Biology subjects

Lee, J.

Publications and source records attributed to Lee, J..

At least 523 records · Page 29Linked to original sources

bioRxiv2023

Contezolid can replace linezolid in a novel combination with bedaquiline and pretomanid in a murine model of tuberculosis

Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 {micro}g/ml, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 10-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has potential to replace linezolid in regimens containing bedaquiline and pretomanid and likely other regimens.

microbiology↗

bioRxiv2023

The principles of peptide selection by the transporter associated with antigen processing

The adaptive immune response eliminates infected and cancer cells through the recognition of antigenic peptides displayed by major compatibility complex class I (MHC-I) molecules1, 2. A single transporter, the transporter associated with antigen processing (TAP), supplies nearly the entire peptide repertoire for the many MHC-I alleles3-5. A fundamental unresolved question is how TAP transports peptides with vast sequence diversity. Here, using cryo-electron microscopy (cryo-EM), we determined seven structures of human TAP in the presence and absence of peptides with different sequences and lengths. We observe that peptides are suspended in the transmembrane cavity of TAP with the peptide N-and C-termini anchored at two distal binding pockets. The central residues of the peptide are unrestricted, making few contacts with TAP. A minimum of eight residues is required to bridge the two binding pockets, aligning with the lower length limit for MHC-I binding6, 7. Mutations in TAP that disrupt hydrogen bonds with the peptide termini nearly abolish MHC-I surface expression, indicating that binding depends on interactions with mainchain atoms at the two termini. By utilizing two spatially separated binding pockets and concentrating interactions at the two ends of the peptide, TAP functions as a molecular caliper, selecting peptides for length while permitting sequence diversity.

biophysics↗

bioRxiv2023

Incorporation of genome-bound cellular proteins into HIV-1 particles regulates viral infection

The initial steps of the human immunodeficiency virus 1 (HIV-1) lifecycle are regulated by cellular RNA-binding proteins (RBPs). To understand the scope of these early host-virus interactions, we developed in virion RNA interactome capture (ivRIC), which allowed the comprehensive and systematic profiling of the proteins that interact with the HIV-1 genomic (g)RNA inside viral particles. ivRIC identified 104 cellular RBPs within the encapsidated HIV-1 ribonucleoprotein, many of which are typically found in the cellular nucleus. Notably, these nuclear RBPs interact with the HIV-1 RBP Rev, suggesting that they associate with HIV-1 gRNA during its nuclear life. Functional assays show that ivRBPs are important for HIV-1, including PURA and PURB, which control viral gene expression and infectivity through interaction with critical sequences in the gRNA. Our characterisation of the composition of the encapsidated ribonucleoprotein of HIV-1 uncovers new host-virus interactions that invokes new mechanisms for controlling HIV-1 infection.

molecular biology↗

bioRxiv2023

Single-molecule studies reveal the off-pathway elemental pause state as a target of streptolydigin inhibition of RNA polymerase and its dramatic enhancement by Gre factors

Antibiotic streptolydigin (Stl) inhibits bacterial transcription by blocking the trigger loop folding in the active center of RNA polymerase (RNAP), which is essential for catalysis. We use acoustic force spectroscopy to characterize the dynamics of transcription elongation in ternary elongation complexes of RNAP (ECs) in the presence of Stl at a single-molecule level. We found that Stl induces long-lived stochastic pauses while the instantaneous velocity of transcription between the pauses is unaffected. Stl enhances the short-lived pauses associated with an off-pathway elemental paused state of the RNAP nucleotide addition cycle. Unexpectedly, we found that transcript cleavage factors GreA and GreB, which were thought to be Stl competitors, do not alleviate the streptolydigin-induced pausing; instead, they synergistically increase transcription inhibition by Stl. This is the first known instance of a transcriptional factor enhancing antibiotic activity. We propose a structural model of the EC-Gre-Stl complex that explains the observed Stl activities and provides insight into possible cooperative action of secondary channel factors and other antibiotics binding at the Stl-pocket. These results offer a new strategy for high-throughput screening for prospective antibacterial agents.

biophysics↗

bioRxiv2023

In vivo evolution of a Klebsiella pneumoniae capsule defect promotes complement-mediated opsono-phagocytosis and persistence during recurrent infection

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) bloodstream infections rarely overwhelm the host but are associated with high mortality. The complement system is a key host defense against bloodstream infection. However, there are varying reports of serum resistance among KPC-Kp isolates. We assessed growth of 59 KPC-Kp clinical isolates in human serum and found increased resistance in 16/59 (27%). We identified five genetically-related bloodstream isolates with varying serum resistance profiles collected from a single patient during an extended hospitalization marked by recurrent KPC-Kp bloodstream infections. We noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ, that emerged during infection was associated with decreased polysaccharide capsule content, and resistance to complement-mediated killing. Surprisingly, disruption of wcaJ increased deposition of complement proteins on the microbial surface compared to the wild-type strain and led to increased complement-mediated opsono-phagocytosis in human whole blood. Disabling opsono-phagocytosis in the airspaces of mice impaired in vivo control of the wcaJ loss-of-function mutant in an acute lung infection model. These findings describe the rise of a capsular mutation that promotes KPC-Kp persistence within the host by enabling co-existence of increased bloodstream fitness and reduced tissue virulence. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/542722v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@155736eorg.highwire.dtl.DTLVardef@10d47c0org.highwire.dtl.DTLVardef@e1ab83org.highwire.dtl.DTLVardef@1c33131_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Created with BioRender.com C_FIG

microbiology↗

bioRxiv2023

Telomeric repeat evolution in the phylum Nematoda revealed by high-quality genome assemblies and subtelomere structures

Telomeres are composed of tandem arrays of telomeric-repeat motifs (TRMs) and telomere-binding proteins (TBPs), which are responsible for ensuring end-protection and end-replication of chromosomes. TRMs are highly conserved due to the sequence specificity of TBPs, but significant alterations in TRM have also been observed in several taxa, except Nematoda. We used public whole-genome sequencing datasets to analyze putative TRMs of 100 nematode species and determined that two distinct branches included specific novel TRMs, suggesting that evolutionary alterations in TRMs occurred in Nematoda. We focused on one of the two branches, the Panagrolaimidae family, and performed a de novo assembly of four high-quality draft genomes of the canonical (TTAGGC) and novel TRM (TTAGAC)-containing isolates; the latter genomes revealed densely clustered arrays of the novel TRM. We then comprehensively analyzed the subtelomeric regions of the genomes to infer how the novel TRM evolved. We identified DNA damage-repair signatures in subtelomeric sequences that were representative of consequences of telomere maintenance mechanisms by alternative lengthening of telomeres. We propose a hypothetical scenario in which TTAGAC-containing units are clustered in subtelomeric regions and pre-existing TBPs capable of binding both canonical and novel TRMs aided the evolution of the novel TRM in the Panagrolaimidae family.

evolutionary biology↗

bioRxiv2023

Colonization and Dissemination of Klebsiella pneumoniae is Dependent on Dietary Carbohydrates

Dysbiosis of the gut microbiota is increasingly appreciated as both a consequence and precipitant of human disease. The outgrowth of the bacterial family Enterobacteriaceae is a common feature of dysbiosis, including the human pathogen Klebsiella pneumoniae. Dietary interventions have proven efficacious in the resolution of dysbiosis, though the specific dietary components involved remain poorly defined. Based on a previous human diet study, we hypothesized that dietary nutrients serve as a key resource for the growth of bacteria found in dysbiosis. Through human sample testing, and ex-vivo, and in vivo modeling, we find that nitrogen is not a limiting resource for the growth of Enterobacteriaceae in the gut, contrary to previous studies. Instead, we identify dietary simple carbohydrates as critical in colonization of K. pneumoniae. We additionally find that dietary fiber is necessary for colonization resistance against K. pneumoniae, mediated by recovery of the commensal microbiota, and protecting the host against dissemination from the gut microbiota during colitis. Targeted dietary therapies based on these findings may offer a therapeutic strategy in susceptible patients with dysbiosis.

microbiology↗

bioRxiv2023

Sequencing, fast and slow: profiling microbiomes in human samples with nanopore sequencing

Rapid and accurate pathogen identification is crucial in effectively combating infectious diseases. However, the current diagnostic tools for bacterial infections predominantly rely on century-old culture-based methods. Furthermore, recent research highlights the significance of host-microbe interactions within the host microbiota in influencing the outcome of infection episodes. As our understanding of science and medicine continues to advance, there is a pressing need for innovative diagnostic methods that can identify pathogens and also rapidly and accurately profile the microbiome landscape in human samples. In clinical settings, such diagnostic tools will become a powerful predictive instrument in directing the diagnosis and prognosis of infectious diseases by providing comprehensive insights into the patients microbiota. Here, we explore the potential of long-read sequencing in profiling the microbiome landscape from various human samples in terms of speed and accuracy. Using nanopore sequencers, we generate native DNA sequences from saliva and stool samples rapidly, from which each long-read is basecalled in real-time to provide downstream analyses such as taxonomic classification and antimicrobial resistance through the built-in software (< 12 hours). Subsequently, we utilize the nanopore sequence data for in-depth analysis of each microbial species in terms of host-microbe interaction types and deep learning-based classification of unidentified reads. We find that the nanopore sequence data encompass complex information regarding the microbiome composition of the host and its microbial communities, and also shed light on the unexplored human mobilome including bacteriophages. In this study, we use two different systems of long-read sequencing to give insights into human microbiome samples in the slow and fast modes, which raises additional inquiries regarding the precision of this novel technology and the feasibility of extracting native DNA sequences from other human microbiomes.

microbiology↗

bioRxiv2023

A QTL influences sex ratios by controlling asymmetric organelle positioning during male spermatogenesis in Auanema freiburgense

Auanema freiburgense is a trioecious nematode with co-existing males, females, and selfing hermaphrodites. Crosses of XO males with XX females result in a low percentage of XO sons due to the elimination of the nullo-X spermatids by the fathers. This process yields most viable sperm containing an X chromosome, leading to a higher transmission probability of the X chromosome compared to expected transmission via random segregation. The mechanism underlying this process involves the asymmetric distribution of essential cellular organelles during sperm formation, which likely depends on the X chromosome. Specifically, sperm components segregate with the X chromosome daughter cell, while other components are discarded in the nullo-X daughter cell. Here we found that intercrossing two strains of A. freiburgense results in lines in which males produce viable nullo-X sperm. Thus, crosses of those hybrid males with females result in a high percentage of sons. To uncover the genetic basis of nullo-spermatid elimination and X-chromosome drive, we generated a genome assembly for A. freiburgense and genotyped the intercrossed lines. We identified a QTL encompassing several genes on the X chromosome that are associated with its non-Mendelian inheritance observed in A. freiburgense. This finding provides valuable clues to the underlying factors involved in asymmetric organelle partitioning during male meiotic division and thus non-Mendelian transmission of the X chromosome and sex ratios.

developmental biology↗

bioRxiv2023

Evolutionary spread of protein L-(iso)aspartyl O-methyltransferases guides the discovery of distinct isoaspartate-containing peptides, pimtides

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity remains largely underexplored, the identification of novel subclasses with unique structural motifs and biosynthetic pathways has been challenging. Here, we report that protein L-(iso)aspartyl O-methyltransferases (PIMTs) present in several RiPP subclasses are highly homologous. Importantly, we discovered that the apparent evolutionary transmission of the PIMT gene could serve as a basis to identify a novel RiPP subclass. Biochemical and structural analyses suggest that these homologous PIMTs commonly convert aspartate to isoaspartate via aspartyl-O-methyl ester and aspartimide intermediates, and often require cyclic or hairpin-like structures for modification. By conducting homology-based bioinformatic analysis of PIMTs, we identified over 2,800 biosynthetic gene clusters (BGCs) for known RiPP subclasses in which PIMTs install a secondary modification, and over 1,500 BGCs in which PIMTs function as a primary modification enzyme, thereby defining a new RiPP subclass, named pimtides. Our results suggest that the genome mining of proteins with secondary biosynthetic roles could be an effective strategy for discovering novel biosynthetic pathways of RiPPs. Insert Table of Contents artwork here O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/540355v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1f8afadorg.highwire.dtl.DTLVardef@1d5b2f3org.highwire.dtl.DTLVardef@d78d2eorg.highwire.dtl.DTLVardef@176070a_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response of an aggressive low TMB squamous cell tumor to ICB could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. The concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

immunology↗

bioRxiv2023

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Single-cell genetic and epigenetic analyses parse the brains billions of neurons into thousands of "cell-type" clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source [->]target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

neuroscience↗

bioRxiv2023

Uncovering the hidden structure of dynamic T cell composition in peripheral blood during cancer immunotherapy: a topic modeling approach

Immune checkpoint inhibitors (ICIs), now mainstays in the treatment of cancer treatment, show great potential but only benefit a subset of patients. A more complete understanding of the immunological mechanisms and pharmacodynamics of ICI in cancer patients will help identify the patients most likely to benefit and will generate knowledge for the development of next-generation ICI regimens. We set out to interrogate the early temporal evolution of T cell populations from longitudinal single-cell flow cytometry data. We developed an innovative statistical and computational approach using a Latent Dirichlet Allocation (LDA) model that extends the concept of topic modeling used in text mining. This powerful unsupervised learning tool allows us to discover compositional topics within immune cell populations that have distinct functional and differentiation states and are biologically and clinically relevant. To illustrate the models utility, we analyzed [~]17 million T cells obtained from 138 pre- and on-treatment peripheral blood samples from a cohort of melanoma patients treated with ICIs. We identified three latent dynamic topics: a T-cell exhaustion topic that recapitulates a LAG3+ predominant patient subgroup with poor clinical outcome; a naive topic that shows association with immune-related toxicity; and an immune activation topic that emerges upon ICI treatment. We identified that a patient subgroup with a high baseline of the naive topic has a higher toxicity grade. While the current application is demonstrated using flow cytometry data, our approach has broader utility and creates a new direction for translating single-cell data into biological and clinical insights.

bioinformatics↗

bioRxiv2023

Evaluation and optimization of sequence-based gene regulatory deep learning models

Neural networks have emerged as immensely powerful tools in predicting functional genomic regions, notably evidenced by recent successes in deciphering gene regulatory logic. However, a systematic evaluation of how model architectures and training strategies impact genomics model performance is lacking. To address this gap, we held a DREAM Challenge where competitors trained models on a dataset of millions of random promoter DNA sequences and corresponding expression levels, experimentally determined in yeast, to best capture the relationship between regulatory DNA and gene expression. For a robust evaluation of the models, we designed a comprehensive suite of benchmarks encompassing various sequence types. While some benchmarks produced similar results across the top-performing models, others differed substantially. All top-performing models used neural networks, but diverged in architectures and novel training strategies, tailored to genomics sequence data. To dissect how architectural and training choices impact performance, we developed the Prix Fixe framework to divide any given model into logically equivalent building blocks. We tested all possible combinations for the top three models and observed performance improvements for each. The DREAM Challenge models not only achieved state-of-the-art results on our comprehensive yeast dataset but also consistently surpassed existing benchmarks on Drosophila and human genomic datasets. Overall, we demonstrate that high-quality gold-standard genomics datasets can drive significant progress in model development.

genomics↗

bioRxiv2023

Tension sensing by FAK governs nuclear mechanotransduction, endothelial transcriptome and fate

Vascular endothelium forms a restrictive barrier to defend the underlying tissue against uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Using endothelial cell (EC)-Fak-/-mice, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK- deleted EC, increased EC tension induced by Rho kinase caused tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Activated emerin stimulated DNMT3a activity and methylation of the KLF2 promoter, impairing the restrictive EC transcriptome, including S1PR1. Inhibiting emerin phosphorylation or DNMT3a activity enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype in EC-Fak-/- lungs. Thus, FAK sensing of tension transmission to the nucleus is crucial for maintaining a restrictive EC fate and lung homeostasis.

cell biology↗

bioRxiv2023

daf-42 is an evolutionarily young gene essential for dauer development in Caenorhabditis elegans

Under adverse environmental conditions, nematodes arrest into dauer, an alternative developmental stage for diapause. Dauer endures unfavorable environments and interacts with host animals to access favorable environments, thus playing a critical role in survival. Here, we report that in Caenorhabditis elegans, daf-42 is essential for development into the dauer stage, as the null mutant of daf-42 exhibited a "no viable dauer" phenotype in which no viable dauers were obtained in any dauer-inducing conditions. Long-term time lapse microscopy of synchonized larvae revealed that daf-42 is involved in developmental changes from the pre-dauer L2d stage to the dauer stage. daf-42 encodes large, disordered proteins of various sizes that are expressed in and secreted from the seam cells within a narrow time window shortly before the molt into dauer stage. Transcriptome analysis showed that the transcription of genes involved in larval physiology and dauer metabolism are highly affected by the daf-42 mutation. Contrary to the notion that essential genes that control the life and death of an organism may well be conserved across diverse species, daf-42 is an evolutionarily young gene conserved only in the Caenorhabditis genus. Our study shows that dauer formation is a vital process that is controlled not only by conserved genes but also by newly emerged genes, providing important insights into evolutionary mechanisms.

developmental biology↗

bioRxiv2023

Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brains 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3 dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brains cellular-spatial and regulatory genome diversity.

genomics↗

bioRxiv2023

Multiple behavioral mechanisms shape social behavioral development in a highly social cichlid fish

Early-life social experiences shape adult phenotype, yet the underlying behavioural mechanisms remain poorly understood. We manipulated early-life social experience in the highly social African cichlid fish Astatotilapia burtoni to investigate the effects on behaviour and neuroendocrine stress axis function. Juveniles experienced different numbers of early-life social partners in stable pairs (1 partner), stable groups (6 fish; 5 partners), and socialized pairs (a novel fish was exchanged every 5 days; 5 partners). Treatments differed in group size (groups vs. pairs) and stability (stable vs. socialized). We then measured behaviour in multiple contexts and collected water-borne cortisol. We found effects of treatment on behaviour across all assays: open field exploration, social cue investigation, dominant behaviour, and subordinate behaviour. Cortisol did not differ across treatments. Principal components (PC) analysis revealed robust co- variation of behaviour across contexts, including with cortisol, to form behavioural syndromes sensitive to early-life social experience. PC1 (25.1%) differed by numbers of social partners: juveniles with more social partners were more active during the social cue investigation, spent less time in the territory, and were more interactive as dominants. Differences in PC5 (8.5%) were based on stability: socialized pairs were more dominant, spent less time in and around the territory, were more socially investigative, and had lower cortisol than stable groups or pairs. Behaviour observations in the home tanks provided further insights into the behavioural mechanisms underlying these effects. These results contribute to our understanding of how early- life social experiences are accrued and exert strong, lasting effects on adult phenotype.

animal behavior and cognition↗