Biology subjects

Wen, W.

Publications and source records attributed to Wen, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Modular Arrangement of Synaptic and Intrinsic Homeostatic Plasticity within Visual Cortical Circuits

Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly, or can be independently recruited to stabilize different network features, is unknown. Here we used pharmacological and genetic perturbations both in vitro and in vivo to determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within L2/3 pyramidal neurons in rodent V1. Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping signaling pathways, they could be independently recruited by manipulating spiking activity or NMDAR signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and intrinsic homeostatic plasticity respond to and stabilize distinct aspects of network activity.

neuroscience↗

bioRxiv2024

An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

neuroscience↗

bioRxiv2024

Amblyopic deficits in monocular processing and binocular interactions revealed by submillimeter 7T fMRI and EEG frequency tagging

Disruption of retinal input early in life can lead to amblyopia, a condition characterized by reduced visual acuity despite corrected optics. Although extensive losses of neural activity have been found in the early visual cortex, it remains unclear whether they reflect deficits in feedforward or feedback processing, or abnormal binocular interactions. Combining submillimeter 7T fMRI and EEG frequency tagging, our study revealed the precise neural deficits in monocular processing and binocular interactions in human adults with unilateral amblyopia. Cortical depth-dependent fMRI revealed monocular response deficits in cortical layers of the primary visual cortex (V1) receiving thalamic input, which carried over to the downstream areas (V2-V4) in feedforward processing. Binocular stimulation produced a greater signal loss in the superficial layers of V1, consistent with suppression from the fellow eye by lateral inhibition. EEG data further demonstrate reduced suppression from the amblyopic eye, weakened binocular integration, and delayed monocular and binocular processing. Our results support attenuated and delayed monocular processing in V1 layers receiving thalamic input in human amblyopia, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers, which further reduced signal strength and processing speed. These precise neural deficits can help developing more targeted and effective treatments for the vision disorder. SignificanceCortical depth-dependent 7T fMRI and EEG frequency tagging revealed attenuated and delayed neural activity in monocular processing and binocular interactions in human amblyopia. Neural deficits in monocular processing arise from the input layers of V1, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers. The precise neural deficits at high spatiotemporal resolution can help developing more targeted and effective treatment for amblyopia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/591076v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@c174d8org.highwire.dtl.DTLVardef@de51eborg.highwire.dtl.DTLVardef@1d443c0org.highwire.dtl.DTLVardef@ac267a_HPS_FORMAT_FIGEXP M_FIG C_FIG This figure illustrates the precise neural deficits of amblyopia in monocular processing and binocular interactions based on the main findings of the current study. Attenuated and delayed neural activity arises from V1 cortical layers receiving thalamic input in monocular processing, followed by imbalanced binocular suppression and weakened binocular integration in the superficial layers, further reducing visual signal strength and processing speed.

neuroscience↗

bioRxiv2024

Impaired central pattern generators due to abnormal EPHA4 signaling leads to idiopathic scoliosis

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we firstly reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings strongly suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.

genetics↗

bioRxiv2024

The sense of agency from active causal inference

This study investigates the active component of the sense of agency (SoA), positing that SoA is fundamentally an outcome of active causal inference regarding ones own actions and their impact on the environment. Participants controlled visual objects via a computer mouse, with tasks designed to test their ability to judge control or detect controlled objects under varying noise conditions. Our findings reveal that participants formed high-level, low-dimensional action plans that were idiosyncratic across but consistent within individuals to infer their degree of control. Employing transformer-LSTM-based autoencoders, we captured these action plans and demonstrated that the geometrical and dynamical properties of these action plans could predict behavioural profiles in the tasks with remarkable accuracy. This suggests that participants sense of control is shaped by actively altering action plans, viewed as generating causal evidence through intervention. Further, participants proactively expanded the diversity of their action plans, facilitating the exploration of available action plan options while accumulating causal evidence for the inference process. Contrarily, patients with schizophrenia exhibited reduced action plan diversity, suggesting impaired active control inference and detection of self-relevant cues. These findings offer a more comprehensive understanding of the sense of agency, deeply rooted in the process of active causal inference.

neuroscience↗

bioRxiv2024

Discriminative histone imputation using chromatin accessibility

Histone modifications (HMs) play a pivot role in various biological processes, including transcription, replication and DNA repair, significantly impacting chromatin structure. These modifications underpin the molecular mechanisms of cell-specific gene expression and complex diseases. However, annotating HMs across different cell types solely using experimental approaches is impractical due to cost and time constraints. Herein, we present dHICA (discriminative histone imputation using chromatin accessibility), a novel deep learning framework that integrates DNA sequences and chromatin accessibility data to predict multiple HM tracks. Employing the Transformer architecture alongside dilated convolutions, dHICA boasts an extensive receptive field and captures more cell-type-specific information. dHICA not only outperforms state-of-the-art baselines but also achieves superior performance in cell-specific loci and gene elements, aligning with biological expectations. Furthermore, dHICAs imputations hold significant potential for downstream applications, including chromatin state segmentation and elucidating the functional implications of SNPs. In conclusion, dHICA serves as an invaluable tool for advancing the understanding of chromatin dynamics, offering enhanced predictive capabilities and interpretability.

bioinformatics↗

bioRxiv2023

Variant Mapping Application: Customize And Annotate Figures Of Voltage-Gated Sodium Channel

Voltage-gated sodium ion channels allow for the initiation and transmission of action potentials. There is a high interest in research and drug development to selectively target these ion channels to treat epilepsy and other disorders such as pain. Scientific literature and presentations often incorporate maps of these integral membrane proteins with markers indicating gene mutations to highlight genotype/phenotype correlations. There is a need for automated tools to create high quality figures with mutation (variant) locations displayed on these channel maps. This manuscript introduces a simple application to create visualization for mutations on alpha voltage-gated sodium channels, created using the D3.js library. The application allows for mapping of variant sequences, as well as important properties like the type of variant and the phenotypes linked to the variant. It also allows for customizability and the production of high-quality images for publication. This application and code base can further be extrapolated to other ion channels as well.

neuroscience↗

bioRxiv2023

Tissue-specific transfer-learning enables retasking of a general comprehensive model to a specific domain

Machine learning (ML) has proven successful in biological data analysis. However, may require massive training data. To allow broader use of ML in the full spectrum of biology and medicine, including sample-sparse domains, re-directing established models to specific tasks by add-on training via a moderate sample may be promising. Transfer learning (TL), a technique migrating pre-trained models to new tasks, fits in this requirement. Here, by TL, we retasked Enformer, a comprehensive model trained by massive data, tailored to breast cancers using breast-specific data. Its performance has been validated through statistical accuracy of predictions, annotation of genetic variants, and mapping of variants associated with breast cancer. By allowing the flexibility of adding dedicated training data, our TL protocol unlocks future discovery within specific domains with moderate add-on samples by standing on the shoulders of giant models.

bioinformatics↗

bioRxiv2023

Neural Dynamic Underlying Coordination Process between Habitual and Goal-Directed Behavior

The coordination between habitual and goal-directed behaviors has significant evolutionary importance. However, the specific cognitive processes and neural mechanisms underlying this coordination process require further research. Since inducing natural habitual responses through repetitive stimuli-response training in a laboratory environment is extremely difficult in humans, well-trained sports experts with automatic perception-action features towards expertise-related stimuli serve as ideal natural samples to address this critical gap. We conducted scalp EEG recordings while sports experts performed an expertise Simon task that involved both automatic and goal-directed processes with moderate space of expertise-related stimuli congruent or incongruent with the response hand. In the congruent condition, sports experts showed larger response-locked LRP and beta band (15-25Hz) activity at the frontal-central region, indicating an enhanced automatic response tendency towards expertise-related stimuli. In the incongruent condition, a larger theta (3-8Hz) dynamic was observed in the superior frontal gyrus when sports experts needed to inhibit the automatic response tendency. The results indicated that sports experts exhibited an enhanced coordination process towards expertise-related stimuli, which was closely related to specific cognitive processes of response preparation and response inhibition in coordinating habitual and goal-directed behaviors

neuroscience↗

bioRxiv2022

3D electron diffraction reveals the chiral nature of the malaria pigment crystal hemozoin

Detoxification of heme in Plasmodium depends on its crystallization into hemozoin. This pathway is a major target of antimalarial drugs. X-ray powder diffraction has established that the unit cell contains a cyclic hematin dimer, yet the pro-chiral nature of heme supports formation of four distinct stereoisomers, two centrosymmetric and two chiral enantiomers. Here we apply emerging methods of in situ cryo-electron tomography and diffraction to obtain a definitive structure of biogenic hemozoin. Individual crystals take a striking polar morphology. Diffraction analysis, supported by density functional theory, indicates a compositional mixture of one centrosymmetric and one chiral dimer, whose absolute configuration has been determined on the basis of crystal morphology and interaction with the aqueous medium. Structural modeling of the heme detoxification protein suggests a mechanism for dimer selection. The refined structure of hemozoin should serve as a guide to new drug development.

microbiology↗

bioRxiv2022

Brain structural covariances in the ageing brain in the UK Biobank

Brain structural covariances or pairwise correlations describe how morphologic properties of brain regions are related to one another across individuals. Although it is reported that brain structural covariance changes during brain development, it is not clear how structural covariance relates to the ageing process. Here we investigated the human brain structural covariances of cortical thickness and subcortical volumes in the ageing brain and their associations with age, cognition, and longevity polygenic risk score (longevity-PRS) by using cross-sectional data from the UK Biobank (N = 42075, aged 45-83 years, M/F=19752 /22323). The sample of participants was divided into 84 non-overlapping groups based on their age. The older the age group, the greater the variability in the whole brain structural covariance. However, there was a differential rate of age-related increase of variance between males and females. The variance of females started lower than those of males and then increased with age with a greater gradient than that of males. There was a consistent and significant enrichment of pairwise correlations within the occipital lobe in ageing process. The cortical thickness and subcortical covariances in older groups were significantly different from those in the youngest group. Sixty-two of the total 528 pairs of cortical thickness correlations and 10 of the total 21 pairs of subcortical volume correlations were significantly associated with age after Bonferroni correction. Specifically, with an increasing age, most decreased cortical thickness correlations were found between the regions within the frontal lobe as well as between the frontal lobe regions and regions in other lobes, while pairwise correlations within occipital lobe regions were all strengthening. Most of these correlations were also associated with global cognition and weakly associated with longevity-PRS. These findings revealed that the structural covariance was not stable during ageing. Given the thinning of the cortex and the volumetric reduction of subcortical structures seen in the ageing process, an increased pairwise correlation between the brain regions in the older brain suggested a strengthened coordinated decline between the brain regions involved. However, some of the brain regions demonstrated a differentiated rate of decline which was shown as the inversed or reduced pairwise correlations between these regions.

neuroscience↗

bioRxiv2022

Minor differences in peptide presentation between chicken MHC class I molecules can explain differences in disease susceptibility

The highly polymorphic classical major histocompatibility complexes (MHCs) can confer resistance or susceptibility to diseases. The chicken MHC is known to confer decisive resistance or susceptibility to various economically-important pathogens, including the iconic oncogenic herpesvirus that causes Mareks disease (MD). Only one classical class I gene, BF2, is expressed at a high level in chickens, so it was relatively easy to discern a hierarchy from well-expressed thermostable fastidious specialist alleles to promiscuous generalist alleles that are less stable and expressed less on the cell surface. The BF2*1901 is more highly expressed and more thermostable than the closely-related BF2*1501, but the data for peptide repertoire available did not obviously correlate as expected. Here, we confirm for newly-developed chicken lines that the chicken haplotype B15 confers resistance to MD compared to B19. Using gas phase sequencing of peptide pools, and using immunopeptidomics involving mass spectroscopy, we find that the BF2*1901 binds a greater variety of amino acids in some anchor positions than BF2*1501. However, by X-ray crystallography, we find that the peptide-binding groove of BF2*1901 is narrower and shallower. Though the self-peptides bound to BF2*1901 may appear more various than those of BF2*1501, the structures show that the wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, correlating with the expected hierarchies for expression level, thermostability and MD resistance. Moreover, the 2 helix of BF2*1901 is higher than BF2*1501, potentially reducing the number of T cell clones that can recognize this fastidious class I molecule. IMPORTANCEDisease susceptibility mechanism is complicated, but chicken infection of Mareks disease (MD) is one of ideal models, considering the only one highly expressed classical MHC class I, BF2. The different susceptibility of the two close alleles BF2*1901 and BF2*1501 with minor difference of expression and thermostability is still unfathomed. Here, we confirm B15 chicken confers resistance to MD compared to B19. But the BF2*1901 binds a broader variety of anchoring peptides than BF2*1501. This mystery was solved by the structural determination of the two molecules with one similar peptide. The wider and deeper peptide-binding groove of BF2*1501 allows it to tightly accept many more peptides overall, which is concordant to the expected hierarchies for expression level, thermostability and MD resistance.

immunology↗

bioRxiv2021

GREPore-seq: A Robust Workflow to Detect Changes after Gene Editing through Long-range PCR and Nanopore Sequencing

To achieve the enormous potential of gene-editing technology in clinical therapies, both the on-target and unintended editing consequences need to be thoroughly evaluated. However, there is a lack of a comprehensive, pipelined, large-scale and economical workflow for detecting genome editing outcomes, in particular insertion or deletion of a large fragment. Here, we describe an approach for efficient and accurate detection of multiple genetic changes after CRISPR-Cas9 editing by pooled nanopore sequencing of barcoded long-range PCR products. To overcome the high error rates and indels of nanopore sequencing, we developed a pipeline to capture the barcoded sequences by grepping reads of nanopore amplicon sequencing (GREPore-seq). GREPore-seq can detect NHEJ-mediated double-stranded oligodeoxynucleotide (dsODN) insertions with comparable accuracy to Illumina next-generation sequencing (NGS). GREPore-seq also identifies HDR-mediated large gene knock-in, which excellently correlates with FACS analysis data. Low-level plasmid backbone insertion after HDR editing was also detected. We have established a practical workflow to identify genetic changes, including quantifying dsODN insertions, knock-ins, plasmid backbone insertions, and large fragment deletions after CRISPR editing. This toolkit for nanopore sequencing of pooled long amplicons should have broad applications in assessing on-target HDR editing and inadvertent large indels of over 1 kb. GREPore-seq is freely available at GitHub (https://github.com/lisiang/GREPore-seq).

bioinformatics↗

bioRxiv2021

Age- and sex-related topological organisation of human brain functional networks and their relationship to cognition

BACKGROUNDAge and sex associated with changes in functional brain network topology and cognition in large population of older adults have been poorly understood. We explored this question further by examining differences in 11 resting-state graph theory measures with respect to age, sex, and their relationships with cognitive performance in 17,127 UK Biobank participants (mean=62.83{+/-}7.41 years). METHODSBrain connectivity toolbox was used to derive the graph theory measures that assessed network integration, segregation, and strength. Multiple linear regression was performed the relationship between age, sex, cognition, and network measures. Subsequently, multivariate analysis was done to further examine the joint effect of the network measures on cognitive functions. RESULTSAge was associated with an overall decrease in the effectiveness of network communication (i.e. integration) and loss of functional specialisation (i.e. segregation) of specific brain regions. Sex differences were also observed, with women showing more efficient networks which were less segregated than in men (FDR adjusted p<.05). Age-related changes were also more apparent in men than women, which suggests that men may be more vulnerable to cognitive decline with age. Interestingly, while network segregation and strength of limbic network were only nominally associated with cognitive performance, the network measures collectively were significantly associated with cognition (FDR adjusted p[≤].002). This may imply that individual measures may be inadequate to capture much of the variance in neural activity or its output and need further refinement. CONCLUSIONThe complexity of the functional brain organisation may be shaped by an individuals age and sex, which ultimately may influence cognitive performance of older adults. Age and sex stratification may be used to inform clinical neuroscience research to identify older adults at risk of cognitive dysfunction.

neuroscience↗

bioRxiv2021

Tracking neural markers of template formation and implementation in attentional inhibition under different distractor consistency

Performing visual search tasks requires optimal attention deployment to promote targets and inhibit distractors. Rejection templates based on the distractors feature can be built to constrain the search process. We measured electroencephalography (EEG) of human participants of both sexes when they performed a visual search task in conditions where the distractor cues were constant within a block (fixed-cueing) or changed on a trial-by-trial basis (varied-cueing). In the fixed-cueing condition, sustained decoding of the cued colors could be achieved during the retention interval and the participants with higher decoding accuracy showed larger suppression benefit of the distractor cueing in the search period. In the varied-cueing condition, the cued color could only be transiently decoded after its onset and the higher decoding accuracy was observed from the participants who demonstrated lower suppression benefit. The differential neural representations of the to-be-ignored color in the two cueing conditions as well as their reverse associations with behavioral performance implied that rejection templates were formed in the fixed-cueing condition but not in the varied-cueing condition. Additionally, we observed stronger posterior alpha lateralization and mid-frontal theta/beta power during the retention interval of the varied-cueing condition, indicating the cognitive costs in template formation caused by the trialwise change of distractor colors. Taken together, our findings revealed the neural markers associated with the critical roles of distractor consistency in linking template formation to successful inhibition.

neuroscience↗

bioRxiv2021

Developmental Regulation of Homeostatic Plasticity in Mouse Primary Visual Cortex

Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we utilized Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to directly suppress neuronal activity in layer (L) 2/3 of mouse primary visual cortex (V1) at two important developmental timepoints: the classic visual system critical period (CP, P24-29), and adulthood (P45-55). We show that 24 hours of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual deprivation. Importantly, manipulations known to block these forms of homeostatic plasticity when induced pharmacologically or via visual deprivation also prevented DREADD-induced homeostatic plasticity. We next used the same paradigm to suppress activity in adult animals. Surprisingly, while excitatory synaptic scaling persisted into adulthood, intrinsic homeostatic plasticity was completely absent. Finally, we found that homeostatic changes in quantal inhibitory input onto L2/3 pyramidal neurons were absent during the CP but present in adults. Thus, the same population of neurons can express distinct sets of homeostatic plasticity mechanisms at different development stages. Our findings suggest that homeostatic forms of plasticity can be recruited in a modular manner according to the evolving needs of a developing neural circuit. Significance statementDeveloping brain circuits are subject to dramatic changes in inputs that could destabilize activity if left uncompensated. This compensation is achieved through a set of homeostatic plasticity mechanisms that provide slow, negative feedback adjustments to excitability. Given that circuits are subject to very different destabilizing forces during distinct developmental stages, the forms of homeostatic plasticity present in the network must be tuned to these evolving needs. Here we developed a method to induce comparable homeostatic compensation during distinct developmental windows, and found that neurons in the juvenile and mature brain engage strikingly different forms of homeostatic plasticity. Thus, homeostatic mechanisms can be recruited in a modular manner according to the developmental needs of the circuit.

neuroscience↗

bioRxiv2020

Layer-dependent loss and enhancement of geniculostriate and retinotectal pathways in adult human amblyopia

Abnormal visual experience during critical period leads to reorganization of neuroarchitectures in primate visual cortex. However, developmental plasticity of human subcortical visual pathways remains elusive. Using high-resolution fMRI and pathway-selective visual stimuli, we investigated layer-dependent response properties and connectivity of subcortical visual pathways of adult human amblyopia. Stimuli presented to the amblyopic eye showed selective response loss in the parvocellular layers of the lateral geniculate nucleus, and also reduced the connectivity to V1. Amblyopic eyes response to isoluminant chromatic stimulus was significantly reduced in the superficial layers of the superior colliculus, while the fellow eyes response robustly increased in the deeper layers associated with increased cortical feedbacks. Therefore, amblyopia led to selective reduction of parvocellular feedforward signals in the geniculostriate pathway, whereas loss and enhancement of parvocellular feedback signals in the retinotectal pathway. These findings shed light for future development of new tools for treating amblyopia and tracking the prognosis. HighlightsO_LIAmblyopia impairs feedforward processing in the P layers of the LGN C_LIO_LILayer-dependent loss and enhancement of cortical feedback signals in the SC C_LIO_LIPathway-specific abnormalities explain amblyopic deficits in visual acuity and attention C_LI Significance statementHow abnormal visual experiences during critical period shape the function and wire the neural circuits of human subcortex remains largely unknown. With high-resolution fMRI and visual stimuli to preferentially activate layer-dependent response in human subcortical pathways, the current study clearly demonstrates that amblyopia shifts the homeostatic interocular balance of human subcortex in a pathway-specific manner. Amblyopia led to selective loss of parvocellular feedforward signals in the geniculostriate pathway, whereas deficit and enhancement of parvocellular feedback signals in the retinotectal pathway. These pathwayspecific functional abnormalities provide the neural basis for amblyopic deficits in visual acuity, control of eye movement and attention. It sheds light for future development of new tools for treating amblyopia and tracking the prognosis.

physiology↗

bioRxiv2020

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19. HIGHLIGHTSO_LILarge-scale scRNA-seq analysis depicts the immune landscape of COVID-19 C_LIO_LILymphopenia and active T and B cell responses coexist and are shaped by age and sex C_LIO_LISARS-CoV-2 infects diverse epithelial and immune cells, inducing distinct responses C_LIO_LICytokine storms with systemic S100A8/A9 are associated with COVID-19 severity C_LI

genomics↗