eLife最新文献

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.

Adaptive goal-directed behavior requires dynamic coordination of movement, motivation, and environmental cues. Among these, cautious actions, where animals adjust their behavior in anticipation of predictable threats, are essential for survival. Yet, their underlying neural mechanisms remain less well understood than those of appetitive behaviors, where caution plays little role. Using calcium imaging in freely moving mice, we show that glutamatergic neurons in the subthalamic nucleus (STN) are robustly engaged by contraversive movement during cue-evoked avoidance and exploratory behavior. Model-based analyses controlling for movement and other covariates revealed that STN neurons additionally encode salient sensory cues, punished errors, and especially cautious responding, where their activity anticipates avoidance actions. Targeted lesions and optogenetic manipulations reveal that STN projections to the midbrain are necessary for executing cued avoidance. These findings identify a critical role for the STN in orchestrating adaptive goal-directed behavior by integrating sensory, motor, and punitive signals to guide timely, cautious actions via its midbrain projections.

Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. Fusion of satellite cell-derived myoblasts (SCMs) is indispensable for generating the multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain incompletely understood. Here, we reveal a critical role for branched actin polymerization in SCM fusion during mouse skeletal muscle regeneration. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors N-WASP and WAVE, we demonstrate that branched actin polymerization is specifically required for SCM fusion but dispensable for satellite cell proliferation, differentiation, and migration. We show that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion and that branched actin polymerization is essential for generating invasive protrusions at fusogenic synapses in SCMs. Together, our study identifies branched-actin regulators as key components of the myoblast fusion machinery and establishes invasive protrusion formation as a critical mechanism enabling myoblast fusion during skeletal muscle regeneration.

Elevated levels of the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) are associated with cardiometabolic disease risk. However, the mechanism(s) linking TMAO production to human disease are incompletely understood. Initiation of the metaorganismal TMAO pathway begins when dietary choline and related metabolites are converted to trimethylamine (TMA) by gut bacteria. Gut microbe-derived TMA can then be further oxidized by host flavin-containing monooxygenases to generate TMAO. Previously, we showed that drugs lowering both TMA and TMAO protect mice against obesity via rewiring of host circadian rhythms (Schugar et al., 2022). Although most mechanistic studies in the literature have focused on the metabolic end product TMAO, here we have instead tested whether the primary metabolite TMA alters host metabolic homeostasis and circadian rhythms via trace amine-associated receptor 5 (TAAR5). Remarkably, mice lacking the host TMA receptor (Taar5^-/-) have altered circadian rhythms in gene expression, metabolic hormones, gut microbiome composition, and diverse behaviors. Also, mice genetically lacking bacterial TMA production or host TMA oxidation have altered circadian rhythms. These results provide new insights into diet-microbe-host interactions relevant to cardiometabolic disease and implicate gut bacterial production of TMA and the host receptor that senses TMA (TAAR5) in the physiologic regulation of circadian rhythms in mice.