PLOS Biology: New Articles

Identity-specific reward expectations in orbitofrontal cortex guide goal-directed choices

2026-07-09T14:00:00Z

by Phillip P. Witkowski, Noelle Henein, Nicole Moussa, Geoffrey Schoenbaum, Thorsten Kahnt

Real-life decisions are typically directed toward specific types of rewards (e.g., a slice of pizza or a bowl of pasta), but reward identity is often neglected in neuroeconomic theories of decision-making. Previous research has shown that the lateral orbitofrontal cortex (lOFC) represents the specific rewards predicted by environmental cues. However, whether and how these expectations influence decision-making remains an open question. To address these questions in humans, we developed a novel behavioral task in which Pavlovian cues associated with specific rewards are presented before participants can make decisions to forage these rewards. Using pattern-based analysis of functional magnetic resonance imaging data, we show that cues predicting distinct reward types evoke identity-specific expectations in lOFC, which in turn predict subsequent choices. This effect is amplified by activity in the nucleus accumbens, which enhances the influence of lOFC reward expectations on action representations in the dorsal anterior cingulate cortex. These results connect representational and motivational accounts of decision-making, highlighting the neural mechanism by which expectations about reward identity guide goal-directed behavior.

Dipteran flight diversity is shaped by aerodynamic constraints, scaling, and evolutionary trade-offs

2026-07-09T14:00:00Z

by Camille Le Roy, Ilam Bharathi, Thomas Engels, Florian T. Muijres

Flight has been a key innovation in insect evolution, yet the selective and mechanistic pressures shaping their flight motor systems remain poorly understood. Here, we present a comprehensive comparative analysis of flight in Diptera (true flies), integrating morphology, wingbeat kinematics, and aerodynamics within a phylogenetic framework. We quantified morphology in 133 species spanning the Dipteran phylogenetic and size range, and for a subset of 46 species, we combined high-speed stereoscopic videography with computational fluid dynamics (CFD) to characterize wingbeat kinematics and aerodynamic performance, respectively. Our results reveal that morphology is strongly structured by phylogeny, whereas wingbeat kinematics are broadly conserved across Diptera, reflecting dominant aerodynamic constraints. Two early-diverged lineages, Culicomorpha (mosquitoes and midges) and Tipulomorpha (crane flies), exhibit strikingly divergent kinematics and aerodynamics, suggesting lineage-specific selective pressures. Combining these data with scaling analyses shows that maintaining in-flight weight support across the dipteran size range requires systematic allometric adjustments in wing morphology, wingbeat kinematics, and flight musculature. Smaller dipterans achieve weight support through relatively larger wings and higher wingbeat frequencies, whereas larger dipterans achieve the same aerodynamic requirement through increased investment in flight musculature to sustain the necessary mechanical power output. These size-dependent trait combinations highlight how different morphological and kinematic adaptations evolved in response to the shared physical requirements of hovering flight across Diptera. Mosquitoes and midges represent an extreme case, exhibiting a pronounced aerodynamic–acoustic trade-off with disproportionately high wingbeat frequencies, large flight musculature and increased aerodynamic and acoustic power, consistent with selection favoring acoustic signaling during in-swarm mating. By integrating comparative morphology, kinematics, and aerodynamics across a major insect radiation, our study uncovers the interplay between physical scaling laws, aerodynamic constraints, and ecological pressures in shaping the evolution of animal flight. These findings provide a mechanistic framework for understanding how complex locomotor systems diversify under multiple selection pressures.

GABA neurons in the sublaterodorsal tegmental nucleus suppress wakefulness in healthy and narcoleptic mice

2026-07-08T14:00:00Z

by HanHee Lee, Jimmy J. Fraigne, John H. Peever

The sleep-wake cycle is generated by competing neural circuits that control the oscillation between wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. While the sublaterodorsal tegmental nucleus (SLD) is recognized for its role in REM sleep generation, the functional contribution of its GABAergic neurons (SLD^GABA) to sleep-wake regulation remains poorly understood. Here, we found that SLD^GABA neurons function as a suppressor of wakefulness in both healthy (i.e., orexin^+/+) and narcoleptic (i.e., orexin^−/−) mice. In healthy mice, optogenetic silencing of SLD^GABA neurons rapidly induced robust wakefulness, while enhancing cortical and motor activity. Conversely, optogenetic activation of these neurons suppressed wakefulness and promoted NREM sleep. We found traces of SLD^GABA axonal projections to wake-promoting brain regions, providing an anatomical basis for their wake-suppressing effects. Importantly, we discovered that SLD^GABA neurons play a pathological role in narcolepsy: their activation in orexin-deficient narcoleptic mice triggered characteristic sleep attacks—rapid intrusions of NREM sleep during active wakefulness—while silencing these neurons rescued animals from both sleep attacks and cataplexy. Collectively, these findings establish SLD^GABA neurons as a key regulator of arousal state transitions and identify them as a novel therapeutic target for the treatment of narcolepsy.

A developmental shift in glucocorticoid receptor expression preserves glucocorticoid sensitivity in the adult suprachiasmatic nucleus

2026-07-07T14:00:00Z

by Kristian Händler, Varun K. A. Sreenivasan, Violetta Pilorz, Celia Martinez-Perez, Iratxe Elorduy, Tomas J. Casas, Marianne Lehmann, Jon Olano Bringas, Laura Escobar Castañondo, Nora Bengoa-Vergniory, Federico N. Soria, Henrik Oster, Malte Spielmann, Mariana Astiz

The circadian system synchronizes physiology, improving the adaptation to daily environmental changes. In mammals, the central pacemaker, in the suprachiasmatic nuclei (SCN) of the hypothalamus, coordinates “wake” functions by inducing the circadian release of glucocorticoids (GCs). GCs entrain the clocks of a wide variety of tissues through GC receptor (GR) activation, however, the influence of GCs on the SCN is unclear and seems to depend on the maturity of the circuit. During the perinatal period, the mouse SCN express GR and respond directly to GCs while the adult SCN express low GR and have been traditionally considered resistant to GCs. To understand the change of sensitivity to GCs we followed the developmental trajectory of the mouse SCN, and found that while GR is expressed in all SCN cells early in life, it remains expressed mainly in astrocytes in the adult. Using a model of prenatal exposure to GCs, we found that offspring from treated mothers, adapt slower to shifted light–dark cycle and shows reduced expression of GR in SCN astrocytes. The adult SCN astrocytes can indeed sense and respond to GCs with rapid astrocytic Ca²⁺ events that propagate across neighboring cells, an effect that is prevented by the specific inhibition of astrocyte–astrocyte communication. Our findings provide a conceptual advance on how the mouse clock develops and on the influence that GCs have on the SCN. This might be relevant to understand how circadian synchrony is restored in conditions of temporal misalignment, such as jet lag.

Sequential neural dynamics underlie unconscious integration and conscious perception of visual stimuli

2026-07-06T14:00:00Z

by Maëlan Q. Menétrey, Michael H. Herzog, David Pascucci

In some forms of postdictive phenomena, later events influence the perception of earlier ones, suggesting that conscious perception may be preceded by extended periods of unconscious processing. An example is the Sequential Metacontrast (SQM) paradigm, in which vernier offsets are unconsciously integrated over several hundred milliseconds before conscious perception. Obviously, the integrated percept can only emerge after each individual element in the stream has been processed. Thus, the SQM provides a unique opportunity to dissociate unconscious from conscious stages of visual processing, as these stages are well separated in time. Using electroencephalography (EEG) recordings in human participants during the SQM, we identified two distinct stages of neural activity: an early occipital EEG activity pattern (~200 ms after the initial vernier) associated with unconscious processing, and a later centro-parietal EEG pattern (~400 to 600 ms after SQM onset) associated with the integrated percept and the behavioral report. We propose that the transition between these neural patterns marks the shift from unconscious encoding of individual visual stimuli to their integrated percept.

Shared memories of event details in the human brain are altered by misinformation and test expectations

2026-07-06T14:00:00Z

by Xuhao Shao, Chuansheng Chen, Elizabeth F. Loftus, Bi Zhu

Shared memories of event details are crucial to eyewitness testimony. When different people encode or recall the same event, similar scene-specific neural activity patterns emerge across individual brains. However, it remains unclear whether these patterns are specific to event details and how test expectancy (i.e., expecting free recall or general memory tests) and misinformation affect them. In this study, 100 participants were randomly assigned to view one of two versions of each event. Both versions featured identical scenarios, but with different details. About half of the participants were informed about the upcoming free recall before viewing events, while the others were told to expect a general memory test. Functional magnetic resonance imaging was used to record their brain activity during four stages: viewing original events, initial free recall, reading misinformation, and final free recall of original events. The neuroimaging data were analyzed based on the similarity of neural patterns across participants. Test expectancy increased the similarity of detail-specific neural activity patterns between individuals when they viewed original events in brain regions relevant for visual attention. Misinformation increased the likelihood of people forming shared false memories of event details. People who formed shared false memories exhibited similar detail-specific patterns of activity in the dorsomedial prefrontal cortex when reading misinformation. People who formed shared true memories exhibited similar detail-specific patterns of activity in the inferior parietal lobe when viewing original events, as well as in the ventrolateral prefrontal cortex and middle temporal gyrus when recalling them after exposure to misinformation. Our findings revealed that different brain regions of the default mode network play distinct roles in the encoding and recall of event details shared by individuals.

Engineering resilient gene drives for sustainable malaria control by predicting, testing and overcoming target site resistance in Anopheles gambiae

2026-07-06T14:00:00Z

by Ioanna Morianou, Lee Phillimore, Bhavin S. Khatri, Louise Marston, Matthew Gribble, Austin Burt, Federica Bernardini, Andrew M. Hammond, Tony Nolan, Andrea Crisanti

CRISPR-based gene drives are selfish genetic elements with the potential to spread through entire insect populations for sustainable vector control. Gene drives designed to disrupt the reproductive capacity of females can suppress laboratory populations of the malaria mosquito, Anopheles gambiae. However, any suppressive intervention will inevitably exert an evolutionary pressure for resistance, and the likelihood of resistance emerging at natural population scales remains poorly defined. Here, we present a pipeline to quantify the evolutionary space for resistance, enabling accelerated discovery, engineering, and testing of both natural and drive-induced variants that could reverse gene drive spread. We applied our approach to stress-test a best-in-class suppression gene drive that has evaded resistance in all laboratory-contained releases to date, known as Ag(QFS)1. We showed that previously undetected resistant alleles can arise at low frequency, including a novel type of partially resistant alleles that can perturb drive-invasion dynamics. Integrating experimentally derived resistance rates with population genetic modeling shows that single-target suppression drives are unlikely to be robust at natural mosquito population sizes, even at highly constrained loci. Here, we engineer and validate multiplexed gene drives in Anopheles gambiae, that target multiple conserved sites, actively removing resistant alleles. Our models predict that such gene drives could supress large natural mosquito populations in the field.

Resistance potentiators: Evolutionary catalysts of antibiotic resistance

2026-07-06T14:00:00Z

by R. Craig MacLean, Adam Mulkern, Liam P. Shaw

Why do even closely-related bacteria differ in their capacity to evolve antibiotic resistance? Drawing on evidence from experimental evolution, pathogen genomics, and molecular microbiology, this Essay argues that the evolution of antibiotic resistance in bacterial genomes is frequently catalyzed by the presence of ‘resistance potentiators’: genes, elements, or pathways that accelerate evolution in a trait-specific manner. Epidemiological evidence suggests that resistance potentiators that modulate phenotypes have been particularly important in successful pathogen lineages. Furthermore, experimental models show that combining antibiotics with inhibitors of resistance potentiators can restrict the evolution of resistance, suggesting that they could be future drug targets or otherwise lead to more evolution-informed antibiotic therapy.

Correction: Cdc42 interacts with chaperone Ydj1 to enhance its stability and partitioning during asymmetric cell division and aging in yeast

2026-07-02T14:00:00Z

by The PLOS Biology Staff

The cell cloud: Adopting systems biology concepts in the era of single-cell immunology

2026-07-02T14:00:00Z

by Tal Shay, Christophe O. Benoist, Ricardo Grieshaber-Bouyer

High-throughput single-cell assays reveal data that defies discrete categorization. The ‘cell cloud’ model, grounded in established systems biology principles, offers a framework to navigate biological plasticity alongside technical variability. Immune cells exist as continuous clouds, not discrete categories. In this Perspective, authors from the Immunological Genome Project reframe immune identity through systems biology, and redirect where immunotherapies should aim: at the dynamics of the cloud, not just its center.

Disinhibitory signaling enables flexible coding of top-down information in cortical networks

2026-07-02T14:00:00Z

by Tomas G. Aquino, Robert Kim, Nuttida Rungratsameetaweemana

Flexible behavior requires the ability to modulate sensory processing based on task context, yet the circuit-level mechanisms supporting this capacity remain poorly understood. Here, we combine recurrent neural network modeling and neural recordings from mouse visual cortex to investigate how task context shapes sensory coding. Networks trained on an instruction-based discrimination task develop a disinhibitory interneuron-to-interneuron motif that dynamically gates task-relevant sensory information. Perturbation and lesion analyses show that this motif is necessary for task performance and for maintaining distinct sensory representations across contexts. We validate key predictions in mouse visual cortex, where interneuron activity patterns exhibit comparable task-dependent modulation. These results identify a biologically plausible circuit motif that supports flexible sensory processing and link recurrent connectivity structure to adaptive context integration in both artificial and biological systems.

Towards globally equitable bioinformatics adoption

2026-07-01T14:00:00Z

by Paulyna Magaña, Piraveen Gopalasingam, Jennifer R. Fleming, Oleg Kovalevskiy, Augustin Žídek, ThankGod Echezona Ebenezer, Agata Laydon, Roz Onions, Eva Akurut, Syed Muktadir Al Sium, Yalbi Itzel Balderas-Martínez, Sanjana Fatema Chowdhury, Saikat Chowdhury, Sylvia Christie, Govinda Rao Dabburu, Fatoumata Gnine Fofana, Ronald Galiwango, Mahipal Ganji, Daudi Jjingo, Fredrick Elishama Kakembo, Grace Kebirungi, Shahiid Kiyaga, Ayoub Ksouri, Sanjeet Kumar Mahtha, Vinicius Maracaja-Coutinho, Jack Mason, Jose Arturo Molina-Mora, Patricia P. N. Nabisubi, Emmanuel Nji, Houcemeddine Othman, Martina Soledad Paoletta, Nicole M. Scherer, Bhagya Senadheera, Adrián Gustavo Turjanski, David Twesigomwe, Andrew Walakira, Sameer Velankar, Cath Brooksbank

Advances in artificial intelligence (AI)-driven bioinformatics promise democratized discovery, yet major inequities persist. Equitable adoption of bioinformatics tools will require sustained investment in infrastructure, training, institutions, and global communities, not just access. Advances in AI-driven bioinformatics promise democratized discovery, yet major inequities persist. This Perspective uses AlphaFold as an illustrative case to argue that equitable adoption of bioinformatics technologies will require sustained global investment, not just provision of access.

Unusual decay: Recombination loss leads to splicing errors in green algae

2026-06-26T14:00:00Z

by Anamaria Necsulea

Recombination suppression leads to genomic erosion through an accumulation of deleterious mutations. A new study in PLOS Biology reveals an outstanding increase in aberrant splicing in non-recombining genomic regions in green algae. Recombination suppression leads to genomic erosion through an accumulation of deleterious mutations. This Primer discusses a new study that reveals an outstanding increase in aberrant splicing in non-recombining genomic regions in green algae.

The human claustrum supports cognitive networks for externally and internally driven task demands

2026-06-26T14:00:00Z

by Brent W. Stewart, Matthew A. Cormie, Michael L. Keaser, Massieh Moayedi, Brian N. Mathur, David A. Seminowicz

Cognitive control is believed to arise from task-dependent interactions among networks of brain regions. Although several debilitating neuropsychiatric disorders are characterized by cognitive network dysfunction, the neural circuit mechanisms supporting task-dependent network activity are largely unknown. External and internal task demands elicit opposing responses from key cognitive networks, and claustrum projections target regions associated with both network states. We tested if claustrum supports task-dependent network activity in humans using fMRI during tasks with externally and internally driven demands: working memory (n = 420) and autobiographical memory (n = 35). Claustrum activity increased in both tasks. Claustrum exhibited anatomical connectivity with regions representing all implicated networks, and claustrum effective connectivity suggested an excitatory influence on regions in multiple task-associated networks. Task response and connectivity measures differed between the claustrum and regions prominently implicated in directing network states—the anterior insula and pulvinar. These findings establish a role for the claustrum in supporting task-dependent network states subserving cognitive control.

Engineered bipaternal mice reveal the consequences of life without a maternal genomic contribution

2026-06-25T14:00:00Z

by Si-Nan Ma, Fan Li, Yu-Long Zhao, Xue-Han Sun, Xue-Song Chen, Tian-Shi Pan, Qing-Tong Shan, Chao Liu, Gui-Hai Feng, Zhi-Kun Li, Qi Zhou, Wei Li

Successful mammalian development normally requires contributions from both maternal and paternal genomes, yet how these parental components jointly shape organismal development remains incompletely understood. Using engineered bipaternal mice generated from androgenetic embryonic stem cells carrying extensive imprinting-region modifications and produced through tetraploid complementation, we examined developmental and physiological consequences of development supported exclusively by paternal genomes. Placental analyses revealed partial normalization of placental growth but persistent differences among conceptuses. Transcriptomic profiling across embryos and postnatal tissues similarly showed broad alterations in gene expression states involving both imprinted and non-imprinted genes. Despite these differences during development, adult physiology showed a more coherent endpoint: integrated transcriptomic and metabolomic analyses revealed that adult livers converge toward an altered metabolic configuration characterized by coordinated perturbations of the tricarboxylic acid cycle and associated lipid metabolism, accompanied by hepatic lipid accumulation and increased systemic fat mass. These findings indicate that paternal-only mammalian development can proceed across multiple stages but follows altered developmental trajectories that culminate in distinct physiological states, providing insight into how maternal and paternal genomic contributions interact to shape mammalian development and physiology.

Angptl5 restricts primitive hematopoiesis by promoting retinoic acid signaling in zebrafish

2026-06-25T14:00:00Z

by Jing Mo, Ding-Hao Zhuo, Min Gao, Ying Huang, Tao Cheng, Yang Dong, Yan-Yi Xing, Yun-Fei Li, Zi-Xin Jin, Xiang Liu, Guo-Qin Zhao, Hai-Rong Pu, Yu-Meng Liu, Li-Ping Shu, Peng-Fei Xu

Homeostasis is essential for hematopoiesis, and its dysregulation can lead to severe pathological conditions. Retinoic acid (RA) is a key regulator that exerts concentration-dependent effects on both embryonic and adult hematopoiesis. However, the mechanisms that modulate RA signaling in hematopoietic processes remain poorly understood. Using zebrafish as a model, we identified angiopoietin-like protein 5 (Angptl5) as a critical regulator of hematopoietic homeostasis. Loss of Angptl5 function resulted in myeloid hyperplasia in the anterior lateral plate mesoderm (ALPM) and anterior expansion of erythroid progenitors in the posterior lateral plate mesoderm (PLPM)—phenotypes consistent with attenuated RA signaling. Molecular analyses confirmed impaired RA signaling in angptl5^Δ10/Δ10 mutants, and exogenous RA supplementation fully rescued the hematopoietic defects. Mechanistically, we found that Angptl5 transcriptionally activates retinol dehydrogenase dhrs9 through its interaction with Integrin α6lβ5. Our findings establish Angptl5 as a novel and essential regulator of embryonic hematopoiesis and reveal a previously unrecognized mechanism controlling hematopoietic homeostasis. These insights position Angptl5 as a potential therapeutic target for hematological disorders.

Multiple adhesion molecules act together in oligodendrocyte-mediated axonal selection and myelin formation

2026-06-25T14:00:00Z

by Swathi Radha, Martina Arends, Georg Kislinger, Agata Rhomberg, Martina Schifferer, Minou Djannatian, Mikael Simons

Rapid information processing in complex organisms depends on myelin, which consists of a multilamellar membrane that tightly adheres to the axonal surface along the internode and at paranodal loops, where specialized adhesion proteins maintain axon-glial contact. Because the decision to myelinate an axon profoundly influences neuronal transmission, this process must be precisely regulated. Yet, it remains unclear which specific molecules enable oligodendrocytes to select appropriate axonal substrates for myelination. Several key myelin-associated adhesion systems have been identified, including Myelin-associated glycoprotein (Mag) and Cell Adhesion Molecule 4 (Cadm4) at the internode, as well as Contactin1 (Cntn1) at the paranode; however, these three adhesion molecules have not previously been deleted in combination. Here, using zebrafish, we systematically disrupted all three myelin-associated adhesion systems. We found that the combined loss of Mag, Cadm4, and Cntn1 severely impairs myelin initiation and destabilizes the few nascent sheaths that do form, resulting in a phenotype characterized by oligodendrocytes exhibiting membrane “stubs”. The failure to form myelin triggered cell death of early myelinating oligodendrocytes and resulted in profound hypomyelination. Our findings reveal that axonal target selection and myelin formation depend on a redundant set of adhesion molecules, and that their simultaneous loss largely abolishes myelin biogenesis.

Splicing deficiency is driven by genomic erosion in non-recombining algal mating-type chromosomes

2026-06-25T14:00:00Z

by Chris Condon, Andrea Galvez, Alexander Kramer, Landen Gozashti, Chris Vollmers, Manuel Ares Jr., Russell Corbett-Detig

Splicing deficiency may represent a critical yet underexplored form of genomic erosion in non-recombining regions. Across four phytoplankton species diverged ~333–639 million years ago, genes within U (female) and V (male) “UV” mating-type regions—non-recombining chromosomal regions that determine mating compatibility—show strikingly elevated intron retention relative to genes in other genomic regions. Long-read data reveal abundant aberrant, likely non-functional mRNA isoforms despite preserved coding potential. This preservation suggests that splicing defects arose early in UV evolution and have persisted over deep time. We propose that these defects arise from evolutionary changes in sequence composition and chromatin organization that accompany recombination suppression, such as reduced GC content, altered nucleosome occupancy, and disrupted methylation, that collectively compromise splicing fidelity. Unlike sex chromosomes, which often degenerate through gene loss, splicing-deficient UV regions in green algae retain hundreds of genes, indicating that transcript-level dysfunction provides an alternative route to functional decay. Our results identify chromatin-mediated splicing deficiency as a novel axis of genomic erosion and position algal UV systems as models for studying how recombination suppression reshapes RNA processing fidelity in essential, non-recombining genomes.

Normative assembly rule reveals fairness in microbial communities

2026-06-24T14:00:00Z

by Teemu Kuosmanen, Juhani Rantanen, Dovydas Kičiatovas, Sanna Pausio, Ville-Petri Friman, Teppo Hiltunen, Ville Mustonen

Understanding and predicting how communities assemble is a paramount challenge in ecology. Here we address these questions normatively by comparing the observed species abundance distribution to a game-theoretically fair distribution based on each species’ Shapley value. By analyzing in total 56 distinct community outcomes, we assess how fairly biomass is distributed in microbial communities displaying both competitive and cooperative interactions in different growth conditions. We find examples of fair communities that closely follow their Shapley value across all environments as well as counterexamples where the true abundances deviate from the species’ objective contribution to community biomass. Next, we develop a fair assembly rule based on the recursive definition of Shapley value and show that also unfair community compositions are consistent with the principles of fair assembly after the lower-level competitive outcomes are known. Our results give unique empirical insights into the distributive function of ecological dynamics and lay down the theoretical foundations of what might become a normative community assembly theory.

Longitudinal lineage tracing reveals early clonal attrition during Drosophila midgut aging

2026-06-24T14:00:00Z

by Han Gong, Kehui Liu, Shanjun Deng, Jinwen Wang, Xionglei He, Li Liu

The dynamics of stem cell maintenance and proliferative patterns are key determinants of tissue aging in multicellular organisms. Leveraging our previously developed SMALT system with enhanced sequencing compatibility, we performed longitudinal lineage tracing of the adult Drosophila melanogaster midgut across different developmental stages. Using ubiquitous Tubulin-GAL4-driven labeling, we first profiled midgut-wide clonal dynamics during early adulthood (3–33 days post-eclosion). Phylogenetic reconstruction revealed that clonal diversity peaked immediately after eclosion and began to decline earlier than anticipated, accompanied by a reduction in effective population size. To further investigate stem cell-specific dynamics during late adulthood, we employed intestinal stem cell (ISC)-specific Dl-GAL4-driven labeling (33–63 days post-eclosion) and observed sustained clonal attrition in the posterior midgut. This progressive loss of diversity was consistent with an age-associated change in effective proliferative behavior and reduced lineage maintenance capacity, as reflected by a decline in net proliferative output inferred from lineage topology. Remarkably, ISC lineages emerging within the first 10 days post-eclosion exhibited sustained clonal dominance in aging populations, with a single lineage comprising over 63% of sampled cells by Day 63. Bayesian survival modeling confirmed that these early-origin lineages have the highest probabilities of long-term persistence, while a graph neural network model accurately predicted their structural evolution across successive stages. Together, we delineate a timeline for clonal attrition and deliver topology-driven predictors of clone survival and structural change, enabling prospective identification of dominant and failing clones during aging.

It’s not just the phase: Frequency-dependent tuning of neuronal firing

2026-06-24T14:00:00Z

by Ying Yao, Simon Hanslmayr

A new study in PLOS Biology shows that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, suggesting an additional dimension in how brain rhythms may organize neural activity. This primer discusses a study in PLOS Biology showing that neuronal firing is selectively tuned to oscillatory frequency in human intracranial recordings, complementary to phase tuning, and suggesting an additional dimension in how brain rhythms may organize neural activity.

Web-based collaborative model development in interdisciplinary consortia: Design principles and practical guidance

2026-06-23T14:00:00Z

by Marvin van Aalst, Alienor Lahlou, Tanvir Hassan, William Gaultier, David Colliaux, Anna Matuszyńska

Web-based modeling platforms can enhance collaboration between modelers and experimentalists during early model development. Drawing on two interdisciplinary case studies, we provide guiding principles on how to build interactive agile modeling tools. Web-based modelling platforms can enhance collaboration between modelers and experimentalists during early model development. This Community Page provides guiding principles on how to build agile interactive modelling tools.

Human neuronal firing varies with the frequency of local field potential oscillations

2026-06-23T14:00:00Z

by Zahra Jourahmad, Raissa K. Mathura, Layth S. Mattar, Melissa C. Franch, Danika L. Paulo, Mohammed Hasen, Nicole R. Provenza, Benjamin Y. Hayden, Sameer A. Sheth, Eleonora Bartoli, Andrew J. Watrous

Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing (“phase tuning”) has been extensively studied in animal models and human invasive recordings, much less is known about whether neurons show preferential firing at specific oscillatory frequencies, termed frequency tuning. Here, we employ human intracranial recordings across several brain regions including hippocampus, entorhinal cortex, anterior and posterior cingulate cortex, and orbitofrontal cortex to test the hypothesis that neurons exhibit frequency-specific firing. We analyzed 357 single units recorded simultaneously with local field potentials in 19 neurosurgical patients during awake resting. We estimated the instantaneous frequency of the LFP using adaptive spectral decomposition and assessed frequency tuning of each neuron while controlling for changes in firing rate unrelated to frequency changes. We found 27% of neurons exhibited increased or decreased firing within specific frequencies, most commonly within the low-frequency range (<10 Hz). Neurons exhibiting frequency tuning were distinct from those displaying phase tuning, and both types of tuning were observed across multiple brain regions with no anatomical preference. Together, our results demonstrate that the instantaneous frequency of neural oscillations modulates neuronal firing which may serve as an additional mechanism for information processing in the human brain, opening new avenues for frequency-targeted neural stimulation.

Sleep deprivation increases levels of the synaptic density marker SV2A in the human brain

2026-06-23T14:00:00Z

by David Elmenhorst, Anna L. Foerges, Ali Gordji-Nejad, Eva-Maria Elmenhorst, Tina Kroll, Andreas Matusch, Simone Beer, Bernd Neumaier, Philipp Krapf, Christoph Lerche, Alexander Drzezga, Andreas Bauer

Sleep is essential for synaptic homeostasis, a proposed mechanism whereby wakefulness leads to synaptic potentiation and sleep facilitates synaptic down-selection. Synaptic vesicle glycoprotein 2A (SV2A), whose availability is quantifiable by [¹⁸F]SynVesT-1 positron emission tomography (PET), is commonly interpreted as a proxy for synaptic density. In this randomized study, we examined 40 healthy adults (mean age 27.5 ± 6.5 years) who underwent two [¹⁸F]SynVesT-1 PET scans on consecutive days. Half of the participants were assigned to the normal sleep (i.e., control) condition and half to the sleep deprivation condition. Scans were performed at the same circadian time point, approximately 4 h after awakening in the control group and during baseline in the sleep deprivation group or after ~28 h of continuous wakefulness in the sleep deprivation group after sleep deprivation. Sleep deprivation led to significant increases in synaptic vesicle glycoprotein 2A binding in multiple brain regions, including the thalamus (+4.6%), hippocampus (+5.6%), and parietal cortex (+3.2%), whereas no changes were observed in controls. The degree of increase in synaptic vesicle glycoprotein 2A positively correlated with elevated slow wave activity during recovery sleep, a physiological marker of sleep pressure. These findings provide in vivo support for the synaptic homeostasis hypothesis in humans and suggest that synaptic vesicle glycoprotein 2A PET imaging is sensitive to sleep-wake dependent synaptic plasticity.

Trial Registration

The study was prospectively registered on 19.01.2022 here: German Clinical Trials Registry: DRKS # DRKS00027867, https://drks.de/search/en/trial/DRKS00027867.

Distinct sources of decision-related signals in visual cortex are represented in different local field potential bands

2026-06-22T14:00:00Z

by Yueyue Sapphire Hou, Pooya Laamerad, Liu D. Liu, Christopher C. Pack

Fluctuations in single-neuron activity in the sensory cortex often correlate with perceptual decisions. This kind of correlation is often hypothesized to reflect a causal influence of sensory signals on decisions, but it can be attributed to various noncausal factors as well. To disentangle these different possibilities, we have examined local field potentials (LFPs) recorded from the middle temporal (MT) area and area V4 of nonhuman primates (Macaca mulatta) while they performed two different perceptual decision-making tasks. Compared to single-neuron spiking, LFPs have the advantage of being decomposable into frequency bands that are associated with different anatomical sources of input. More importantly, they persist when spiking activity is inactivated, which precludes a causal influence of the corresponding neural activity on behavior. We found that high-gamma frequency (70–150 Hz) LFP power was correlated with perceptual decisions and that this correlation disappeared when spikes were inactivated, consistent with a causal role for this frequency band in decision-making. These signals overlapped in time with decision signals in the lower gamma band (30–70 Hz), which persisted after spiking inactivation, suggesting a noncausal input. Interestingly, lower-frequency LFP signals (5–30 Hz) reflected both impending perceptual decisions and the outcome of preceding trials, suggesting a modulatory influence of recent experience on neural dynamics. Our results, therefore, reveal that neural activity multiplexes different sources of information about perceptual decisions and that these types of information can be estimated reliably from different LFP frequencies.

The total mass, copy number, and distribution of hormones in the human bloodstream

2026-06-22T14:00:00Z

by Ron Sender, Tal Kedar, Yoav Navon, Moriya Raz, Shirley Bikel, Rina Hemi, Ron Milo, Shai Fuchs

The human endocrine system orchestrates critical physiological processes, yet a systematic quantitative synthesis of clinically relevant circulating hormones has been lacking. Here, we present a comprehensive, integrative analysis of circulating human hormones, leveraging clinically validated reference intervals across major endocrine subsystems. We use clinically validated reference intervals that we further validate using published datasets. Our analysis reveals that the total mass of circulating hormones is approximately 40 ± 2 mg. We find that this mass in healthy young adults is dominated by Adiponectin and DHEAS, which constitute over 90% of both total hormone weight and copy number. We show there are on the order of a million hormone molecules per cell in the human body. Females have about half the number of circulating hormone molecules compared to males. Across 56 hormones with curated affinity data, free (receptor-available) concentration correlates with receptor binding affinity, with class-specific scaling. Bioavailability mechanisms segregate by chemical class, consistent with chemical structure constraining available buffering strategies. Together, these data provide a quantitative reference for the human endocrine system and highlight relationships linking receptor affinity, bioavailability, and chemical class.

Growth arrest of Mycobacterium tuberculosis in acidic environments enhances their survival of antibiotic treatment

2026-06-22T14:00:00Z

by Eun Seon Chung, William C. Johnson, Maliwan Kamkaew, Timothy A. Fitzgerald, Morgan E. McNellis, Trever C. Smith II, Srinivasan Vijay, Nguyen Thuy Thuong Thuong, Shumin Tan, Bree B. Aldridge

The ability of Mycobacterium tuberculosis (Mtb) to dynamically adjust its growth behavior in response to host environments is critical for survival under immune and drug stress, but how these behaviors shift at the single-cell level remains poorly understood. Here, using high-resolution single-cell analysis, we show that Mtb adapts to acidic conditions by increasing the proportion of bacteria in a growth-arrested state, rather than uniformly slowing the growth rate of the entire population. This nongrowing subpopulation exhibits enhanced tolerance to ethambutol, highlighting its role in drug survival. Clinical strains displayed higher proportions of growth-arrested cells under both neutral and acidic conditions, suggesting that growth arrest may serve as one of the strategies for persistence during infection. While the PhoPR two-component system partially regulates this state, our RNA sequencing analysis revealed additional transcriptional regulators that are upregulated following acidic adaptation and may contribute to entry into the growth-arrested state and increased tolerance to ethambutol. Our study demonstrates that increasing the proportion of nongrowing subpopulations is an active adaptive strategy that can influence antibiotic susceptibility under acidic conditions, offering new perspectives for targeting bacterial heterogeneity in tuberculosis therapy.

The microglia-derived protein Sema4ab attenuates regenerative neurogenesis after spinal cord injury in zebrafish

2026-06-18T14:00:00Z

by Alberto Docampo-Seara, Mehmet Ilyas Cosacak, Kim Heilemann, Friederike Kessel, Ana-Maria Oprişoreanu, Markus Westphal, Özge Çark, Daniela Zöller, Josi Arnold, Anja Bretschneider, Alisa Hnatiuk, Nikolay Ninov, Catherina G. Becker, Thomas Becker

Zebrafish, in contrast to mammals, regenerate neurons after spinal cord injury, but little is known about the control mechanisms of this process. Here we use scRNA-seq and in vivo experiments to show that sema4ab, mainly expressed by lesion-reactive microglia, attenuates regenerative neurogenesis by changing the complex lesion environment. After spinal injury, disruption of sema4ab doubles the number of newly generated progenitor cells and neurons but attenuates axon regrowth and recovery of swimming function. Disruption of the plxnb1a/b receptors, selectively expressed by neural progenitor cells, increases regenerative neurogenesis. In addition, disruption of sema4ab alters activation state and cytokine expression of microglia, such that fibroblasts increase expression of the cytokine tgfb3, which strongly promotes regenerative neurogenesis. Hence, we propose that sema4ab expression in microglia attenuates regenerative neurogenesis in multiple ways, likely directly through plxnb1a/b receptors and indirectly, by controlling the inflammatory milieu and tgfb3 levels. Targeting Sema4A-dependent signaling in non-regenerating vertebrates may be a future strategy to improve regenerative outcomes.

Learning engages transient and sustained cellular mechanisms in the human brain

2026-06-18T14:00:00Z

by Guillermina Griffa, Marco Palombo, Abraham Yeffal, Hong-Hsi Lee, Agustin Solano, Susie Y. Huang, Valeria Della-Maggiore

Structural neuroplasticity supports learning, development, and shapes vulnerability to brain disorders, making it a central priority in neuroscience research. However, progress in humans has remained limited by the inability to probe cellular processes in vivo, leaving mechanistic insight largely dependent on animal models. To address this gap, here we combined the sub-voxel sensitivity of ultra–high-gradient diffusion MRI with the cell-compartment specificity of the Soma and Neurite Density Imaging (SANDI) model to probe structural plasticity directly in the living human brain. By tracking how learning modulates the temporal dynamics of cell bodies and cell processes, we aimed to distinguish plastic from nonplastic biological processes driving changes in microstructure. We found that learning a motor skill triggered two distinct temporal responses: a transient expansion of cell bodies across all brain regions engaged by the task, consistent with a short-lived homeostatic mechanism, and a sustained increase in cell-process density restricted to key motor regions, consistent with structural plasticity. Our approach provides a mechanistic window into human neuroplasticity and marks a significant step toward bridging the gap between animal and human neuroscience.

Argonaute 2 drives resistance to immune checkpoint inhibitors in immunorefractory non-small cell lung cancer

2026-06-18T14:00:00Z

by Dario Pasquale Anobile, Layla Barbar, Emile Maucotel, Alexis Cornec, Valeria Manriquez, Wilfrid Richer, Jordan Denizeau, Christine Sedlik, Charlie Bories, Elodie Couderc, Renaud Leclere, Judith Sobas, Emeline Papillon, Rafael Mena Osuna, Jimena Tosello-Boari, Marianne Burbage, Eliane Piaggio, Enzo Z. Poirier

One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlate with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.