Science Journals

Neuronal intrinsic excitability is a mechanism implicated in learning and memory that is distinct from synaptic plasticity. Prior work in songbirds established that intrinsic properties (IPs) of premotor basal-ganglia-projecting neurons (HVC_X) relate to learned song. Here, we find that temporal song structure is related to specific HVC_X IPs: HVC_X from birds who sang longer songs, including longer invariant vocalizations (harmonic stacks), had IPs that reflected increased post-inhibitory rebound. This suggests a rebound excitation mechanism underlying the ability of HVC_X neurons to integrate over long periods of time throughout the song and represent sequence information. To explore this, we constructed a network model of realistic neurons showing how in vivo HVC bursting properties link rebound excitation to network structure and behavior. These results demonstrate an explicit link between neuronal IPs and learned behavior. We propose that sequential behaviors exhibiting temporal regularity require IPs to be included in realistic network-level descriptions.

We have developed a robust workflow to identify proline hydroxylation sites in proteins, combining hydrophilic interaction chromatography (HILIC) enrichment and high-resolution nano-liquid chromatography-mass spectrometry (LC-MS) with refining and filtering parameters during data analysis. Using this approach, we have combined data from cell lines treated with either the prolyl hydroxylase (PHD) inhibitor, Roxadustat (FG-4592), or with the proteasome inhibitor MG-132, or with a DMSO control, to identify a total of 4993 and 3247 proline hydroxylation sites, respectively, in HEK293 and RCC4 cells. Of these, 1954 (HEK293) and 1253 (RCC4) high-confidence non-collagen sites were inhibited by FG-4592. Hydroxylated peptides showed consistent characteristics across both datasets, including enrichment in more hydrophilic HILIC fractions and distinct charge and mass distributions compared to unmodified or oxidised peptides. The intensity of the diagnostic hydroxyproline immonium ion varied with MS collision energy, peptide concentration, and adjacent amino acid sequence. Using synthetic peptides, we demonstrate that combining LC retention time with optimised MS parameters enables reliable site identification, even with multiple proline residues present. Proteins with FG-4592-inhibited hydroxylation sites were enriched for roles in RNA metabolism, mRNA splicing, and cell cycle regulation, including the phosphatase 1 regulatory subunit Repo-Man (CDCA2).

Chen X-W, Wang H, Bajaj K, Zhang P, Meng Z-X, Ma D, Bai Y, Liu H-H, Adams E, Baines A, Yu G, Sartor MA, Zhang B, Yi Z, Lin J, Young SG, Schekman R, Ginsburg D. 2013. SEC24A deficiency lowers plasma cholesterol through reduced PCSK9 secretion. eLife 2:e00444. doi: 10.7554/eLife.00444. Published 9 April 2013 We have been made aware through a notification from PubPeer that, in the above publication, the lung image in Figure 1 (the lower right section of panel F) appears to be a duplicate of an image in an earlier publication from our research group (lower right panel from Figure 5 in Thrombosis Research, 123:785–792, 2009, PMID: 18774162). The lung histologies in both animals (a wild-type control mouse in the 2009 paper and a Sec24agt/gt mouse in the 2013 eLife paper) were entirely normal, as determined by the expert pathologist who extensively reviewed the tissues in both animals, prepared both figures, and is a co-author on both papers. We have concluded that the error likely occurred during preparation of the eLife figure, at which time the earlier image of normal lung histology was accidentally inserted in place of an image of similar normal lung histology from the Sec24agt/gt mouse. We sincerely apologize for this error. To correct this error in the eLife manuscript, panel F from Figure 1 has been removed, and the description of panel F in the Figure 1 legend has also been removed. Also, the text in the second paragraph of Results has been modified as follows: Corrected text: Gross and routine microscopic survey of multiple tissues failed to identify any obvious morphologic abnormalities in adult Sec24agt/gt mice. Original text: Gross and routine microscopic survey of multiple tissues failed to identify any obvious morphologic abnormalities in adult Sec24agt/gt mice (Figure 1F). The corrected Figure 1 (with Panel F removed) is shown here: Corrected Figure 1 legend text: Figure 1. SEC24A null mice are viable and exhibit normal survival and development. (A) Schem…

Arousal fluctuates continuously during wakefulness, yet how these moment-to-moment variations shape large-scale functional connectivity (FC) remains unclear. Here, we combined 7T fMRI with concurrent pupillometry to quantify, for every functional connection, how time-varying FC covaries with spontaneous arousal in the awake human brain. Rather than exerting a uniform influence across the connectome, arousal organized FC into a low-dimensional set of seven connectivity communities, each defined by characteristic network compositions. These communities exhibited systematic hemispheric asymmetries, specifically identifying a ‘left-hemisphere centripetal architecture’ where the left hemisphere serves as a structural sink for the asymmetric convergence of arousal-modulated signals. Importantly, hemispheric asymmetry did not arise from global shifts in connectivity strength but instead reflected structured spatial heterogeneity embedded within community architecture. This modular and asymmetric organization was highly preserved during naturalistic movie watching, indicating that arousal-related modulation of FC reflects intrinsic principles that generalize across awake cognitive contexts. Together, these findings demonstrate that moment-to-moment arousal fluctuations shape large-scale FC through structured, hemispherically asymmetric network organization during wakefulness.

Tagging all proteins encoded by an animal genome with a fluorescent tag would open many windows to the discovery of unexpected patterns of protein expression and localization. To scale such an approach, it would be beneficial to introduce multiple, spectrally distinct fluorophore tags in parallel. As proof of concept for scalable pooled tagging, we undertook a pilot study in the nematode <i>Caenorhabditis elegans,</i> in which we set out to tag 30 different genetic loci with three different fluorophores, with three tags being introduced at a time. By choosing essential genes, predicted based on transcriptomics to cover a range of expression levels, we explore issues relating to disrupting gene function and visibility of tagged proteins. We demonstrate that such a tagging approach is highly efficient and indeed reveals unanticipated patterns of cellular and subcellular sites of protein expression and localization. We hope that this pilot study will motivate attempts to scale this tagging approach to more loci and, ultimately, the whole genome.

During the first period of life, human infants rapidly and effortlessly acquire the languages they are exposed to. Although memory is central to this process, the nature of early verbal memory systems, and the factors that determine retention and forgetting, remain largely unknown. Behavioral and brain measures have demonstrated memory formation in newborns. However, word traces fade in the face of acoustic overlap, leading to interference and forgetting. Here, we investigate whether speakers' identity changes facilitate the separation into distinct acoustic episodes and the creation of non-overlapping verbal memories. Newborns (0–4 days-old) were tested in a familiarization-interference-test protocol, while neural cortical activity was recorded using functional Near-Infrared Spectroscopy (fNIRS). The results showed higher neural activation to novel words than to familiar ones during the test phase, indicating that the infants recognized the familiar words despite potentially interfering sounds. The recognition response was measured over the left inferior frontal gyrus (IFG) and superior temporal gyrus (STG) areas known to be crucial for encoding auditory information and language processing. The neural response also included the right IFG and STG, involved in interpreting vocal social cues and speaker recognition. The results indicate that speaker identity is a key feature in the formation of verbal memories from birth, facilitating separability, possibly through early source–content binding (i.e. what–who), a precursor to fully mature episodic memory.

Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by <i>GBA1</i> mutations, leading to defective acid β-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifest severe neurological symptoms, but current animal models fail to fully recapitulate the human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells of nGD patients with <i>GBA1</i>^L444P/P415R and <i>GBA1</i>^{L444P/RecNcil} mutations to model nGD brain pathogenesis. These nGD MLOs exhibited GCase deficiency, resulting in diminished enzymatic function, accumulation of lipid substrates, widespread transcriptomic changes, and impaired dopaminergic neuron differentiation, mirroring nGD pathology. <i>GBA1</i> mutation correction mediated by CRISPR/Cas9 restored GCase activity, normalized lipid substrate levels, and rescued dopaminergic neuron function, confirming the causal role of <i>GBA1</i> mutations during early brain development. Using this novel platform, we further evaluated therapeutic strategies, including SapC-DOPS nanovesicles delivering GCase, AAV9-GBA1 gene therapy, and substrate reduction therapy with GZ452, a glucosylceramide synthase inhibitor currently under clinical investigation. These treatments either restored GCase activity, reduced lipid substrate accumulation, improved autophagic and lysosomal abnormalities, or ameliorated dysregulated genes involved in neural development. These patient-specific, 3D neural models offer a transformative, physiologically relevant platform for unraveling disease mechanisms and accelerating the discovery of therapies for patients with nGD.

High multiplicity of infection (MOI), the number of genetically distinct parasite strains co-infecting a host, characterizes falciparum malaria and other infectious diseases under high transmission. High MOI in <i>Plasmodium falciparum</i> accompanies high prevalence of asymptomatic infection despite high exposure, creating a large transmission reservoir that challenges intervention. This pattern is enabled by parasite immune evasion through extensive antigenic diversity. The force of infection (FOI), the number of new infections acquired by an individual host over a given time interval, is the dynamic counterpart of MOI and a key epidemiological parameter for monitoring antimalarial interventions. FOI is difficult and costly to measure, especially in high-transmission regions, requiring cohort studies or model-based inference from repeated cross-sectional surveys. Here, we apply queuing theory to estimate FOI from MOI with two approaches: a two-moment approximation and Little’s Law. We illustrate these methods using MOI estimates obtained under sparse sampling schemes with the ‘<i>var</i>coding’ approach. Both methods rely on infection duration data from naive malaria therapy patients and are therefore suitable for subpopulations with limited immunity, such as toddlers. We evaluate their performance using output from a stochastic agent-based model and apply the methods to an interrupted time-series study in northern Ghana, before and immediately after a three-round transient indoor residual spraying intervention. By accounting for sampling limitations with a Bayesian framework and bootstrap imputation, both methods yield good and replicable FOI estimates across various simulated scenarios. Their application to the surveys of 1- to 5-year-old children in Ghana indicates a larger than 70% reduction in annual FOI immediately after intervention.

The size and shape of cytoskeletal bundles, essential regulators of cell function, emerge from collective filament assembly rather than precise size-control mechanisms.

Intraflagellar transport (IFT) is a fundamental process driving ciliogenesis in most eukaryotic organisms. IFT172, the largest protein of the IFT complex, plays a crucial role in cilium formation, and several disease-causing IFT172 variants have been identified in ciliopathy patients. While IFT172 is tethered to the IFT-B complex via its N-terminal domains, the function of its C-terminal domains has remained elusive. Here, using both human and <i>Chlamydomonas reinhardtii</i> IFT172, we reveal that the C-terminal part of IFT172 interacts with IFT-A complex subunits, providing a molecular basis for the role of IFT172 in bridging IFT-A and IFT-B complexes. We determine the crystal structure of the C-terminal part of IFT172, uncovering a conserved U-box-like domain often found in E3 ubiquitin ligases. This domain exhibits ubiquitin-binding properties, and IFT172 undergoes ubiquitin conjugation in vitro, an activity that is reduced in the C1727R patient ciliopathy variant. We use CRISPR-engineered RPE-1 cells to demonstrate that the U-box-like domain is essential for IFT172 protein stability and proper cilium formation. Notably, RPE-1 cells with heterozygous deletion of the U-box domain show altered TGF-β signaling responses, particularly in SMAD2 phosphorylation levels and AKT activation. Our findings suggest that IFT172, beyond its structural role in bridging IFT-A and IFT-B complexes within IFT trains, harbors a conserved U-box-like domain with potential involvement in ciliary ubiquitination processes and signaling, providing new insights into the molecular mechanisms underlying IFT172-related ciliopathies.

‘<i>Candidatus</i> Liberibacter asiaticus’ (<i>C</i>Las), the causal agent of citrus huanglongbing, is transmitted by the Asian citrus psyllid <i>Diaphorina citri</i>. While <i>C</i>Las-positive (<i>C</i>Las+) females exhibit increased fecundity and metabolic demands, their neuroendocrine regulation mechanisms remain unclear. We propose <i>C</i>Las manipulates dopamine (DA) signaling to enhance psyllid fecundity and <i>C</i>Las proliferation. Metabolomics revealed elevated DA in <i>C</i>Las+ females. Silencing DA synthesis genes and receptor <i>DcDop2</i> via RNAi reduced lipid reserves, fecundity, and ovarian <i>C</i>Las titers. Through combined <i>in vivo</i> and <i>in vitro</i> experiments, we demonstrated that the microRNA miR-31a suppresses <i>DcDop2</i> expression by binding to its 3’ untranslated region. Overexpression of miR-31a resulted in decreased <i>DcDop2</i> expression and <i>C</i>Las titers in the ovaries, eliciting phenotypic defects akin to <i>DcDop2</i> knockdown. Furthermore, <i>DcDop2</i> knockdown and miR-31a overexpression reduced juvenile hormone (JH) levels and adipokinetic hormone (AKH) signaling in fat bodies and ovaries. Consequently, <i>C</i>Las regulates the DA-<i>DcDop2</i> signaling axis to improve <i>D. citri</i> lipid metabolism and fecundity, while simultaneously promoting its replication. These findings reveal a coevolution between <i>C</i>Las proliferation and ovarian development in the insect host. This discovery enhances our understanding of the molecular interplay between plant pathogens and vector insects and offers novel targets and strategies for HLB field management.

Animals integrate knowledge about how the state of the environment evolves to choose actions that maximise reward. Such goal-directed behaviour – or model-based (MB) reinforcement learning (RL) – can flexibly adapt choice to changes, being thus distinct from simpler habitual – or model-free (MF) RL – strategies. Previous inactivation and neuroimaging work implicates prefrontal cortex (PFC) and the caudate striatal region in MB-RL; however, details are scarce about its implementation at the single-neuron level. Here, we recorded from two PFC regions – the dorsal anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC), and two striatal regions, caudate and putamen – while two rhesus macaques performed a sequential decision-making (two-step) task in which MB-RL involves knowledge about the statistics of reward and state transitions. All four regions, but particularly the ACC, encoded the rewards received and tracked the probabilistic state transitions that occurred. However, ACC (and to a lesser extent caudate) encoded the key variables of the task – namely the interaction between reward, transition, and choice – which underlies MB decision-making. ACC and caudate neurons also encoded MB-derived estimates of choice values. Moreover, caudate value estimates of the choice options flipped when a rare transition occurred, demonstrating value update based on structural knowledge of the task. The striatal regions were unique (relative to PFC) in encoding the current and previous rewards with opposing polarities, reminiscent of dopaminergic neurons, and indicative of an MF prediction error. Our findings provide a deeper understanding of selective and temporally dissociable neural mechanisms underlying goal-directed behaviour.

APOE4, the major genetic risk factor for Alzheimer’s disease (AD), and ATP-binding cassette-A1 (ABCA1), required for lipidation of APOE are gene products of the liver X receptor (LXR) receptor. LXR agonists have been validated in animal models as therapeutics for AD, atherosclerosis, and many other diseases. Clinical progress has been thwarted by unwanted hepatic lipogenesis. Structurally diverse LXR ligands were profiled in coregulator TR-FRET (CRT) assays analyzing ligand-induced coactivator recruitment, coactivator selectivity, corepressor dissociation, and LXR isoform selectivity. A multiplex CRT assay was developed to measure synchronous ligand-induced displacement of corepressor by coactivator. Potency for coactivator recruitment to LXRβ correlated with induction of ABCA1 in human astrocytoma cells. Correlation with lipogenic activation of sterol response element (SRE) in hepatocarcinoma cells, was more complex. CRT response was diverse revealing ligands with theoretical full agonist, partial agonist, antagonist, inverse agonist, and other signatures within the same chemical series, suggesting the scope for precision CRT to guide nonlipogenic LXR agonist design.

Exposure to stress can cause long-lasting enhancement of fear and other defensive responses that extend beyond the cues or contexts associated with the original traumatic event. These nonassociative consequences of stress, referred to as fear sensitization, are thought to underlie some symptoms of trauma-related disorders. Fear sensitization has been predominantly studied using the stress-enhanced fear learning (SEFL) paradigm, which models the stress-induced amplification of fear learning. Less is known about the mechanisms through which unlearned fear responses are sensitized by stress. Here, we investigated the neural mechanisms for sensitization of unlearned fear responses using a paradigm we termed stress-enhanced fear responding (SEFR). In this model, mice exposed to a single session of footshock stress exhibit enhanced freezing to a novel tone stimulus. To investigate brain regions that might mediate SEFR, we first used c-Fos mapping to identify neural activity changes associated with stress-induced enhancement of unlearned fear. Our c-Fos screen identified the posterior paraventricular thalamus (pPVT) as a region that was persistently hyperactive after footshock stress and whose activity correlated with behavioral expression of SEFR. Using fiber photometry, we observed that SEFR, but not SEFL, was associated with increased activity in the pPVT. Next, we found that chemogenetic inhibition of the pPVT blocked both the induction of SEFR during stress and its later expression, while artificial stimulation of pPVT in stress-naive mice was sufficient to recapitulate SEFR. Interestingly, pPVT inhibition or stimulation did not affect acquisition or expression of SEFL. In conclusion, our results indicate that sensitization of fear learning (SEFL) and sensitization of unlearned fear (SEFR) have distinct neural mechanisms. Our results identify pPVT hyperactivity as a mechanism for stress-induced sensitization of unlearned fear and highlight pPVT as a potential targe…

The quality of stable long-term recordings from chronically implanted electrode arrays is essential for experimental neuroscience and brain-computer interfaces. This work uses scanning electron microscopy (SEM) to image and analyze eight 96-channel Utah arrays previously implanted in motor cortical regions of four subjects (subject H = 2242 days implanted, F = 1875, U = 2680, C = 594), providing important contributions to a growing body of long-term implant research leveraging this imaging technology. Four of these arrays have been used in electrolytic lesioning experiments (H = 10 lesions, F = 1, U = 4, C = 1), a recently developed electrolytic perturbation technique demonstrated compatible with continued neuroelectrophysiology using small direct currents. Previously, our group showed that electrolytic lesioning can be used as a technique to create regions of controlled neuron loss without significantly changing recording quality (Bray, Clarke et al., 2024). Here, by surveying physical damage such as biological debris and material deterioration, we show that electrolytic lesioning causes no statistically significant material damage to the implanted electrode arrays. In addition to surveying physical damage, such as biological debris and material deterioration, this work also analyzes whether electrolytic lesioning created damage beyond what is typical for these arrays. These findings also indicate that there are no statistically significant differences between the damage observed on normal electrodes versus those used for electrolytic lesioning, yielding no evidence that electrolytic lesioning significantly affects the material quality of chronically implanted electrode arrays. Finally, this work also includes the largest collection of single-electrode SEM images for previously implanted multielectrode Utah arrays, spanning 11 different intact arrays and one broken array. As the clinical relevance of chronically implanted electrodes with single-neuron resolution…

Mating and other behaviors emerge during adolescence through the coordinated actions of steroid hormone signaling throughout the nervous system and periphery. In this study, we investigated the transcriptional dynamics of the medial preoptic area (MPOA), a critical region for reproductive behavior, using single-cell RNA sequencing (scRNA-seq) and in situ hybridization techniques in male and female mice throughout adolescence development. Our findings reveal that estrogen receptor 1 (Esr1) plays a pivotal role in the transcriptional maturation of GABAergic neurons within the MPOA during adolescence. Deletion of the estrogen receptor gene, <i>Esr1</i>, in GABAergic neurons (Vgat+) disrupted the developmental progression of mating behaviors in both sexes, while its deletion in glutamatergic neurons (Vglut2+) had no observable effect. In males and females, these neurons displayed distinct transcriptional trajectories, with hormone-dependent gene expression patterns emerging throughout adolescence and regulated by <i>Esr1. Esr1</i> deletion in MPOA GABAergic neurons, prior to adolescence, arrested adolescent transcriptional progression of these cells and uncovered sex-specific gene-regulatory networks associated with <i>Esr1</i> signaling. Our results underscore the critical role of <i>Esr1</i> in orchestrating sex-specific transcriptional dynamics during adolescence, revealing gene regulatory networks implicated in the development of hypothalamic-controlled reproductive behaviors.

The central nervous system (CNS) can effectively control body movements despite environmental changes. While much is known about adaptation to external environmental changes, less is known about responses to internal bodily changes. This study investigates how the CNS adapts to long-term alterations in the musculoskeletal system using a tendon transfer model in nonhuman primates (<i>Macaca fuscata</i>). We surgically relocated finger flexor and extensor muscles to examine how the CNS adapts its strategy for finger movement control by measuring muscle activities during grasping tasks. Two months post-surgery, the monkeys demonstrated significant recovery of grasping function despite the initial disruption. Our findings suggest a two-phase CNS adaptation process: an initial phase enabling function with the transferred muscles, followed by a later phase abandoning this enabled function and restoring a control strategy that, while potentially less conflicted than the maladaptive state, resembled the original pattern, possibly representing a ‘good enough’ solution. These results highlight a multi-phase CNS adaptation process with distinct time constants in response to sudden bodily changes, offering potential insights into understanding and treating movement disorders.

Trained immunity (TI) is defined as a form of innate immune memory characterised by a long-lasting ability to develop enhanced responses to a secondary challenge, whether of the same or a different nature than the initial stimulus. This process is mediated by several established hallmarks, most prominently the existence of activating epigenetic marks and metabolic adaptations. The activating epigenetic marks prime the expression of immune-related genes and are a direct driving force behind the increased cytokine production after secondary stimulation of trained monocytes and macrophages. Training stimuli also induce specific metabolic adaptations, such as the upregulation of glycolysis and lactate production or the activation of glutaminolysis leading to fumarate accumulation, which in turn promotes epigenetic changes. However, the mechanisms linking these epigenetic and metabolic changes to a TI phenotype are varied, and not all stimuli that increase glycolysis promote training, whereas some stimuli such as lipopolysaccharide (LPS) display a non-monotonic induction of TI. In addition to metabolism directly driving epigenetic changes, early gene expression changes can also reshape cell metabolism to promote a trained phenotype. In this review we aim to separate two main types of metabolic rewiring that have not been previously uncoupled. Firstly, those primary metabolic changes occurring during the initial stimulation, which precede TI induction by altering the epigenomic landscape around inflammatory genes. Secondly, those metabolic adaptations arising later as a consequence of the first wave of epigenetic regulation, which support an enhanced functional state of macrophages.

High-speed volumetric imaging of the brain is essential for linking diverse cellular events to tissue-level functions. However, the brain’s structural and dynamic heterogeneity—spanning microns to millimeters and milliseconds to hours—requires imaging techniques with tunable spatiotemporal resolution, flexible 3D sampling, and compatibility with targeted perturbations. Here, we present tunable Bessel beam two-photon fluorescence microscopy (tBessel-TPFM), a compact, low-cost, and versatile platform for intravital brain imaging across millimeter scale with subcellular resolution. tBessel-TPFM transforms slow 3D volume scans into fast 2D frame scans via an axially elongated Bessel focus, achieving acquisition rates ~100 fold faster and reduced motion artifacts compared with conventional TPFM. Exploiting its full tunability of the Bessel focus, we applied tBessel-TPFM for quantitative mapping of cerebral blood flow and neurovascular coupling in normal and ischemic stroke mice. Unlike existing Bessel focus generation methods, the axial center of tBessel-TPFM remains fixed at the objective focal plane during profile tuning. Leveraging this advantage, we integrated tBessel-TPFM with simultaneous 3D targeted optogenetic stimulation for volumetric neuronal connectivity mapping. We also tracked microglial process dynamics following single-cell laser ablation, revealing diverse neuroimmune responses across spatial and temporal scales. By combining high speed, deep penetration, tunable sampling, and multimodal perturbation, tBessel-TPFM empowers a broad spectrum of neurobiological investigations—from vascular physiology and functional connectivity to neuroimmune interactions.

Synchronized spontaneous neural activity is a fundamental feature of developing central nervous systems and is thought to be essential for proper brain development. However, the mechanisms that regulate this synchronization and its long-term impact on brain function remain unclear. Here, we identify a previously unrecognized role of oligodendrocytes in orchestrating synchronized spontaneous activity during a critical developmental window, with lasting consequences for adult behavior. Using oligodendrocyte-specific genetic manipulation in the mouse cerebellum, we demonstrate that oligodendrocyte deficiency during early postnatal development, but not after weaning, disrupts the synchronization of Purkinje cell activity both during development and in adulthood. The early disruption produced persistent deficits in cerebellar-dependent behaviors, including anxiety, sociality, and motor function. Optogenetic re-synchronization in adulthood restored motor and social functions but not anxiety-like behavior, demonstrating that reduced Purkinje cell synchrony specifically drives the motor and social impairments. Our findings establish a causal link between developmental oligodendrocyte-regulated neural synchrony and the emergence of complex brain functions, which depend on the proper developmental trajectory necessary for driving brain function.

Enterovirus D68 (EV-D68) is an important pathogen associated with acute flaccid myelitis (AFM). The pathogenesis of AFM involves infection of spinal motor neurons and motor neuron death; however, the mechanisms linking EV-D68 infection to selective neurotoxicity are not well understood. Dysfunction of the nuclear pore complex (NPC) has been implicated in motor neuron injury in neurodegenerative diseases such as amyotrophic lateral sclerosis, and the NPC is also modified by picornavirus proteases during infection. We therefore sought to determine the impact of EV-D68 proteases on NPC composition and function. We demonstrate widespread disruption of NPC composition by EV-D68 2A and 3C proteases via direct cleavage of a relatively small number of nucleoporins, notably Nup98 and POM121, by 2A^pro. Using reporter systems, we demonstrate that 2A^pro inhibits nuclear transport of protein cargoes and disrupts the permeability barrier of the NPC, while having no apparent effect on RNA export. Independently, we show 2A^pro is toxic to induced pluripotent stem cell-derived motor neurons by demonstrating a rescue of toxicity with the 2A^pro inhibitor telaprevir at concentrations insufficient to inhibit viral replication. These findings expand our understanding of EV-D68 neuropathogenesis and provide a rationale for studying the NPC or 2A^pro as therapeutic targets in AFM.

Multicellularity has emerged in the three branches of the tree of life. The formation of simple multicellular entities can either result from cells aggregating or staying together after mitosis. However, it is not yet fully understood how, once formed, these simple multicellular entities could be maintained or even selected for. Here, using the <i>ace2</i> yeast snowflake model of simple multicellularity, we aimed at identifying genetic conditions favoring its maintenance. Growth-competition experiments revealed that, while the <i>ace2</i> mutation by itself does not provide any fitness advantage or disadvantage, the <i>ace2</i> snowflakes were strongly selected when combined with conditions affecting regulators of the G1/S transition of the cell cycle, such as Cln3 or Whi5. We show that this selection results from a faster exit from quiescence of the <i>ace2</i> snowflake cells. Importantly, this advantage is not dependent on the multicellular phenotype, but rather on the <i>ace2</i> genotype itself. We found that the <i>ace2</i> selective advantage in the <i>cln3</i> background fully depends on the <i>KSS1</i> gene, a target of the Ace2 transcription factor. Finally, we show that phenotypes observed for <i>ace2</i> mutants are phenocopied by the <i>AMN1^368D</i> allelic form found in ‘non-laboratory’ yeast strains, hence adding physiological relevance to these observations. Altogether, our results support the hypothesis that simple multicellularity could, in some cases, persist, not because it provides a direct selective advantage due to multicellularity itself, but rather as a ‘passenger’ phenotype that is maintained alongside other selected traits.

Chen H, Xiong T, Guan B, Huang J, Zhao D, Chen Y, Liang H, Li Y, Wu J, Ye S, Li T, Shu W, Li J-T, Wang Y. 2025. Exogenous myristate fuels the growth of symbiotic arbuscular mycorrhizal fungi but disrupts their carbon-phosphorus exchange with host plants. eLife 14:RP109524. doi: 10.7554/eLife.109524. Published 19 December 2025 We are retracting the eLife paper cited above, which proposed the uptake of external myristate by symbiotic arbuscular mycorrhizal fungi (AMF) and its subsequent disruption of carbon-phosphorus exchange in arbuscular mycorrhiza (AM) symbiosis. Following publication, the editorial office raised concerns regarding the presentation and analysis of a small portion of data — specifically, instances of potentially duplicated values, the inappropriate use of shared controls, and incorrect statistical analyses. Upon a thorough internal review by the authors, we identified several errors resulting from unintentional oversights. Specifically, In Figure 1C, background (control) 13C levels in R. irregularis Trial 2 and R. diaphanus extrardical hyphae were combined as a single non-labelled control group, which was displayed in a misleading manner. Regarding the concerns of three pairs of seemingly identical 13C abundance values in the raw data file, we confirm that these values are indeed very close, as is common for 13C background measurements, but are not identical. We have provided the original raw outputs from the EA-IRMS instrument in our communication with the editorial office to substantiate this clarification. We acknowledge that several statistical analyses in Figures 2c, 3f, 5d, 6e, and Supplementary Figures S1-2 were performed incorrectly. This resulted in inaccurate statistical significance labels, although the impact on the primary conclusions of this study is minimal. In the supplementary material, the measurement precision of the EA-IRMS device was incorrectly stated as ±0.2‰. The actual precision for the 13C:12C ratio of CO2 from combuste…

When <i>Escherichia coli</i> ribosomes are assembled in vitro, manipulation of incubation temperature and magnesium ion concentration has been an essential procedure, which is a crucial step for the assembly of active large subunits. The present study tackles this issue to develop a single-step procedure, which can be performed in near-physiological conditions, where cell-free protein synthesis is active. We found that GTPase factors EngA and ObgE can complement the changes in temperature and magnesium ion concentrations. In the presence of these factors, both the ribosome assembly and translation processes were successfully integrated in the reconstituted cell-free protein synthesis system. Furthermore, we found that these GTPase factors can reassemble the ribosomes to an active state, whose structure was disrupted by EDTA chelation of magnesium ions, indicating that these two factors can reversibly induce the ribosome structure to an intact state. The findings are essential for the bottom-up construction of synthetic cells.