Biology subjects

Zhou, Z.

Publications and source records attributed to Zhou, Z..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

Dietary quorum quenching AHL lactonase impairs the adaptation of commensal bacterium to host innate immunity

Quorum sensing (QS) is the communication system of bacteria that depends on QS signals. Quorum quenching (QQ) enzymes degrade QS signals and are promising alternatives of antibiotics to treat bacterial infections. Here, we found that dietary QQ N-acyl homoserine (AHL) lactonase led to microbiota dysbiosis in zebrafish, with reduction of Aeromonas and enrichment of Plesiomonas. Through gnotobiotic zebrafish colonized with a minimal microbiota, we found that QQ-mediated microbial alteration relies on host Myd88 signaling and neutrophil elastase. Mechanistically, quorum quenching increased the susceptibility of commensal Aeromonas to host neutrophil elastase by impairing bacterial lateral flagellar system, leading to reduced colonization of Aeromonas and subsequent enrichment of Plesiomonas due to ecological competition of the two species. Together, we found that dietary QQ lactonase led to microbiota alteration by impairing the adaptation of commensal Aeromonas to host innate immunity, which provided novel insight in the role of quorum sensing in host-microbiota interaction.

microbiology↗

bioRxiv2025

GenomeOcean: An Efficient Genome Foundation Model Trained on Large-Scale Metagenomic Assemblies

Functional genomic sequences occupy an infinitesimal fraction of the astronomically large DNA sequence space, implying that evolution explores a low-dimensional manifold shaped by universal biochemical and evolutionary constraints. To investigate this underexplored Genomic Manifold Hypothesis using scalable, data-driven evidence, we developed GenomeOcean, a 4-billion-parameter generative model trained on 219 TB of diverse, co-assembled global environmental metagenomic data using an optimized transformer. The model captures both universal phylogenetic syntax and protein-coding fidelity. Furthermore, we validate the embeddings intrinsic low dimensionality. Crucially, comparisons with the independently trained Evo 2 model demonstrate a strong linear correspondence between their embedding spaces and convergent generative behaviors. These results suggest that the genomic manifold represents a fundamental biological principle, offering a unified framework for understanding evolutionary constraints and guiding synthetic biology.

bioinformatics↗

bioRxiv2025

Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model

Genetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. We developed a CGD model using Ncf2-/- mice through controlled environmental exposure. Unlike in specific pathogen-free environment, these mice spontaneously developed pulmonary granulomas under clean-grade conditions. Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2high-neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. Spatial transcriptomics demonstrated that NOS2high-neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. Pharmacological targeting of MIF, deletion of the pro-survival gene Morrbid, and elimination of Il1r1 all suppressed granuloma formation by mitigating inflammation. This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions. HighlightsO_LIThrough installing a mutation in a NOX2 subunit gene Ncf2 and changing the husbandry environment, we generated a natural CGD mouse model with progressive pulmonary granuloma formation. C_LIO_LINOS2high neutrophils located in the core region of CGD lung granulomas, exhibit a pro-inflammatory transcriptional profile. C_LIO_LIMonocyte-derived macrophages marked by Nos2 and Arg1 are located at the periphery of granulomas and exhibit a profibrotic transcriptional profile. C_LIO_LIThe transcriptomic studies assist the development of three effective perturbations for treating the rare disease CGD via targeting Il1r1, Morrbid, and Mif respectively. C_LI

immunology↗

bioRxiv2025

High-speed mapping of whole-mouse peripheral nerves at subcellular resolution

In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping the peripheral nervous system has remained challenging due to the bodys size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 hours. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease. HighlightsO_LIImaging of whole adult mouse at uniform subcellular resolution within 40 hours C_LIO_LIReconstruction of 191 thoracic spinal neuron projections for Thy1-EGFP mice C_LIO_LIMapping of immunolabeled sympathetic projections and their perivascular patterns C_LIO_LIResolving virus-labeled architecture of vagus nerves and complex single-fiber routes C_LI

neuroscience↗

bioRxiv2025

Decoding Mechanisms of PTEN Missense Mutations in Cancer and Autism Spectrum Disorder using Interpretable Machine Learning Approaches

Missense mutations in oncogenic proteins that are concurrently associated with neurodevelopmental disorders have garnered significant attention. Phosphatase and tensin homolog (PTEN) serves as a paradigmatic model for mapping its mutational landscape and identifying genotypic predictors of distinct phenotypic outcomes, including cancer and autism spectrum disorder (ASD). Despite extensive research into the genotype-phenotype correlations of PTEN mutations, the mechanisms underlying the dual association of specific PTEN mutations with both cancer and ASD (PTEN-cancer/ASD mutations) remain elusive. This study introduces an integrative approach that combines machine learning (ML) with structural dynamics to elucidate the molecular effects of PTEN-cancer/ASD mutations. Analysis of biophysical and network biology-based signatures reveals a complex energetic and functional landscape. Subsequently, an ML model and corresponding integrated score were developed to classify and predict PTEN-cancer/ASD mutations, underscoring the significance of protein dynamics in predicting cellular phenotypes. Further molecular dynamics simulations demonstrated that PTEN-cancer/ASD mutations induce dynamic alterations characterized by open conformational changes restricted to the P loop and coupled with inter-domain allosteric regulation. This research aims to enhance the genotypic and phenotypic understanding of PTEN-cancer/ASD mutations through an interpretable ML model integrated with structural dynamics analysis. By identifying shared mechanisms between cancer and ASD, the findings pave the way for the development of novel therapeutic strategies.

bioinformatics↗

bioRxiv2025

Precision mRNA Nanomedicine for Targeted Vascular Therapies in ARDS and Atherosclerosis

Vascular diseases, including acute respiratory distress syndrome (ARDS) and atherosclerosis, are leading causes of global morbidity and mortality, underscoring the critical need for innovative therapies. While human genetics has uncovered specific molecular mechanisms in endothelial cells that drive acute and chronic vascular inflammation central to these conditions, effective in vivo strategies to spatiotemporally target these disease-causing pathways using therapeutic mRNAs remain limited. Here, we present a modular and tunable nanoparticle platform (PROGRAMMED nanoparticles) engineered to selectively deliver therapeutic mRNAs to target cells with distinct molecular signatures, such as inflamed endothelial cells expressing vascular cell adhesion molecule 1 (VCAM1). This approach restores key genetics-informed endothelial pathways implicated in disease, including the loss of Kruppel-like factor 2 (KLF2) in acute inflammation underlying ARDS and the suppression of phospholipid phosphatase 3 (PLPP3) in chronic inflammation driving atherosclerosis. In multiple preclinical models, these precision mRNA nanomedicine strategies demonstrated compelling therapeutic efficacy. VCAM1-targeting PROGRAMMED nanoparticles delivering KLF2 mRNA to inflamed lung microvascular endothelial cells significantly improved microvascular health and alleviated virus-induced ARDS. Similarly, PLPP3 mRNA delivery by VCAM1-targeting PROGRAMMED nanoparticles attenuated arterial inflammation, slowed atherosclerosis progression, and promoted regression of advanced plaques. This innovative platform offers a transformative approach for spatiotemporal mRNA therapies targeting inflamed endothelial cells, providing a minimally invasive and highly specific strategy to address acute and chronic vascular diseases. Moreover, the modularity of PROGRAMMED nanoparticles, particularly their ability to display diverse targeting motifs, holds substantial potential for addressing a broad spectrum of vascular complications and other diseases that require precise spatiotemporal correction of dysregulated genes.

bioengineering↗

bioRxiv2025

Keystone engineering enables collective range expansion in microbial communities

Keystone engineers profoundly influence microbial communities by altering their shared environment, often by modifying key resources. Here, we show that in an antibiotic-treated microbial community, bacterial spread is controlled by keystone engineering affecting dispersal--an effect hidden in well-mixed environments. Focusing on two pathogens, non-motile Klebsiella pneumoniae and motile Pseudomonas aeruginosa, we found that both tolerate a {beta}-lactam antibiotic, with Pseudomonas being more resilient and dominating in well-mixed cultures. During range expansion, however, the antibiotic inhibits Pseudomonas ability to spread unless it is near Klebsiella--Klebsiella degrades the antibiotic to create a "clear zone" that allows Pseudomonas to expand, at the expense of Klebsiellas own growth, thus acting as a keystone engineer. As Pseudomonas spreads, it competitively suppresses Klebsiella. Our modeling and experimental analyses reveal that this keystone effect operates at a millimeter scale. We also observed similar keystone engineering by a Bacillus species isolated from a hospital sink, in both pairwise and eight-member bacterial communities with its co-isolates. These findings suggest that spatially explicit experiments are essential to understand certain keystone engineering mechanisms and have implications for surface-associated microbial communities like biofilms, as well as for diagnosing and treating polymicrobial infections involving drug-degrading, non-motile (e.g., Klebsiella), and drug-tolerant, motile (e.g., Pseudomonas) bacteria.

ecology↗

bioRxiv2025

Systematic Identification of Microtubule Inner Proteins Reveals JPT2 as a Key Regulator of Lumen Microenvironment and Drug Sensitivity

Microtubules are primarily studied for the interactions of proteins that bind to their outer surfaces and ends, while the regulatory mechanisms within the microtubule lumen, particularly in singlet microtubules critical for essential cellular processes, remain largely unexplored. Our study provides the first systematic identification of key regulatory proteins within the single microtubule lumen. Using proximity-dependent biotin identification (Bio-ID) coupled with mass spectrometry, we identified candidate microtubule inner proteins (MIPs), including Jupiter microtubule-associated homolog 2 (JPT2). JPT2 binds directly to microtubules and specifically localizes within the lumen, where it modulates the luminal environment by inhibiting acetylase MEC17 and independently affects the binding and efficacy of Paclitaxel. Furthermore, our screening identified additional MIPs that influence cellular sensitivity to Paclitaxel, indicating a link between luminal regulation and drug responsiveness. These discoveries reveal JPT2s critical role in singlet microtubule regulation and suggest new therapeutic targets for enhancing cancer drug sensitivity.

cell biology↗

bioRxiv2024

Single-cell analysis reveals distinct immune characteristics of hepatocellular carcinoma in HBV-positive versus HBV-negative cases

Infection with the Hepatitis B virus (HBV) is a key risk factor for Hepatocellular carcinoma (HCC) development and progression. It is widely recognized that immunopathological mechanisms are pivotal in developing HBV-related HCC. Nevertheless, the specific mechanisms by which HBV-induced modifications within the tumor microenvironment (TME) contribute to HCC pathogenesis are still not well understood. Here, we utilized single-cell RNA sequencing to analyze and compare the immune landscapes between HBV-positive and HBV-negative HCC. We discovered that HBV infection significantly modifies the immune cell makeup and state, and leads to the suppression and exhaustion of T cells within the TME. Specifically, an increase in SLC4A10+ CD8+ T cells and IFITM3+ macrophages was observed, along with the upregulation of the gene SLC35F1 in various immune cell subtypes. These findings offer valuable insights into the alteration of the immunological microenvironment in HCC associated with HBV infection, suggesting possible targets for immunotherapeutic intervention.

bioinformatics↗

bioRxiv2024

Skeletal trait measurements for thousands of bird species

Large comparative datasets of avian functional traits have been used to address a wide range of questions in ecology and evolution. To date, this work has been constrained by the limited availability of skeletal trait datasets that include extensive inter- and intra-specific sampling. We use computer vision to identify and measure bones from photographs of museum skeletal specimens to assemble an extensive dataset of functionally important skeletal elements in birds. The dataset spans 2,057 species of birds (Aves: Passeriformes) and includes measurements of 12 skeletal elements from 14,419 individuals. In addition to the trait values directly measured from photographs, we leverage the multi-dimensional nature of our dataset and known phylogenetic relationships of the species to impute missing data under an evolutionary model. To facilitate use of the dataset, the taxonomy has been reconciled with an existing comprehensive avian phylogeny and an additional dataset of external functional traits for all birds.

evolutionary biology↗

bioRxiv2024

UTX Epigenetically Imposes a Cytolytic Effector Program in Autoreactive Stem-like CD8+ T cell Progenitors

Type 1 Diabetes Mellitus (T1D) is a chronic disease caused by an unremitting autoimmune attack on pancreatic beta cells. This autoimmune chronicity is mediated by stem-like progenitor CD8+ T cells that continually repopulate the pool of beta cell-specific cytolytic effectors. Factors governing the conversion of progenitors to effectors, however, remain unclear. T1D has been linked to a chromosomal region (Xp13-p11) that contains the epigenetic regulator UTX, which suggests a key role for UTX in T1D pathogenesis. Here, we show that T cell-specific UTX deletion in NOD mice protects against T1D development. In T cells of NOD mice and T1D patients, UTX ablation resulted in the accumulation of CD8+ progenitor cells with concomitant deficiency of effectors, suggesting a key role for UTX in poising progenitors for transition to effectors. Mechanistically, UTXs role in T1D was independent of its inherent histone demethylase activity but instead relied on binding with transcription factors (TCF1 and STAT3) to co-regulate genes important in the maintenance and differentiation of progenitor CD8+ T cells. Together, these findings identify a critical role for UTX in T1D and the UTX:TCF1:STAT3 complex as a therapeutic target for terminating the long-lived autoimmune response.

immunology↗

bioRxiv2024

Abnormal eNK cells contribute to endometrial fibrosis in intrauterine adhesions patients

Endometrial natural killer cells (eNK) at the proliferative phase are one of the major lymphocytes in the endometrium, but their phenotype and function remain elucidated. Here, we demonstrated that eNK cells had three subtypes and were different from peripheral blood NK (pbNK) and decidual NK (dNK) cells. They played an important role in maintaining the homeostasis of the endometrium through preventing endometrial stromal cells (ESCs) from the differentiation into myofibroblasts physiologically. However, in the fibrotic endometria of patients with intrauterine adhesions (IUA), eNK cells were significantly decreased and highly negatively correlated with an increase in myofibroblasts. In vitro experiments showed that eNK cells could inhibit the differentiation of ESCs into myofibroblasts and promote the dedifferentiation of myofibroblasts, in which the main effector molecules from eNK cells was Prostaglandin D2 (PGD2). PGD2 downregulated the expression of ZNF521 to decrease profibrotic protein synthesis. Furthermore, we confirmed the anti-endometrial fibrosis effect of eNK cells and its mechanism in an IUA-like murine model. These findings reveal an important role of eNK cells in endometrial homeostasis and provide potential therapeutic approaches for IUA patients.

immunology↗

bioRxiv2024

Insights into Intestinal Barrier Disruption During Long-Term Gut Chlamydia Colonization in Mice: A Single-Cell Transcriptomic Approach

Chlamydia trachomatis, an intracellular pathogen, stands as the most prevalent sexually transmitted bacterial infection among women globally. Traditionally recognized as a genital pathogen, recent research indicates that the gastrointestinal tract may also act as a reservoir for its long-term colonization. However, the mechanisms underlying Chlamydias ability to persist in the gut remain poorly understood. This gap in knowledge limits our ability to develop effective treatments for persistent Chlamydia infections. In this study we utilized single-cell RNA sequencing to analyze the gene expression profiles and cellular heterogeneity of mouse colonic tissues during Chlamydia long-term infection. This approach provided detailed insights into the transcriptional changes and cellular interactions involved in the persistence of Chlamydia in the gut. Our results revealed significant alterations in the gene expression profiles of various intestinal cell populations, with distinct molecular pathways contributing to Chlamydia persistence. Notably, we observed a reduction in the expression of markers associated with epithelial tight junctions, indicating a potential breakdown of the intestinal epithelial barrier. This impairment may facilitate the penetration of Chlamydia into deeper tissues and contribute to the initiation of infection. We also found dysregulation of the transcriptional networks in goblet cells and an imbalance in communication between immune and epithelial cells. These disruptions were linked to the pathogens ability to establish persistent colonization and infection. IMPORTANCEFew studies have explored Chlamydia persistence in the gastrointestinal tract. In this study, we use single-cell RNA sequencing to identify the molecular and cellular mechanisms driving the pathogens long-term colonization. Our findings provide crucial insights into how Chlamydia overcomes the hosts immune defenses and epithelial barriers to establish chronic infection in the gut. Notably, we identify disruption of epithelial tight junctions and an imbalance in immune-cell interactions, offering new avenues for therapeutic interventions aimed at restoring mucosal integrity and preventing persistent infection.

microbiology↗

bioRxiv2024

pnetr: An R package for the PnET family of forest ecosystem models

O_LIEcosystem models offer a rigorous way to formalize scientific theories and are critical to evaluating complex interactions among ecological and biogeochemical processes. In addition to simulation and prediction, ecosystem models are a valuable tool for testing hypotheses about mechanisms and empirical findings because they reveal critical internal processes that are difficult to observe directly. C_LIO_LIHowever, many ecosystem models are difficult to manage and apply by scientists who lack advanced computing skills due to complex model structures, lack of consistent documentation, and low-level programming implementation, which facilitates computing but reduces accessibility. C_LIO_LIHere, we present the pnetr R package, which is designed to provide an easy-to-manage ecosystem modeling framework and detailed documentation in both model structure and programming. The framework implements a family of widely used PnET (net photosynthesis, evapotranspiration) ecosystem models, which are relatively parsimonious but capture essential biogeochemical cycles of water, carbon, and nutrients. We chose the R programming language since it is familiar to many ecologists and has abundant statistical modeling resources. We showcase examples of model simulations and test the effects of phenology on carbon assimilation and wood production using data measured by the Environmental Measurement Station (EMS) eddy-covariance flux tower at Harvard Forest, MA. C_LIO_LIWe hope pnetr can facilitate further development of ecological theory and increase the accessibility of ecosystem modeling and ecological forecasting. C_LI

ecology↗

bioRxiv2024

TRAIT: A Comprehensive Database for T-cell Receptor-Antigen Interactions

Comprehensive and integrated resources on interactions between T-cell receptors and antigens are still lacking for adoptive T-cell-based immunotherapies, highlighting a significant gap that must be addressed to fully comprehend the mechanisms of antigen recognition by T-cells. In this study, we present TRAIT, a comprehensive database that profiles the interactions between T-cell receptors (TCRs) and antigens. TRAIT stands out due to its comprehensive description of TCR-antigen interactions by integrating sequences, structures and affinities. It provides nearly 8 million experimentally validated TCR-antigen pairs, resulting in an exhaustive landscape of antigen-specific TCRs. Notably, TRAIT emphasizes single-cell omics as a major reliable data source for TCR-antigen interactions and includes millions of reliable non-interactive TCRs. Additionally, it thoroughly demonstrates the interactions between mutations of TCRs and antigens, thereby benefiting affinity maturation of engineered TCRs as well as vaccine design. TCRs on clinical trials were innovatively provided. With the significant efforts made towards elucidating the complex interactions between TCRs and antigens, TRAIT is expected to ultimately contribute superior algorithms and substantial advancements in the field of T-cell-based immunotherapies. TRAIT is freely accessible at https://pgx.zju.edu.cn/traitdb.

immunology↗

bioRxiv2024

Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches

Recent studies have identified a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain the least understood CAF subtype. To gain a comprehensive understanding of the origin and function apCAFs, we construct a fibroblast molecular atlas across 14 types of solid tumors. Our integration study unexpectedly reveals two distinct apCAF lineages present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF lineages. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with tertiary lymphoid structures. Additionally, we discover that both apCAF lineages can up-regulate the secreted protein SPP1, which facilitates primary tumor formation and peritoneal metastasis. Taken together, this study offers an unprecedented resolution in analyzing apCAF lineages and their spatial niches.

cancer biology↗

bioRxiv2024

A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics

The three-dimensional organization of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed that sex is the dominant factor segregating changes in chromatin accessibility. A lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene, Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex. HighlightsATAC-Seq, RNA-Seq, and FCG model-integrated analysis unravel sex differences in chromatin accessibility and transcriptome responses to dietary challenges. Lipid-rich diet led to sex-biased chromatin confirmation at promoter regions. Gonadal sex emerged as the most prevalent determinant of the sex bias hepatic chromatin modulation by lipid-rich diets. The critical sex-dimorphic GWAS gene Pnpla3 is suppressed by testosterone, which underlies hepatic differences in expression between the sexes.

molecular biology↗

bioRxiv2024

Novel MRI-based Biotypes of Human Neurodevelopment associated with Impulsivity performance

IntroductionAdequate neurodevelopment is critical to the proper advancement of cognitive and emotional processing; however, variation in neurodevelopment has emerged as a potential risk factor for subsequent drug use. The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing and longitudinal study to determine the developmental trajectories of the brain and how experiences impact brain development, which makes it an ideal framework study to determine proper neurodevelopmental trajectories associated with healthy executive function behavioral development and their neurobiology. MethodBased on the availability of ABCD (Release 5.1) tabulated data, we selected 1368 subjects with neuroimaging records on multiple time points. To focus on the frontal cortex, we preprocess 20 ROIs (including ten regions with right and left cerebral hemispheres) cortical thickness measurements for SuStaIn. Once SuStaIn determined the potential control and phenotype (subtypes) group, we conducted t-tests between the control and phenotype groups on their delay discounting measurements. To overserve possible trajectories, we also investigated the correlation of the thickness measurements with delay discounting under the suggested phenotype by SuStaIn. ResultsSuStaIn identified four subtypes and one potential control group, validated by cross-validation test as the optimal solution for balancing model accuracy and complexity. Among the t-tests on delay discounting results between the control group and each subtype, subtype1 tends to show low significance on the 3-month indifference point (p=0.067), subtype 2 identifies a significant reduction in impulsivity on the 1-month indifference point (p=0.017), subtype 4 stands significant reduction at on 3-month indifference point (p=0.0092) and significance on 1-year indifference point (p=0.00418). For the correlations between each selected ROI, we identified a negative correlation (R=-0.18, p=0.0095) between the thickness of the left hemisphere caudal-anterior-cingulate and delay discounting indifference point at 3 months. ConclusionWe successfully identified four subtypes of the ABCD, which may be putative abnormal trajectories of executive function accelerated development. Three of the four subtypes reflect impulsive behavioral phenotype, and one displays an association with cortical thinning. Overall, we present evidence that there are putative neurobiological signs of potential executive function disruption as early as nine years of age.

neuroscience↗