Rubinić M, Yu Y, Arias-Rojas A
… +8 more, Martinez KA, Klimek W, Frahm D, Brinkmann V, Paczia N, Alagesan K, Duneau D, Iatsenko I
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341050
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Sexual dimorphism in infection outcomes is widespread, yet its underlying mechanisms remain incompletely understood. Utilizing intestinal infection in we demonstrate that sex differences in intestinal redox processes c...Sexual dimorphism in infection outcomes is widespread, yet its underlying mechanisms remain incompletely understood. Utilizing intestinal infection in we demonstrate that sex differences in intestinal redox processes contribute to female-biased susceptibility to infection. Female inability to overcome pathogen-induced oxidative stress results in defecation blockage, pathogen persistence, and host death. Male flies exhibit increased carbohydrate metabolism and pentose phosphate pathway activity-a key antioxidant defense system. This allows males to withstand oxidative stress-induced defecation blockage and clear the pathogen from the intestine, resulting in survival. Notably, we uncovered that Duox-dependent processes contribute to pathology independently of total ROS levels. In parallel, showed increased expression of several virulence factors, including RNA-binding protein Hfq, in the female gut, contributing to female-biased virulence of . Thus, the effect of the gut metabolic environment on host defenses and pathogen virulence determines the sex differences in intestinal infection outcomes.
Zelderen APAV, Masters-Waage TC, Affinito SJ
… +38 more, Bekbergenova A, Cowan K, Hartmann T, Hausfeld MM, Jolink A, Korbel JJ, Lynn T, Renier L, Singh DP, Wu S, Banakou D, Bayro A, Bosse T, Derous E, Draschkow D, Ferguson KA, Fritz T, Gomez-Zara D, Hauser C, He VF, Howe LC, Jain D, Kinias Z, Lukic YX, Menges JI, Mortezapour A, Nagaraj A, Park CH, Persky S, Remund M, Sanchez DR, Schellaert M, Streuber S, Viganò E, Villano M, Vleugels W, Zank M, Hubbard TD
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341049
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By immersing participants in consistent virtual environments, VR enhances study realism, reduces confounding variables, and improves procedural control, offering a promising solution for scientists interested in studying...By immersing participants in consistent virtual environments, VR enhances study realism, reduces confounding variables, and improves procedural control, offering a promising solution for scientists interested in studying behavior "in the wild." The availability and documentation of data enabled by VR also help address replicability challenges. Despite vast potential, VR research is hindered by fragmentation, proprietary tools, and a lack of standardized practices, which limit its overall impact. This collaborative study presents an interactive checklist to support VR research from across disciplines to meet three essential protocols-interoperability, procedural standardization, and data sharing-that address these challenges by promoting open science and providing a common, easy-to-evaluate format for researchers to present projects to ethics boards, reviewers, and beyond. Together, these protocols can help VR research overcome replication barriers, democratize access to advanced tools, and establish VR as a robust method for rigorous, replicable scientific inquiry.
Hao Y, Yuan X, Xi X
… +3 more, Zeng Z, Forzieri G, Wu P
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341048
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It is generally believed that CO physiological forcing can partially mitigate land surface drying under global warming by reducing stomatal conductance and evapotranspiration. Most of this type of study focuses on the di...It is generally believed that CO physiological forcing can partially mitigate land surface drying under global warming by reducing stomatal conductance and evapotranspiration. Most of this type of study focuses on the direct regulation by vegetation physiology, overlooking interactive feedback from the atmosphere. Using fully coupled earth system model simulations, we find that the physiological benefit may have been optimistically overestimated. Vegetation-induced energy change may in turn further affect atmospheric vapor pressure deficit (VPD), exerting extra evapotranspiration demand indirectly. Indirect VPD feedback over northern mid-high latitudes could offset 54% (±26%) of evapotranspiration reduction driven by stomatal closure under current CO condition, and that proportion increases to 68% (±18%) at 4 × CO. The enhanced VPD feedback is largely driven by vegetation-mediated albedo decline and temperature rise in northern mid-high latitudes, which intensifies evapotranspiration loss as stomatal constraints are minimal. These are important findings, substantially limiting the physiological benefits of CO with extra pressure on surface aridification and water resources.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341047
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The process by which neocortical neurons and circuits amplify their response to an unexpected change in stimulus, typically referred to as deviance detection (DD), has traditionally been thought to be the product of spec...The process by which neocortical neurons and circuits amplify their response to an unexpected change in stimulus, typically referred to as deviance detection (DD), has traditionally been thought to be the product of specialized cell types and/or routing from distinct brain areas. Here, we explore a different theory, whereby DD emerges intrinsically from local network-level interactions driven by a deviant increase or decrease in exogenous input to a neocortical column. We propose that deviance-driven neural dynamics are generated by ensembles of excitatory and inhibitory neurons that have a fundamental inhibitory connectivity motif: competitive inhibition between reciprocally connected neural representations under modulation from feed-forward selective (dis)inhibition. Implementing this motif in two computational models with different levels of biophysical abstraction, we were able to simulate a variety of phenomena pertaining to the experimentally observed shifts in neural tuning during DD across neurons, time, and stimulus history. We further tested hypotheses related to our theory and examined the robustness of emergent phenomena consistent with prior experimental observations. Our results show that ensemble priming via competitive inhibition under modulation from selective (dis)inhibition can serve as a local mechanism for encoding short-term stimulus memory, enabling deviance-driven shifts in stimulus representation. This work establishes a theoretical paradigm that resolves previously confounding aspects of predictive sensory processing in Neocortex, and we provide a number of corollary predictions that can be tested in future in vivo studies.
de Celis JF, Baena-López LA, Baonza A
… +1 more, Extavour C
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341046
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Antonio García-Bellido was a pioneer of developmental biology in Spain who had the rare ability to see beyond the trees and grasp not just the forest, but entire landscapes. Intellectually and personally, he was indefati...Antonio García-Bellido was a pioneer of developmental biology in Spain who had the rare ability to see beyond the trees and grasp not just the forest, but entire landscapes. Intellectually and personally, he was indefatigable, uncompromising, and wholly committed to science. He led his trainees by example in his unflagging demands on honoring the data above all else. Antonio discovered the existence of "developmental compartments" in the wing of and proposed that these territories corresponded to the realm of action of homeotic genes. He was a fierce defender of hypotheses that he thought best explained available data but did not cling blindly to ideas when they no longer served to understand the phenomena at hand. With his distinctive style he founded a successful school of developmental geneticists that will sorely miss his unparalleled passion for science.
Jaber Y, Raviv A, Nassar M
… +7 more, Jaber NS, Yacoub S, Netanely-Rimon Y, Naamneh R, Tabib Y, Wilensky A, Hovav AH
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341044
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Barrier tissues with stratified epithelia rely on Langerhans cells (LCs) to maintain immune surveillance. While TAM signaling regulates skin LC homeostasis, its role in mucosal LC development remains unclear. Here, we id...Barrier tissues with stratified epithelia rely on Langerhans cells (LCs) to maintain immune surveillance. While TAM signaling regulates skin LC homeostasis, its role in mucosal LC development remains unclear. Here, we identify the TAM ligand GAS6 as a central regulator of oral mucosal LC biology. GAS6 preserves epithelial integrity and restrains local inflammation, while fine-tuning LC abundance by controlling their retention within the tissue. At the precursor level, GAS6 facilitates the proliferation and differentiation of predendritic cells (pre-DCs), particularly pre-DC1. Moreover, GAS6 preferentially supports AXL pre-DC-derived LCs, without affecting AXLMERTK monocyte-derived LCs, leading to a greater contribution of monocytes to the mucosal LC pool. Together, these findings identify GAS6 as a dual-level orchestrator of mucosal LC development and homeostasis.
Kim T, Biswas A, Kandel S
… +3 more, Kuroda M, Halfmann PJ, Kawaoka Y
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341043
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The genomic flexibility of orthocoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is showcased by the presence of accessory genes, which vary in number among virus species and strains...The genomic flexibility of orthocoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is showcased by the presence of accessory genes, which vary in number among virus species and strains. Given this flexibility, the viral coding capacity can be artificially expanded to express a heterologous gene from the viral genome, thereby enabling the development of a viral vector platform. Here, we systematically explored the extra gene coding capacity of SARS-CoV-2 by inserting an extra reporter gene at every intergenic region in its genome. We revealed the entire scheme of its extra gene expression and identified a genomic location that stably expresses reporter genes while maintaining the wild-type viral phenotype. Using this construct, we developed a set of fluorescent and luminescent reporter SARS-CoV-2 viruses available for in vivo flow cytometry and in vitro antiviral screening. Flow cytometric analysis with these reporter viruses revealed cell type-specific dynamics of SARS-CoV-2 infection in the lung tissue of K18-hACE2 mice. Our findings offer a platform for SARS-CoV-2 genome engineering, providing a set of reporter viruses for research applications.
Li G, Li Q, Zhang J
… +8 more, Huang Y, Tao W, Cheng Y, Sun J, Yuan J, Zhang R, Liu XM, Zhou J
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341042
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The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving depletion-caused cancer regression by s...The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving depletion-caused cancer regression by sustaining mitochondrial respiration. The methyltransferase METTL5 is upregulated in non-small cell lung cancer (NSCLC) and associated with advanced tumor grade and poor prognosis. Depletion of impairs NSCLC cell proliferation and migration in vitro and in vivo, with p53-null cells displaying enhanced sensitivity. While -depletion inhibits cytoplasmic translation in both p53-WT and p53-null cells, only cells lacking p53 exhibit severe tumor regression due to defective mitochondrial protein synthesis and consequent respiratory dysfunction. Mechanistically, p53 binds 5'UTR of , the crucial gatekeeper of mitochondrial protein import, to enforce its exclusion from translation. loss promotes p53 nuclear retention via inhibiting MDM2-mediated p53 ubiquitination, alleviating its translational suppression of , and supporting oxidative phosphorylation. Remarkably, the combination targeting of and synergistically attenuates the proliferation and migration in p53-WT cancer cells. Our study elucidates the essential role of p53 in supporting tumor viability upon deficiency by maintaining mitochondrial respiration. Meanwhile, it provides a molecular foundation for developing therapeutic strategies regarding cancers with WT p53.
Liu D, Li Y, Huang S
… +7 more, Xu Y, Sun L, Li W, O'Kane CJ, Rubinsztein DC, Lu B, Li S
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341041
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments...Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.
Synowiec A, Lie LK, Owczarek K
… +21 more, Johannesson N, Mickiewicz N, Chen HC, Szczepański A, Strine MS, Filler RB, Borowiec M, Pietrusiński M, Dróżdż I, Robaszkiewicz A, Bochenek M, Zilbauer M, Rymarowicz J, Pędziwiatr M, Konnikova L, Wilen CB, Pajkrt D, Wolthers KC, Calitz C, Sridhar A, Pyrc K
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341040
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Human coronaviruses have been primarily associated with upper respiratory tract infections, yet cases of gastrointestinal symptoms in COVID-19 patients have highlighted their potential to cause systemic disease. Here, we...Human coronaviruses have been primarily associated with upper respiratory tract infections, yet cases of gastrointestinal symptoms in COVID-19 patients have highlighted their potential to cause systemic disease. Here, we detail the infection of intestinal epithelia by an endemic, low-pathogenic human coronavirus, human alphacoronavirus 229E, using patient-derived human intestinal enteroids (HIEs) from donors of various ages. Using fetal, pediatric, and adult HIEs, we investigated how physiologically relevant temperatures: 37 °C and 32 °C, reflecting gastrointestinal and upper-airway conditions, respectively, modulate epithelial responses and viral infection dynamics. We show that there is temperature-dependent transcriptional reprogramming, indicating strong temperature-dependent regulation of virus replication and epithelial responses. Among the seasonal coronaviruses tested, only HCoV-229E productively infects HIEs. At 32 °C, HCoV-229E replicates efficiently in enteroids from all donor ages and releases high titers of infectious progeny. In contrast, at 37 °C, productive replication is largely confined to fetal and a subset of pediatric tissues, revealing a developmental and temperature-sensitive restriction on infection. Confocal and flow cytometry analyses identify enterocytes as the primary target cells for HCoV-229E. Furthermore, we show that camostat, a serine protease inhibitor, significantly reduces HCoV-229E replication in HIEs, confirming a critical role for host serine protease activity. Collectively, these findings establish HIEs as a relevant model for HCoV-229E-host interactions and reveal temperature- and age-dependent determinants governing intestinal permissiveness to this seasonal coronavirus.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341039
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Cell migration through spatially confined microenvironments occurs in many biological processes such as embryonic development, immune surveillance, and cancer metastasis. A major bottleneck during such migration is the n...Cell migration through spatially confined microenvironments occurs in many biological processes such as embryonic development, immune surveillance, and cancer metastasis. A major bottleneck during such migration is the nucleus, which acts not only as a rigid mechanical obstacle but also as a crucial mechanosensor that modulates downstream signaling pathways. However, it remains poorly understood how nuclear deformation and mechanosensation together regulate cell migration through confined spaces. Here, we propose a three-dimensional (3D) mechanochemical model of confined nuclear translocation that integrates nuclear deformation with deformation-induced calcium signaling and subsequent regulation of cytoskeletal contractility. We show that cells undergo adaptive nuclear deformation, including nuclear envelope elongation and 3D buckling, to efficiently navigate confinements of varying sizes. There exists a biphasic relation between nuclear velocity and confinement size, arising from the interplay between nuclear deformability and mechanosensitive feedback. We demonstrate that local nuclear envelope rupture can occur under large deformation, enabling nuclear translocation through extreme confinements, as observed in prior experiments. Furthermore, we elucidate the critical roles of chromatin organization in nuclear translocation. This work reveals key mechanochemical mechanisms driving confined cell migration and provides a theoretical framework for studying nuclear dynamics across physiological and pathological contexts.
Duan Z, Duan W, Zhang Z
… +14 more, Li K, Wang S, Yang J, Xiao B, Zhang T, Ma J, Li B, Wang P, Cao Y, Galbraith DW, Hetherington AM, Xing J, Guo S, Song CP
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341038
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Asymmetric cell division underpins cellular diversity in multicellular plants. These divisions are mechanosensitive, and preprophase band (PPB) formation hinges on cell-wall mechanical properties in plant cells. Yet, the...Asymmetric cell division underpins cellular diversity in multicellular plants. These divisions are mechanosensitive, and preprophase band (PPB) formation hinges on cell-wall mechanical properties in plant cells. Yet, the spatial control mechanism governing this process in plants remains elusive. During grass stomatal development, mechanical cues originate from differential growth rates and cell wall modifications at the interface of guard mother cell/subsidiary mother cell (SMC). In this work, we have identified a maize receptor-like protein, KAI1, that functions as a master regulator of subsidiary cell formation within the stomatal complex. KAI1 governs division-plane orientation in SMCs through mechanochemical signaling: It perceives cell wall rigidity via pectin interaction, and subsequently recruits tubulin for PPB positioning, thereby directing division-plane specification. This work uncovers a plant-unique mechanosensitive protein that mediates extracellular matrix cues to cytoskeletal reorganization during asymmetric division for cell diversity. Our findings establish that KAI1 governs a cell wall mechanics-dependent PPB positioning to control the exact division plane alignment of the SMC. This mechanism subsequently mediates the regulation of SMC polarization and subsidiary cell morphogenesis during stomatal development.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341037
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John P. Smol has spent more than four decades demonstrating how lake sediment cores can reveal environmental changes spanning decades to centuries. His pioneering work established paleolimnology as a credible scientific...John P. Smol has spent more than four decades demonstrating how lake sediment cores can reveal environmental changes spanning decades to centuries. His pioneering work established paleolimnology as a credible scientific discipline, first, by documenting the impact of acid rain on North American lakes in the 1980s and, later, by tracking Arctic climate warming. Through continuous monitoring of High Arctic ponds and lakes, Smol has shown how ice cover duration influences aquatic ecosystems. His recent research reveals that even the deepest Arctic lakes are now crossing ecological thresholds due to accelerated warming, with implications for Indigenous fisheries and northern communities.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42341036
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Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond cli...Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond clinical and cultural frameworks, their ecological origins and evolutionary trajectories may help explain why such potent modulators of perception, emotion, and cognition persist in nature. Here, integrating chemical ecology, comparative genomics, biosynthetic logic, and evolutionary biology, we propose that these molecules may function as defensive agents or symbiosis-associated manipulators of herbivore and pollinator behavior. A "building-block" biosynthetic logic links primary metabolism to convergent psychotropic scaffolds via a recurrent set of tailoring reactions, including decarboxylations and methylations. Recent advances illuminate mescaline biosynthesis in cacti, horizontal gene transfer of psilocybin clusters in fungi, and symbiont-derived alkaloids in grasses. We also assess the debate surrounding endogenous mammalian tryptamines, arguing that the leading hypothesis points toward sigma-1 receptor-mediated cytoprotection and stress responses, supported by convergent pharmacological and cellular evidence, rather than inherent hallucinogenic functions. Across kingdoms, natural hallucinogens appear to converge on conserved neural targets, including serotonergic and other neuromodulatory systems that are shared across phyla. From this perspective, human psychoactivity is likely an evolutionary by-product of molecules selected for ecological interactions with animals possessing deeply conserved receptor architectures. Framing hallucinogens through chemical ecology not only clarifies their origins but also highlights translational opportunities in target discovery, pathway engineering, and sustainable production, while emphasizing the need to integrate conservation, ethical sourcing, and benefit-sharing into the current hallucinogenic renaissance.
Zhang Y, Wang H, Liu Y
… +14 more, Qin Z, He Y, Wang HL, Huang X, Li J, Xie S, Huang S, Huang Z, Cheng X, Hu Z, Wu J, Yan B, Ma R, Fan XY
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335242
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Upon activation, macrophages generate substantial levels of reactive nitrogen species, which can induce alkylating damage in the DNA of intracellular () and thereby restrict bacterial replication. However, the molecular...Upon activation, macrophages generate substantial levels of reactive nitrogen species, which can induce alkylating damage in the DNA of intracellular () and thereby restrict bacterial replication. However, the molecular mechanisms by which repairs such DNA lesions remain poorly understood. Here, we identified genes required for survival in distinct macrophage subsets using transposon insertion sequencing. Among these, displayed a specialized role in survival in M1-polarized macrophages, as well as in mice at 4 wk postinfection, a stage when macrophages are biased toward an M1-polarized state. Mechanistically, TagA conferred resistance to the DNA alkylating agent methyl methanesulfonate through its 3-methyladenine (3-MA) excision activity with Glu48 serving as a key catalytic residue for substrate binding. Critically, TagA was found to protect the genome from alkylation damage caused by nitrosative stress-a hallmark of the M1-polarized macrophage microenvironment. Furthermore, pharmacological inhibition of inducible nitric oxide synthase (iNOS) with S-methylisothiourea sulfate in mice or genetic deletion of in zebrafish markedly rescued the survival defect of Δ. Together, these findings reveal a previously unappreciated mechanism by which the DNA repair enzyme TagA protects against 3-MA DNA damage under nitrosative stress, thereby promoting bacterial survival in M1-polarized macrophages and during in vivo infection.
Habault J, Salomao N, Wang L
… +16 more, Malbert-Colas L, Daskalogianni C, Vadivel Gnanasundram S, Dongre M, Spagnardi M, Martinkova L, Chen S, Hernychová L, Robidas L, Kucera J, Bonczek O, Öhlund D, Garabedian MJ, Logan SK, Vojtesek B, Fahraeus R
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335241
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The p53 tumor suppressor and the c-Myc oncogene are among the most frequently deregulated genes in human cancers, yet the molecular cross talk between these pathways remains poorly understood. MDM2 is a key negative regu...The p53 tumor suppressor and the c-Myc oncogene are among the most frequently deregulated genes in human cancers, yet the molecular cross talk between these pathways remains poorly understood. MDM2 is a key negative regulator of p53 and a target for emerging cancer therapies designed to activate p53. Likewise, targeting c-Myc is a long-standing but challenging goal in cancer therapy. Here, we report that the small MDM2-binding drug Milademetan promotes an interaction between MDM2 and the 5' untranslated region of the mRNA, causing a suppression of mRNA translation without affecting c-Myc RNA levels. The interaction also occurs under nonproliferative conditions in the absence of drug. Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status. These findings reveal an unexpected mechanism by which MDM2 coordinates two of the most frequently altered pathways in cancer and provide a rationale for targeting c-Myc-driven tumors, including those lacking functional p53, through MDM2 modulators.
Barrodia P, Saw AK, Jeter-Jones SL
… +8 more, Chang CC, Shao J, Arslan E, Singh AK, Satpati S, Jenq RR, Rai K, Piwnica-Worms H
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335240
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Fasting enhances small intestinal regeneration after radiation, but the contribution of the gut microbiome to this process remains uncharacterized. We identify () as a key mediator of this response. was enriched in fas...Fasting enhances small intestinal regeneration after radiation, but the contribution of the gut microbiome to this process remains uncharacterized. We identify () as a key mediator of this response. was enriched in fasted mice and its antibiotic depletion abrogated radioprotection, whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with 's metabolic output. -conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced -dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of primed persister cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including , , These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister cells for rapid regeneration of the intestinal epithelium following radiation-induced injury.
Stefanski KM, Li GC, Luu DD
… +12 more, Fosu KK, Guadarrama E, Hutchison JM, Saksena N, Zuy Y, Fisch AJ, Hasaka TP, Bauer JA, George AL, Kenworthy AK, Horn WDV, Sanders CR
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335239
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Membrane order and fluidity influence many biological processes. However, tools to manipulate membranes under physiological conditions have been limited. In the process of high-throughput screening for molecules that shi...Membrane order and fluidity influence many biological processes. However, tools to manipulate membranes under physiological conditions have been limited. In the process of high-throughput screening for molecules that shift the phase partitioning between ordered and disordered membrane phases of the tetraspan membrane protein peripheral myelin protein 22 (PMP22), we identified two chemically similar compounds, VU0615562 and VU0619195, that shift PMP22 toward the disordered phase and destabilize the "lipid raft"-like ordered phase. Follow-up experiments showed that this latter activity is, counterintuitively, enhanced by the presence of PMP22, which normally stabilizes the ordered phase. Biophysical studies indicate that these compounds reduce raft stability through a mechanism that involves both direct interactions with proteins and the disruption of lipid packing. We further observed that acute treatment of live cells with VU0619195 modulated membrane fluidity and TRPM8 channel function while both compounds altered KCNQ1 channel activity, providing examples of practical applications for these compounds. These protein-enhanced raft modulators reveal distinct lipid and protein-based forces that destabilize membrane order and may be useful as pharmacological tools for manipulating and probing the biological roles of ordered membrane domains in cells.
Proc Natl Acad Sci U S A
· 2026 Jun · PMID 42335238
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The rapid global spread of antimicrobial resistance via β-lactamase (bla) demands targeted strategies that selectively eliminate resistant pathogens without exacerbating resistance. Herein, we report , a photosensitizer...The rapid global spread of antimicrobial resistance via β-lactamase (bla) demands targeted strategies that selectively eliminate resistant pathogens without exacerbating resistance. Herein, we report , a photosensitizer (PS) that enables bla-selective activation and-more importantly-covalent retention and accumulation within resistant bacteria, allowing potent photodynamic eradication of bla-expressing pathogens and exerting counter-selection pressure. adopts an enzyme-triggered "one-to-multi" design: Upon bla hydrolysis, it undergoes a hydrophilic-to-hydrophobic and low-to-high permeability transition, facilitating uptake and generating a reactive quinone methide intermediate that covalently binds intracellular proteins, leading to >2,000-fold accumulation within resistant bacteria, thiol depletion and light-triggered reactive oxygen species generation. In vitro, demonstrated bla-specific activation, selective enrichment in bla-expressing MRSA, and potent photodynamic killing (>99.999% reduction), outperforming the corresponding uncaged photosensitizer. Crucially, it selectively eradicates bla-producing MRSA within mixed populations, exerting counter-selection pressure against resistant strains. The PS also activates and accumulates in bla-expressing Gram-negative , albeit with reduced killing efficiency compared to Gram-positive bacteria. In vivo, it exhibited prolonged retention at infection sites and targeted imaging capability in murine myositis and abscess models. Notably, -mediated photodynamic therapy effectively cleared MRSA infections across multiple models-including thigh infection, wound, and biofilm-associated infections-achieving >5-log reduction in bacterial load and surpassing vancomycin in efficacy. This work presents a targeted antimicrobial platform that exploits bacterial resistance mechanisms to achieve species-specific eradication, offering a promising strategy to combat multidrug-resistant infections and alleviate the selection pressure that drives the enrichment of resistant strains.