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  • HuD controls widespread RNA stability to drive neuronal activity-dependent responses
    by Duffy, E. E., Patop, I., Kalaora, S., Assad, E. G., Koren, S. A., Traunmüller, L., Krüttner, S., Pajarillo, N. S., Finander, B., Barsdale, Z., Macias, M. M., Feng, M. Y., Paulo, J. A., Griffith, E. C., Kalish, B. T., Gygi, S. P., Churchman, L. S., Greenberg, M. E.
    Neuronal activity shapes brain development and refines synaptic connectivity in part through dynamic changes in gene expression. While activity-regulated transcriptional programs have been extensively characterized, the holistic effects of neuronal activity on the full RNA life cycle remain relatively unexplored. Here, we show that neuronal activity influences multiple stages of RNA metabolism in vitro and in vivo. Among these, RNA stability emerges as a previously underappreciated regulator of gene expression, exerting a stronger influence than transcription on total RNA levels […]
  • Compositional neural dynamics during reaching
    by Kashefi, M., Michaels, J. A., Kersten, R., Lau, J. C., Diedrichsen, J., Pruszynski, J. A.
    The complex mechanics of the arm make the neural control of reaching inherently posture dependent. Because previous reaching studies confound reach direction with final posture, it remains unknown how neural population dynamics in the motor cortex account for arm posture. Here we address this gap with high-density neural recordings and a reaching task in which the same targets serve as start points on some trials and end points on others. We show that neural population dynamics in monkey primary motor […]
  • The human factor: development and characterization of a scalable calcium imaging assay using human iPSC-derived neurons
    by Haustein, M. D., Deymier, C., Schlienger, S., Lexcellent-Bissler, L., Mawet, J., Gutknecht, E., Thenoz, L., Brazauskas, P., Renault, B., Brun, S., Winnistörfer, S., Portmann, T.
    Neuroscience drug discovery is challenged by the brain's structural and cell-type complexity, which is difficult to model in cellular systems compatible with high-throughput screening methods. Calcium oscillation assays, that harness neurons' intrinsic capability to develop functional neural networks in cell culture, are currently the closest cellular models with a relevant functional endpoint to model human neuronal circuitry in a dish. Here we further develop this useful assay towards scalable drug discovery applications. We show the importance of defined neuron-to-astrocyte ratios […]
  • Benefits of Music Training for Learning to Read: Evidence from Cortical Tracking of Speech in Children
    by Garcia-de-Soria, M. C., Mathias, B., Keitel, A., Klimovich-Gray, A.
    Musical training has long been argued to boost early phonological and reading abilities. Cortical tracking of speech (CTS) has been proposed as a mechanism for this music-to-literacy transfer. In this study, we examined how musical training shapes CTS in young readers and whether it facilitates literacy benefits. In a sample of 57 children aged 5-9, musical training was linked to enhanced reading and phonological awareness (PA). EEG during story listening revealed that higher left-hemispheric and lower right-hemispheric CTS were also […]
  • A universal dynamic routing architecture governs the flow of human cortical activity
    by Vinao-Carl, M., Peach, R. L., Gosztolai, A., David, M. C. B., Mallas, E.-J., Kurtin, D., Jaramillo, V., Violante, I. R., Sharp, D. J., Grossman, N.
    Behaviour requires distributed neural processing to be flexibly integrated and segregated, which in turn demands that information be dynamically routed across the brain. However, whether a unifying principle governs the routing of neural activity remains unknown. Here, we report that the flow of cortical activity is directed through canonical routing modes that are conserved across individuals, robust to variations in age, frequency band, brain state, and even the presence of neurodegeneration. These modes are constructed from the divergence and vorticity […]
  • Spatial grouping modulates the link between individual alpha frequency and temporal integration windows in crowding
    by Santoni, A., Ronconi, L., Samaha, J.
    Previous research has linked endogenous alpha oscillations (~7-13 Hz) to temporal integration windows in visual perception, with higher individual alpha frequency (IAF) predicting improved temporal segregation. Here, we investigated whether alpha-rhythmic temporal integration is a factor in visual crowding and whether this relationship is mediated by spatial grouping mechanisms. 47 participants performed a Vernier discrimination task, in which we manipulated both the stimulus onset asynchrony (SOA) between flankers and targets, and the spatial configuration of the flankers. Specifically, flankers were […]
  • Sensory Compression as a Unifying Principle for Action Chunking and Time Coding in the Brain
    by Kumar, S., Le Cauchois, M. B., Mathis, A., Duncker, L., Howlett, J. R., Mattar, M. G.
    The brain seamlessly transforms sensory information into precisely-timed movements, enabling us to type familiar words, play musical instruments, or perform complex motor routines with millisecond precision. This process often involves organizing actions into stereotyped "chunks''. Intriguingly, brain regions that are critical for action chunking, such as the dorsolateral striatum (DLS), also exhibit neural dynamics that encode the passage of time. How such brain regions support both task-specific motor habits and task-invariant internal timing, two seemingly distinct functions, remains a fundamental […]
  • Complementary regulation of memory flexibility and stabilization by dentate gyrus granule cells and mossy cells
    by GoodSmith, D., Carson, W. H., Sheffield, M. E.
    Accurate memory formation requires hippocampal spatial representations to balance stability, for later recall, with flexibility, to incorporate new information. The dentate gyrus (DG) is essential to memory formation, but the distinct roles of its excitatory cell types, granule cells (GCs) and mossy cells (MCs), remain unclear. To evaluate how GC and MC activity affect hippocampal output, we recorded from CA1 using two-photon calcium imaging as head-fixed mice navigated familiar and novel virtual environments. DREADD-mediated MC inhibition disrupted initial map stabilization, […]
  • Neural Subspaces Encode Sequential Working Memory, but Neural Sequences Do Not
    by Santo-Angles, A., Yang, J., Zhou, Y., Chu, W. K. H., Lindsay, G. W., Sreenivasan, K. K.
    The neural mechanisms of multiple-item working memory are not well understood. In the current study, we address two competing hypotheses about the neural basis of sequential working memory: neural subspaces versus neural sequences. Using broadband MEG data from human participants, we applied dimensionality reduction and multivariate decoding techniques to test whether sequential items are maintained during the retention period through the reactivation of individual items in sequence (neural sequences), or by organizing them into distinct low-dimensional subspaces (neural subspaces). Our […]
  • Gene-Culture Coevolution Favours the Emergence of Traditions in Mate Choice through Conformist Social Learning
    by Federico, D., Cosme, M., Dechaume-Moncharmont, F.-X., Ferdy, J.-B., Pocheville, A.
    The emergence of cultural traditions has long been considered dependent on sophisticated social learning mechanisms, particularly conformist transmission exhibiting a disproportionate bias towards majority behaviours. We challenge this assumption by demonstrating that gene-culture coevolutionary dynamics can fundamentally alter the conditions required for tradition formation, especially in the context of mate choice. Using simulation models of mate choice where female preferences are socially transmitted and male traits are genetically inherited, we show that the interaction between cultural and genetic transmission creates […]
  • Enhancers mediate euchromatin hopping at chromatin contact points
    by Mitchell, J. A., Mullany, S., Taylor, T., Li, H., Zhao, Y., Suri, A., Sexton, T., Davies, J. O.
    Enhancer-mediated gene activation involves the recruitment of chromatin modifiers and RNA polymerase to target promoters, but it is unknown if enhancers influence chromatin beyond their target genes. Euchromatin and heterochromatin associated histone modifications separate the genome into opposing nuclear compartments. Whereas heterochromatin marks are known to spread from one modified nucleosome to another, no such ability has been ascribed to euchromatin. Using mono-allelic enhancer deletions, native ChIP-seq, and an engineered interaction between an enhancer and transcriptionally inert DNA, we show […]
  • ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA
    by Virdee, S., Fletcher, A. J., Squair, D. R., Rivers, E., Sowar, H., Balci, A., Harmo, R., Wright, D. J., Beniwal, G., Soetens, M., Mathur, S., Tollervey, A., Stanton, C.
    The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion and RNA sequestration. Mutations in the gene ZNFX1 cause severe paediatric immunodeficiencies, including chronic viral infection and autoinflammation. Here, we show that ZNFX1 is an RNA helicase with cryptic and unusual bifurcating E3 ubiquitin ligase activity. Nucleotide-dependent RNA binding stimulates ZNFX1 to generate complex ubiquitin chains via a two-component ubiquitin circuit wired in parallel, with ubiquitin flux occurring via either […]
  • Adenovirus phagocytosis by neutrophils triggers a pro-inflammatory response
    by Laurans, S., Huerre, S., Dellis, O., Ferard, C., Jalaber, H., Vanbergue, C., Brun, E., Jelin, R., Nüsse, O., Benihoud, K., Dupre-Crochet, S.
    Adenoviruses are common pathogens that have been engineered and used for medical purposes. Their recognition by innate immune cells such as macrophages and dendritic cells has been widely studied, but very little information is available on adenovirus interaction with neutrophils. Using cytometry and confocal and electron microscopy, we showed that neutrophils bind to antibody-coated adenoviruses and engulf them in a phagosome. Using a single-cell transcriptomic approach, we found that adenovirus phagocytosis activates a specific transcriptional program in neutrophils. It also […]
  • A Validated LC-MS/MS Method for Quantifying Phenolic Acids, Lignans, and Enterolignans from Human Fecal Samples
    by Dicksion, C. A., Chao, D. N., Rickmeyer, J. D., Bess, E. N.
    The human gut microbiome is home to numerous small molecules that impact health. Three prominent classes of molecules in this environment include phenolic acids, lignans, and enterolignans, which have been linked to anti-inflammatory and anti-oxidant effects as well as protection from cancer, cardiovascular disease, and neurodegeneration. The abundance of these molecules in the gut microbiome as well as their biological significance motivated the development of the LC-MS/MS method reported herein, which provides a simple, robust, and high-throughput approach to simultaneously […]
  • H+ ions and ATP reshape the conformational landscape of an RNA recognition motif and regulate its fibrillation
    by Aazmi, O., Aswale, A. R., Chugh, J.
    Proteins exist as dynamic ensembles, with their native states comprising interconverting conformational substates critical to their physiological functions and participation in disease states. Fused in Sarcoma (FUS), an RNA-binding protein implicated in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), contains an RNA recognition motif (RRM) known to form fibrillar aggregates. Here, we investigate the conformational plasticity of FUS-RRM in its native state using advanced NMR techniques, particularly 15N chemical exchange saturation transfer and heteronuclear adiabatic […]
  • Membrane binding of a cyanobacterial ESCRT-III protein crucially involves the helix α1-3 hairpin conserved in all superfamily members
    by Schlösser, L., Kutzner, M., Hellmann, N., Kiesewetter, D., Bieber, J., Quarta, N., Ge, X., Goetze, T., Junglas, B., Matsumura, F., Bonn, M., Gräter, F., Sachse, C., Liu, L.-N., Schmidt, C., Aponte-Santamaria, C., Schneider, D.
    IM30, the inner membrane-associated protein of 30 kDa (also known as Vipp1) is essential for thylakoid membrane biogenesis and/or maintenance in chloroplasts and cyanobacteria. IM30 and its bacterial homolog PspA belong to the ESCRT-III superfamily, proteins previously thought to be restricted to eukaryotes and archaea. Despite low sequence similarity, IM30 shares key structural and functional features with eukaryotic ESCRT-IIIs, including a conserved 1-2 helical hairpin core and the ability to form oligomeric barrel- or rod assemblies that mediate membrane remodeling. […]
  • BASP1 Couples Ca2+ Signaling and Actin Polymerization to Mitochondrial Fission Essential for Neurite Outgrowth
    by Grebenik, E., Zaichick, S., Gomez, A., Caraveo, G.
    Actin-mediated mitochondrial fission is essential for cellular homeostasis, yet the mechanisms by which actin is recruited to mitochondria and how it couples the outer and inner mitochondrial membranes (IMM) remain poorly understood. Using a phosphoproteomic screen in a rat model of -synucleinopathy, we identified BASP1 as a calcineurin-dependent substrate that is constitutively dephosphorylated under pathological Ca2+ elevations and phosphorylated under neuroprotective calcineurin inhibition. Immunoprecipitation and mass spectrometry of phosphomutant BASP1 expressed in neurons revealed that dephosphorylation promotes interactions with actin […]
  • Molecular adaptation reflects taxon-specific mutational biases
    by Gitschlag, B. L., Stoltzfus, A., McCandlish, D. M.
    A fundamental question in molecular evolution is the extent to which patterns of adaptive change are shaped by mutational biases that make some variants more likely than others to arise. Past studies provide support for important effects of mutation bias on adaptive change, but leave open the empirical question of how strongly and how broadly evolutionary patterns depend on taxon-specific mutational tendencies. To characterize this effect quantitatively, we aggregated frequency spectra of adaptive amino acid changes from 14 species, comprising […]
  • Spatio-temporal factors shape mosquito virome diversity and composition in a host and virus phylogeny-dependent manner
    by Koh, C., Butkovic, A., Frangeul, L., Blanc, H., Gibaud, A., Henrion Lacritick, A., Chitale, R., Boyer, S., Duchemin, J.-B., Dussart, P., Girod, R., Grau, N., Ngoagouni, C., Saleh, M.-C.
    Mosquito-borne viruses invade and transiently participate in the virus communities of their vector hosts to complete their dual-host transmission cycles. Within the mosquito, they are entangled in complex interactions with resident viruses that may affect transmission outcomes by the mosquito host and can therefore contribute towards arbovirus emergence risk. Mosquito viromes have been reported to be highly diverse and dynamic, under the influence of host and ecological factors. However, the spatio-temporal flux in virome compositions remains to be understood due […]
  • WNK-Dependent Phosphorylation of Gephyrin Tunes GABAA Receptors at Inhibitory Synapses and Modulates Anxiety Behavior
    by Merlaud, Z., Delhaye, C., Nabais, M., Imani, Z., Pol, E., Russeau, M., Tostain, M., Gouhier, J., Rahir, R., Le Magueresse, C., Nosten-Bertrand, M., Levi, S.
    The role of the chloride-sensitive kinase WNK1 and its effector SPAK in the brain remains poorly understood. Here, we identify a regulatory mechanism involving WNK signaling that directly controls the synaptic diffusion and clustering, as well as the membrane stability and endocytosis of inhibitory GABAA receptors (GABAARs). We show that activation of WNK signaling stabilizes GABAARs at inhibitory synapses, while inhibition enhances receptor internalization. This regulation depends on the phosphorylation state of two previously uncharacterized residues in the central linker […]

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