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.
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.
The brain's functional connectivity dynamics have been explained by a critically tuned model, but such models miss occasional reconfigurations. A new PLOS Biology study shows that modulatory control near a critical point can account for these rare events.
Ongoing brain activity displays rich temporal variability associated with efficient cognition, with functional connectivity (FC) continually reconfiguring over time. The resulting functional connectivity dynamics (FCD) specifically show complex, fat-tailed statistics that alternate between persistent epochs and faster reconfiguration transients. While nonlinear whole-brain models tuned nearby a critical point have reproduced some aspects of FCD, they fall short of capturing its full temporal complexity. We propose that slow fluctuations in arousal offer a biologically plausible mechanism for exploring critical regimes in large-scale brain dynamics and thus enrich FCD. Using a connectome-based model of coupled cortical populations, we identified phase boundaries where system dynamics transition between regimes of faster or slower FCD. We then phenomenologically incorporated arousal changes, modeling them as stochastic fluctuations in key parameters such as cortical excitability, input gain, and noise amplitude. This explicitly time-dependent formulation enables the system to roam dynamically across regime boundaries, flexibly tuning its distance from critical transition lines and producing intermittent transitions that mirror the stochastic evolution observed in empirical FCD. Fitting these models to human resting-state fMRI and performing model comparison, we find that arousal-driven models more accurately reproduce the distinctive quantitative features of FCD, with the greatest improvements coming from the previously poorly accounted fat-tailed portions of the distributions. Together, these results suggest that arousal fluctuations-likely mediated by changes in neuromodulatory tone-shape the brain's attractor landscape over time, expanding the repertoire of accessible functional network states and providing a mechanistic basis for the complexity of spontaneous functional dynamics.
Cells must sense and respond to nutrients to survive. To efficiently grow in mixed carbon environments, microbes repress genes necessary to utilize carbon sources that require substantial resources to catabolize when a simpler carbon source, such as glucose, is present. This process is known as carbon catabolite repression. Canonically, in fungi, nutrient sensing transcriptional networks are composed of carbon source-specific transcription factors that activate carbon source utilization genes and carbon catabolite repression regulators, which broadly repress all nonpreferred carbon source utilization genes when a preferred carbohydrate is present. In contrast to this model, we identified a transcription factor (Cbr1) in the basidiomycete yeast Rhodotorula (Rhodosporidium) toruloides that specifically inhibits glucose-mediated repression of disaccharide and proline utilization, presenting a mechanism of tailored carbon catabolite repression regulation that combats a negative feedback loop formed when glucose is released during disaccharide utilization. Cbr1 is also required for cellobiose, gentiobiose, carboxylic acid, and fucose utilization. Using transcriptomic and molecular analyses, we demonstrated that catabolism of these carbon sources is not metabolically linked, but genes necessary for their utilization are coactivated by Cbr1 in response to each of the carbon sources. This coactivation suggests R. toruloides may encounter these carbon sources together, potentially during complex interactions among microbes in nature. Coregulation of nutrient-specific gene activation and carbon catabolite repression by a transcription factor establishes a previously uncharacterized mechanism for building nutrient sensing transcriptional networks in fungi. Characterizing diverse nutrient sensing regulatory mechanisms is critical for understanding resource acquisition during fungal pathogenesis, where carbon catabolite repression is important for virulence and drug tolerance, and metabolically engineering fungi for green biotechnology.
One hundred diatom species have been selected for genome and transcriptome sequencing. The 100 Diatom Genomes Project aims to provide a scalable framework for understanding diatom biodiversity, ecology and evolution, and for investigating their use in biotechnology.
Candida parapsilosis is a major human fungal pathogen, with recent global outbreaks driven by fluconazole-resistant (FLCR-Cp) isolates that are difficult to eradicate and associated with poor clinical outcomes. However, the microbial traits enabling persistence of these outbreak lineages remain poorly defined. Here, we show that FLCR-Cp isolates responsible for prolonged, multi-country outbreaks consistently exhibit a striking low-biofilm-producing (LBP) phenotype. Contrary to the prevailing view that robust biofilm formation promotes persistence, LBP strains displayed enhanced stress tolerance, increased cell wall masking, and reduced immune recognition. These traits conferred resistance to neutrophil and macrophage killing and enhanced survival in immune cell-rich organs during systemic infection. Genome-wide transcriptomic profiling revealed extensive metabolic and regulatory rewiring in LBP strains. Whole-genome sequencing (WGS) of a global isolate collection further demonstrated that the LBP phenotype has emerged independently multiple times, supporting convergent evolution under host selection. Functional genomic analyses suggest that biofilm attenuation arises through multigenic changes, and disruption of key biofilm-associated transcriptional regulators enhanced fitness during immune interactions. Together, our findings overturn the assumption that robust biofilm formation drives outbreak persistence and instead identify biofilm attenuation as an adaptive tradeoff that promotes immune evasion and long-term survival. These results redefine our understanding of C. parapsilosis adaptation during healthcare-associated outbreaks and shift attention toward host-driven evolutionary processes than environmental persistence alone.
Obsessive‑compulsive disorder (OCD) is characterized by an insight‑action dissociation, in which people with OCD recognize that their behavior is irrational but still struggle to inhibit habitual responses. This dissociation may be related to abnormally strong motivational biases, reflected in excessive tendencies to approach reward and avoid punishment. We employed a motivational Go/NoGo learning task, combined with computational modeling and electroencephalography (EEG), to investigate how 36 people with OCD and 37 healthy controls (HC) regulate maladaptive biases during motivated action. People with OCD showed stronger Pavlovian bias and lower learning rates. Similar to HC, people with OCD also showed increased midfrontal theta power related to conflict detection and to the generation of a control demand to increase the weighting of instrumental action values during choice, suggesting that they were able to detect the mismatch between their behavior and task goals. However, in OCD, conflict‑related theta enhancement overlapped with the response window, indicating that control signals emerged or arrived too late to effectively influence choice. Midfrontal‑motor theta phase synchrony provided the strongest model evidence for the modulation of maladaptive biases in OCD, yet this pathway showed no significant conflict‑related enhancement and failed to effectively modulate motivational biases under conflict. Taken together, these findings suggest a neural mechanism underlying the insight‑action dissociation in OCD and identify midfrontal‑motor theta phase synchrony as a potential treatment target.
Renewed interest in phage therapy has highlighted a need to understand how bacteria subvert phage infection through antiphage defense systems. Traditionally, strategies to identify antiphage defense systems lack throughput or have limitations for bacterial species where antiphage defense systems are understudied. Herein, we developed a bioinformatic pipeline that uses a small serine recombinase to identify known and unknown antiphage defense systems. Using this approach to query reference genomes and metagenomes, we show that small serine recombinase genes are genetically linked to antiphage defense systems and serve as bait for finding these systems across diverse bacterial phyla. Using co-transcription predictions and statistical analysis of protein domain abundances, we experimentally validated our bioinformatic approach by discovering that KAP P-loop NTPases are fused to putative antiphage domains and reinforce prokaryotic Schlafen proteins as a new class of antiphage defense. Our work shows that small serine recombinases are a reliable genetic marker for the discovery of antiphage defenses across diverse bacterial phyla.
Visual motion is known to influence perceptions of tilt, verticality, and translation, suggesting that optic flow is combined with vestibular cues to estimate orientation relative to gravity. The cerebellar nodulus and ventral uvula (NU) are a prime candidate to perform this computation because this region uniquely receives convergent semicircular canal, otolith, and proprioceptive inputs, and in non-primate species full-field visual motion robustly modulates NU activity. Here, we tested whether visual roll motion, known to bias perceived orientation relative to gravity, alters the internal gravity-referenced transformation used by NU neurons to encode vestibular self-motion. To test this, we recorded single-unit activity from NU Purkinje cells in rhesus macaques during whole-body translations in darkness, either without visual stimulation or after prolonged full-field optokinetic roll motion. We hypothesized that visual motion simulating head tilt would bias the NU's internal gravity estimate, leading to altered translation-evoked responses. Contrary to this prediction, visual motion had no effect on either baseline firing rates or vestibular responses. Moreover, a computational model predicting visually induced shifts in neural tuning was not supported by the data. These results show that visual roll motion, although known to influence perceived orientation, does not bias gravity-referenced vestibular coding in the primate NU. This specialization may preserve a fast, body-anchored gravity estimate for postural and reflexive motor control, delegating visual-vestibular integration for perception to downstream circuits.
Bacterial outer membrane proteins (OMPs) are critical players in host-pathogen interactions and environmental adaptation. Here we describe the newly developed "Gradient Enrichment of Native Targets from Lipid Environments" (GENTLE) methodology and use this approach to elucidate the structures of Campylobacter jejuni OMPs directly from native, detergent-solubilized crude membranes. We identify and solve high-resolution cryo-EM structures of PorA, OMP50, and Cj0034c from C. jejuni membranes, all of which are required for Campylobacter invasion, adhesion, and initiation of host infection. Notably, our results provide the first structural information of OMP50, revealing a two-domain architecture constructed with an all β-stranded transmembrane domain and an all α-helical periplasmic domain. This structure depicts that all tyrosine residues, many of which are expected to be critical for phosphorylation and host-pathogen interaction, are localized to the outer membrane of C. jejuni. Our studies also led to the first structure of the full-length Cj0034c protein, which assembles as a nonamer with each protomer containing a single-spanning transmembrane helix and a large periplasmic domain. The nine protomers stack side-by-side to form a channel that spans the entire lipid bilayer. However, whether Cj0034c spans the outer membrane (OM) or inner membrane (IM) of C. jejuni must await further experimental studies. In addition, we observed that the surface-exposed extracellular loop L4 of PorA is very flexible, which may be critical for the virulence of this porin. Collectively, this work provides novel structural information for functionally important OMPs and sheds light on how they assemble in native bacterial membranes. These findings further demonstrate that it is possible to obtain high-resolution structural information for targeted membrane proteins from crude native membranes without their overexpression and purification.
Bacterial genomes are remarkably dynamic, shaped by horizontal gene transfer. Plasmids are key actors in this process, fueling rapid bacterial adaptation to stresses such as antibiotics. Yet, plasmids follow evolutionary trajectories of their own, defying traditional genetic frameworks. Beyond the co-evolution of traits directly involved in plasmid-host relationships, it is now essential to draw from ecological theory to understand plasmid assemblages. By viewing plasmids as ecological entities competing for a shared resource, the bacterial host, we show that their distribution within bacterial genomes mirrors the structure of ecological communities. Our minimal stochastic model, inspired by community ecology, reveals that plasmid diversity arises from the combined action of niche differentiation and neutral processes. These results challenge deterministic views of genome organization, highlighting the central role of stochasticity and drift. This work establishes a theoretical bridge between microbial genomics and ecology, offering a new framework to understand-and potentially control-the evolution of bacterial genomes.
Despite recent progress in clinical research into Women's Health, basic research is still lagging behind. Until we understand the fundamental physiology of women across the life span, we cannot expect to bring about meaningful change.
Tissue homeostasis relies on the balance between proliferation of stem cells and death of differentiated cells. In Drosophila gut enterocytes, we recently identified a novel form of cell death, termed erebosis. Erebosis is a nonapoptotic, nonautophagic, and nonnecrotic process, in which affected cells accumulate Ance (angiotensin-converting enzyme) and lose many other proteins, ultimately leading to the loss of organelles and the nucleus. The underlying molecular mechanism of erebosis has remained unclear. Here, through single-cell RNA sequencing and genetic approaches, we found that the small metabolite heme regulates erebosis. Cells undergoing erebosis up-regulate the heme-degrading enzyme Heme oxygenase (Ho) and the heme exporter Mrp5 , and decrease intracellular amounts of heme. Heme depletion by Mrp5 overexpression promotes erebosis, whereas heme accumulation by knockdown of Ho or Mrp5 , or by feeding a heme precursor, suppresses it. Downstream of heme, Dpp signaling suppresses erebosis. Inhibition of erebosis reduces intestinal stem cell proliferation, indicating a cross-talk mechanism between enterocyte death and stem cell division. Our results demonstrate that reduction of cytoplasmic heme is a critical step in initiating enterocyte erebosis and coordinating stem cell proliferation, thereby maintaining gut tissue homeostasis. This work provides the first insight into the molecular mechanism regulating erebosis.
Computational and experimental advances have led to the discovery of a large and diverse repertoire of bioactive peptides encrypted within proteins from across the tree of life. Mounting evidence suggests that these peptides can contribute to host defense not only through direct antimicrobial activity, but also through immunomodulatory and potentially broader physiological functions. This Essay synthesizes this emerging field from a broader biological perspective and explains the conceptual logic of immunity mediated by encrypted peptides. It proposes that such ‘encrypted immunity’ represents a previously underappreciated layer of host defense and physiology, with potential implications for therapeutics, diagnostics, and fundamental biology.
Host range expansion and virus emergence depend on whether viral life-cycle processes align with the ecological, developmental and physiological traits of new hosts. Spillover therefore succeeds only when pathogens clear a hierarchy of mechanistic barriers, from entry and replication to transmission and evolutionary persistence, but how these barriers map onto whole-organism host competence remains poorly resolved. Here we dissect spillover barriers experimentally using the Caenorhabditis -Orsay virus system, integrating within-host viral kinetics, cellular progression, transmission, virulence and experimental evolution across six closely related host species. We show that host species identity deterministically reshapes the timing and completeness of the viral life cycle, generating distinct host-competence phenotypes that range from permissive to restrictive and evolutionary dead-end hosts. Alternative hosts disrupt viral life-cycle synchrony through delayed replication, imbalanced genomic segment production, impaired egress or truncated infection windows, reducing transmission despite occasional high viral loads. These mechanistic mismatches prevent sustained viral adaptation upon serial passage, revealing how multiple partially permeable barriers compound to block emergence. By resolving spillover barriers across biological scales, our results provide a mechanistic framework linking viral life-history traits to eco-evolutionary theory of host range, and show how temporal and stoichiometric mismatches can determine whether cross-species infections become epidemiologically and evolutionarily viable.
A fundamental challenge for memory systems is balancing two opposing demands: sensitivity, which enables the encoding of subtle differences between similar experiences, and consistency, which preserves stable representations against interference. How the brain resolves this trade-off has remained unclear. Here, we identify inhibition in the dentate gyrus (DG) as a regulator of this balance, shifting hippocampal computation between sensitivity- and consistency-dominated regimes. Using an integrative approach that combines cell-type-specific pharmacogenetics in mice, behavioral assays, and computational modeling, we demonstrate that reducing inhibition during the encoding of overlapping experiences enhances later discrimination during recall. Computational modeling further predicted that, besides discrimination enhancement, disinhibition also increases susceptibility to interference, an effect that becomes particularly critical under high memory load, and compromises memory consistency across experiences. Conversely, increased inhibition stabilized memory representations, but reduced sensitivity, rendering similar experiences indistinguishable. These specific predictions were confirmed experimentally, showing that the DG inhibition tunes a sensitivity-consistency continuum. Together, our results uncover a systems-level principle by which hippocampal circuits dynamically prioritize flexibility or stability in memory formation depending on inhibitory tone. This framework advances our understanding of how the brain balances competing computational demands and has implications for neuropsychiatric and neurodegenerative disorders in which excitation-inhibition balance is disrupted.
Wherever we look, insect numbers are declining, but most insect life on Earth is found in locations we are not actively monitoring. The defining task of the next decade will be to build the planetary observatory that biodiversity science requires.
