional environments and medical and communication technologies. The overall pattern across ages, genders, team attributes, environments, technological categories, and time periods supports the conclusion that opportunity, ingenuity, and environment all play key roles in the inventiveness phase of the innovation process: creative individuals in particular ecological environments and social settings come up with novel solutions to specific practical problems. Similar innovation patterns have been observed for tool use among nonhuman primates, highlighting unifying processes of innovation. Our macroecological approach offers valuable insights into the emergence and drivers of innovation and material culture.