PLOS Biology: New Articles

Pathogen subversion of neuro-epidermal signaling impairs lysosomal function to disrupt collagen homeostasis in Caenorhabditis elegans

2026-09-22T14:00:00Z

by Qian Li, Yating Liu, Hanyi Chen, Weilie Xiao, Bin Qi

The epidermis relies on collagen-rich extracellular matrices (ECMs) to maintain barrier integrity against pathogens. Lysosomes regulate cuticle collagen turnover, yet how neuronal signaling modulates epidermal lysosomal function and collagen organization during infection remains unclear. Using Pseudomonas aeruginosa PA14-Caenorhabditis elegans infection model, we demonstrate that pathogen-induced neuronal signaling disrupts epidermal lysosomal activity and collagen remodeling. PA14 infection triggers neurons to secrete NSIF-1 (Neuronal Secreted Immune Factor 1), which translocates to the epidermis and impairs lysosomal acidification, maturation, and degradation by suppressing the transcription factor ELT-3. This disruption leads to disorganized collagen structure, compromising cuticle integrity and host resistance. Genetic mutation of nsif-1 restores lysosomal function, enhances collagen density, and improves survival, while neuron-specific nsif-1 knockdown confirms its neuronal origin. Moreover, NSIF-1 inhibits ELT-3 nuclear localization, blocking its role in lysosomal-dependent ECM repair. Our study reveals a neuro-epidermal axis wherein pathogens exploit neuronal signals to disrupt lysosomal function and collagen homeostasis, identifying NSIF-1 and ELT-3 as potential targets to counteract infection-driven ECM dysregulation.

Coordinated P450–UGT detoxification contributes to furanocoumarin tolerance associated with host plant range divergence in Helicoverpa

2026-09-22T14:00:00Z

by Huidong Wang, Yajie Kong, Xinyue Su, Yu Shi, Jianpeng Zhang, Yinjia Wang, Yajuan Xiao, Xing Geng, Jing Song, Yueru Ye, Kairan Zuo, Chris Bass, Shutang Zhou

Plants and herbivorous insects are engaged in a continuous evolutionary arms race driven by chemical defences and counter-defences. How insects integrate distinct detoxification systems to overcome diverse phytochemicals, and how such mechanisms contribute to host-range divergence, remains poorly understood. Here, we uncover a cooperative cytochrome P450–UDP-glycosyltransferase (UGT) cascade that mediates furanocoumarin tolerance in Helicoverpa armigera. Comparative genomic analyses across Helicoverpa and related noctuid species revealed that the UGT33 family is the most extensively expanded and dynamically diversified UGT lineage in Helicoverpa. Targeted CRISPR–Cas9 knockouts of UGT33 gene clusters in polyphagous H. armigera demonstrated their essential roles in detoxifying the furanocoumarins xanthotoxin and imperatorin. Combined metabolic and functional assays further established a sequential detoxification pathway, in which the cytochrome P450 CYP6AE19 catalyses either the O-dealkylation of xanthotoxin to yield xanthotoxol or the aromatic-carbon hydroxylation of xanthotoxin to form 5-hydroxyxanthotoxin, which are subsequently glycosylated by UGT33 enzymes to form their less-toxic glucosides. In contrast, impaired CYP6AE19–UGT33 coordination in the oligophagous Helicoverpa assulta was associated with reduced xanthotoxin detoxification and high sensitivity to this compound. Together, these findings provide direct evidence for coordinated Phase I–Phase II detoxification of a plant defensive compound in insects and show that functional divergence in this pathway contributes to interspecific differences in plant toxin tolerance, which are associated with contrasting dietary breadth in closely related herbivorous insects.

Antibodies targeting phage fiber and nozzle proteins impair Acinetobacter baumannii phage therapy by blocking infection and promoting immune clearance

2026-09-22T14:00:00Z

by Heng Xue, Xinfeng Li, Guibo Rao, Fen Hu, Mingyue Zhong, Paulina Miernikiewicz, Rui Qiu, Sheng Cao, Krystyna Dąbrowska, Hang Yang

Phage therapy represents a promising strategy to tackle the growing threat of antimicrobial resistance. Increasing evidence has demonstrated that phage-specific antibodies may compromise the efficacy of phage therapy. Nevertheless, little is known about how phage protein specificity of antibodies modulates phage therapeutic outcomes. Herein, we utilized AbP20, a podovirus against Acinetobacter baumannii, to explore the effects of antibodies elicited by each structural protein on phage therapy efficacy in a mouse infection model. Intraperitoneal administration of AbP20 once a day for 7 consecutive days induced robust phage-specific antibody responses that impaired phage therapy. Genome-guided antigen screening identified that antibodies elicited by the nozzle and fiber proteins of AbP20, rather than those targeting the portal, capsid, or adaptor proteins, are the dominant drivers of phage therapy failure. Specifically, fiber-specific and nozzle-specific antibodies block bacterial adsorption and genomic injection of AbP20, respectively. Meanwhile, both antibody subsets efficiently induce large phage aggregates and potentiate macrophage phagocytosis via an Fc receptor-independent pathway. An evolved AbP20 variant with improved neutralization escape capacity exhibited comparable antibody-accelerated phagocytosis and host immune clearance, yet partially rescued therapeutic failure caused by neutralizing antibodies. Collectively, this study elucidates that nozzle- and fiber-elicited neutralizing antibodies impair phage therapy via dual synergistic mechanisms, which offers novel insights into the multifaceted modulation of phage-specific antibodies against phage therapeutic efficacy.

Who Eats Whom? A global food web derived from citizen science

2026-09-22T14:00:00Z

by Bradley C. Allf, Aditi Mallavarapu, David W. Kikuchi, Nikhil Vasudeva, Robert R. Dunn

Citizen science contains abundant yet underutilized data about species interactions. We present Who Eats Whom, a database and public engagement tool for searching and visualizing thousands of feeding relationships derived from iNaturalist data. Citizen science photographs contain a vast and underused record of species interactions. This Community Page introduces Who Eats Whom, an interactive, searchable food web created from photographs uploaded to iNaturalist.

Regeneration programs buffer genetic defects in animal development

2026-09-21T14:00:00Z

by Kazunori Ando, Sushant Bangru, John Welsby, John D. Thompson, Kenneth D. Poss

Regeneration programs enable animals to restore damaged or lost tissues, and the range of stimuli for these programs is incompletely understood. Here, we used zebrafish, a vertebrate species with exceptional regenerative capacity, to identify chemically induced mutations that alter regeneration-associated gene activation. Transgenic zebrafish with a permissive promoter and EGFP cassette inserted in the vicinity of the pro-regenerative factor gene fgf20a were mutagenized, and larvae homozygous for ENU-induced mutations were assessed for disruptions in fgf20a-directed reporter gene expression following fin fold amputation. One line was identified with heritable, elevated fgf20a:EGFP presence in the absence of experimental injury, localized to regions of fin fold tissue undergoing degeneration. Whole-genome sequencing (WGS) identified a mutation within exon 72 of the fraser syndrome 1 (fras1) gene, mutated in patients with inherited skin disease. fras1 mutant larvae spontaneously displayed broader signatures of regeneration, and zebrafish crispants for homologs of other genes mutated in human developmental diseases also displayed regeneration-associated gene expression in regions of dysmorphology. Tempering Fgf signaling by transgenic expression of a dominant-negative Fgf receptor in fras1 mutants exacerbated the disease phenotype. Our findings provide evidence that regeneration programs are harnessed in response to developmental defects caused by genetic mutations, potentially buffering deleterious phenotypes.

Monovalent cations differentially regulate the activity of eukaryotic fluoride channels and impact fluoride resistance

2026-09-21T14:00:00Z

by Chia-Yu Kang, Sahar Heidari, Sabrina Kolb, Minjun An, Melanie D. Ohi, Hedieh Torabifard, Randy B. Stockbridge

Fluoride is an environmentally prevalent inhibitor of fungi, plants, and other eukaryotes. The fluoride exporter (FEX) is the major resistance mechanism that prevents intracellular fluoride accumulation in eukaryotes. FEX activity is sodium-dependent, but the mechanism for Na⁺ activation and the impact of other cations on FEX function remain poorly understood. Here, we show that sodium and lithium have different effects on channel activity. We leverage these differences to understand how monovalent cations regulate FEX. Functional assays in a reconstituted system show that lithium acts as a competitive antagonist of channel activation by competing with sodium for the central cation binding site. We further demonstrate that lithium markedly reduces fluoride tolerance of yeast. A cryo-EM structure of Candida albicans FEX with Li⁺, together with molecular dynamics (MD) simulations, reveals that differences in the preferred coordination sphere underlie the cation dependence of FEX activity. Whereas sodium binding supports a dynamic structure with a broader pore radius, lithium coordination favors a more rigid conformation that is more compact in the channel’s vestibule. These changes perturb the tilt angle of a pore lining helix, and alter the rotamer of a key phenylalanine in the pore, which together constrict the permeation pathway. In addition to providing general insight into the mechanism of fluoride channel regulation by monovalent cations, these results identify lithium as a previously unknown environmental antagonist of eukaryotic fluoride export and tie cellular fluoride stress tolerance to the abundance of additional ions in the cellular milieu.

The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system

2026-09-21T14:00:00Z

by Levon Tokmakjian, Duhyun Han, Kateryna Sihuta, Aanchal Aggarwal, Somayeh Pirhadi, Yao Wang, Andrew R. Burns, Brittany Cooke, Siyue Ren, Marios Gavrielatos, Jiabao Liu, Henry M. Krause, Carolyn L. Cummins, Justin Nodwell, David R. Koes, Peter J. Roy

Cationic Amphiphilic Drugs (CADs) severely disrupt lysosomal function, which leads to a cellular pathology in humans characterized by excess phospholipids called phospholipidosis. Through a forward genetic screen and mining of published datasets, we discovered that CADs induce the expression of the CYP-35B family of cytochrome P450s and the PGP-13 p-glycoprotein pump via the nuclear receptors NHR-70 and NHR-107 in the nematode C. elegans. A pgp-13 fluorescent reporter revealed hundreds of human drugs that up-regulate the CAD defense system in vivo. Chemoinformatic analyses indicate that the pgp-13 reporter may be useful in identifying CADs that have pathogenic potential in humans. Mutant analyses coupled to metabolomics and structural modeling show that the CYP-35Bs are necessary and sufficient for CAD metabolism, and that CYP-35B2 D311 is key in mediating electrostatic interactions with the positively charged CADs. We also show that CAD metabolites are effluxed via PGP-13 acting partially redundantly with PGP-14 and that an intact defense system is necessary to resist CAD-induced pathology. Finally, we demonstrate that bacteria that likely cohabitate with C. elegans in nature trigger the CAD defense system, providing a plausible explanation for why a pathway that protects against anthropogenic small molecules exists in nematodes.

Gene flow drives periods of both evolutionary stasis and change in a wild bird population

2026-09-21T14:00:00Z

by Simon Robin Evans, Henri Bouwmeester, Arie J. van Noordwijk, Marcel E. Visser, Erik Postma

The struggle to explain the absence of evolutionary change in heritable, fitness-related traits of free-living populations has become emblematic of our ignorance of the evolutionary process in the wild. Yet while this ‘paradox of stasis’ has been the subject of much discussion, it is primarily identified a posteriori and rarely subject to direct quantification. We examined the evolution of clutch size in neighbouring populations of great tits (Parus major) before, during and after an experimental evolutionary perturbation. Interannual genetic changes in clutch size were directionally consistent with selection (refuting absolute stasis) but were smaller than predicted by adaptive evolutionary models (supporting relative stasis). Yet accounting for the contribution of post-selective immigration (i.e., explicitly recognising the distinction between adaptation and evolution) greatly improved our forecast accuracy and this tendency toward overprediction. Indeed, attributing interannual genetic change to its contributing demographic processes revealed immigration to be key to explaining periods of both evolutionary stasis and change, with its evolutionary impact varying across time and space in a manner analogous to the dynamism of natural selection. Our multi-decadal study of clutch size evolution thus shows that recognising the impact of gene flow is crucial to explaining contemporary evolutionary change and stasis of a key determinant of life history.

AlloPool is a deep learning framework that infers protein allostery from molecular dynamics simulations

2026-09-21T14:00:00Z

by Matthieu Marfoglia, Miguel A. Pedraza-Joya, Lucas Guirardel, Aisima Chatzi Souleiman, Patrick Barth

Recent advances in artificial intelligence have transformed protein structure prediction and design. However, protein function is governed not only by static structures but also by the conformational dynamics that allow proteins to access distinct functional states. Predicting these dynamic transitions, central to many biological processes, remains challenging due to the scarcity of high-resolution experimental data, which limits the training of machine-learning models for dynamic and energetic property prediction. Here, we present AlloPool, a graph neural network (GNN)-based framework that interprets molecular dynamics simulations by iteratively pruning residue–residue interactions to uncover minimal, time-resolved interaction networks that govern protein conformational dynamics and structural responses to chemical or mechanical perturbations, collectively known as allostery. By integrating temporal attention with graph aggregation, AlloPool learns evolving interaction graphs from equilibrium and non-equilibrium molecular dynamics simulations, enabling accurate reconstruction of dynamic trajectories and the interaction networks that drive conformational transitions. Validated across diverse dynamic protein systems, including binding domains, mechanosensors, signaling receptors, and enzymes, AlloPool maps allosteric communication pathways, predicts the effects of ligand binding, mechanical forces, and mutations, discovers transient dynamic states and outperforms existing machine-learning approaches in dynamic trajectory reconstruction. This advance provides a general framework for interpreting protein dynamics with broad implications for drug discovery, synthetic biology, and protein engineering.

Myelin sheath lengths in the central nervous system scale to axon diameter via oligodendroglial Piezo1

2026-09-21T14:00:00Z

by Amanda R. Young, Ashley Galfano, Jacob Reyngoudt, Ryan W. Lewis, Martha Cash, Beckam Polis, Myah Zalusky, Avipsha Datta, Marie E. Bechler

Myelin sheath lengths vary by an order of magnitude in the central nervous system (CNS) and tune the timing of neuronal signaling. Thus, variation in myelin sheath length has been proposed to coordinate the timing of neuronal signaling to ultimately impact behavior. The mechanisms to establish myelin sheath length are unknown. For decades, reports have documented that in vivo myelin sheath size scales with the diameter of the ensheathed axon. We previously demonstrated diameter is sufficient to instruct myelin sheath lengths formed by rat oligodendrocytes using a synthetic axon culture system. The mechanisms of oligodendrocyte diameter-sensing and its translation into sheath elongation are still unknown. Here, we demonstrate that diameter-sensing and sheath length is locally regulated: each individual myelin sheath responds to the underlying fiber diameter. We uncover a novel mechanism for scaling myelin sheath length to fiber diameter, through mechanosensitive ion channel Piezo1. In mice in vivo, Piezo1 impacts the elongation of myelin sheaths on large diameter axons, recapitulating our in vitro results. Yet, surprisingly, there is no impact on myelin thickness with conditional Piezo1 loss. We propose Piezo1 provides a mechanism to establish hard-wired myelin sheath patterns, where oligodendrocytes transduce axon diameter into generating myelin segments with vastly different lengths.

MucD regulates alginate biosynthesis through the proteolytic control of AlgX and AlgK in Pseudomonas aeruginosa

2026-09-21T14:00:00Z

by Yujun Jiang, Xin-Fu Yan, Rya Ero, Chao Wang, Kanaga Sabapathy, Yong-Gui Gao

Pseudomonas aeruginosa is an opportunistic human pathogen capable of infecting a wide range of tissues and organs. Its persistence during chronic infection is strongly associated with biofilm formation, which depends on extracellular polysaccharides such as alginate. The HtrA-like periplasmic serine protease MucD is a key regulator of bacterial virulence, stress response, and alginate production, yet its molecular mechanism has remained largely unclear. Here, we discovered the alginate acetylation and export proteins AlgX and AlgK as MucD substrates, and characterized their degradation by mass spectrometry and bioinformatic analysis. We further determined the cryo-EM structure of MucD bound to an AlgK-derived substrate peptide, offering atomic insights into MucD oligomerization assembly, substrate recognition, and specificity. Together with structure-guided mutagenesis and biochemical assays, our results revealed that MucD proteolytic activity is governed by an equilibrium between a resting 12-mer and an active trimer. Crucially, we demonstrate that MucD represses alginate biosynthesis post-translationally, in addition to its previously implicated role in transcriptional regulation. These findings define a distinct activation mechanism and regulatory function for MucD and provide new insight into bacterial HtrA-like serine proteases.

The kinetoplastid-specific transcription factor mtTF1 is essential for mitochondrial gene expression and maxicircle replication in Trypanosoma brucei

2026-09-21T14:00:00Z

by Bianca Manuela Berger, Enrico Santini, Himaja Manjunatha, Lea Trost, Markus Gerber, Hauke S. Hillen, Torsten Ochsenreiter

Mitochondrial DNA replication and gene expression are essential for cell survival. In Trypanosoma brucei, a protozoan animal and human parasite, the mitochondrial RNA polymerase (mtRNAP, Tb927.11.5780) plays roles in both transcription and DNA replication. This study identifies and characterizes the first mitochondrial transcription factor (mtTF1, Tb927.6.4510) in the Kinetoplastea. The mtRNAP and mtTF1 form a high-molecular-weight complex that localizes to the kinetoplast DNA (kDNA) and is essential for parasite survival in both life cycle stages. Their localization is interdependent, and both proteins influence maxicircle replication, but not minicircle replication. Knockdown of either protein results in altered gene expression, particularly affecting the minor strand of the mitochondrial genome. mTF1 specifically binds to kDNA and since it is unique to the Kinetoplastea, it might prove to be a promising drug target.

Regional signaling controls stem cell-mediated regeneration in an invertebrate chordate

2026-09-18T14:00:00Z

by Tal Gordon, Tom Levy, Chester Jiamu Yu, Benyamin Rosental, Lauren Lubeck, Lucia Manni, Irving L. Weissman, Ayelet Voskoboynik

Many tissues harbor quiescent stem cells that activate after injury, yet how local signals regulate this transition is not well understood. The solitary ascidian Ciona robusta provides a unique model, as bottom body fragments regenerate while upper fragments fail to do so. By comparing these regenerative and non-regenerative contexts, we reveal striking differences in transcriptional dynamics and signaling environments. Combining flow cytometry, scRNA-seq, transplantation, and fate mapping, we identified a candidate stem cell population with robust proliferative and differentiation potential following transplantation. However, regenerative capacity does not simply reflect stem cell abundance, but instead depends on region-specific signaling cues. Local expression of metabolic, immune and differentiation-related factors further underscores the importance of spatially distinct environments in shaping outcomes. Our findings show how a shared injury response is associated with divergent regenerative outcomes, highlighting principles that may inform strategies to enhance tissue repair in other systems.

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation

2026-09-18T14:00:00Z

by Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero

Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)−4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1−4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.

An engineered bacterial symbiont maps micron-scale sugar gradients in the honeybee gut

2026-09-16T14:00:00Z

by Audam Chhun, Andrew Quinn, Alicia I. Pérez-Lorente, Théodora Steiner, Florian Zoppi, Thi Huong Giang Nguyen, Philipp Engel, Yolanda Schaerli

The honeybee gut microbiota plays a key role in shaping host health and susceptibility to disease. Yet, the nutrient environment it experiences within the gut remains poorly characterized. In particular, little is known about the spatial distribution of nutrients across the microbial community, as resolving such fine gradients in vivo has been technically challenging. Here, we engineer the native honeybee symbiont Snodgrassella alvi as a living biosensor to quantify the bioavailability of the dietary sugar arabinose within the gut. By expanding the genetic toolkit for S. alvi through chromosomal integration of high-burden genes and a suite of low-strength promoters, we achieve stable multi-gene expression without compromising host colonization. The resulting biosensor generates a specific, dose-dependent fluorescent response to arabinose in the living host, enabling visualization of sugar gradients across gut-associated bacterial biofilms at micron-scale resolution. Upon co-colonization with distinct Gilliamella species that differ in arabinose metabolism, the biosensor reported differential in vivo arabinose consumption, directly validating species-specific metabolic specialization within the host. Feeding bees with pollen further uncovered pronounced radial heterogeneity in the distribution of pollen-derived arabinose. These findings demonstrate how diet composition and microbial specialization generate fine-scale microenvironments within the gut. More broadly, this work establishes S. alvi as a genetically tractable platform for in situ biosensing, opening new avenues for dissecting metabolic interactions and nutrient distribution within living hosts.

Turning a phage anti-defense weapon into an immunity trigger

2026-09-16T14:00:00Z

by Anna B. Adelstein, Naama Aviram

Most bacterial immune systems raise an alarm when they sense a phage. A new study in PLOS Biology shows how type II Panoptes reverses this logic by maintaining a quiet signal and sensing infection through its sudden disappearance. Most bacterial immune systems raise an alarm when they sense a phage. A new study in PLOS Biology shows how type II Panoptes reverses this logic by maintaining a quiet signal and sensing infection through its sudden disappearance

SpaMOAL is a deep learning method that enables accurate spatial domain identification from multi-omics data

2026-09-16T14:00:00Z

by Jinxia Wang, Yuying Huo, Rui Zhao, Yan Pan, Jianqiang Wu, Han Wang, Xiangyu Li

Recent advances in spatial multi-omics technologies have opened new avenues for characterizing tissue architecture and function in situ, by simultaneously providing multimodal and complementary information—such as spatially resolved transcriptomic, epigenomic, and proteomic features. Current computational approaches face substantial challenges, such as effective integration of multi-omics molecular information with spatial information and corresponding high-resolution histology images. To address this challenge, we proposed SpaMOAL (Spatially Multi-Omics graph contrAstive Learning), a graph-based contrastive learning approach for spatial domain identification. SpaMOAL learns clustering-friendly representations from spatial multi-omics data by integrating spatial coordinates, histological image features, and molecular profiles, enabling accurate delineation of spatial tissue domains. Benchmarking across multiple recent paired spatial multi-omics datasets from mouse and human demonstrated that SpaMOAL consistently outperforms existing methods. By enabling accurate spatial domain delineation, SpaMOAL provides a powerful framework for interpreting tissue organization and cellular microenvironments.

R1-32-like public antibodies acquire tolerance to SARS-CoV-2 antigenic drift through somatic hypermutation

2026-09-15T14:00:00Z

by Chuanying Niu, Xiaohan Huang, Qihong Yan, Banghui Liu, Xijie Gao, Yidong Song, Jingjing Wang, Longyu Wang, Zimu Li, Huiran Zheng, Ping He, Xiaodong Huang, Hang Yuan, Binqian Zou, Yuedong Yang, Fandi Wu, Yicheng Yao, Gul Habib, Xinwen Chen, Ling Chen, Jun He, Jianhua Yao, Jincun Zhao, Xiaoli Xiong

R1-32-like public antibodies, characterized by shared IGHV1-69/IGLV1-40 usage, are elicited in more than 50% of individuals with COVID-19 and have been implicated in driving recurrent mutations at L452_SARS2 and F490_SARS2 within their convergent epitope in the SARS-CoV-2 spike receptor-binding domain. These mutations effectively mediate escape from non-affinity-matured R1-32-like antibodies with germline-like sequences. Here, we characterize four affinity-matured human R1-32-like antibodies, C092, C807, BD56-104, and BD56-597, that tolerate L452_SARS2 and F490_SARS2 mutations. We show that this tolerance arises from residues introduced by somatic hypermutation at convergent positions across multiple CDR loops and surrounding regions, thereby creating additional contacts that reinforce epitope binding. An unusual N354_SARS2 glycosylation site, which emerged in BA.2.86 and became fixed in its descendants, is linked to escape from affinity-matured R1-32-like antibodies, implying ongoing selection by this public antibody class. Using an AI model trained on extensive neutralization data, we further identified ZL525, an ultrapotent human R1-32-like antibody with pan-SARS-CoV-2 variant activity, including against the highly evasive KP.3 variant carrying the N354_SARS2 glycosylation, and broad sarbecovirus cross-reactivity extending to SARS-CoV-1. Together, these findings show how affinity maturation enables public antibodies to adapt to viral antigenic drift, reveal their role in shaping SARS-CoV-2 antigenic evolution, and demonstrate the potential of AI-empowered strategies for discovering broadly neutralizing antibodies.

Does acute inflammation triggered by infection promote cancer progression?

2026-09-15T14:00:00Z

by Felipe Valença-Pereira, Bryan Johnson, James DeGregori, Mercedes Rincon

Chronic infections are associated with cancer incidence and progression in human epidemiological data, but less is known about how such infections might promote cancer progression. Recent data implicate acute infection with common respiratory viruses, such as influenza and SARS-CoV-2, in cancer progression, providing evidence that infection-driven inflammation can promote tumor expansion and dissemination in experimental systems. The resulting acute inflammatory cascade and dynamic immune cell reprogramming can rapidly remodel the tissue microenvironment to favor cancer cell survival, growth, and evasion of immune elimination. However, acute infections can also elicit anti-tumor immune responses. Defining how infections differentially skew immune programs to promote or restrain cancer progression will therefore be essential for developing future strategies to target this disease.

Cyclic tri-adenylate controls a CARF-TM effector in type II Panoptes anti-phage systems

2026-09-15T14:00:00Z

by Sabine Grüschow, Peter Wotherspoon, Emma Hilton-Balfe, Shirley Graham, Malcolm F. White

Cyclic nucleotide second messengers are used in all domains of life to amplify viral infection signals and activate cellular defences. In prokaryotes, CBASS (cyclic nucleotide-based antiphage signalling system) and type III CRISPR-Cas systems generate a range of cyclic nucleotides which bind and allosterically activate effector proteins to mount an anti-viral response. Viruses have evolved counter measures to antagonise these signalling pathways in the form of cyclic nucleotide sponges and phosphodiesterases that sequester or degrade these molecules to subvert immunity. Recently, the Panoptes system was shown to function as a guard against these viral tactics. The type I Panoptes polymerase, mCpol, generates cyclic dinucleotides as decoy molecules that, when sequestered by phage proteins, results in the activation of the membrane-permeabilising effector 2TMβ to halt the phage infection cycle. Here, we investigate the type II Panoptes system, demonstrating that it generates cyclic tri-adenylate (cA₃) to maintain a CRISPR-associated Rossmann fold-transmembrane (CARF-TM) effector in an inactive, dimeric state. When cA₃ is sequestered or degraded, the CARF protein undergoes conformational changes. In vivo, the absence of cA₃ results in membrane disruption and growth arrest. Type II Panoptes provides defence against phages that express the cA₃-degrading enzyme Acb1; phage escapers introduce mutations into the acb1 gene to avoid triggering the Panoptes system. These findings expand our understanding of the guard systems that constitute a fascinating component of the bacterial immune system.

Atlastin-2-mediated endoplasmic reticulum membrane tethering is critical for flavivirus replication

2026-09-15T14:00:00Z

by Jonathan Einterz Owen, Cheyanne Lynn Bemis, Qingyi Wang, Ambarish C. Varadan, Jacob W. Vander Velden, Laura Andačić, Olus Uyar, Mansi Gupta, Christopher D. Scharer, Laurent Chatel-Chaix, Pietro Scaturro, Mehul S. Suthar, Christopher J. Neufeldt

Flaviviruses (genus Orthoflavivirus) are arthropod-borne viruses which cause approximately 400 million annual global infections in humans. Flavivirus infection requires cellular machinery to facilitate replication and spread. All known flaviviruses replicate in association with the host endoplasmic reticulum (ER), where genome replication is confined within virus-induced ER invaginations called viral replication organelles (vROs). Despite the central role of these structures during flavivirus infection, the mechanisms underlying vRO biogenesis remain undefined—particularly the membrane rearrangements required for their formation. In this work, we report a conserved role for a cellular ER remodeling protein, atlastin-2 (ATL2), in the organization of vROs within infected cells. Using confocal and electron microscopy, we show that ATL2 depletion leads to a reduction in vRO spatial distribution in flavivirus-infected cells. Changes in vRO distribution corresponded with a decrease in virus production and robust induction of innate immune responses. We also demonstrate that ATL2 accumulates in areas of vRO formation during flavivirus infection. Critically, mutational analysis showed that a tethering-competent but fusion-defective ATL2 mutant was sufficient to rescue DENV and ZIKV replication in ATL2-knockout cells. Finally, targeting of ATL2 activity using synthetic peptides significantly reduced DENV replication in both immortalized and human primary cells, suggesting a possible avenue for targeting host ER functions to limit flavivirus replication. Taken together, these results show that membrane tethering plays a critical and conserved role in flavivirus infection, functioning to organize membranes for vRO biogenesis and limit cellular immune activation. Importantly, we provide evidence that ATL2-mediated membrane organization can be targeted to inhibit viral replication.

How the mosquito’s carbon dioxide sense gets an internal boost

2026-09-11T14:00:00Z

by Chih-Ying Su

Mosquitoes use CO2 as a critical cue to sense if humans are nearby. A new study in PLOS Biology reveals that CO2-sensing neurons in mosquitoes can amplify each other’s signals, creating a neural echo chamber that may explain the remarkable sensitivity of mosquitoes to human presence. Mosquitoes use carbon dioxide as a critical cue to sense if humans are nearby. This Primer explores a new study in PLOS Biology that reveals that carbon dioxide-sensing neurons in mosquitoes can amplify each other’s signals, creating a neural echo chamber that may explain the remarkablesensitivity of mosquitoes to human presence.

Recurrent synapses between CO₂-sensitive olfactory sensory neurons enable robust CO₂ detection in Aedes aegypti mosquitoes

2026-09-10T14:00:00Z

by Jialu Bao, Wesley Alford, Avinash Khandelwal, Laurel Walsh, George Lantz, Santiago Poncio, Laia Serratosa Capdevila, Yervand Azatian, Brian DePasquale, David G. C. Hildebrand, Meg A. Younger, Wei-Chung Allen Lee

The mosquito Aedes aegypti’s human host-seeking behavior depends on the integration of multiple sensory cues. One of these cues, carbon dioxide (CO₂), gates odorant and heat pathways and activates host-seeking behavior. The neuronal circuits underlying processing of CO₂ information remain unclear. We used automated serial-section transmission electron microscopy (EM) to image and reconstruct the circuitry of the glomeruli that are innervated by the Ae. aegypti maxillary palp, including the glomerulus that responds to CO₂. Notably, CO₂-sensitive olfactory sensory neurons (OSNs) make high levels of recurrent synaptic connections with one another, while making a low density of feedforward synapses. At some of these contacts between CO₂ OSNs, we observe ribbon-like presynaptic structures, which may further enhance recurrent signaling. We compared both feedforward and recurrent connectivity with all olfactory glomeruli in Drosophila melanogaster, and we found more recurrent connections between the Ae. aegypti CO₂-responsive OSNs than in any D. melanogaster glomeruli. We developed a computational circuit model that demonstrates recurrent synapses are necessary for robust CO₂ detection under normal physiological conditions. Together, elevated levels of recurrent connectivity and ribbon-like structures may amplify sensory information detected by CO₂-sensitive OSNs to support mosquito activation and sensitization by CO₂, even in the presence of high levels of other odorants in the environment. We propose that this circuit organization supports the salience of CO₂ as a mosquito host cue.

Brain structural and functional connectivity converge prenatally but diverge after birth

2026-09-09T14:00:00Z

by Ruoke Zhao, Mingyang Li, Yuqi Zhang, Ruike Chen, Chenglin Ning, Zhiyong Zhao, Zhihan Yan, Meihao Wang, Dan Wu

Brain anatomical architecture supports its functional activity and complex cognitive processes. However, how the structure–function (SF) relationship establishes and develops during early life, as well as its underlying mechanisms, remain largely unclear. To address these questions, we leveraged multimodal MRI data from two large-scale public databases, the developing Human Connectome Project (dHCP) and the Baby Connectome Project (BCP), to characterize the spatiotemporal dynamics of SF coupling from the perinatal period to toddlerhood. Our results revealed that SF coupling at birth exhibited a spatial variation along the sensorimotor-association cortical axis. During the perinatal period (26–44 postmenstrual weeks), SF coupling strengthened drastically and followed three distinct developmental trajectories across the cortex, with sensorimotor and visual areas showing the fastest growth and the earliest plateau. After birth, SF coupling shifted toward a weakening pattern across the cortex during infancy and toddlerhood (1–28 months). These developmental changes of SF coupling were more strongly associated with the maturation of functional connectivity, which first converged toward the local structural architecture prenatally and then diverged postnatally through the expansion of global inter-modular pathways. Furthermore, SF coupling at birth, the developmental transition point, exhibited a significant association with individual differences in cognition and language outcomes at 18 months of age. Collectively, these findings offer valuable insights into the organizational principles underlying structural and functional network development during early life as well as the complex evolving relationship between them.

Growth-rate coordination across the width of a leaf preserves its flatness

2026-09-08T14:00:00Z

by Kate Harline, Brendan Lane, Maura J. Zimmermann, Antoine Fruleux, Gabriella Mosca, Sören Strauss, Nik Tavakolian, James W. Satterlee, Chun-Biu Li, Abhyudai Singh, Arezki Boudaoud, Richard S. Smith, Adrienne H. K. Roeder

The growth and division of cells in plant leaves is highly dynamic in time and space, even though cells cannot move relative to their neighbors. Thus, organ shape must emerge from carefully coordinated growth, especially in leaves that remain relatively flat as they grow. Here we explored the phenotype of the jagged and wavy (jaw-D) mutant in Arabidopsis thaliana, in which the leaves do not remain flat. It has previously been shown that the jaw-D mutant phenotype is caused by the overexpression of miR319, which represses TCP transcription factors, thus delaying maturation of the leaf. We analyzed cell dynamics in wild type and jaw-D by performing time-lapse live imaging of developing leaves. We found that the progression of maturation from the tip of the leaf downward was delayed in jaw-D relative to wild type based on several markers of maturation, in agreement with the role of TCP transcription factors in promoting maturation. We further found that these changes in maturation were accompanied by differences in the coordination of growth across the leaf, particularly across the mediolateral axis, causing growth conflicts that prevent the leaf from remaining flat. Modeling revealed that curvature develops when growth is uneven across the leaf in the direction perpendicular to the direction of growth. Although leaf flatness is often framed as a problem that requires the local synchronization of growth on the abaxial versus adaxial sides (bottom versus top) of the leaf, our results based on the jaw-D phenotype suggest that wild-type plants also need to coordinate growth more globally across the leaf blade to maintain flatness.

Discovery Stack Pilot demonstrates the feasibility and outcomes of a scientist-designed peer-review model that separates quality and impact

2026-09-08T14:00:00Z

by Maureen A. McGargill, Beiyun C. Liu, Michael S. Kuhns, Daniel Mucida, Isabella Rauch, Lauren B. Rodda, Meghan A. Koch, Hugo Gonzalez Velozo, Ken Cadwell, Tanya S. Freedman, Tiffany C. Scharschmidt, Richard Sever, Jose Ordovas-Montanes, Sara Suliman, Andrew Oberst, Brooke Runnette, Matthew F. Krummel

Peer review serves as the cornerstone of scientific quality control. Yet, the current journal-centric system is hindered by long timelines, high publication costs, inconsistent review quality, systemic biases, and editorial gatekeeping. Notably, the system relies on misaligned measures of impact that are tethered to journal branding and conflate scientific rigor (Quality) with perceived significance (Impact). Here, we report findings from the Discovery Stack Pilot Study, which tested a scientist-designed, journal-independent peer review model. The Discovery Stack model integrates in-line reviewer comments to promote constructive feedback and separately evaluates scientific Quality and Impact using defined criteria. To examine feasibility and effectiveness, manuscripts were reviewed in parallel with traditional journal review. A total of 162 reviews were completed, and survey data from 86 participants were analyzed. The results showed that reviewers effectively evaluated Quality and Impact as separate dimensions, with Quality scores being more consistent across reviewers than Impact scores. Participants strongly supported the core elements of the Discovery Stack model and expressed enthusiasm for its broader adoption to enhance transparency, efficiency, and value in peer review. Future studies will explore integrating this model into a digital platform for reviewing and curating scientific discoveries to improve the production and dissemination of high-quality research.

The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals

2026-09-08T14:00:00Z

by Meixi Lin, Sneha Chakraborty, Carlos Eduardo G. Amorim, Sergio F. Nigenda-Morales, Annabel C. Beichman, Paulina G. Nuñez-Valencia, Jonathan C. Mah, Jacqueline A. Robinson, Christopher C. Kyriazis, Christian D. Huber, Andrew E. Webb, Sarah D. Kocher, Frederick I. Archer, Andrés Moreno-Estrada, Robert K. Wayne, Kirk E. Lohmueller

The distribution of fitness effects (DFE) describes the selection coefficients of newly arising mutations and fundamentally influences population genetic processes. However, the extent and mechanisms of differences in the DFE for non-synonymous mutations have not been systematically investigated across species with divergent phylogenetic histories and ecologies. Here, we inferred the DFE in natural populations of 11 animal (sub)species, including humans, mice, fin whales, vaquitas, wolves, collared flycatchers, pied flycatchers, halictid bees, Drosophila, and mosquitoes. We found that mammals have a higher proportion of strongly deleterious mutations (defined as s≤−0.01; 22% to 47% in mammals; 0.0% to 5.4% in insects and birds) and a lower proportion of weakly deleterious mutations than insects and birds. Further, the DFE co-varies with phylogeny, such that the mean mutation effects are more similar in closely related species (Pagel’s λ = 0.84, P = 0.01). Next, we investigated whether various summary statistics of the DFE were related to variation in life-history traits across these organisms. We found some support for genome size, body mass, and long-term effective population size being correlated with the DFE. Overall, our findings are consistent with predictions derived independently from the Fisher’s Geometric Model (FGM), which defines organismal complexity as the number of phenotypes under selection. FGM predicts that mutations are more deleterious in complex organisms, while strongly deleterious mutations occur more frequently in smaller populations. Our study demonstrates strong phylogenetic signal in the evolution of a fundamental population genetics parameter, and proposes that, through mechanisms of epistasis, long-term population size and organismal complexity could be underlying variation in the DFE across animals.

Seaweed carbon removal cannot keep up with climate-driven loss

2026-09-08T14:00:00Z

by Karen Filbee-Dexter, Albert Pessarrodona, Kira A. Krumhansl, Thomas Wernberg

The prevailing narrative of seaweed carbon as a possible climate change mitigation solution overlooks the central challenge that climate change itself is adversely impacting seaweed forests worldwide, potentially shifting these ecosystems from carbon sinks to carbon sources. In this Essay, we show that climate-induced seaweed forest loss is eroding their carbon sink capacity three to four orders of magnitude (1,000–10,000×) faster than it can currently be restored or recovered through active interventions. We consider that this stark disparity calls for a fundamental shift in seaweed carbon research away from a focus on future sequestration gains and toward explicitly assessing the risk of carbon emissions from climate-driven ecosystem loss.

Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism

2026-09-03T14:00:00Z

by Jie Ran, Changfeng Wei, Yang Yang, Yufei Zhang, Guizhi Guo, Nan Ma, Long Yin, Hongjun Fan, Jingrui Li, Heng Guo, Renshuai Zhang, Runa Wang, Dengwen Li, Min Liu

Primary cilia are essential microtubule-based sensory organelles, and their dysfunction has been increasingly linked to metabolic stress. However, the underlying molecular mechanisms remain poorly understood. Herein, we reveal that ciliary defects in retinal photoreceptors and renal tubules exacerbate tissue damage during the progression of diabetic complications. Under hyperglycemic stress, protein arginine methyltransferase 1 (PRMT1) and histone deacetylase 6 (HDAC6) are significantly upregulated in both retinal and renal tissues. Genetic ablation of either enzyme effectively preserves ciliary architecture and restores organ function in diabetic mice. Mechanistically, PRMT1 localizes to the basal body, where it interacts with and methylates HDAC6 at arginine 16, consequently enhancing HDAC6 stability. In turn, HDAC6 mediates the deacetylation of PRMT1 at lysine 128, which elevates PRMT1 protein levels. This mutual modification crosstalk establishes a pathological positive feedback loop that stabilizes a pro-disassembly complex at the basal body, thereby potentiating ciliary impairment and expediting the progression of diabetic complications. Pharmacological inhibition of the PRMT1-HDAC6 loop significantly attenuates the pathological features of both diabetic retinopathy and nephropathy. Collectively, our findings uncover a reciprocal regulatory mechanism mediated by deacetylation and arginine methylation that drives cilium disassembly under hyperglycemic stress, providing promising therapeutic targets for the treatment of metabolic ciliopathies.

No evidence for modulation of the readiness potential by respiratory phase during natural breathing

2026-09-02T14:00:00Z

by Lucas Jeay-Bizot, Raniyah Chishti, Uri Maoz, Aaron Schurger

Respiratory processes are increasingly implicated in shaping neural activity and behavior. Recent studies have reported a coupling between respiratory phase and the cortical readiness potential (RP), suggesting that breathing may modulate the neural processes preceding voluntary action. Here, using electroencephalography recordings in humans, we re-examine this claim using the original dataset and a new independent dataset, as well as in simulated data with no coupling. We show that the reported association arises from a confound: both RP amplitude and respiratory phase are coupled to movement onset. The original analysis does not control for this dependency, leading to a spurious effect that is also observed in simulated data. When trials are instead grouped by respiratory phase at the time of movement, thereby controlling for this confound, the apparent coupling disappears. Across datasets, Bayesian analyses provide evidence for the absence of an effect under natural breathing conditions. These findings indicate that respiratory phase does not directly modulate RP amplitude during spontaneous behavior. More broadly, they reveal a shortcoming of phase-amplitude coupling analyses applied to epoched data with slowly varying signals, and highlight the importance of controlling for shared dependencies when interpreting physiological–neural relationships.

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R1-32-like public antibodies acquire tolerance to SARS-CoV-2 antigenic drift through somatic hypermutation

Does acute inflammation triggered by infection promote cancer progression?

Cyclic tri-adenylate controls a CARF-TM effector in type II Panoptes anti-phage systems

Atlastin-2-mediated endoplasmic reticulum membrane tethering is critical for flavivirus replication

How the mosquito’s carbon dioxide sense gets an internal boost

Recurrent synapses between CO2-sensitive olfactory sensory neurons enable robust CO2 detection in Aedes aegypti mosquitoes

Brain structural and functional connectivity converge prenatally but diverge after birth

Growth-rate coordination across the width of a leaf preserves its flatness

Discovery Stack Pilot demonstrates the feasibility and outcomes of a scientist-designed peer-review model that separates quality and impact

The distribution of fitness effects of nonsynonymous mutations varies phylogenetically across animals

Seaweed carbon removal cannot keep up with climate-driven loss

Hyperglycemic stress aggravates diabetic retinopathy and nephropathy by promoting cilium disassembly via a deacetylation- and methylation-mediated regulatory mechanism

No evidence for modulation of the readiness potential by respiratory phase during natural breathing

Recurrent synapses between CO₂-sensitive olfactory sensory neurons enable robust CO₂ detection in Aedes aegypti mosquitoes