PLOS Biology: New Articles

The carbohydrate utilization regulator Cbr1 coordinates nutrient-specific gene activation with selective carbon catabolite repression in a basidiomycete yeast

2026-09-01T14:00:00Z

by Brandon Reyes-Chavez, Joshua D. Kerkaert, Lori B. Huberman

Cells must sense and respond to nutrients to survive. To efficiently grow in mixed carbon environments, microbes repress genes necessary to utilize carbon sources that require substantial resources to catabolize when a simpler carbon source, such as glucose, is present. This process is known as carbon catabolite repression. Canonically, in fungi, nutrient sensing transcriptional networks are composed of carbon source-specific transcription factors that activate carbon source utilization genes and carbon catabolite repression regulators, which broadly repress all nonpreferred carbon source utilization genes when a preferred carbohydrate is present. In contrast to this model, we identified a transcription factor (Cbr1) in the basidiomycete yeast Rhodotorula (Rhodosporidium) toruloides that specifically inhibits glucose-mediated repression of disaccharide and proline utilization, presenting a mechanism of tailored carbon catabolite repression regulation that combats a negative feedback loop formed when glucose is released during disaccharide utilization. Cbr1 is also required for cellobiose, gentiobiose, carboxylic acid, and fucose utilization. Using transcriptomic and molecular analyses, we demonstrated that catabolism of these carbon sources is not metabolically linked, but genes necessary for their utilization are coactivated by Cbr1 in response to each of the carbon sources. This coactivation suggests R. toruloides may encounter these carbon sources together, potentially during complex interactions among microbes in nature. Coregulation of nutrient-specific gene activation and carbon catabolite repression by a transcription factor establishes a previously uncharacterized mechanism for building nutrient sensing transcriptional networks in fungi. Characterizing diverse nutrient sensing regulatory mechanisms is critical for understanding resource acquisition during fungal pathogenesis, where carbon catabolite repression is important for virulence and drug tolerance, and metabolically engineering fungi for green biotechnology.

Impaired midfrontal‑motor theta phase synchronization characterizes maladaptive motivational behavior in people with obsessive‑compulsive disorder

2026-09-01T14:00:00Z

by Yu Pang, Dongsheng Zhou, Ziwen Peng, Wanting Liu, Ruojie Huang, Carol A. Seger, Qi Chen

Obsessive‑compulsive disorder (OCD) is characterized by an insight‑action dissociation, in which people with OCD recognize that their behavior is irrational but still struggle to inhibit habitual responses. This dissociation may be related to abnormally strong motivational biases, reflected in excessive tendencies to approach reward and avoid punishment. We employed a motivational Go/NoGo learning task, combined with computational modeling and electroencephalography (EEG), to investigate how 36 people with OCD and 37 healthy controls (HC) regulate maladaptive biases during motivated action. People with OCD showed stronger Pavlovian bias and lower learning rates. Similar to HC, people with OCD also showed increased midfrontal theta power related to conflict detection and to the generation of a control demand to increase the weighting of instrumental action values during choice, suggesting that they were able to detect the mismatch between their behavior and task goals. However, in OCD, conflict‑related theta enhancement overlapped with the response window, indicating that control signals emerged or arrived too late to effectively influence choice. Midfrontal‑motor theta phase synchrony provided the strongest model evidence for the modulation of maladaptive biases in OCD, yet this pathway showed no significant conflict‑related enhancement and failed to effectively modulate motivational biases under conflict. Taken together, these findings suggest a neural mechanism underlying the insight‑action dissociation in OCD and identify midfrontal‑motor theta phase synchrony as a potential treatment target.

Outbreaks of fluconazole-resistant Candida parapsilosis are driven by low-biofilm-producing isolates that emerge under host selection

2026-09-01T14:00:00Z

by Farnaz Daneshnia, Deepika Gunasekaran, Sean Bergin, Lisa Lombardi, Austin M. Perry, Liuyang Cai, Louise A. Walker, Tibor Nemeth, Süleyha Hilmioglu-Polat, Letal I. Salzberg, Arefeh Ebadati, Tobias Köhler, Gabriel Braune, João N. de Almeida, Giuseppina Caggiano, Julianne V. Kus, Pegah Mosharaf Ghahfarokhy, Julieta Munoz, Daniel J. Floyd, Diego Fuentes-Palacios, Samuel M. Gonçalves, Relber A. Gonçales, Mostafa Salehi, Jigar V. Desai, Agostinho Carvalho, Shenglin Mei, Carol A. Munro, Alex Hopke, Toni Gabaldón, Attila Gacser, Oliver Kurzai, Geraldine Butler, David S. Perlin, Wenjie Fang, Clarissa J. Nobile, Michael K. Mansour, Amir Arastehfar

Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by fluconazole-resistant (FLCR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbial traits enabling persistence of these outbreak lineages remain poorly defined. Here, we show that FLCR-Cp isolates responsible for prolonged, multi-country outbreaks consistently exhibit a striking low-biofilm-producing (LBP) phenotype. Contrary to the prevailing view that robust biofilm formation promotes persistence, LBP strains displayed enhanced stress tolerance, increased cell wall masking, and reduced immune recognition. These traits conferred resistance to neutrophil and macrophage killing and enhanced survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains. Whole-genome sequencing (WGS) of a global isolate collection further demonstrated that the LBP phenotype has emerged independently multiple times, supporting convergent evolution under host selection. Functional genomic analyses suggest that biofilm attenuation arises through multigenic changes, and disruption of key biofilm-associated transcriptional regulators enhanced fitness during immune interactions. Together, our findings overturn the assumption that robust biofilm formation drives outbreak persistence and instead identify biofilm attenuation as an adaptive tradeoff that promotes immune evasion and long-term survival. These results redefine our understanding of C. parapsilosis adaptation during healthcare-associated outbreaks and shift attention toward host-driven evolutionary processes than environmental persistence alone.

The 100 Diatom Genomes Project

2026-09-01T14:00:00Z

by Thomas Mock, Gust Bilcke, Eliott Flaum, Shunan Fu, Lilian Hoch, Kevin Moog, Nadine Rijsdijk, Elizabeth C. Ruck, Ian W. Bishop, Carole Duchene, Reuben Gilbertson, Amanda Hopes, Christopher Johns, Francesco Manfellotto, Wade R. Roberts, Nigel Belshaw, Udita Chandola, Peter Chaerle, Olga Chepurnova, Daan Deleu, Sofie D’hondt, Federica Di Costanzo, Omaya Dudin, Serena Flori, Trupti Gaikwad, Agnes Groisillier, Andrea Hall, Pengyu Ji, Louis J. Lavier-Aydat, William H. Lewis, Samuel Menicot, Eveline Pinseel, Eléonore Pottier, Krisztina Sarkozi, Arianna Smerilli, Jan Strauss, Sander Thierens, Andrew Toseland, Yousef Touhami, Robert Utting, Michiel Van Bel, Cock van Oosterhout, Yue Wu, Feng Yang, Erika Allhusen, John J. Bolton, Chris Bowler, Thorsten Brinkhoff, Anja Poehlein, Tim Brovarone, Nansheng Chen, Greg Clark, Matthew D. Clark, Dario Copetti, Zongmei Cui, Beini Deng, Jianbo Jian, Uwe John, Anne D. Jungblut, JiHeon Kang, Jon Bent Kristoffersen, JunMo Lee, Shuya Liu, David G. Mann, Linda Medlin, Vincent Moulton, Jelena Radojicic, Shinya Sato, Rosa Trobajo, Klara Wolf, Norico Yamada, Naihao Ye, Libin Zhang, Yunyun Zhuang, Gautam Dey, Valeria Di Dato, Katherine Helliwell, Marianne Jaubert, Peter G. Kroth, Marina Montresor, Giovanna Romano, Tatiana A. Rynearson, Jayson Talag, Klaus U. Valentin, Flora Vincent, Ross F. Waller, Glen Wheeler, Andrew J. Alverson, Kerrie Barry, LoriBeth Boston, Angela Falciatore, Maria Immacolata Ferrante, Jie Guo, Jane Grimwood, Richard Hayes, Andrei Herdean, Jerry Jenkins, Min Kim, Wiebe HCF Kooistra, Alan Kuo, Anna Lipzen, Nicole Poulsen, Jeremy Schmutz, Leïla Tirichine, Klaas Vandepoele, Frédéric Verret, Wim Vyverman, Igor V. Grigoriev

One hundred diatom species have been selected for genome and transcriptome sequencing. The 100 Diatom Genomes Project aims to provide a scalable framework for understanding diatom biodiversity, ecology and evolution, and for investigating their use in biotechnology. This Community Page presents the 100 Diatom Genomes Project, which aims to sequence the genomes and transcriptomes of 100 diatom species across major lineages, life forms and ecological strategies. This resource will provide a scalable framework for understanding diatom biodiversity, ecology and evolution, and for investigating their use in biotechnology.

Arousal-driven critical roaming reproduces human functional connectivity dynamics

2026-09-01T14:00:00Z

by Anagh Pathak, Demian Battaglia

Ongoing brain activity displays rich temporal variability associated with efficient cognition, with functional connectivity (FC) continually reconfiguring over time. The resulting functional connectivity dynamics (FCD) specifically show complex, fat-tailed statistics that alternate between persistent epochs and faster reconfiguration transients. While nonlinear whole-brain models tuned nearby a critical point have reproduced some aspects of FCD, they fall short of capturing its full temporal complexity. We propose that slow fluctuations in arousal offer a biologically plausible mechanism for exploring critical regimes in large-scale brain dynamics and thus enrich FCD. Using a connectome-based model of coupled cortical populations, we identified phase boundaries where system dynamics transition between regimes of faster or slower FCD. We then phenomenologically incorporated arousal changes, modeling them as stochastic fluctuations in key parameters such as cortical excitability, input gain, and noise amplitude. This explicitly time-dependent formulation enables the system to roam dynamically across regime boundaries, flexibly tuning its distance from critical transition lines and producing intermittent transitions that mirror the stochastic evolution observed in empirical FCD. Fitting these models to human resting-state fMRI and performing model comparison, we find that arousal-driven models more accurately reproduce the distinctive quantitative features of FCD, with the greatest improvements coming from the previously poorly accounted fat-tailed portions of the distributions. Together, these results suggest that arousal fluctuations—likely mediated by changes in neuromodulatory tone—shape the brain’s attractor landscape over time, expanding the repertoire of accessible functional network states and providing a mechanistic basis for the complexity of spontaneous functional dynamics.

Small serine recombinases are markers for antiphage defense system discovery

2026-08-31T14:00:00Z

by Shelby E. Andersen, Joshua M. Kirsch, Navtej Singh, Stephen R. Garrett, John C. Whitney, Jay R. Hesselberth, Breck A. Duerkop

Renewed interest in phage therapy has highlighted a need to understand how bacteria subvert phage infection through antiphage defense systems. Traditionally, strategies to identify antiphage defense systems lack throughput or have limitations for bacterial species where antiphage defense systems are understudied. Herein, we developed a bioinformatic pipeline that uses a small serine recombinase to identify known and unknown antiphage defense systems. Using this approach to query reference genomes and metagenomes, we show that small serine recombinase genes are genetically linked to antiphage defense systems and serve as bait for finding these systems across diverse bacterial phyla. Using co-transcription predictions and statistical analysis of protein domain abundances, we experimentally validated our bioinformatic approach by discovering that KAP P-loop NTPases are fused to putative antiphage domains and reinforce prokaryotic Schlafen proteins as a new class of antiphage defense. Our work shows that small serine recombinases are a reliable genetic marker for the discovery of antiphage defenses across diverse bacterial phyla.

Correction: Animal acoustic communication has a conserved optimal rhythm within the neural delta range

2026-08-31T14:00:00Z

by Theophane Piette, Chundra Cathcart, Chiara Barbieri, Keesha Martin Ming, Didier Grandjean, Balthasar Bickel, Eloïse Déaux, Anne-Lise Giraud

Visual motion does not bias gravity-referenced vestibular coding in the primate cerebellar nodulus and uvula

2026-08-31T14:00:00Z

by Lex J. Gómez, Robyn L. Mildren, Faisal Karmali, Kathleen E. Cullen

Visual motion is known to influence perceptions of tilt, verticality, and translation, suggesting that optic flow is combined with vestibular cues to estimate orientation relative to gravity. The cerebellar nodulus and ventral uvula (NU) are a prime candidate to perform this computation because this region uniquely receives convergent semicircular canal, otolith, and proprioceptive inputs, and in non-primate species full-field visual motion robustly modulates NU activity. Here, we tested whether visual roll motion, known to bias perceived orientation relative to gravity, alters the internal gravity-referenced transformation used by NU neurons to encode vestibular self-motion. To test this, we recorded single-unit activity from NU Purkinje cells in rhesus macaques during whole-body translations in darkness, either without visual stimulation or after prolonged full-field optokinetic roll motion. We hypothesized that visual motion simulating head tilt would bias the NU’s internal gravity estimate, leading to altered translation-evoked responses. Contrary to this prediction, visual motion had no effect on either baseline firing rates or vestibular responses. Moreover, a computational model predicting visually induced shifts in neural tuning was not supported by the data. These results show that visual roll motion, although known to influence perceived orientation, does not bias gravity-referenced vestibular coding in the primate NU. This specialization may preserve a fast, body-anchored gravity estimate for postural and reflexive motor control, delegating visual–vestibular integration for perception to downstream circuits.

Basic research into Women’s Health should be a priority for all

2026-08-28T14:00:00Z

by Joanna Clarke, on behalf of the PLOS Biology Staff Editors

Despite recent progress in clinical research into Women’s Health, basic research is still lagging behind. Until we understand the fundamental physiology of women across the life span, we cannot expect to bring about meaningful change. Despite recent progress in clinical research into Women’s Health, basic research is still lagging behind. This Editorial calls for a renewed focus on basic physiology research into both sexes to close the gap.

Structural insights into the outer membrane proteins PorA, OMP50 and Cj0034c from native Campylobacter jejuni membranes

2026-08-28T14:00:00Z

by Zhemin Zhang, William D. Gregor, Muslum Ilgu, Yue Yin, Philip A. Klenotic, Qijing Zhang, Edward W. Yu

Bacterial outer membrane proteins (OMPs) are critical players in host–pathogen interactions and environmental adaptation. Here we describe the newly developed “Gradient Enrichment of Native Targets from Lipid Environments” (GENTLE) methodology and use this approach to elucidate the structures of Campylobacter jejuni OMPs directly from native, detergent-solubilized crude membranes. We identify and solve high-resolution cryo-EM structures of PorA, OMP50, and Cj0034c from C. jejuni membranes, all of which are required for Campylobacter invasion, adhesion, and initiation of host infection. Notably, our results provide the first structural information of OMP50, revealing a two-domain architecture constructed with an all β-stranded transmembrane domain and an all α-helical periplasmic domain. This structure depicts that all tyrosine residues, many of which are expected to be critical for phosphorylation and host–pathogen interaction, are localized to the outer membrane of C. jejuni. Our studies also led to the first structure of the full-length Cj0034c protein, which assembles as a nonamer with each protomer containing a single-spanning transmembrane helix and a large periplasmic domain. The nine protomers stack side-by-side to form a channel that spans the entire lipid bilayer. However, whether Cj0034c spans the outer membrane (OM) or inner membrane (IM) of C. jejuni must await further experimental studies. In addition, we observed that the surface-exposed extracellular loop L4 of PorA is very flexible, which may be critical for the virulence of this porin. Collectively, this work provides novel structural information for functionally important OMPs and sheds light on how they assemble in native bacterial membranes. These findings further demonstrate that it is possible to obtain high-resolution structural information for targeted membrane proteins from crude native membranes without their overexpression and purification.

Ecological theory sheds light on plasmid diversity and dynamics

2026-08-28T14:00:00Z

by Rémi Tuffet, Emma Acacia, Charles Coluzzi, Xavier Charpentier, Thomas Koffel, Samuel Venner

Bacterial genomes are remarkably dynamic, shaped by horizontal gene transfer. Plasmids are key actors in this process, fueling rapid bacterial adaptation to stresses such as antibiotics. Yet, plasmids follow evolutionary trajectories of their own, defying traditional genetic frameworks. Beyond the co-evolution of traits directly involved in plasmid-host relationships, it is now essential to draw from ecological theory to understand plasmid assemblages. By viewing plasmids as ecological entities competing for a shared resource, the bacterial host, we show that their distribution within bacterial genomes mirrors the structure of ecological communities. Our minimal stochastic model, inspired by community ecology, reveals that plasmid diversity arises from the combined action of niche differentiation and neutral processes. These results challenge deterministic views of genome organization, highlighting the central role of stochasticity and drift. This work establishes a theoretical bridge between microbial genomics and ecology, offering a new framework to understand—and potentially control—the evolution of bacterial genomes.

Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling

2026-08-28T14:00:00Z

by Jie Zhang, Qian Shan, Xin Wang, Meijiao Li, Yang Yang, Mei Duan, Ruofeng Tang, Junxiang Zhou, Fengyang Wang, Yuehui Shi, Kai Jiang, Chonglin Yang

Mitochondria catabolize nutrients by generating sequentially-ordered organic acid intermediates that are oxidized through the tricarboxylic acid cycle. Pathogenic accumulation of metabolic organic acids manifests as devastating organic acidemias/acidurias and other severe diseases, but the underlying mechanisms are largely unknown. Using unbiased C. elegans genetic screening, we here reveal that mutations in the phosphoenolpyruvate carboxykinases PCK-1 and PCK-2 cause buildup of oxaloacetate, a key tricarboxylic acid cycle intermediate, leading to severe mitochondrial damage. Depletion of mitochondrial GOT-2.1 or GOT-2.2, which catalyze oxaloacetate conversion to aspartate, also causes oxaloacetate accumulation and defective mitochondria with disrupted cristae. We demonstrate that oxaloacetate binds the MICOS complex subunit CHCH-3/MIC19 and inhibits its function of promoting IMMT-1/MIC60-dependent membrane shaping and remodeling. In mammalian cells, aberrant OAA buildup similarly causes mitochondrial impairment through MIC19 and MIC60. These findings not only provide important mechanistic insights into mitochondrial damage in the context of defective oxaloacetate metabolism, but also suggest therapeutic strategies for oxaloacetate-related mitochondriopathies.

STRIPAK-associated greenbeard proteins DOC1 and DOC2 regulate MAK2 signaling and sexual development in Sordaria macrospora

2026-08-27T14:00:00Z

by Lucas S. Hollstein, Kerstin Schmitt, Lucas Well, André Fleißner, Oliver Valerius, Stefanie Pöggeler

Hyphal fusion and sexual development in filamentous fungi rely on coordinated signaling of numerous conserved nodes such as the striatin-interacting phosphatase and kinase (STRIPAK) complex or the pheromone response (PR) MAP kinase cascade (MIK2, MEK2, MAK2, HAM5). Here, we used the homothallic ascomycete Sordaria macrospora (Sm) to screen for putative protein interactors of the SmSTRIPAK complex. Using the STRIPAK complex interactor 1 (SCI1) subunit of the complex as bait, we enriched and identified canonical SmSTRIPAK components and a determinant of communication (DOC) protein. The DOC proteins were previously described in the closely related and heterothallic species Neurospora crassa, functioning in allorecognition of germlings and hyphal fusions. We generated ΔSmdoc1, ΔSmdoc2 single-deletion strains and the double deletion mutant ΔSmdoc1ΔSmdoc2 in S. macrospora. Deletion phenotypes were paradoxical: single knockouts (ΔSmdoc1 or ΔSmdoc2) were nearly sterile, and sexual development was impaired, yet the double mutant (ΔSmdoc1ΔSmdoc2) exhibited wild-type fertility and development, demonstrating non-redundant and mutually antagonistic roles. Using gene tagging at the native locus, we performed TurboID-based proximity mapping with SmDOC1 and SmDOC2 as bait proteins. This proximity mapping demonstrated close ties of SmDOC1/2 to components of the PR MAP kinase pathway and revealed mutual SmDOC1 – SmDOC2 proximity. Yeast two-hybrid experiments with SmDOC1 confirmed the direct interaction with the MAP kinases MEK2 and MAK2. Fluorescence microscopy revealed that SmDOC1-TagRFP-T localized to structures near septal pores. Our results demonstrate that the DOC system is not restricted to heterothallic N. crassa but also plays an essential role in the development of fruiting bodies in the homothallic fungus S. macrospora. These findings suggest the DOC1/2 proteins as a novel system that integrates STRIPAK and PR pathways, providing a possible mechanistic explanation for their non-additive deletion strain phenotypes.

Beat- and Side-family cell-surface molecules are expressed combinatorially in the partner neurons of the olfactory circuit in Drosophila

2026-08-27T14:00:00Z

by Qichen Duan, Sumie Okuwa, Rachel Estrella, Chun Yeung, Yu-Chieh David Chen, Laura Quintana Rio, Chengcheng Du, Khanh M. Vien, Pelin Cayirlioglu Volkan

Over the past decades, many molecular players have been uncovered to control distinct steps of olfactory circuit assembly in Drosophila. Among these, multi-member gene families encoding cell-surface proteins are of interest as they can act as neuron-specific recognition tags in combinations and contribute to circuit assembly in complex brains. Recently, a multi-protein interactome has been described between Beat and Side families of IgSF proteins. Here, we use newly generated gene trap transgenic driver lines to probe the spatial expression pattern of beat/side genes in olfactory receptor neurons (ORNs) and their synaptic target projection neurons (PNs). Our results revealed that each ORN/PN class expresses a specific combination of beat/side genes, hierarchically regulated by lineage-specific genetic programs. To explore whether the class-specific expression of beats/sides defines ORN-PN matching specificity, we perturbed presynaptic beat-IIa and postsynaptic side-IV in two ORN-PN partners. However, disruption of Beat-IIa-Side-IV interaction did not produce any significant mistargeting in these two examined glomeruli. Our expression mapping revealed that the Beat/Side interactome between ORNs and PNs appears to be error-tolerant, supporting the robust trans-synaptic recognition. Though without affecting general glomerular targeting, knockdown of side in ORNs leads to the reduction of synaptic development. Interestingly, we found conserved expression patterns of beat/side orthologs across ORNs in ants and mosquitoes, indicating the shared regulatory strategies specifying the expression of these duplicated paralogs in insect evolution. This also implies the biological significance of beats/sides in ORN circuit development or function, which is preserved under selective pressure across divergent insect lineages. Overall, this comprehensive analysis of expression patterns lays a foundation for in-depth functional investigations into how Beat/Side combinatorial expression contributes to the olfactory circuit assembly.

Theta oscillations tag episodic memories for sleep-dependent consolidation

2026-08-27T14:00:00Z

by Dan Denis, Zhiyi Chen, Manroop Kaur, Benjamin Clayden, Thomas Schreiner, Scott A. Cairney

How does the brain select which experiences to consolidate into long-term memory? Numerous neurobiological frameworks suggest that certain memories are “tagged” at learning for consolidation during later sleep. However, experimental evidence of such a tagging mechanism in the human brain is lacking. Employing multivariate classification of human electroencephalography data, we reliably decoded brain states for episodic memories that are tagged at learning for consolidation across sleep or wakefulness. The tagging of memories for consolidation across sleep (but not wakefulness) was linked to 3–8 Hz theta rhythms during learning. The magnitude of this tagging-related theta response predicted the coupling of slow oscillations to sleep spindles during post-learning sleep (an established neural correlate of sleep-dependent memory processing). In turn, slow oscillation-spindle coupling was associated with better memory performance at the post-sleep test. These findings provide new insights into the neural mechanisms through which our brains determine which information is retained for the future.

Polymorphisms in a bacterial signalling pathway alter evolutionary routes of antibiotic resistance in Escherichia coli

2026-08-26T14:00:00Z

by Chetna Yelpure, Saillesh Chinnaraj, Kush Topiwala, Jay Phadke, Nishad Matange

Antibiotic resistance in bacteria frequently evolves due to mutations in drug-target or detoxifying genes. Pre-existing polymorphisms in these genes are likely to influence the evolvability of drug resistance. However, the role of polymorphisms in driving resistance evolution and the underlying molecular mechanisms are poorly understood. Here, we demonstrate that polymorphisms in a signalling pathway impact the evolvability of trimethoprim (TMP) resistance in Escherichia coli. When challenged with TMP, de-repression of the PhoQ-PhoP two-component signalling system in E. coli transcriptionally upregulates the drug target Dihydrofolate Reductase (DHFR), leading to drug resistance. We identified and characterised naturally occurring polymorphisms in PhoQ and DHFR that modulate intrinsic antibiotic susceptibility. These variants also altered the ability of E. coli to evolve de novo TMP resistance as a result of epistasis with adaptive mutations. Interestingly, a strain harbouring a less-evolvable DHFR variant acquired a novel mutation in PhoQ under TMP pressure that hyperactivated the signalling pathway, conferring high-level resistance but at a large fitness cost. This mutation was not observed in wild type but reached fixation rapidly in the background of the DHFR variant. Using RNA-sequencing we compare how natural variants and adaptive mutations in PhoQ affect the expression of PhoP-target genes and downstream regulatory pathways in E. coli. Finally, we uncouple the roles of resistance level by DHFR overproduction and fitness cost by activation of the RpoS regulon to explain why E. coli more frequently evolves to de-repress PhoQ than hyperactivate it under drug pressure. Our study, thus, demonstrates that pre-existing polymorphisms alter both, evolvability and mutation landscapes during antibiotic adaptation. This work establishes the PhoQ-PhoP-DHFR pathway as an experimental paradigm to understand the evolution of signalling pathways under environmental selection.

Behavioral engagement and stimulus regularities coordinate auditory-prefrontal network activity

2026-08-26T14:00:00Z

by Haoxuan Xu, Peirun Song, Hangting Ye, Ana Belén Lao-Rodríguez, Qichen Zhang, Yuying Zhai, Xuehui Bao, Ishrat Mehmood, Hisashi Tanigawa, Zhiyi Tu, Lingling Zhang, Xuan Zhao, David Pérez-González, Manuel S. Malmierca, Xiongjie Yu

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band GC-defined interactions indicative of a shared predictive state. Deviant stimuli triggered earlier AC responses followed by PFC activation and increased GC-defined directed interactions across theta, alpha, and conventional gamma bands. Behavioral engagement amplified both repetition-related and deviance-related ECoG responses, strengthening cortical network coordination. Together, these findings reveal behaviorally gated auditory–prefrontal dynamics that are consistent with hierarchical predictive-processing accounts, while also allowing for contributions from repetition-, novelty-, and salience-related mechanisms.

Dynamic Landscape Analysis of cell fate decisions provides predictive models of neural development from single-cell data

2026-08-26T14:00:00Z

by Marine Fontaine, M. Joaquina Delás, Meritxell Sáez, Rory J. Maizels, Elizabeth Finnie, James Briscoe, David A. Rand

Building a mechanistic understanding of cell fate decisions remains a fundamental goal of developmental biology, with implications for stem cell therapies, regenerative medicine and understanding disease mechanisms. Single-cell transcriptomics provides a detailed picture of the cellular states observed during these decisions, but building dynamic and predictive models from these data remains a challenge. Here, we present dynamic landscape analysis (DLA), an integrative framework that applies dynamical systems theory to identify stable cell states, map transition pathways, and generate a predictive cell fate decision landscape from single-cell data. Applying this framework to vertebrate neural tube development revealed that progenitor specification by Sonic Hedgehog (Shh) can be captured in a landscape with an unexpected topology in which initially divergent lineages converge to the same fate through multiple distinct routes. The model accurately predicted cellular responses and cell fate allocation for unseen dynamic signalling regimes. Cross-species validation using human embryonic organoid data demonstrated conservation of this decision-making architecture. By modelling the dynamic responses that drive cell fate decisions, the DLA framework provides a quantitative and generative framework for extracting mechanistic insights from high-dimensional single-cell data.

Harnessing pathogen stress-hormone sensing for living medicines

2026-08-26T14:00:00Z

by Weston R. Whitaker

Pathogens sense host stress hormones in the gut and use them to regulate motility and virulence. A new study in PLOS Biology transfers this pathway to Escherichia coli Nissle and redesigns its regulation to drive programmable outputs. Pathogens sense host stress hormones in the gut and use them to regulate motility and virulence. This Primer discusses a new PLOS Biology study which transfers this pathway to Escherichia coli Nissle and redesigns its regulation to drive programmable outputs.

How do anthropogenic changes affect wildlife microbiomes?

2026-08-26T14:00:00Z

by Katherine M. Lagerstrom, Andrew P. Dobson, Shane Campbell-Staton, Andrew H. Moeller

Human activities are transforming ecosystems, but their effects on wildlife microbiota remain poorly understood. Pollution, habitat transformation, and altered host contact networks can reshape host-associated microbiota in context-dependent ways, including through symbiont loss, selection for antimicrobial resistance, shifts toward human-associated community states, and increased among-host variability. Whether these changes are transient or persistent, harmful or adaptive, or consequential for wildlife health and disease risk is largely unknown. This Unsolved Mystery highlights key mechanistic gaps and outlines future research strategies for the field, including studies that distinguish environmental filtering, dispersal limitation, host physiological responses, and cross-species microbial transmission.

IP₃R2-mediated inter-organelle calcium signaling suppresses melanosome degradation

2026-08-25T14:00:00Z

by Suman Saurav, Anuradha Jadon, Rajender K. Motiani

Organelle turnover is fundamental to cellular homeostasis and regulates both physiological processes and pathological outcomes. Skin pigmentation is determined by the balance between melanosome biogenesis and degradation. However, the mechanisms governing melanosome degradation, i.e., melanophagy remain largely unappreciated. Here, we reveal Inositol 1,4,5-trisphosphate receptor 2 (IP₃R2) as a selective suppressor of melanophagy. To enable real-time monitoring of melanophagy, we developed and characterized two novel ratiometric live-cell imaging probes. Using a multi-pronged strategy combining live-cell imaging with the probes, biochemical studies, ultrastructural analyses, molecular approaches, and calcium imaging, we demonstrate that IP₃R2 suppresses melanophagy. Importantly, in vivo studies in zebrafish model and meta-analysis of human skin microarrays substantiate the physiological relevance of IP₃R2 in pigmentation. Mechanistically, IP₃R2 depletion impairs mitochondrial Ca²⁺ uptake, elevates the ADP/ATP ratio and initiates melanophagy. Concurrently, IP₃R2 loss enhances ER–lysosome contacts, increases lysosomal Ca²⁺ levels via TMEM165, and activates TRPML1 and nuclear translocation of TFEB. This in turn transcriptionally induces melanophagy receptor and E3 ligase. Collectively, IP₃R2 acts as a critical determinant of melanophagy and a potential therapeutic target for pigmentary disorders and skin malignancies.

Brachyury expression levels predict lineage potential and axis-forming ability of in vitro-derived neuromesodermal progenitors

2026-08-25T14:00:00Z

by Anahí Binagui-Casas, Anna Granés, Alberto S. Ceccarelli, Matthew French, Filip J. Wymeersch, Rosa Portero Migueles, Jennifer Annoh, Yali Huang, Eleni P. Karagianni, Frederick C. K. Wong, Raffee Wright, Anna Sophie Brumm, Daniel Lopez Ramajo, Minoru Takasato, Sally Lowell, Osvaldo Chara, Valerie Wilson

Neuromesodermal progenitors (NMPs) produce the spinal cord and musculoskeleton in the elongating anterior-posterior axis. In vivo, NMPs possess dual potency, coinciding with regions co-expressing SOX2 and Brachyury (TBXT). In vitro, SOX2/TBXT co-expressing cells can be produced from pluripotent cells and, like their in vivo counterparts, can produce neural tube and somitic mesoderm. However, the functional characteristics of in vitro SOX2/TBXT co-expressing cells remain unclear, confounding comparisons with in vivo data. To address this, we developed a dual Sox2/Tbxt reporter mouse ESC line. SOX2/TBXT reporter-positive cells emerge in vitro from pluripotent populations with dynamics that mirror their appearance in the embryo. Purified SOX2/TBXT co-expressing populations can differentiate towards neurectoderm or mesoderm, including lateral mesoderm upon BMP stimulation. In gastruloids, quantitative live imaging shows that WNT or NOTCH inhibition rapidly leads to downregulation of TBXT expression and diminished axial extension. We show that clonally plated SOX2/TBXT co-expressing cells are bipotent NMPs that can also self-propagate. By combining clonal analysis with mathematical inference, we identify two thresholds of TBXT and/or SOX2 expression, switching clonal output from neural- to mesoderm-biased, and from mesoderm-biased to mesoderm-specified. Image analysis of embryonic NMPs supports a model whereby SOX2 and TBXT independently influence neuromesodermal differentiation. Thus, this Sox2/Tbxt double reporter cell line highlights unsuspected heterogeneity in NMPs, and together with image analysis of embryonic SOX2/TBXT levels, challenges the assumption that neuromesodermal fate choice is primarily governed by mutual antagonism between SOX2/TBXT.

Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells

2026-08-25T14:00:00Z

by Yu-ping Dong, Yi-Min Chen, Min Tang, Hu Zhou, Lin Wang, Ping Zheng

Embryonic stem cells (ESCs) exhibit a hyperactive chromatin state at ribosomal RNA (rRNA) genes, which not only plays roles in active rRNA synthesis and ribosome biogenesis (RiBi), but also links to genome architecture. However, how this active chromatin state is maintained in ESCs remains poorly understood. Here, we identify Tcf15, a mouse ESC-specific factor, as a novel regulator of ribosomal DNA (rDNA) chromatin state. Tcf15 localizes to the nucleolus, binds the coding region of rRNA genes, and independently recruits epigenetic modifiers—either Tet2 or Rbbp5 (a core component of H3K4 methyltransferases)—to promote an active chromatin configuration. Depletion of Tcf15 increases DNA methylation and H3K27me3 levels at rDNA. Intriguingly, the Tcf15-Rbbp5 axis ensures precursor rRNA transcription and RiBi, whereas the Tcf15-Tet2 axis is not involved in rRNA synthesis. Ribosome profiling further revealed compromised translation of a subset of mRNAs involved in DNA replication, damage response, and repair. Consequently, Tcf15- or Rbbp5-deficient ESCs exhibit severe genomic instability. Our findings add a new regulatory layer of chromatin state in rDNA of stem cells, and reveal a previously unrecognized phenotypic consequence of defective RiBi in ESCs.

Recognition of pathogenic bacteria by intestinal stem cells promotes adult Drosophila midgut regeneration

2026-08-25T14:00:00Z

by Bhavin Uttekar, Marie Srotyr, Sanket Sudam Ravale, Liliana Ewertowska, Rebecca Wafer, Martina Legido, Parthive H. Patel

When enteropathogenic bacteria breach the intestinal epithelium, they are recognised by epithelial and immune cells that elicit an intestinal regenerative response. However, less is known about whether and how intestinal stem cells (ISCs) directly detect invading pathogenic bacteria and couple this to their proliferation. Here, we show that adult Drosophila midgut ISCs recognise pathogenic bacteria through the peptidoglycan recognition proteins, PGRP-LC and PGRP-LE, and translate this into their proliferation by stimulating Imd-Mkk3-p38 signalling. Moreover, we find that PGRP-LC/LE-Imd-Mkk3-p38 signalling in ISCs regulates p38 activation throughout the midgut epithelium after infection, indicating that ISCs can influence the regenerative microenvironment in a non-cell autonomous manner. Whilst it was previously thought that ISC proliferation in both mammals and flies is driven solely by damage-induced signals after infection, our work reveals that ISCs can directly recognise pathogenic bacteria and mount a strong parallel regenerative response that spreads throughout the midgut epithelium. Increased ISC proliferation after bacterial recognition may also serve as a strategy to repopulate the epithelium with uninfected cells.

Mycodnaviridae is a clade of giant viruses that persistently infect zoosporic fungi

2026-08-25T14:00:00Z

by Jillian M. Myers, Frederik Schulz, Saleh Rahimlou, Vikas Yadav, Kevin R. Amses, David Rabern Simmons, Sheng Sun, Michelle Orozco-Quime, Joseph Heitman, Jason E. Stajich, Timothy Y. James

Giant viruses of the phylum Nucleocytoviricota have emerged as particularly notable due to their increasingly recognized impacts on eukaryotic genome evolution. Their origins are hypothesized to predate or coincide with the diversification of eukaryotes, and they have been detected in hosts that span the eukaryotic tree of life. But surprisingly, such viruses have not been definitively found in Kingdom Fungi, though earlier genomic and metagenomic work suggests putative associations. Here we report both “viral fossils” and active infection by giant viruses in fungi, particularly in the zoosporic phyla Blastocladiomycota and Chytridiomycota. The recovered viral assemblies span up to 350 kb, encode over 300 genes, and form a monophyletic family-level clade within the Nucleocytoviricota related to orders Imitervirales and Algavirales, which we name Mycodnaviridae. We observed variation in infection status among the isolates including apparent active infection and transcriptionally suppressed states, suggesting that viral activation may be constrained to certain life stages of the host. Our experimental findings add to the limited natural virus-host systems available in culture for the study of giant viruses and expand the known host range of Nucleocytoviricota into a new kingdom that contains many model species. Mycodnaviridae have a global distribution, which invites inquiry into the implications of these infections for host traits, host genome evolution, and the metabolic impacts on ecosystems.

Retracing the origin and evolution of a cryptic antimicrobial peptide within mammalian lactoferrin

2026-08-25T14:00:00Z

by Titas Sil, Caitlin H. Kowalski, Sierra Scamfer, Natalie Copeland, Matthew F. Barber

Antimicrobial peptides (AMPs) constitute key components of innate immunity across the tree of life. Canonical AMPs are typically translated as small proteins and secreted from host cells to act against microbes. However, cryptic AMP-like domains are also embedded within diverse proteins not classically associated with antimicrobial function. How such embedded AMPs first emerge and diversify remains unclear. Here we retrace the origin and evolution of the abundant mammalian protein lactoferrin and its embedded AMP, lactoferricin. By resurrecting extinct lactoferrin ancestors dating back to the earliest mammals, we identify an enrichment of cationic and hydrophobic amino acids in the lactoferricin domain over time. These changes enabled ancient lactoferricin to first rupture bacterial membranes, an activity that was later enhanced in extant mammals conferring potent bactericidal activity. In addition, we find that natural selection within the lactoferricin domain has continued to modulate antimicrobial activity on recent evolutionary timescales. In particular, we pinpoint a single rapidly evolving site in lactoferricin among great apes that significantly enhances antimicrobial potency against major pathogenic bacteria. Together, our study illustrates how novel immune protein functions can arise, evolve, and diversify to strengthen host defense against microbial pathogens.

Engineering inter-kingdom adrenergic signaling in commensals couples host stress hormone sensing to programmable biological outputs

2026-08-25T14:00:00Z

by Santosh Kumar Srivastava, Guo Wei Foo, Haosheng Shen, Yuanzhi He, Kwok Soon Wun, In Young Hwang, Michael S. Goodson, Nikhil Aggarwal, Matthew Wook Chang

Host stress is associated with elevated catecholamine neurohormones that influence gut physiology and host–microbe interactions, yet how bacterial systems detect and interpret these signals remains incompletely understood. Enteric pathogens exploit inter-kingdom adrenergic signaling to sense host-derived norepinephrine and epinephrine, but whether such pathways can be rationally rewired to produce predictable, programmable outputs has not been systematically explored. Here, we reconstitute adrenergic signaling in Escherichia coli Nissle 1917 by repurposing the enterohemorrhagic E. coli QseBC two-component system. Transcriptomic profiling revealed robust catecholamine-dependent activation of QseBC-regulated pathways in the engineered strain. Guided by these data, we redesigned a QseBC-responsive promoter through rational truncation, sigma-factor replacement, and optimization of QseBC expression, generating a synthetic promoter with enhanced sensitivity and dose-dependent responsiveness to stress hormones. Structure-guided mutagenesis of the QseC sensor kinase identified key residues required for catecholamine recognition, providing mechanistic insight into adrenergic hormone sensing. To demonstrate functional signal transduction beyond transcriptional reporting, we coupled the sensing module to a secretion cassette encoding a corticotropin-releasing factor (CRF) receptor antagonist as a model bioactive output and validated bioactivity in vitro. Together, this work elucidates principles governing bacterial stress hormone sensing and demonstrates how inter-kingdom signaling pathways can be engineered to yield programmable biological outputs.

Metabolic and developmental rate divergence between serially homologous cells underlies an evolutionary innovation in Drosophila

2026-08-24T14:00:00Z

by Ben R. Hopkins, Olga Barmina, Xinying Wang, Mandy M. Situ, Haley A. Bolanos, Shizhan Nie, Artyom Kopp

The individualization of serially repeated homologs is one route through which novel traits are thought to evolve. Under this model, a repeated character—like a limb, digit, or sensory bristle—is individualized from its homologs by changes in the regulatory apparatus (‘character identity network’, ChIN) that specifies its development. Individualization then enables downstream gene networks that build the repeated character to diverge from one another in different parts of the body, ultimately allowing new phenotypic endpoints to be reached. Despite this model’s intuitive appeal, the genetic mechanisms through which new ChINs rewire trait-building gene networks remain largely uncharacterized. A promising system in which to study this process is the Drosophila sex comb. Found in a sublineage of Drosophila species, the sex comb is a recently evolved, male-specific innovation that evolved from a more evolutionarily ancient precursor—the mechanosensory (MS) bristle—following the gain of a novel ChIN centered on the sex determination gene dsx and HOX gene Scr. Here, we use time-series single-cell RNA-seq to show that rather than co-opting new genes, this new ChIN orchestrates quantitative and heterochronic changes in the ancestral MS bristle transcriptome. These changes affect gene modules that control energy metabolism, endoreplication, and actin dynamics. The net effect of these changes is an organ-specific shift in developmental rate, leading to accelerated growth in sex comb teeth. Collectively, our work suggests that morphological innovation can proceed without the co-option of new genes into downstream trait-building networks and instead through metabolically driven differences in developmental rate between serial homologs.

Microsaccadic eye movement generation is sufficient to enhance peripheral visual sensitivity

2026-08-21T14:00:00Z

by Tong Zhang, Xiaoguang Tian, Tatiana Malevich, Matthias P. Baumann, Ziad M. Hafed

Microsaccades have been convincingly linked to extrafoveal covert attention shifts for more than two decades. However, the direction of causality between individual microsaccade generation and an alteration in both extrafoveal visual sensitivity and behavior remains debated: do microsaccades merely reflect, perhaps probabilistically, an altered extrafoveal sensitivity, or is the act of generating microsaccades sufficient, on its own, to modify such sensitivity? Using a novel exploitation of real-time retinal image stabilization, behavior, and neurophysiology in the superior colliculus of rhesus macaque monkeys, we show that exclusive experimental control over foveal oculomotor state is entirely sufficient to influence extrafoveal sensitivity. This happens for eccentricities as large as ~50 times those associated with microsaccades, and it also takes place in the absence of any differential attentional demands. Most importantly, such influence is mediated through well-known, classic pre- and post-saccadic visual processing changes. These results were also confirmed, and extended to larger saccades, using human psychophysical experiments. Thus, seemingly-innocuous subliminal eye movements do constitute an integral component of cognitive processes like attention.

Correction: Self-allocation bias in performance-based cooperative decisions is driven by self-interest rather than distorted performance encoding

2026-08-21T14:00:00Z

by Sihui Zhang, Xue Yong, Yina Ma, Christoph W. Korn

PLOS Biology: New Articles

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Oxaloacetate damages mitochondria by perturbing MIC60-dependent membrane remodeling

STRIPAK-associated greenbeard proteins DOC1 and DOC2 regulate MAK2 signaling and sexual development in Sordaria macrospora

Beat- and Side-family cell-surface molecules are expressed combinatorially in the partner neurons of the olfactory circuit in Drosophila

Theta oscillations tag episodic memories for sleep-dependent consolidation

Polymorphisms in a bacterial signalling pathway alter evolutionary routes of antibiotic resistance in Escherichia coli

Behavioral engagement and stimulus regularities coordinate auditory-prefrontal network activity

Dynamic Landscape Analysis of cell fate decisions provides predictive models of neural development from single-cell data

Harnessing pathogen stress-hormone sensing for living medicines

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IP3R2-mediated inter-organelle calcium signaling suppresses melanosome degradation

Brachyury expression levels predict lineage potential and axis-forming ability of in vitro-derived neuromesodermal progenitors

Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells

Recognition of pathogenic bacteria by intestinal stem cells promotes adult Drosophila midgut regeneration

Mycodnaviridae is a clade of giant viruses that persistently infect zoosporic fungi

Retracing the origin and evolution of a cryptic antimicrobial peptide within mammalian lactoferrin

Engineering inter-kingdom adrenergic signaling in commensals couples host stress hormone sensing to programmable biological outputs

Metabolic and developmental rate divergence between serially homologous cells underlies an evolutionary innovation in Drosophila

Microsaccadic eye movement generation is sufficient to enhance peripheral visual sensitivity

Correction: Self-allocation bias in performance-based cooperative decisions is driven by self-interest rather than distorted performance encoding

IP₃R2-mediated inter-organelle calcium signaling suppresses melanosome degradation