Search bioRxiv⌕ Search

Biology subjects

Wang, G.

Publications and source records attributed to Wang, G..

At least 379 records · Page 21Linked to original sources

The developing mouse coronal suture at single-cell resolution

Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. To uncover the cellular diversity within sutures, we generated single-cell transcriptomes and performed extensive expression validation of the embryonic murine coronal suture. We identify Erg and Pthlh as markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. In the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones. In the dura mater underlying the suture, we detect a chondrocyte-like signature potentially linked to cartilage formation under pathological conditions. Genes mutated in coronal synostosis are preferentially expressed in proliferative osteogenic cells, as well as meningeal layers, suggesting discrete cell types that may be altered in different syndromes. This single-cell atlas provides a resource for understanding development of the coronal suture, the suture most commonly fused in monogenic craniosynostosis.

developmental biology↗

Talaromyces marneffei promotes M2 polarization of human macrophages by downregulating SOCS3 expression and activating TLR9 pathway

Little is known about how Talaromyces marneffei, a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1 and fungal-promoting M2 types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei. Here, we demonstrated that T. marneffei promotes its survival in human macrophages by inducing them towards M2 polarization. Our investigations of the mechanism revealed that T. marneffei infection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2 polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1 polarization and plays an important role in limiting M2 polarization. Furthermore, we found that inhibition of TLR9 pathway partially blocked T. marneffei-induced M2 polarization and significantly enhanced the killing activity of macrophages against T. marneffei. Collectively, these results reveal a novel mechanism by which T. marneffei evades the immune response of human macrophages.

microbiology↗

SARS-CoV-2 nucleocapsid protein dually regulates innate immune responses

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and a cytokine storm in the late stage of infection, however, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein interacted with the tripartite motif protein 25 (TRIM25), thereby dually regulating the phosphorylation and nuclear translocation of IRF3, STAT1 and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress retinoic acid-inducible gene I (RIG-I) ubiquitination and activation. Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

microbiology↗

Methylomic alteration in peripheral blood lymphocytes of prodromal stage and first-episode Chinese Han schizophrenia patients

BackgroundAlthough epigenetic dysregulation has long been proposed to promote the onset of schizophrenia, the landscape of the methylomic changes across the whole genome is yet established. MethodsUsing Infinium Human Methylation 850 BeadChip Array and MethylTarget sequencing method, we investigated the genome-wide methylation profiles and further validated methylation profiles of target genes in peripheral blood lymphocytes between individuals with psychosis risk syndrome (PRS), patients with first-episode schizophrenia (FES) and healthy controls (HC) in Chinese Han population. ResultsWe detected 372 sites between psychosis risk syndrome (PRS) and healthy controls (HC), which increased to 460 sites in first-episode schizophrenia (FES) with 207 sites shared. Both PRS and FES featured profound hypomethylation within gene body. Gene ontology and network annotation merged on loci enriched in disease associated signaling pathways (MAPK(Mitogen Activated Protein Kinases), Glutamatergic, GABAergic etc.). ConclusionsOur study implicated characteristic hypomethylation in both the discovery and validation cohorts in SYNGAP1, one of the frequently studied genes in neurodevelopmental disorders. This is the first methylome-wide association study between PRS and FES in Chinese Han population. Our findings provide potential biomarkers that can be used for future development of disease therapy and management.

genetics↗

P4HA2-induced prolyl hydroxylation suppresses YAP1-mediated prostate cancer cell migration, invasion, and metastasis

Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1 led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2 led to an increase in cell migration and invasion, which was reversed upon Yap1 KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.

cancer biology↗

Ubiquitin ligase RIPLET mediates polyubiquitination of RIG-I and LGP2 and regulates the innate immune responses to SARS-CoV-2 infection

RIG-I, a cytoplasmic viral RNA sensor, is crucial for innate antiviral immune responses; however, there are controversies about RIG-Is regulatory mechanism by several ubiquitin ligases and LGP2. Our genetic study revealed that the RIPLET ubiquitin ligase was a general activating factor for RIG-I signaling, whereas another ubiquitin ligase, TRIM25, activated RIG-I in a cell-type-specific manner. These RIPLET and TRIM25 functions were modulated by accessory factors, such as ZCCH3C and NLRP12. Interestingly, we found an additional role of RIPLET in innate immune responses. RIPLET induced delayed polyubiquitination of LGP, resulting in the attenuation of excessive cytokine expression at the late phase. Moreover, RIPLET was involved in the innate immune responses against SARS-CoV-2 infection, a cause of the recent COVID-19 pandemic. Our data indicate that RIPLET fine-tunes innate immune responses via polyubiquitination of RIG-I and LGP2 against virus infection, including SARS-CoV-2.

immunology↗

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Mammalian cochlear outer hair cells (OHCs) are essential for hearing. OHC degeneration causes severe hearing impairment. Previous attempts of regenerating new OHCs from cochlear supporting cells (SCs) had yielded cells lacking Prestin, a key motor protein for OHC function. Thus, regeneration of Prestin+ OHCs remains a challenge for repairing OHC damage in vivo. Here, we reported that successful in vivo conversion of adult cochlear SCs into Prestin+ OHC-like cells could be achieved by simultaneous expression of Atoh1 and Ikzf2, two key transcriptional factors necessary for OHC development. New OHC-like cells exhibited upregulation of hundreds of OHC genes and downregulation of SC genes. Single cell transcriptomic analysis demonstrated that the differentiation status of these OHC-like cells was much more advanced than previously achieved. Thus, we have established an efficient approach to promote regeneration of Prestin+ OHCs and paved the way for repairing damaged cochlea in vivo via transdifferentiation of SCs.

developmental biology↗

Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission and Map2k7 expression in GABAergic interneurons

Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations were mentally retarded. To test its role in development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. We found a decreasing trend on parvalbumin+ interneuron differentiation. Moreover, increased firing threshold, decreased number of evoked APs, and a reduced amplitude of mIPSCs were observed before any significant change of MAP2+ dendritic morphology and in vivo migration appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.

neuroscience↗

A Bacterial Bile Acid Metabolite Modulates Treg Activity through the Nuclear Hormone Receptor NR4A1

Bile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4+ T cells into distinct T cell subsets. The bile acid metabolite isoallolithocholic acid (isoalloLCA) enhances the differentiation of anti-inflammatory regulatory T cells (Treg cells) by facilitating the formation of a permissive chromatin structure in the promoter region of the transcription factor forkhead box P3 (Foxp3). Here, we identify gut bacteria that synthesize isoalloLCA from 3-oxolithocholic acid and uncover a gene cluster responsible for the conversion in members of the abundant human gut bacterial phylum Bacteroidetes. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on Treg cells. Moreover, the levels of isoalloLCA and its biosynthetic genes are significantly reduced in patients with inflammatory bowel diseases, suggesting that isoalloLCA and its bacterial producers may play a critical role in maintaining immune homeostasis in humans.

immunology↗

High-fidelity fast volumetric brain MRI using a hybrid denoising generative adversarial network (HDnGAN)

PurposeReducing scan times is important for wider adoption of high-resolution volumetric MRI in research and clinical practice. Emerging fast imaging and deep learning techniques provide promising strategies to accelerate volumetric MRI without compromising image quality. In this study, we aim to leverage an advanced fast imaging technique, wave-controlled aliasing in parallel imaging (Wave-CAIPI), and a novel denoising generative adversarial network (GAN) to achieve accelerated high-fidelity, high-signal-to-noise-ratio (SNR) volumetric MRI. Methods3D T2-weighted fluid-attenuated inversion recovery (FLAIR) image data were acquired on 33 multiple sclerosis (MS) patients using a prototype Wave-CAIPI sequence (acceleration factor R=3x2, 2.75 minutes) and a standard T2-SPACE FLAIR sequence (R=2, 7.25 minutes). A hybrid denoising GAN entitled "HDnGAN" composed of a 3D generator (i.e., a modified 3D U-Net entitled MU-Net) and a 2D discriminator was proposed to denoise Wave-CAIPI images with the standard FLAIR images as the target. HDnGAN was trained and validated on data from 25 MS patients by minimizing a combined content loss (i.e., mean squared error (MSE)) and adversarial loss with adjustable weight{lambda} , and evaluated on data from 8 patients unseen during training. The quality of HDnGAN-denoised images was compared to those from other denoising methods including AONLM, BM4D, MU-Net, and 3D GAN in terms of their similarity to standard FLAIR images, quantified using MSE and VGG perceptual loss. The images from different methods were assessed by two neuroradiologists using a five-point score regarding sharpness, SNR, lesion conspicuity, and overall quality. Finally, the performance of these denoising methods was compared at higher noise levels using simulated data with added Rician noise. ResultsHDnGAN effectively denoised noisy Wave-CAIPI images with sharpness and rich textural details, which could be adjusted by controlling{lambda} . Quantitatively, HDnGAN ({lambda}=10-3) achieved low MSE (7.43 x10-4{+/-}0.94x10-4) and the lowest VGG perceptual loss (1.09x10-2{+/-}0.18x10-2). The reader study showed that HDnGAN ({lambda}=10-3) significantly improved the SNR of Wave-CAIPI images (4.19{+/-}0.39 vs. 2.94{+/-}0.24, P<0.001), outperformed AONLM (4.25{+/-}0.56 vs. 3.75{+/-}0.90, P=0.015), BM4D (3.31{+/-}0.46, P<0.001), MU-Net (3.13{+/-}0.99, P<0.001) and 3D GAN ({lambda}=10-3) (3.31{+/-}0.46, P<0.001) regarding image sharpness, and outperformed MU-Net (4.21{+/-}0.67 vs. 3.29{+/-}1.28, P<0.001) and 3D GAN ({lambda}=10-3) (3.5{+/-}0.82, P=0.001) regarding lesion conspicuity. The overall quality score of HDnGAN ({lambda}=10-3) (4.25{+/-}0.43) was significantly higher than those from Wave-CAIPI (3.69{+/-}0.46, P=0.003), BM4D (3.50{+/-}0.71, P=0.001), MU-Net (3.25{+/-}0.75, P<0.001), and 3D GAN ({lambda}=10-3) (3.50{+/-}0.50, P<0.001), with no significant difference compared to standard FLAIR images (4.38{+/-}0.48, P=0.333). The advantages of HDnGAN over other methods were more obvious at higher noise levels. ConclusionHDnGAN provides robust and feasible denoising while preserving rich textural detail in empirical volumetric MRI data and is superior on both quantitative and qualitative evaluation compared to the original Wave-CAIPI images and images denoised using standard methods. HDnGAN concurrently benefits from the improved image synthesis performance of the 3D convolution and the increased number of samples for training the 2D discriminator from a limited number of subjects. Our study supports the use of HDnGAN in combination with modern fast imaging techniques such as Wave-CAIPI to achieve high-fidelity fast volumetric MRI.

neuroscience↗

GNS561, a new autophagy inhibitor active against cancer stem cells in hepatocellular carcinoma and hepatic metastasis from colorectal cancer

Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and have the ability to regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed in vivo in HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45-). Accordingly, GNS561, which was in a global phase 1b clinical trial in liver cancers that was recently successful, offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population.

cancer biology↗

Fast and scalable lipid nanoparticle formulation of niclosamide (nano NCM) effectively inhibits SARS-CoV-2 replication in vitro

As exemplified by the COVID-19 pandemic, highly infective respiratory viruses can spread rapidly in the population because of lack of effective approaches to control viral replication and spread. Niclosamide (NCM) is an old anthelminthic drug (World Health Organization essential medicine list) with pleiotropic pharmacological activities. Several recent publications demonstrated that NCM has broad antiviral activities and potently inhibits viral replication, including replication of SARS-CoV-2, SARS-CoV, and dengue viruses. Unfortunately, NCM is almost completely insoluble in water, which limits its clinical use. We developed a highly scalable and cost-effective nanoparticle formulation of NCM (nano NCM) using only FDA-approved excipient and demonstrated potency against SARS-CoV-2 infection in cells (Vero E6 and ACE2-expressing lung epithelium cells). Our ultimate goal is to develop the nano NCM formulation for treatment of COVID-19 patients.

pharmacology and toxicology↗

Distinct protocerebral neuropils associated with attractive and aversive female-produced odorants in the male moth brain

The pheromone system of heliothine moths is an optimal model for studying principles underlying higher-order olfactory processing. In Helicoverpa armigera, three male-specific glomeruli receive input about three female-produced signals, the primary pheromone component, serving as an attractant, and two minor constituents, serving a dual function, i.e. attraction versus inhibition of attraction. From the antennal-lobe glomeruli, the information is conveyed to higher olfactory centers, including the lateral protocerebrum, via three main paths - of which the medial tract is the most prominent. In this study, we traced physiologically identified medial-tract projection neurons from each of the three male-specific glomeruli with the aim of mapping their terminal branches in the lateral protocerebrum. Our data suggest that the neurons wide-spread projections are organized according to behavioral significance, including a spatial separation of signals representing attraction versus inhibition - however, with a unique capacity of switching behavioral consequence based on the amount of the minor components.

neuroscience↗

Spatial organization of the transcriptome in individual neurons

Neurons are highly polarized cells with complex neurite morphology. Spatial organization and local translation of RNAs in dendrites and axons play an important role in many neuronal functions. Here we performed super-resolution spatial profiling of RNAs inside individual neurons at the genome scale using multiplexed error-robust fluorescence in situ hybridization (MERFISH), and mapped the spatial organization of up to [~]4,200 RNA species (genes) across multiple length scales, ranging from sub-micrometer to millimeters. Our data generated a quantitative intra-neuronal atlas of RNAs with distinct transcriptome compositions in somata, dendrites, and axons, and revealed diverse sub-dendritic distribution patterns of RNAs. Moreover, our spatial analysis identified distinct groups of genes exhibiting specific spatial clustering of transcripts at the sub-micrometer scale that were dependent on protein synthesis and differentially dependent on synaptic activity. Overall, these data provide a rich resource for characterizing the subcellular organization of the transcriptome in neurons with high spatial resolution.

cell biology↗

ATP drives efficient terpene biosynthesis in marine thraustochytrids

Understanding carbon flux-controlling mechanisms in a tangled metabolic network is an essential question of cell metabolism. Secondary metabolism, such as terpene biosynthesis, has evolved with low carbon flux due to inherent pathway constraints. Thraustochytrids are a group of heterotrophic marine unicellular protists, and can accumulate terpenoids under the high salt condition in their natural environment. However, the mechanism behind the terpene accumulation is not well understood. Here we show that terpene biosynthesis in Thraustochytrium sp. ATCC 26185 is constrained by local thermodynamics in the mevalonate pathway. Thermodynamic analysis reveals the metabolite limitation in the nondecarboxylative Claisen condensation of acetyl-CoA to acetoacetyl-CoA step catalyzed by the acetyl-CoA acetyltransferase (ACAT). Through a sodium elicited mechanism, higher respiration leads to increased ATP investment into the mevalonate pathway, providing a strong thermodynamic driving force for enhanced terpene biosynthesis. The proteomic analysis further indicates that the increased ATP demands are fulfilled by shifting energy generation from carbohydrate to lipid metabolism. This study demonstrates a unique strategy in nature using ATP to drive a low-flux metabolic pathway, providing an alternative solution for efficient terpene metabolic engineering. IMPORTANCETerpenoids are a large class of lipid molecules with important biological functions, and diverse industrial and medicinal applications. Metabolic engineering for terpene production has been hindered by the low flux distribution to its biosynthesis pathway. In practice, a high substrate load is generally required to reach high product titers. Here we show that the mevalonate-derived terpene biosynthesis is constrained by local pathway thermodynamics, which can only be partially relieved by increasing substrate levels. Through comparative proteomic and biochemical analyses, we discovered a unique mechanism for high terpene accumulation in marine protists thraustochytrids. Through a sodium induced mechanism, thraustochytrids shift their energy metabolism from carbohydrate to lipid metabolism for enhanced ATP production, providing a strong thermodynamic driving force for efficient terpene biosynthesis. This study reveals an important mechanism in eukaryotes to overcome the thermodynamic constraint in low-flux pathways by increased ATP consumption. Engineering energy metabolism thus provides an important alternative to relieve flux constraints in low-flux and energy-consuming pathways.

systems biology↗

Chemoproteomics Maps Glycolytic Targetome in Cancer Cells

Hyperactivated glycolysis, favoring uncontrolled growth and metastasis by producing essential metabolic intermediates engaging bioenergetics and biosynthesis, is a metabolic hallmark of most cancer cells. Although sporadic information has revealed glycolytic metabolites also possess non-metabolic function as signaling molecules, it remains largely elusive how these metabolites interact with and functionally regulate their binding targets. Here we introduce a Target Responsive Accessibility Profiling (TRAP) approach that measures ligand binding-induced steric hindrance in protein targets via global profiling accessibility changes in reactive lysines, and mapped 913 target candidates and 2,487 interactions for 10 major glycolytic metabolites in cancer cells via TRAP. The elucidated targetome uncovers diverse regulatory modalities of glycolytic metabolites involving the direct perturbation of carbohydrate metabolism enzymes, intervention of transcriptional control, modulation of proteome-level acetylation and protein complex assemblies. The advantages gained from glycolysis by cancer cells are expanded by discovering lactate as a ligand for an orphan transcriptional regulator TRIM 28 that promotes p53 degradation, and by identifying pyruvate acting against a cell apoptosis inducer trichostatin A via attenuating protein acetylation. Lastly, the inhibition of glycolytic key enzymes led to identify an intrinsically active glycolytic intermediate glyceraldehyde 3-phosphate that elicits its cytotoxicity by engaging with ENO1 and MTHFD1. Collectively, the glycolytic targetome depicted by TRAP constitutes a fertile resource for understanding how glycolysis finely tunes metabolism and signaling in support of cancer cells, and fostering the exploitation of glycolytic targetome as promising nodes for anti-cancer therapeutics development.

cancer biology↗

ACE2-Targeting Monoclonal Antibody As A "Pan" Coronavirus Blocker In Vitro and In A Mouse Model

The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1 and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 "knock-in" mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and "alanine walk" studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and "broad-spectrum" management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

immunology↗

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↗