Biology subjects

Yao, Z.

Publications and source records attributed to Yao, Z..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Improvement in Outcomes and Prevention of Multiple Organ Dysfunction Syndrome After Cardiac Arrest and Successful Cardiopulmonary Resuscitation by Systemic Administration of Bumetanide in Male Mice

BACKGROUNDCardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR) cause post-CA brain injury (PCABI) and extracerebral multiple organ dysfunction (EMOD), leading to low survival and disability in resuscitated patients. The pathogenesis of PCABI is still poorly understood, and no therapeutic-related factors have been identified to improve survival and neurological outcomes to date. Bumetanide is a promising pharmaceutical intervention for some neurological disorders that have some common pathophysiology with PCABI, and it also exhibit systemic protective effects on vital organs under pathological conditions. This study aims to investigate the protective effects of bumetanide on PCABI and EMOD after CA/CPR, and uncover the pathogenesis and biomarkers of PCABI at protein level. METHODSWe generated a hyperkalemia-induced asystole CA/CPR mouse model with bumetanide/vehicle treatment after resuscitation. Survival, neurological outcome, functional outcome, key pathophysiological process underlying PCABI, and injury level of EMOD were evaluated. Proteomics analysis of cerebral cortex was performed for investigating mechanisms of PCABI. RESULTSBumetanide significantly improved outcomes after CA/CPR and reduced the main pathophysiological processes of PCABI, including seizures, neurodegeneration, neuroinflammation, decreased cerebral blood flow, blood-brain barrier disruption, and oxidative stress. CA/CPR-induced injury in heart, lung, liver, kidney, spleen, adrenal gland, spinal cord, pennis, and urinary bladder were also alleviated by bumetanide. Proteomic study and experimental verification identified LCN2/NGAL is a potential biomarker for early neuroprognostication and has association with PCABI severity. CONCLUSIONSSystemic administration of bumetanide improved outcomes and prevented multiple organ dysfunction after CA/CPR. LCN2/NGAL is a novel biomarker for early neuroprognostication at 24 hours after CA/CPR. Clinical PerspectiveO_LIWhat Is New? O_LIPost-resuscitation bumetanide treatment could improve outcomes and prevent brain injury and extracerebral multiple organ dysfunction after hyperkalemia-induced asystole cardiac arrest in mice. C_LIO_LINeuronal subpopulations in cerebral cortex were selectively vulnerable, and all major organs had obvious tissue damage with inflammatory cell infiltration and tissue edema after resuscitation. C_LIO_LIThis the first study to identify the pathogenesis and biomarkers of post-cardiac arrest brain injury with proteomic studies, and LCN2/NGAL had a strong and graded association with pathogenesis of PCABI, which could be a marker for monitoring and neuroprognostication. C_LI C_LIO_LIWhat Are the Clinical Implications? O_LIBumetanide may be a novel pharmacological therapy to improve survival and neurological outcomes in post-resuscitation care, and cerebral-specific quantification of LCN2/NGAL could be used for early neuroprognostication at 24 hours after cardiac arrest. C_LIO_LIExtracerebral multiple organ injury is common and severe after resuscitation, which needs to be given more attention in clinical management. C_LI C_LI

physiology↗

bioRxiv2024

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Genetic variation in the regulation of gene expression contributes substantially to phenotypic variation. Understanding how variation in DNA sequences and epigentic modifications leads to gene expression variation remains a challenging task. In hybrid animals where cellular environments are homogeneous, differences between the expression of paternal and maternal alleles must be due to cis sequence or epigenic differences. Therefore, hybrid mapping is a powerful approach to efficiently identify and characterize genes under regulation through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we performed a comprehensive multi-omic characterization of regulatory variation across brain, liver, muscle, and placenta in four developmental stages. We produced one of the largest multi-omic datasets to date in pigs, including 16 whole genome sequenced genomes, 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We developed a novel read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We showed that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identified 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. By integrating methylation, chromatin accessibility, and gene expression data, many of these allele specific expression can be explained by allele specific methylation and/or chromatin accessibility. This study provides one of the most comprehensive characterizations of regulatory variation across multiple tissues and developmental stages in pigs and offers new opportunity of genetic improvement for this important food animal species.

developmental biology↗

bioRxiv2023

Modulating social learning-induced evaluation updating during human sleep

People often change their evaluations upon learning about their peers evaluations, i.e., social learning. Given sleeps vital role in consolidating daytime experiences, sleep may facilitate social learning and thereby further changing peoples evaluations. Combining a social learning task and the sleep-based targeted memory reactivation technique, we asked whether social learning-induced evaluation changes can be modulated during sleep. After participants indicated their initial evaluation for snacks, they learned about their peers evaluation while hearing the snacks spoken names. During the post-learning non-rapid-eye-movement sleep, we re-played half of the snack names (i.e., cued snack) to reactivate the associated peers evaluations. Upon waking up, we found that the social learning-induced evaluation changes further enlarged for both cued and uncued snacks. Examining sleep electroencephalogram (EEG) activity revealed that cue-elicited delta-theta EEG power and the overnight N2 sleep spindle density predicted post-sleep evaluation changes for cued but not for uncued snacks. Our findings suggested that sleep-mediated memory reactivation processes could strengthen social learning-induced evaluation changes.

neuroscience↗

bioRxiv2023

Aversive memories can be weakened during human sleepvia the reactivation of positive interfering memories

Recollecting painful or traumatic experiences can be deeply troubling. Sleep may offer an opportunity to reduce such suffering. We developed a procedure to weaken older aversive memories by reactivating newer positive memories during sleep. Participants viewed 48 nonsense words each paired with a unique aversive image, followed by an overnight sleep. In the next evening, participants learned associations between half of the words and additional positive images, creating interference. During the following non-rapid-eye-movement sleep, auditory memory cues were unobtrusively delivered. Upon waking, presenting cues associated with both aversive and positive images during sleep, as opposed to not presenting cues, weakened aversive memory recall while increasing positive memory intrusions. Substantiating these memory benefits, computational modeling revealed that cueing facilitated evidence accumulation toward positive affect judgments. Moreover, cue-elicited theta brain rhythms during sleep predominantly predicted the recall of positive memories. A noninvasive sleep intervention can thus modify aversive recollection and affective responses. Significance StatementNot all memories are welcome: recollection and involuntary intrusions of aversive memories can be debilitating. Prior research shows that reactivating positive memories benefits psychological health, and memory reactivation can be externally triggered during human sleep. Here, we introduced a novel sleep-based memory updating procedure to weaken older aversive memories by reactivating newer positive memories. We found that such reactivation not only weakened the recall of aversive memories, but also increased involuntary intrusion of positive memories. Moreover, reactivation enhanced positive affect judgments. Our findings open new avenues for weakening aversive or traumatic memories during human sleep.

neuroscience↗

bioRxiv2023

Multi-scale photocatalytic proximity labeling reveals cell surface neighbors on and between cells

The cell membrane proteome is the primary biohub for cell communication, yet we are only beginning to understand the dynamic protein neighborhoods that form on the cell surface and between cells. Proximity labeling proteomics (PLP) strategies using chemically reactive probes are powerful approaches to yield snapshots of protein neighborhoods but are currently limited to one single resolution based on the probe labeling radius. Here, we describe a multi-scale PLP method with tunable resolution using a commercially available histological dye, Eosin Y, which upon visible light illumination, activates three different photo-probes with labeling radii ranging from [~]100 to 3000 [A]. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor (EGFR) and orthogonally validated >20 neighbors using immuno-assays and AlphaFold-Multimer prediction that generated plausible binary interaction models. We further profiled the protein neighborhoods of cell-cell synapses induced by bi-specific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)T cells at longer length scales. This integrated multi-scale PLP platform maps local and distal protein networks on cell surfaces and between cells. We believe this information will aid in the systematic construction of the cell surface interactome and reveal new opportunities for immunotherapeutics.

biochemistry↗

bioRxiv2023

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have also revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and the astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity across transgenes and in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

neuroscience↗

bioRxiv2023

AAV-HBV mouse model replicates immune exhaustion patterns of chronic HBV patients at single-cell level

Background and AimsUnresolved hepatitis B virus (HBV) infection leads to a progressive state of immune exhaustion that impairs resolution of infection, leading to chronic infection (CHB). The immune-competent AAV-HBV mouse is a common HBV preclinical immune competent model, though a comprehensive characterization of the liver immune microenvironment and its translatability to human infection is still lacking. We investigated the intrahepatic immune profile of the AAV-HBV mouse model at a single-cell level and compared with data from CHB patients in immune tolerant (IT) and immune active (IA) clinical stages. MethodsImmune exhaustion was profiled through an iterative subclustering approach for cell-typing analyses of single-cell RNA-sequencing data in CHB donors and compared to the AAV-HBV mouse model 24-weeks post-transduction to assess its translatability. This was validated using an exhaustion flow cytometry panel at 40 weeks post-transduction. ResultsUsing single-cell RNA-sequencing, CD8 pre-exhausted T-cells with self-renewing capacity (TCF7+), and terminally exhausted CD8 T-cells (TCF7-) were detected in the AAV-HBV model. These terminally exhausted CD8 T-cells (expressing Pdcd1, Tox, Lag3, Tigit) were significantly enriched versus control mice and independently identified through flow cytometry. Importantly, comparison to CHB human data showed a similar exhausted CD8 T-cell population in IT and IA donors, but not in healthy individuals. ConclusionsLong term high titer AAV-HBV mouse liver transduction led to T-cell exhaustion, as evidenced by expression of classical immune checkpoint markers at mRNA and protein levels. In both IT and IA donors, a similar CD8 exhausted T-cell population was identified, with increased frequency observed in IA donors. These data support the use of the AAV-HBV mouse model to study T-cell exhaustion in HBV infection and the effect of immune-based therapeutic interventions. Lay SummaryThe AAV-HBV mouse model is used as a research tool to study hepatitis B infection. In this study we evaluated the translation value from mouse to human with regards to T-cell exhaustion. HighlightsO_LIAAV-HBV mice transduced with a high titer vector showed presence of CD8 exhausted T-cells after 24 weeks. C_LIO_LIHigh titer transduced mice, but not lower titer show increased expression of LAG-3, TOX, TIM-3 and TIGIT in CD8 T-cells. PD-1 was increased in CD8 T-cells, independent of HBV transduction titer. C_LIO_LIA similar exhausted CD8 T-cell population could be found in chronic HBV donors, but not in healthy individuals. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/552328v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@17db34dorg.highwire.dtl.DTLVardef@186a0b1org.highwire.dtl.DTLVardef@19fd39borg.highwire.dtl.DTLVardef@1fd9f64_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Cell-type specific molecular signatures of aging revealed in a brain-wide transcriptomic cell-type atlas

Biological aging can be defined as a gradual loss of homeostasis across various aspects of molecular and cellular function. Aging is a complex and dynamic process which influences distinct cell types in a myriad of ways. The cellular architecture of the mammalian brain is heterogeneous and diverse, making it challenging to identify precise areas and cell types of the brain that are more susceptible to aging than others. Here, we present a high-resolution single-cell RNA sequencing dataset containing [~]1.2 million high-quality single-cell transcriptomic profiles of brain cells from young adult and aged mice across both sexes, including areas spanning the forebrain, midbrain, and hindbrain. We find age-associated gene expression signatures across nearly all 130+ neuronal and non-neuronal cell subclasses we identified. We detect the greatest gene expression changes in non-neuronal cell types, suggesting that different cell types in the brain vary in their susceptibility to aging. We identify specific, age-enriched clusters within specific glial, vascular, and immune cell types from both cortical and subcortical regions of the brain, and specific gene expression changes associated with cell senescence, inflammation, decrease in new myelination, and decreased vasculature integrity. We also identify genes with expression changes across multiple cell subclasses, pointing to certain mechanisms of aging that may occur across wide regions or broad cell types of the brain. Finally, we discover the greatest gene expression changes in cell types localized to the third ventricle of the hypothalamus, including tanycytes, ependymal cells, and Tbx3+ neurons found in the arcuate nucleus that are part of the neuronal circuits regulating food intake and energy homeostasis. These findings suggest that the area surrounding the third ventricle in the hypothalamus may be a hub for aging in the mouse brain. Overall, we reveal a dynamic landscape of cell-type-specific transcriptomic changes in the brain associated with normal aging that will serve as a foundation for the investigation of functional changes in the aging process and the interaction of aging and diseases.

neuroscience↗

bioRxiv2023

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

Viral pandemics and epidemics pose a significant global threat, with emerging and re-emerging viruses responsible for four pandemics in the 21st century alone. While macaques have been utilized as a model for understanding viral disease in a controlled setting, it remains unclear how conserved the antiviral responses to diverse viruses are between macaques and humans. To address this critical knowledge gap, we conducted a comprehensive cross-species analysis of transcriptomic data from over 6000 blood samples from macaques and humans infected with one of 31 viruses, including Lassa, Ebola, Marburg, Zika, and dengue. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses which are consistent regardless of infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Moreover, by leveraging longitudinal data from experimental challenges, we identified virus-specific response dynamics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Additionally, through comparative analysis of immune responses across viruses, we identified a unique enrichment of lymphoid cellular response modules in macaque Flaviviridae infection that persists in human responses to dengue. Our results underscore macaque studies as a powerful tool for gaining new insights into viral pathogenesis and immune responses that translate to humans, which can inform viral therapeutic development and enable pandemic preparedness. One sentence summaryUsing longitudinal macaque viral challenge studies, we identified shared and virus-specific responses to infection that replicate in human viral disease - thereby demonstrating the utility of macaque models of viral infection to understand antiviral biology and for pandemic preparedness.

immunology↗

bioRxiv2023

Chikungunya virus glycoproteins transform macrophages into productive viral dissemination vessels.

Despite their role as innate sentinels, macrophages are cellular reservoirs for chikungunya virus (CHIKV), a highly pathogenic arthropod-borne alphavirus that has caused unprecedented epidemics worldwide. Here, we took interdisciplinary approaches to elucidate the CHIKV determinants that subvert macrophages into virion dissemination vessels. Through comparative infection using chimeric alphaviruses and evolutionary selection analyses, we discovered for the first time that CHIKV glycoproteins E2 and E1 coordinate efficient virion production in macrophages with the domains involved under positive selection. We performed proteomics on CHIKV-infected macrophages to identify cellular proteins interacting with the precursor and/or mature forms of viral glycoproteins. We uncovered two E1-binding proteins, signal peptidase complex subunit 3 (SPCS3) and eukaryotic translation initiation factor 3 (eIF3k), with novel inhibitory activities against CHIKV production. These results highlight how CHIKV E2 and E1 have been evolutionarily selected for viral dissemination likely through counteracting host restriction factors, making them attractive targets for therapeutic intervention.

microbiology↗

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

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

Redundant and distinct roles of two 14-3-3 proteins in Fusarium sacchari, pathogen of sugarcane Pokkah boeng disease

Fusarium sacchari is one of the most important sugarcane pathogens that causes Pokkah boeng disease (PBD) in China. 14-3-3 proteins have been shown to play vital roles in developmental processes in dimorphic transition, signal transduction and carbon metabolism in some phytopathogenic fungi, but were poorly understood in F. sacchari. In this study, two 14-3-3 protein-encoding genes, FsBmh1 and FsBmh2 in F. sacchari, were investigated. Although both FsBmh1 and FsBmh2 were expressed at vegetative growth stage, FsBmh1 was repressed at sporulation stage in vitro. In order to clarify the roles of FsBmh1 and FsBmh2, deletion mutants {Delta}FsBmh1 and {Delta}FsBmh2 were constructed. Phenotypic defects, including hyphal branching, hyphal septation, conidiation, spore germination and colony growth, were more severe in {Delta}FsBmh2 than in {Delta}FsBmh1, although virulence attenuation was observed in both mutants. To further explore the relationship between FsBmh1 and FsBmh2, the combination of deletion and silencing ({Delta}FsBmh/sFsBmh) and overexpression (O-FsBmh) mutants were constructed and characterized. Compared to the single allele deletion, combinations of {Delta}FsBmh1/sFsBmh2 or {Delta}FsBmh2/sFsBmh1 showed more severe manifestations in general, suggesting a redundancy in function of the two 14-3-3 genes. Comparative transcriptome analysis revealed that more functional genes were affected in {Delta}FsBmh2 than in {Delta}FsBmh1. Redundancy in function between FsBmh1 and FsBmh2 suggests that 14-3-3 is vitally important for the organism and distinction in roles between the two isoforms may be resulted from the divergence in evolution. To the best of our knowledge, this was the first report on the distinct roles of 14-3-3 protein isoforms in a pathogenic fungus. Knowledge gained from this study should be of help to further understand the regulation mechanism of pathogenicity-related traits in fungal pathogens and for the development of new strategy for control of PBD in particular.

microbiology↗

bioRxiv2023

A molecularly defined and spatially resolved cell atlas of the whole mouse brain

In mammalian brains, tens of millions to billions of cells form complex interaction networks to enable a wide range of functions. The enormous diversity and intricate organization of cells in the brain have so far hindered our understanding of the molecular and cellular basis of its functions. Recent advances in spatially resolved single-cell transcriptomics have allowed systematic mapping of the spatial organization of molecularly defined cell types in complex tissues1-3. However, these approaches have only been applied to a few brain regions1-11 and a comprehensive cell atlas of the whole brain is still missing. Here, we imaged a panel of >1,100 genes in [~]8 million cells across the entire adult mouse brain using multiplexed error-robust fluorescence in situ hybridization (MERFISH)12 and performed spatially resolved, single-cell expression profiling at the whole-transcriptome scale by integrating MERFISH and single-cell RNA-sequencing (scRNA-seq) data. Using this approach, we generated a comprehensive cell atlas of >5,000 transcriptionally distinct cell clusters, belonging to [~]300 major cell types, in the whole mouse brain with high molecular and spatial resolution. Registration of the MERFISH images to the common coordinate framework (CCF) of the mouse brain further allowed systematic quantifications of the cell composition and organization in individual brain regions defined in the CCF. We further identified spatial modules characterized by distinct cell-type compositions and spatial gradients featuring gradual changes in the gene-expression profiles of cells. Finally, this high-resolution spatial map of cells, with a transcriptome-wide expression profile associated with each cell, allowed us to infer cell-type-specific interactions between several hundred pairs of molecularly defined cell types and predict potential molecular (ligand-receptor) basis and functional implications of these cell-cell interactions. These results provide rich insights into the molecular and cellular architecture of the brain and a valuable resource for future functional investigations of neural circuits and their dysfunction in diseases.

neuroscience↗

bioRxiv2023

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single- cell RNA-sequencing (scRNA-seq) dataset of [~]7 million cells profiled, and a spatially resolved transcriptomic dataset of [~]4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

neuroscience↗

bioRxiv2023

In-group Social Conformity Updates the Neural Representation of Facial Attractiveness

People readily change their behavior to comply with others. However, to which extent they will internalize the social influence remains elusive. In this preregistered electroencephalogram (EEG) study, we investigated how learning from ones in-group or out-group members about facial attractiveness would change explicit attractiveness ratings and spontaneous neural representations of facial attractiveness. Specifically, we quantified the neural representational similarities of learned faces with prototypical attractive faces during a face perception task without overt social influence and intentional evaluation. We found that participants changed their explicit attractiveness ratings to both in-group and out-group influences. Moreover, social conformity updated spontaneous neural representation of facial attractiveness, an effect particularly evident when participants learned from their in-group members and among those who perceived tighter social norms. These findings offer insights into how group affiliations and individual differences in perceived social norms modulate the internalization of social influence.

neuroscience↗

bioRxiv2023

Item-specific memory reactivation supports overnight memory consolidation

Memory consolidation stabilizes newly acquired information. Understanding how individual memories are reactivated during sleep is essential in theorizing memory consolidation. Via unobtrusively re-playing auditory memory cues to sleeping human participants, we identified the reactivation of individual memories during slow-wave sleep (SWS). Using representational similarity analysis (RSA) on cue-elicited electroencephalogram (EEG), we found functionally segregated item-specific representations: the early post-cue EEG activity (0-2 seconds) contained comparable representations for memory cues and for non-memory control cues, thus reflecting sensory processing. Critically, the later EEG activity (2.5-3 s) showed greater item-specific representations for post-sleep remembered items than for forgotten and control cues, demonstrating the reactivation and consolidation of individual memories. Moreover, spindles preferentially supported item-specific memory reactivation for items that were not tested before sleep. These findings delineated how cue-triggered item-specific memory reactivation, subserved by spindles during SWS, contributed to memory consolidation. These results will benefit future research aiming to perturb specific memory episodes during sleep.

neuroscience↗

bioRxiv2023

Omicron Spike Protein Is Vulnerable to Reduction

SARS-CoV-2 virus spike (S) protein is an envelope protein responsible for binding to the ACE2 receptor, driving subsequent entry into host cells. The existence of multiple disulfide bonds in the S protein makes it potentially susceptible to reductive cleavage. Using a tri-part split luciferase-based binding assay, we evaluated the impacts of chemical reduction on S proteins from different virus variants and found that those from the Omicron family are highly vulnerable to reduction. Through manipulation of different Omicron mutations, we found that alterations in the receptor binding module (RBM) are the major determinants of this vulnerability. Specifically we discovered that Omicron mutations facilitate the cleavage of C480-C488 and C379-C432 disulfides, which consequently impairs binding activity and protein stability. The vulnerability of Omicron S proteins suggests a mechanism that can be harnessed to treat specific SARS-CoV-2 strains.

biochemistry↗