eLife最新文献

In the peripheral nervous system, sensory and motor axons are generally covered by wrapping glial cell processes. This neuron-glia interaction requires an intricate coordination of glial growth and differentiation. How this is controlled molecularly remains largely unknown. At the example of Drosophila larval nerves, we show that glial growth, which occurs without any cell division, is initially triggered by the FGF-receptor tyrosine kinase Heartless (Htl). In a screen for genes acting downstream of activated FGF-receptor, we identified the large membrane protein Uninflatable (Uif), which supports the growth of excessive plasma membrane domains but does not support glial axon wrapping. Uif is also known to inhibit Notch. Surprisingly, we find that Notch signaling is required in postmitotic wrapping glia. While compromised Notch signaling results in a reduced wrapping efficiency, gain of Notch activity in wrapping glia leads to a hyperwrapping phenotype. Thus, Notch signaling is both necessary and sufficient for glial wrapping in Drosophila larvae. In addition, Notch suppresses both uif and htl function and thus stabilizes the switch between glial growth and glial axon wrapping. Given the general conservation of signaling mechanisms controlling glia development in mice and flies, similar mechanisms may act in the mammalian nervous system to control final glial differentiation.

Movement flexibility and automaticity are necessary to successfully navigate different environments. When encountering difficult terrains such as a muddy trail, we can change how we step almost immediately so that we can continue walking. This flexibility comes at a cost since we initially must pay deliberate attention to how we are moving. Gradually, after a few minutes on the trail, stepping becomes automatic so that we do not need to think about our movements. Canonical theory indicates that different adaptive motor learning mechanisms confer these essential properties to movement: explicit control confers rapid flexibility, while forward model recalibration confers automaticity. Here, we uncover a distinct mechanism of treadmill walking adaptation - an automatic stimulus-response mapping - that confers both properties to movement. The mechanism is flexible as it learns stepping patterns that can be rapidly changed to suit a range of treadmill configurations. It is also automatic as it can operate without deliberate control or explicit awareness by the participants. Our findings reveal a tandem architecture of forward model recalibration and automatic stimulus-response mapping mechanisms for walking, reconciling different findings of motor adaptation and perceptual realignment.

Chromatin organisation and transcriptional regulation are tightly coordinated processes that are essential for maintaining cellular identity and function. ATP-dependent chromatin remodelling proteins play critical roles in control of genome structure and in regulating transcription across eukaryotes. Their essential nature, however, has made it difficult to define exactly how these functions are mediated. The chromatin remodeller CHD4 has been shown to be capable of sliding nucleosomes in vitro, and to regulate chromatin accessibility and gene expression in vivo. Using an inducible depletion system, here we identify a second mechanism of action for CHD4 in actively restricting the residence time of transcription factors (TFs) on chromatin. Together, these activities result in distinct, context-dependent outcomes: at highly accessible regulatory elements, CHD4 limits TF binding to maintain regulatory function, while at low-accessibility euchromatic regions, it prevents TF engagement and sustains chromatin compaction, thereby silencing cryptic enhancers. Collectively, these mechanisms enable CHD4 to reduce transcriptional noise while preserving the responsiveness of active regulatory networks.

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in human HR-proficient ovarian and breast cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP inhibitor combinations in HR-proficient ovarian and breast cancers.

More than four decades ago, Gibbon and Balsam (1981) showed that the acquisition of Pavlovian conditioning in pigeons is directly related to the informativeness of the conditioning stimulus (CS) about the unconditioned stimulus (US), where informativeness is defined as the ratio of the US-US interval (C) to the CS-US interval (T). However, the evidence for this relationship in other species has been equivocal. Here, we describe an experiment that measured the acquisition of appetitive Pavlovian conditioning in 14 groups of rats trained with different C/T ratios (ranging from 1.5 to 300) to establish how learning is related to informativeness. We show that the number of trials required for rats to start responding to the CS is determined by the C/T ratio, and the specific scalar relationship between the rate of learning and informativeness is similar to that previously obtained with pigeons. We also found that the response rate after extended conditioning is strongly related to T, with the terminal CS response rate being a scalar function of the CS reinforcement rate (1 /T). Moreover, this same scalar relationship extended to the rats' response rates during the inter-trial interval, which was directly proportional to the overall rate of reinforcement in the context (1 /C). The findings establish that animals encode rates of reinforcement, and that conditioning is directly related to how much information the CS provides about the US. The consistency of these observations across species, captured by a simple regression function, suggests a universal model of conditioning.

Reducing the echo time of a whole-body MRI scanner makes it possible to image collagen, an important structural protein found in bones and tendons.

Tendons and ligaments are crucial connective tissues linking bones and muscles, yet achieving full functional recovery after injury remains challenging. We investigated the characteristics of tendon stem/progenitor cells (TSPCs) by focusing on the declining tendon repair capacity with growth. Using single-cell RNA sequencing on Achilles tendon cells from 2- and 6-week-old mice, we identified Cd55 and Cd248 as novel surface antigen markers for TSPCs. Combining single-cell RNA sequencing with single-nucleus RNA and ATAC sequencing analyses revealed that Cd55- and Cd248-positive fractions in tendon tissue represent TSPCs, as confirmed by their expression of established TSPC markers, with this population decreasing at 6 weeks. We also identified candidate upstream transcription factors regulating these fractions. Functional analyses of isolated CD55/CD248-positive cells demonstrated high clonogenic potential and tendon differentiation capacity, forming functional tendon-like tissue in vitro. This study establishes CD55 and CD248 as novel TSPC surface antigens, potentially advancing tendon regenerative medicine and contributing to the development of new treatment strategies for tendon and ligament injuries.

Previously, we showed that adult human olfaction retains plasticity in the unilateral processing of molecular chirality (Feng and Zhou, 2019). Using a similar unilateral discrimination protocol across three experiments with human adults (n = 96; 1295 sessions), we now reveal distinct patterns of specificity, generalization, and persistence in olfactory learning, independent of adaptation or task difficulty. Training with binary odor mixtures at varying ratios consistently produced durable gains that transferred across nostrils and generalized to novel mixtures differing in both structure and perceptual quality. Conversely, training with odor enantiomers or concentration differences yielded neither transfer nor generalization, and concentration discrimination learning was short-lived. These results indicate that mixture configural quality is a distinct olfactory attribute from chirality or relative concentration, and that discrimination learning engages plasticity at different stages of olfactory processing depending on the task-relevant attribute. Moreover, they identify mixture discrimination training as a promising strategy for rehabilitating smell loss and cultivating olfactory expertise.

Facial expression recognition develops rapidly during infancy and improves from childhood to adulthood. As a critical component of social communication, this skill enables individuals to interpret others' emotions and intentions. However, the brain mechanisms driving the development of this skill remain largely unclear due to the difficulty of obtaining data with both high spatial and temporal resolution from young children. By analyzing intracranial EEG data collected from childhood (5-10 years old) and post-childhood groups (13-55 years old), we find differential involvement of high-level brain area in processing facial expression information. For the post-childhood group, both the posterior superior temporal cortex (pSTC) and the dorsolateral prefrontal cortex (DLPFC) encode facial emotion features from a high-dimensional space. However, in children, the facial expression information is only significantly represented in the pSTC, not in the DLPFC. Furthermore, the encoding of complex emotions in pSTC is shown to increase with age. Taken together, young children rely more on low-level sensory areas than on the prefrontal cortex for facial emotion processing, suggesting that the prefrontal cortex matures with development to enable a full understanding of facial emotions, especially complex emotions that require social and life experience to comprehend.

Humans and animals can flexibly choose their actions based on different information, ranging from objective states of the environment (e.g., apples are bigger than cherries) to subjective preferences (e.g., cherries are tastier than apples). Whether the brain instantiates these different choices by recruiting either specialised or shared neural circuitry remains debated. Specifically, domain-general accounts of prefrontal cortex (PFC) function propose that prefrontal areas flexibly process either perceptual or value-based evidence depending on what is required for the present choice, whereas domain-specific theories posit that PFC sub-areas, such as the left superior frontal sulcus (SFS), selectively integrate evidence relevant for perceptual decisions. Here, we comprehensively test the functional role of the left SFS for choices based on perceptual- and value-based evidence, by combining functional magnetic resonance imaging with a behavioural paradigm, computational modelling, and transcranial magnetic stimulation (TMS). Confirming predictions by a sequential sampling model, we show that TMS-induced excitability reduction of the left SFS selectively changes the processing of decision-relevant perceptual information and associated neural processes. In contrast, value-based decision-making and associated neural processes remain unaffected. This specificity of SFS function is evident at all levels of analysis (behavioural, computational, and neural, including functional connectivity), demonstrating that the left SFS causally contributes to evidence integration for perceptual but not value-based decisions.