eLife最新文献

Ethel Browne Harvey and Hilde Pröscholdt Mangold did pioneering research in embryology, Ida Henrietta Hyde helped develop the first microelectrodes for the stimulation of single cells, and Marthe Gautier had a vital role in discovering that Down syndrome is caused by an extra copy of chromosome 21. So why are their names so little known by the scientific community at large?

Acute myeloid leukemia (AML) is characterized by cellular and genetic heterogeneity, which correlates with clinical course. Although single-cell RNA sequencing (scRNA-seq) reflects this diversity to some extent, the low sample numbers in individual studies limit the analytic potential when comparing specific patient groups. We performed large-scale integration of published scRNA-seq datasets to create a unique single-cell transcriptomic atlas for AML (AML scAtlas), totaling 748,679 cells, from 159 AML patients and 51 healthy donors from 20 different studies. This is the largest single-cell data resource for human AML to our knowledge, publicly available at https://cellxgene.cziscience.com/collections/071b706a-7ea7-47a4-bddf-6457725839fc. This AML scAtlas allowed investigations into 20 patients with t(8;21) AML, where we explored the clinical importance of age, given the in-utero origin of pediatric disease. We uncovered age-associated gene regulatory network (GRN) signatures, which we validated using bulk RNA sequencing data to delineate distinct groups with divergent biological characteristics. Furthermore, using an additional multiomic dataset (scRNA-seq and scATAC-seq), we validated our initial findings and created a de-noised enhancer-driven GRN reflecting the previously defined age-related signatures. Applying integrated data analysis of the AML scAtlas, we reveal age-dependent gene regulation in t(8;21) AML, potentially reflecting immature/fetal HSC origin in prenatal origin disease vs postnatal origin. Our analysis revealed that BCLAF1, which is particularly enriched in pediatric AML with t(8;21) of inferred in-utero origin, is a promising prognostic indicator. The AML scAtlas provides a powerful resource to investigate molecular mechanisms underlying different AML subtypes.

An animal's survival hinges on its ability to integrate past information to modify future behavior. The nematode Caenorhabditis elegans adapts its behavior based on prior experiences with pathogen exposure, transitioning from attraction to avoidance of the pathogen. A systematic screen for the neural circuits that integrate the information of previous pathogen exposure to modify behavior has not been feasible because of the lack of tools for neuron type-specific perturbations. We overcame this challenge using methods based on compressed sensing to efficiently determine the roles of individual neuron types in learned avoidance behavior. Our screen revealed that distinct sets of neurons drive exit from lawns of pathogenic bacteria and prevent lawn re-entry. Using calcium imaging of freely behaving animals and optogenetic perturbations, we determined the neural dynamics that regulate one key behavioral transition after infection: stalled re-entry into bacterial lawns. We find that key neuron types govern pathogen lawn-specific stalling but allow the animal to enter nonpathogenic Escherichia coli lawns. Our study shows that learned pathogen avoidance requires coordinated transitions in discrete neural circuits and reveals the modular structure of this complex adaptive behavioral response to infection.

Short-term facilitation of recurrent excitatory synapses within the cortical network has been proposed to support persistent activity during working memory tasks, yet the underlying mechanisms remain poorly understood. We characterized short-term plasticity at the local excitatory synapses in layer 2/3 of the rat medial prefrontal cortex and studied its presynaptic mechanisms. Low-frequency stimulation induced slowly developing facilitation, whereas high-frequency stimulation initially induced strong depression followed by rapid facilitation. This non-monotonic delayed facilitation after a brief depression resulted from a high vesicular fusion probability and slow activation of Ca²⁺-dependent vesicle replenishment, which led to the overfilling of release sites beyond their basal occupancy. Pharmacological and gene knockdown (KD) experiments revealed that the facilitation was mediated by phospholipase C/diacylglycerol signaling and synaptotagmin 7 (Syt7). Notably, Syt7 KD abolished facilitation and slowed the refilling rate of vesicles with high fusion probability. Furthermore, Syt7 deficiency in layer 2/3 pyramidal neurons impaired the acquisition of trace fear memory and reduced c-Fos activity. In conclusion, Ca²⁺- and Syt7-dependent overfilling of release sites mediates synaptic facilitation at layer 2/3 recurrent excitatory synapses and contributes to temporal associative learning.

Planarian regeneration and tissue turnover involve fate specification in pluripotent stem cells called neoblasts. Neoblasts select fates through the expression of fate-specific transcription factors, generating specialized neoblasts. Specialized neoblasts are spatially intermingled and can be dispersed broadly, frequently being present far from their target tissue. The post-mitotic progeny of neoblasts, serving as progenitors, can migrate and differentiate into mature cell types. Pattern formation is thus strongly influenced by the migratory assortment and differentiation of fate-specified progenitors in precise locations, which we refer to as progenitor targeting. This central step of pattern maintenance and formation, however, is poorly understood. Here, we describe a requirement for the conserved map3k1 gene in targeting, restricting post-mitotic progenitor differentiation to precise locations. RNAi of map3k1 causes ectopic differentiation of eye progenitors along their migratory path, resulting in dispersed, ectopic eye cells and eyes. Other neural tissues similarly display ectopic posterior differentiation, and ectopic pharynx cells emerge dispersed laterally and anteriorly in map3k1 RNAi animals. Ectopic differentiated cells are also found within the incorrect organs after map3k1 RNAi, and ultimately, teratomas form. These findings implicate map3k1 signaling in controlling the positional regulation of progenitor behavior - restricting progenitor differentiation to targeted locations in response to external cues in the local tissue environment.

While the infralimbic cortex (IL) is recognized as critical for behavioral inhibition, the content of the inhibitory memories stored in this region remains elusive. To probe this content, we examined some of the conditions that allow retrieval and facilitation of an inhibitory memory stored in the IL using optogenetic stimulation in female and male rats. We found that IL stimulation did not facilitate an initial fear extinction session. However, prior experience with fear extinction enabled IL stimulation to facilitate subsequent fear extinction. Importantly, the facilitative effects of IL stimulation were not limited to fear extinction experience, as prior exposure to backward fear conditioning also enabled IL stimulation to enhance later fear extinction. The effects were stimulus-specific and did not depend on the motivational context present during the prior experience, as backward appetitive conditioning allowed IL stimulation to facilitate later fear extinction. Additional experiments ruled out stimulus familiarity as an explanation for the facilitative effects of IL stimulation and demonstrated that IL-mediated facilitations occur in procedures other than fear extinction. Together, these findings demonstrate that the IL stores inhibitory memories that are extremely flexible since they can be retrieved and used across many inhibitory procedures and distinct motivational contexts. These features establish the IL as a critical hub for the flexible application of inhibitory knowledge that allows adaptive responses in dynamic environments.

Stress is one of the most pervasive causes of mental ill health across the lifespan. Subjective dimensions of stress perception, such as perceived control, are especially potent in shaping stress responses. While the impact of reduced or no control over stress is well understood, much less is known about whether heightened feelings of control buffer against the negative impact of later stress. We designed a novel paradigm with excellent psychometric properties to sensitively capture and induce different states of subjective control. Across two studies with a non-clinical sample of 768 adults, we show a robust association between sense of control and stress as well as symptoms of mental ill health. More importantly, in a subsample of 295 participants, we show that compared to a neutral control group, inducing a heightened state of subjective control buffers against the impact of later stress. These findings demonstrate a causal role for a heightened sense of control in mitigating the negative impact of stressful experiences and spell out important directions for future preventative interventions.

Sex peptide (SP) transferred during mating induces female post-mating responses including refractoriness to re-mate and increased oviposition in Drosophila. Yet, where SP-target neurons reside remained uncertain. Here, we show that expression of membrane-tethered SP (mSP) predominantly in the head or trunk either reduces receptivity or increases oviposition, respectively. Using fragments from large regulatory regions of Sex Peptide Receptor, fruitless, and doublesex genes together with intersectional expression of mSP, we identified distinct interneurons in the brain and abdominal ganglion controlling receptivity and oviposition. These SP response-inducing neurons (SPRINz) can induce post-mating responses through SP received by mating. Trans-synaptic mapping of neuronal connections reveals input from sensory processing neurons and two post-synaptic trajectories as output. Hence, SP-target neurons operate as key integrators of sensory information for decision-making of behavioural outputs. Multi-modularity of SP-targets further allows females to adjust SP-mediated male manipulation to physiological state and environmental conditions for maximising reproductive success.

A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants, such as H6R, impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3-17, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD.