Biology subjects

Lan, Y.

Publications and source records attributed to Lan, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Embryonic Mast Cells Arise from Cpa3-expressing Precursors Independent of Granulocyte-Monocyte Progenitors

Most of the mast cells (MCs) in connective tissues, such as skin, are long-lived embryonic-derived immune cells that play important roles in host defense and various immunological diseases, including allergies. Their embryonic origin and ontogeny remain to be fully studied since several overlapping waves of embryonic hematopoiesis have been shown to give rise to these cells. Here, combining single-cell RNA sequencing and new genetic fate mapping models, we identified a Cpa3-expressing population sequentially appearing in the yolk sac, fetal liver, and peripheral tissues which gives rise to dermal MCs during embryonic days 11.5 to 14.5. Using in vitro differentiation and in vivo transplant methods, we identified a Ter119-F4/80- CD45+CD117+CD16/32+CD135-CD115-Ly6C-CD34lo population as potential fetal liver MC precursors. Fate mapping with Cpa3CreERT2and Zbtb16CreERT2 models, as well as the granulocyte-monocyte progenitor (GMP) models Ms4a3Cre and ElaneCre, demonstrated that MCs arise from Cpa3+ progenitors rather than Ms4a3+ or Elane+ GMPs. A corresponding population with a similar developmental trajectory was also identified in human early yolk sac and fetal liver, suggesting a conserved MC developmental program across species. These findings delineate the detailed developmental path of MCs in embryos, permitting future functional studies in immunity and development. HighlightsO_LICpa3-expressing cells in the yolk sac and fetal liver contain mast cell precursors C_LIO_LICpa3CreERT2 labels embryonic mast cells and their precursors C_LIO_LIEmbryonic mast cells arise through Cpa3+ mast cell precursors, but not Elane+/Ms4a3+ GMPs C_LIO_LIThe seeding of MCPs to embryonic skin slows down after E14.5 C_LI

immunology↗

bioRxiv2024

CIGB-300 reverses chemo-resistance in MDR1-transfected lung squamous cancer cells

BackgroundInhibition of ABC transporter protein activity is considered to be the most effective method to reverse multidrug resistance (MDR). In this study, we evaluated the MDR reversal potential of CIGB-300, a potent CK2 kinase inhibitor. MethodsABCB1 overexpressing lung adenocarcinoma NCI-H226 cells were constructed using lentivirus, and the expression of ABCB1 gene and protein was detected by real-time fluorescence quantitative PCR and Western blotting. MTT assay was used to assess the cytotoxicity and MDR reversal effect of CIGB-300.The effect of CIGB-300 on ABCB1 expression was determined by Western Blotting. Cell surface expression and subcellular localization of ABCB1 were examined by Flow Cytometry and Immunofluorescence Staining. Rh123 efflux and accumulation were measured by Fluorescent Enzyme Labeler and Flow Cytometry. ResultsCIGB-300 significantly increased the sensitivity of drug-resistant cells overexpressing the ABCB1 drug efflux pump (NCI-H226-ABCB1), while it had no effect on their parental cell lines. At the same time, its mechanism of action may be related to the inhibition of ABCB1 expression, which was dose-dependent, Moreover, in addition, we demonstrated that CIGB-300 reduced the expression of NFKB and CDC37 proteins. ConclusionsOur study elucidated that CIGB-300 reverses ABCB1-mediated MDR by inhibiting ABCB1 protein expression or intracellular signaling and provides a potential therapeutic strategy to improve tumor chemosensitivity.

cancer biology↗

bioRxiv2024

Strong segregation promotes self-destructive cooperation

Self-destructive cooperator (SDC), where individuals sacrifice themselves for others, poses significant personal costs yet is widespread in nature. Traditional group selection theory struggles to explain its persistence, as the extreme cost of self-destruction typically exceeds the benefit to these individuals. Here, we predict that this behavior can endure in structured environments with strong segregation, where populations are divided into homogenous groups originating from one or two founding members. In such contexts, the benefits derived from SDC are primarily confined within the homogenous SDC groups, thus preserving the value of this altruistic sacrifice and ensuring its maintenance. To validate our hypothesis, we employ a synthetic system with engineered bacteria to mimic both SDC and non-sacrificing cheaters. We then conduct automated experiments facilitated by biofoundry technology to monitor and operate the subgroups with diverse growth behaviors stemming from a restricted number of initial cells because of strong segregation. Eventually, we demonstrate that SDC indeed maintains under strong segregation, and high stress benefits SDC because it reduces the benefits received by cheaters in heterogenous subgroups. This study extends the group selection theory to encompass even the most extreme manifestations of altruism and highlights the potential of automation in evolutionary research.

microbiology↗

bioRxiv2024

Deep contrastive learning enables genome-wide virtual screening

Numerous protein-coding genes are associated with human diseases, yet approximately 90% of them lack targeted therapeutic intervention. While conventional computational methods, such as molecular docking, have facilitated the discovery of potential hit compounds, the development of genome-wide virtual screening against the expansive chemical space remains a formidable challenge. Here we introduce DrugCLIP, a novel framework that combines contrastive learning and dense retrieval to achieve rapid and accurate virtual screening. Compared to traditional docking methods, DrugCLIP improves the speed of virtual screening by up to seven orders of magnitude. In terms of performance, DrugCLIP not only surpasses docking and other deep learning-based methods across two standard benchmark datasets, but also demonstrates high efficacy in wet-lab experiments. Specifically, DrugCLIP successfully identified agonists with < 100 nM affinities for 5HT2AR, a key target in psychiatric diseases. For another target NET, whose structure is newly solved and not included in the training set, our method achieved a hit rate of 15%, with 12 diverse molecules exhibiting affinities better than bupropion. Additionally, two chemically novel inhibitors were validated by structure determination with Cryo-EM. Finally, a novel potential drug target TRIP12, with no experimental structures and inhibitors for reference, was used to challenge DrugCLIP. DrugCLIP achieved a hit rate of 17.5% by screening a pocket identified on an AlphaFold2-predicted structure, verified with multi-cycle SPR assays. Molecules with the highest affinities also showed a dose-dependent inhibition to the enzymatic function of TRIP12. Building on this foundation, we present the results of a pioneering trillion-scale genome-wide virtual screening, encompassing approximately 10,000 AlphaFold2 predicted proteins within the human genome and 500 million molecules from the ZINC and Enamine REAL database. This work provides an innovative perspective on drug discovery in the post-AlphaFold era, where comprehensive targeting of all disease-related proteins is within reach.

bioinformatics↗

bioRxiv2024

Insomnia score: predictive ability of insomnia, high-diagnostic and prognostic value for cancer.

ObjectiveThis study utilized bioinformatics methods to investigate the association between insomnia and cancer. MethodsWe identified key insomnia-related genes and constructed an insomnia score (riskScore = {sum} Expressiongene * Coefficient) based on an insomnia dataset using differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictive ability of the insomnia score was validated in the insomnia dataset using Receiver Operating Characteristic (ROC) analysis. Finally, the diagnostic and prognostic value of the insomnia score was assessed in a pan-cancer cohort. ResultsDifferential analysis, WGCNA, and LASSO screening of the insomnia dataset yielded three key insomnia-related genes (PTMA, NLRP8, and CCBE1). An insomnia score was then constructed using the formula: riskScore = -0.8039667 * ExpressionPTMA + - 3.1975230 * ExpressionNLRP8 + -0.4957560 * ExpressionCCBE1. The ROC analysis demonstrated that the insomnia score has excellent predictive ability for insomnia. Furthermore, pan-cancer analysis illustrated the diagnostic and prognostic value of the insomnia score across various cancers. ConclusionWe successfully constructed an insomnia score and demonstrated its diagnostic and prognostic value in multiple cancers.

bioinformatics↗

bioRxiv2024

Dynamical forces drive organ morphology changes during embryonic development

Cells, tissues, and organs must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffers vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffers vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt cell and organ shape during embryo development. Significance StatementWe aim to understand the mechanisms that control precise cell and tissue shape changes required for organ function. Many studies focused on cell shapes have ignored the role of dynamic forces self-generated by slow tissue flows, but recent work showing tissues are near a jamming transition with diverging relaxation timescales suggests slow motion could give rise to large forces. Through a combination of mathematical modeling, imaging, and mechanical perturbations to in vivo experiments, our work demonstrates that tissue-scale dynamic forces are sculpting the shape of an epithelial organ in the zebrafish embryo called Kupffers vesicle (KV). Because there are many processes during development that occur at similarly slow rates, this suggests that self-generated dynamic forces should be investigated more broadly.

developmental biology↗

bioRxiv2024

Single-cell landscapes of long non-coding RNAs in early vascular endothelial development and hemogenic specification

Understanding the molecular regulation of arterial and hemogenic specification during early embryonic vascular development is crucial for guiding vascular and hematopoietic regeneration. Accumulating evidence emphasizes the role of long non-coding RNAs (lncRNAs) in cell fate decision. However, the dynamic expression and the potential roles of lncRNAs in early vascular development are still unknown. Here, we first constructed a single-cell landscape of lncRNA expression based on the deeply sequenced tag-based single-cell transcriptome data of early embryonic vascular endothelial cells (VECs). We revealed the contribution of lncRNAs to VEC heterogeneity and identified 295 lncRNAs with specific expression in eight VEC populations. Furthermore, we identified a series of lncRNAs potentially involved in regulating the two waves of arterial specification and hemogenic specification. We uncovered a transient downregulation of H19 in the hemogenic endothelial population during endothelial-to-hematopoietic transition. Additionally, we constructed a transcription factor regulatory network composed of 287 regulons for early VEC development. We further revealed differential activation patterns of regulons and modules in the eight VEC populations, and predicted potential lncRNA-regulon regulatory network. Moreover, unsupervised analysis of the lncRNA expression profile revealed novel VEC subpopulations strongly associated with the maturation of VECs, suggesting the prominent roles of lncRNAs in endothelial maturation. In summary, our study fills the gap in understanding of lncRNA regulatory networks in early vascular development and provides insights into the fields of vascular and hematopoietic regeneration research.

developmental biology↗

bioRxiv2024

Temporal and anteriorly positioned mitotic zones drive asymmetric microtubule patterns needed for Left-Right Organizer development.

Cellular proliferation is vital for tissue development, including the Left-Right Organizer (LRO), a transient organ critical for establishing the vertebrate LR body plan. This study investigates cell redistribution and the role of specific progenitor cells in LRO formation, focusing on cell lineage and behavior. Using zebrafish as a model, we mapped all mitotic events in Kupffers Vesicle (KV), revealing an FGF-dependent, anteriorly enriched mitotic pattern. With a KV-specific fluorescent microtubule (MT) line, we observed that mitotic spindles align along the KVs longest axis until the rosette stage, spindles that form after spin, and are excluded from KV. Early aligned spindles assemble cytokinetic bridges that point MT bundles toward a tight junction where a rosette will initially form. Post-abscission, repurposed MT bundles remain targeted at the rosette center, facilitating actin recruitment. Additional cells, both cytokinetic and non-cytokinetic, are incorporated into the rosette, repurposing or assembling MT bundles before actin recruitment. These findings show that initial divisions are crucial for rosette assembly, MT patterning, and actin remodeling during KV development.

developmental biology↗

bioRxiv2024

The chromatin conformation landscape of Alzheimer's disease

We have been investigating epigenetic alterations in the brain during human aging and Alzheimers disease (AD), and have evidence for histone acetylation both protecting the aging epigenome and driving AD. Here we extend our studies to chromatin architecture via looping studies, and with binding studies of key proteins required for looping: CTCF and RAD21. We detected changes in CTCF and RAD21 levels and localization, finding major changes in CTCF in AD compared to fewer changes in healthy aging. In our study of 3D genome conformation changes, we identified stable topological associating domains (TADs) in Old and AD; in contrast, in AD, there is loss of interaction at genomic sites/loops within TADs, likely reflecting the loss of CTCF. We identified genes and potential transcription factor binding at the loops that are lost in AD. in addition, we found enrichment of CTCF peak losses for AD eQTLs, suggesting that architectural dysfunction has a role in Alzheimers. Functional experiments lowering the homologues of several key genes in a Drosophila model of A{beta}42 toxicity exacerbate neurodegeneration. Taken together, these data indicate both functional protections and losses occur in the Alzheimers brain genome compared to normal aging.

neuroscience↗

bioRxiv2024

Low protein diet protects liver function upon Salmonella infection by metabolic reprogramming of macrophages

Background & AimsWestern diets are the underlying cause of metabolic and liver diseases. Recent trend to limit the consumption of protein-rich animal products has become more prominent. This dietary change entails decreased protein consumption; however, it is still unknown how this affects innate immunity. Here, we studied the influence of a low protein diet (LPD) on the liver response to bacterial infection. MethodsMice were fed a LPD and exposed to Salmonella enterica serotype Typhimurium infection. Mechanistic studies were done in vitro where bone marrow derived macrophages were cultured in a low-aa media to mimic in vivo reduction of protein availability and challenged with bacterial endotoxin. ResultsWe found that a LPD protects from S Typhimurium-induced liver damage. Bulk- and 10xsingle cell-RNA sequencing of liver tissues and isolated immune cells showed reduced activation of myeloid cells in mice fed with LPD after S Typhimurium infection. Mechanistically, we found reduced activation of the mammalian target of rapamycin (mTOR) pathway whilst increased phagocytosis and activation of autophagy in LPD-programmed macrophages. Dietary restoration of leucine reverted the protective effects of a LPD and restored the damaging effects of Salmonella on liver parenchyma in mice. ConclusionsLow protein diet protects the liver form S Typhimurium-induced tissue damage via modulating macrophage autophagy and phagocytosis. Our result support the causal role of dietary components on the fitness of the immune system. SYNOPSISLow protein diet protects the liver from Salmonella-mediated liver injury that associates with reduced mTOR activation and increased autophagy in macrophages. Restoration of the mTOR pathway with aminoacid supplementation reverses the protection of a low protein diet from Salmonella-liver damage.

immunology↗

bioRxiv2024

EI24-RTRAF interaction represses Nox4 translation, vital for redox balance and insulin production

As a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3-UTRs of Nox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake on Nox4 mRNA translation, and thus, the uncontrolled translation of Nox4 leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to the Ins2 gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restored MafA translation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specific Ei24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2 and normal biological functions under physiological conditions.

cell biology↗

bioRxiv2023

GET: a foundation model of transcription across human cell types

Transcriptional regulation, involving the complex interplay between regulatory sequences and proteins, directs all biological processes. Computational models of transcription lack generalizability to accurately extrapolate in unseen cell types and conditions. Here, we introduce GET, an interpretable foundation model designed to uncover regulatory grammars across 213 human fetal and adult cell types. Relying exclusively on chromatin accessibility data and sequence information, GET achieves experimental-level accuracy in predicting gene expression even in previously unseen cell types. GET showcases remarkable adaptability across new sequencing platforms and assays, enabling regulatory inference across a broad range of cell types and conditions, and uncovering universal and cell type specific transcription factor interaction networks. We evaluated its performance on prediction of regulatory activity, inference of regulatory elements and regulators, and identification of physical interactions between transcription factors. Specifically, we show GET outperforms current models in predicting lentivirus-based massive parallel reporter assay readout with reduced input data. In fetal erythroblasts, we identify distal (>1Mbp) regulatory regions that were missed by previous models. In B cells, we identified a lymphocyte-specific transcription factor-transcription factor interaction that explains the functional significance of a leukemia-risk predisposing germline mutation. In sum, we provide a generalizable and accurate model for transcription together with catalogs of gene regulation and transcription factor interactions, all with cell type specificity.

bioinformatics↗

bioRxiv2023

Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify 3 clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 & ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons. Significance StatementThe anterolateral system (ALS) is a major ascending pathway from the spinal cord that underlies perception of pain, itch and skin temperature. It is therefore an important target for the development of new treatments for chronic pain. Our understanding of this system has been hampered by the considerable diversity of its constituent cells. Here we dissect the complex heterogeneity of these cells by using high-resolution RNA sequencing. We reveal five distinct types of ALS neurons, which are differentially distributed within the spinal cord, and probably represent functional populations. Our data provide novel insights into the molecular architecture of the ALS, and will be important for future studies to define the roles of different ALS cell types in sensory processing.

neuroscience↗

bioRxiv2023

Discovery of fibrotic intervertebral disc in mice

Intervertebral discs are crucial to spine flexibility and stability during locomotion, but the mechanism of their mechanoadaptation to stress remains inadequately elucidated. We discovered spontaneous collagenesis in discs at the tail base in mice occurring from 14 days post-natal development. These discs termed as type C, differ from typical discs by exhibiting intensive collagen II and reduced aggrecan deposition contributing to the stiffening of the extracellular matrix (ECM), without typical degenerative markers. The reinforced mechanical properties enable type C discs to withstand high mechanical stress during flexion. Further analysis revealed that type C discs experience a turnover in cell composition, with the emergence of Procr+ progenitor cells and depletion of notochord cells. We demonstrated the essential role of mechanical stress in type C disc formation, suggesting a mechanoadaptive process rather than a pathological condition. Mechanistically, we identified TRPV4, as pivotal factors in collagen II synthesis in type C discs, highlighting the role of mechanotransduction in this adaptation. Our findings introduce a novel mechanoadaptive process of intervertebral disc by orchestrating collagenesis, advancing understanding of diverse disc functions in spine development and homeostasis, thereby providing insights for leveraging this mechanism to address spinal disorders.

pathology↗

bioRxiv2023

DNA Storage Designer: A practical and holistic design platform for storing digital information in DNA sequence

DNA molecules, as natural information carriers, have several benefits over conventional digital storage mediums, including high information density and long-term durability. It is expected to be a promising candidate for information storage. However, despite significant research in this field, the pace of development has been slow due to the lack of complete encoding-decoding platform and simulaton-evaluation system. And the mutation in DNA sequences during synthesis and sequencing requires multiple experiments, and wet experiments can be costly. Thus, a silicon-based simulation platform is urgently needed for promoting research. Therefore, we proposed DNA Storage Designer, the first online platform to simulate the whole process of DNA storage experiments. Our platform offers classical and novel technologies and experimental settings that simulate three key processes: encoding, error simulation, and decoding for DNA storage system. Fisrt, 8 mainstream encoding methods were embedded in the encoding process to convert files to DNA sequences. Secondly, to uncover potential mutations and sequence distribution changes in actual experiments we integrate the simulation setting for five typical experiment sub-processes (synthesis, decay, PCR, sampling, and sequencing) in the error simulation stage. Finally, the corresponding decoding process realizes the conversion of DNA sequence to binary sequence. All the above simulation processes correspond to an analysis report will provide guides for better experiment design for researchers convenience. In short, DNA Storage Designer is an easy-to-use and automatic web-server for simulating DNA storage experiments, which could advance the development of DNA storage-related research. And it is freely available for all users at: https://dmci.xmu.edu.cn/dna/. Author summaryDNA storage technology is an emerging and promising storage technology. At the same time, DNA storage is an interdisciplinary technology that requires researchers to know both computer cryptography and biological experiments knowledge. However, DNA storage experiments are costly and lengthy, many studies have been prevented by the lack of a comprehensive design and evaluation platform to guide DNA storage experiments. Herein, we introduce DNA Storage Designer, the first integrated and practical web server for providing the simulation of the whole process of DNA storage application, from encoding, error simulation during preservation, to decoding. In the encoding process, we not only provided the coding DNA sequences but also analyzed the sequence stability. In the error simulation process, we simulated as many experimental situations as possible, such as different mutation probabilities of DNA sequences due to being stored in different bacteria hosts or different sequencing platforms. The platform provides high freedom in that users could not only encode their files and conduct the entire operation but also could upload FASTA files and only simulate the sustaining process of sequences and imitate the mutation errors together with distribution changes of sequences.

bioinformatics↗

bioRxiv2022

Restoring glucose homeostasis with stomach-derived human insulin-secreting organoids

Gut stem cells are accessible by biopsy and propagate robustly in culture, offering an invaluable resource for autologous cell therapies. Insulin-producing cells can be induced in mouse gut, but it has not been possible to generate abundant and durable insulin-secreting cells from human gut tissues to evaluate their potential as a cell therapy for diabetes. Here we describe a protocol to differentiate cultured human gastric stem cells (hGSCs) into pancreatic islet-like organoids containing gastric insulin-secreting (GINS) cells that resemble {beta}-cells in molecular hallmarks and function. Sequential activation of the inducing factors NGN3 and PDX1-MAFA led hGSCs onto a novel differentiation path, including a SOX4High endocrine and GalaninHigh GINS precursor, before adopting {beta}-cell identity, at efficiencies close to 70%. GINS organoids acquired glucose-stimulated insulin secretion in 10 days and restored glucose homeostasis for over 100 days in diabetic mice after transplantation, providing proof of concept for a new approach to treat diabetes.

cell biology↗

bioRxiv2022

A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin

Plasticity between cell lineages is a fundamental but poorly understood property of regenerative tissues. In the gut tube, small intestine absorbs nutrients whereas colon absorbs electrolytes. In a striking display of inherent plasticity, adult colonic mucosa lacking the chromatin factor SATB2 is converted to small intestine. Using proteomics and CRISPR-Cas9 screen, we identified MTA2 as a crucial component of the molecular machinery that, together with SATB2, restrain colonic plasticity. MTA2 loss in adult mouse colon activated lipid absorptive genes and functional lipid uptake. Mechanistically, MTA2 co-binds with HNF4A, an activating pan-intestine transcription factor (TF), on colonic chromatin. MTA2 loss leads to HNF4A release from colonic and gain on small intestinal chromatin. SATB2 similarly restrains colonic plasticity through a HNF4A-dependent mechanism. Our study provides a generalizable model of lineage plasticity in which broadly-expressed TFs are retained on tissue-specific enhancers to maintain cell identity and prevent activation of alternative lineages; their release unleashes plasticity.

developmental biology↗

bioRxiv2022

Identifying Patients with Cognitive Motor Dissociation Using Resting-state Temporal Stability

BackgroundUsing task-dependent neuroimaging techniques, recent studies discovered a fraction of patients with disorders of consciousness (DOC) who had no command-following behaviors but showed a clear sign of awareness, which was defined as cognitive motor dissociation (CMD). Although many efforts were made to identify the CMD, existing task-dependent approaches might fail when patients had multiple cognitive function (e.g., attention, memory) impairments, and thus lead to false-negative findings. However, recent advances in resting-state fMRI (rs-fMRI) analysis allow investigation of the dynamic change of spontaneous brain activity, which might be a powerful tool to test the patients cognitive functions, while its capacity in identifying CMD was unclear. MethodsThe rs-fMRI study included 119 participants from three independent research sites. A sliding-window approach was used to investigate the dynamic functional connectivity of the brain in two aspects: the global and regional temporal stability, which measures how stable the brain functional architecture is across time. The temporal stability was compared in the first dataset (36/16 DOC/controls), and then a Support Vector Machine (SVM) classifier was built to discriminate DOC patients from controls. Furthermore, the generalizability of the SVM classifier was tested in the second independent dataset (35/21 DOC/controls). Finally, the SVM classifier was applied to the third independent dataset where patients underwent an rs-fMRI and brain-computer interface assessment (4/7 CMD/potential non-CMD), to test its performance in identifying CMD. ResultsOur results showed that the global and regional temporal stability were impaired in DOC patients, especially in regions from the cingulo-opercular task control, default mode, fronto-parietal task control, and salience network. Using the temporal stability as features, the SVM model not only showed a good performance in the first dataset (accuracy = 90 %), but a good generalizability in the second dataset (accuracy = 82 %). Most importantly, the SVM model generalized well in identifying CMD in the third dataset (accuracy = 91 %). ConclusionThe current findings suggested that rs-fMRI could be a potential tool to assist in diagnosing CMD. Furthermore, the temporal stability investigated in this study also contributed to a deeper understanding of the neural mechanism of the consciousness.

neuroscience↗