Biology subjects

Yu, H.

Publications and source records attributed to Yu, H..

At least 361 records · Page 20Linked to original sources

bioRxiv2021

Classical swine fever virus NS5A inhibits NF-κB signaling by targeting NEMO

The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation and regulation of cellular signaling pathways, and assembly of infectious virus particles. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-{kappa}B) signaling induced by poly(I:C); however, the mechanism was not elucidated. Here, we report that NS5A interacts with NF-{kappa}B essential modulator (NEMO),a regulatory subunit of the I{kappa}B kinase (IKK) complex, and that the zinc finger domain of NEMO essential for NEMO ubiquitination and IKK activation is required for the interaction of NEMO with NS5A. Viral infection or NS5A expression by itself reduced the protein level of NEMO. Mechanistic analysis revealed that NS5A mediated proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced K27-but not K48-linked polyubiquitination of NEMO. In addition, NS5A blocked k63-linked polyubiquitination of NEMO, thereby inhibiting activation of IKK and NF-{kappa}B. These findings indicate that NS5A inhibits NF-{kappa}B signaling by mediating proteasomal degradation of NEMO and blocking k63-linked polyubiquitination of NEMO, thereby revealing a novel mechanism by which CSFV inhibits host innate immunity. ImportanceClassical swine fever (CSF) is a economically important swine viral disease leading to hemorrhagic fever and immuno-suppression. In order to successfully infect and replicate in a host cell, viruses have evolved various strategies to antagonize host innate immunity. It is known that CSFV non-structural protein Npro interacts with interferon regulatory factor 3 (IRF3) and mediates its proteasomal degradation, thereby inhibiting the production of type I interferon. However, no other mechanism by which CSFV antagonizes host innate immunity has so far been reported. Here, we show that NS5A inhibits NF-{kappa}B signaling by mediating proteasomal degradation of NEMO and by blocking k63-linked polyubiquitination of NEMO, thereby revealing a novel mechanism by which CSFV antagonizes host innate immunity.

microbiology↗

bioRxiv2021

Minicells from Highly Genome Reduced Escherichia coli: Cytoplasmic and Surface Expression of Recombinant Proteins and Incorporation in the Minicells

Minicells, small cells lacking a chromosome, produced by bacteria with mutated min genes, which control cell division septum placement, have many potential uses. Minicells have contributed to basic bacterial physiology studies and can enable new biotechnological applications, including drug delivery and vaccines. Genome-reduced (GR) bacteria are another informative area of investigation. Investigators identified that with even almost 30% of the E. coli genome deleted, the bacteria still live. In biotechnology and synthetic biology, GR bacteria offer certain advantages. With GR bacteria, more recombinant genes can be placed into GR chromosomes and fewer cell resources are devoted to purposes apart from biotechnological goals. Here, we show that these two technologies can be combined: min mutants can be made in GR E. coli. The minCminD mutant GR E. coli produce minicells that concentrate engineered recombinant proteins within these spherical delivery systems. We expressed recombinant GFP protein in the cytoplasm of GR bacteria and showed that it is concentrated within the minicells. We also expressed proteins on the surfaces of minicells made from GR bacteria using a recombinant Gram-negative AIDA-I autotransporter expression cassette. As some autotransporters, like AIDA-I, are concentrated at the bacterial poles, where minicells bud, and because the surface-to-volume ratio of the small minicells is higher than bacteria, recombinant proteins expressed on surfaces of the GR bacteria are concentrated on the minicells. Minicells made from GR bacteria can enable useful biotechnological innovations, such as drug delivery vehicles and vaccine immunogens.

synthetic biology↗

bioRxiv2021

Endogenous RNA editing of a nuclear gene BOSS triggers flowering in tomato

RNA editing is defined as the production of transcripts with RNA sequences different from those of the DNA template. Most of previous RNA editing studies have focused on organelles, while RNA editing of nuclear transcripts is largely unknown. Here, we describe the first example of nuclear transcript RNA editing in plant, the BOSS RNA editing regulates tomato flowering. The SNP (SNP1) located in the 5UTR of BOSS gene (the Balancer of SP and SFT) is associated with tomato early flowering, and two transcripts of BOSS produced by SNP1 associated RNA editing show functional differentiation, where BOSS-{beta} transcript promotes flowering while BOSS- does not. Furthermore, these two transcripts of BOSS are shown to regulate SP (anti-florigen) pathway at transcription level in the shoot apical meristem (SAM). Our findings reveal a new layer of complexity in the control of plant stem cell proliferation and provide the evidence of RNA-editing of a single gene for flowering, suggesting that molecular breeding programs to increase the RNA-editing efficiency may improve the productivity of tomatoes and other agricultural organisms.

plant biology↗

bioRxiv2021

Systematic comparison of experimental assays and analytical pipelines for identification of active enhancers genome-wide

Mounting evidence supports the idea that transcriptional patterns serve as more specific identifiers of active enhancers than histone marks1,2; however, the optimal strategy to identify active enhancers both experimentally and computationally has not been determined. In this study, we compared 13 genome-wide RNA sequencing assays in K562 cells and showed that the nuclear run-on followed by cap-selection assay (namely, GRO/PRO-cap) has significant advantages in eRNA detection and active enhancer identification. We also introduced a new analytical tool, Peak Identifier for Nascent-Transcript Sequencing (PINTS), to identify active promoters and enhancers genome-wide and pinpoint the precise location of the 5 transcription start sites (TSSs) within these regulatory elements. Finally, we compiled a comprehensive enhancer candidate compendium based on the detected eRNA TSSs available in 120 cell and tissue types. To facilitate the exploration and prioritization of these enhancer candidates, we also built a user-friendly web server (https://pints.yulab.org) for the compendium with various additional genomic and epigenomic annotations. With the knowledge of the best available assays and pipelines, this large-scale annotation of candidate enhancers will pave the road for selection and characterization of their functions in a time-, labor-, and cost-effective manner in the future.

genomics↗

bioRxiv2021

Sialoglycan microarray encoding reveals differential sialoglycan binding of phylogenetically-related bacterial AB5 toxin B subunits

Vertebrate sialic acids (Sias) display much diversity in modifications, linkages and underlying glycans. Slide microarrays allow high-throughput explorations of sialoglycan-protein interactions. A microarray presenting [~]150 structurally-defined sialyltrisaccharides with various Sias linkages and modifications still poses challenges in planning, data sorting, visualization and analysis. To address these issues, we devised a simple 9-digit code for sialyltrisaccharides with terminal Sias and underlying two monosaccharides assigned from the non-reducing end, with three digits assigning a monosaccharide, its modifications, and linkage. Calculations based on the encoding system reveals >113,000 likely linear sialyltrisaccharides in nature. Notably a biantennary N-glycan with two terminal sialyltrisaccharides could thus have >1010 potential combinations and a triantennary N-glycan with three terminal sequences, >1015 potential combinations. While all possibilities likely do not exist in nature, sialoglycans encode enormous diversity. While glycomic approaches are used to probe such diverse sialomes, naturally-occurring bacterial AB5 toxin B subunits are simpler tools to track the dynamic sialome in biological systems. Sialoglycan microarray was utilized to compare sialoglycan-recognizing bacterial toxin B subunits. Unlike the poor correlation between B subunits and species phylogeny, there is stronger correlation with Sia-epitope preferences. Further supporting this pattern, we report a B subunit (YenB) from Yersinia enterocolitica (broad host range) recognizing almost all sialoglycans in the microarray, including 4-O-acetylated-Sias not recognized by a Y. pestis orthologue (YpeB). Differential Sia-binding patterns were also observed with phylogenetically-related B subunits from Escherichia coli (SubB), Salmonella Typhi (PltB), S. Typhimurium (ArtB), extra-intestinal E.coli (EcPltB), Vibrio cholera (CtxB), and cholera family homologue of E. coli (EcxB).

molecular biology↗

bioRxiv2021

Rapid evolution of bacterial AB5 toxin B subunits independent of A subunits: sialic acid binding preferences correlate with host range and toxicity

Cytotoxic A subunits of bacterial AB5 toxins enter the cytosol following B subunit binding to host cell glycans. We report that A subunit phylogeny evolves independently of B subunits and suggest a future B subunit nomenclature based on species name. Phylogenetic analysis of B subunits that bind sialic acids (Sias) with homologous molecules in databases also show poor correlation with phylogeny. These data indicate ongoing lateral gene transfers between species, with mixing of A and B subunits. Some B subunits are not even associated with A subunits e.g., YpeB of Yersinia pestis, the etiologic agent of plague epidemics. Plague cannot be eradicated because of Y. pestis adaptability to numerous hosts. YpeB shares 58% identity/79% similarity with the homo-pentameric B subunit of E. coli Subtilase cytotoxin, and 48% identity/68% similarity with the B subunit of S. Typhi typhoid toxin. We previously showed selective binding of B5 pentamers to a sialoglycan microarray, with Sia preferences corresponding to hosts e.g., N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Consistent with much broader host range of Y. pestis, YpeB binds all mammalian sialic acid types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, abolished by a mutation (Y77F) eliminating Sia recognition, suggesting cell proliferation and death via lectin-like cross-linking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties.

molecular biology↗

bioRxiv2021

Development and applications of sialoglycan-recognizing probes (SGRPs) with defined specificities: exploring the dynamic mammalian sialoglycome

Glycans that are abundantly displayed on vertebrate cell surface and secreted molecules are often capped with terminal sialic acids (Sias). These diverse 9-carbon-backbone monosaccharides are involved in numerous intrinsic biological processes. They also interact with commensals and pathogens, while undergoing dynamic changes in time and space, often influenced by environmental conditions. However, most of this sialoglycan complexity and variation remains poorly characterized by conventional techniques, which often tend to destroy or overlook crucial aspects of Sia diversity and/or fail to elucidate native structures in biological systems i.e., in the intact sialome. To date, in situ detection and analysis of sialoglycans has largely relied on the use of plant lectins, sialidases or antibodies, whose preferences (with certain exceptions) are limited and/or uncertain. We took advantage of naturally-evolved microbial molecules (bacterial adhesins, toxin subunits and viral hemagglutinin-esterases) that recognize sialoglycans with defined specificity to delineate 9 classes of Sialoglycan Recognizing Probes (SGRPs: SGRP1-SGRP9) that can be used to explore mammalian sialome changes in a simple and systematic manner, using techniques common in most laboratories. SGRP candidates with specificity defined by sialoglycan microarray studies were engineered as tagged probes, each with a corresponding non-binding mutant probe as a simple and reliable negative control. The optimized panel of SGRPs can be used in methods commonly available in most bioscience labs, such as ELISA, Western Blot, flow cytometry and histochemistry. To demonstrate the utility of this approach, we provide examples of sialoglycome differences in tissues from C57BL/6 wild type mice and human-like Cmah-/- mice.

molecular biology↗

bioRxiv2021

Golden pompano genome resource enables discovery of valuable gene determining growth traits

One important goal of fish genetic breeding is to identify valuable loci and genes that can facilitate growth and thereby productivity. Few such loci or genes have been identified in golden pompano (Trachinotus ovatus), a species of significant economic value. In this study, we produced a high-quality chromosome-level genome assembly of the golden pompano by de novo sequencing and assemblies for 2 parents and 200 F1 offspring by genome re-sequencing. We exploited these assemblies to identify loci and genes by QTL mapping, Kompetitive Allele Specific PCR (KASP) genotyping, and haplotype-based regional association analysis based on growth records of a 64 biparental and 147 individuals from a naturally occurring population. At a locus 291kb from BSNP21031, we identified a somatostatin receptor type 1-like (designated as gpsstr1) gene in which the BSNP1369 of the promoter region was highly associated with growth. Loss of sstr1a, the homolog of gpsstr1 in zebrafish, caused growth retardation. Sstr1a mediated growth via sstr2 and Wnt-gsk-3{beta} signaling pathways. Our findings provide new insights into the underlying mechanisms controlling growth. Our strategy can serve as an effective way to uncover novel genomic information and facilitate improvement of fish growth.

genomics↗

bioRxiv2021

Characterization of the subunit composition and structure of native adult glycine receptors

The strychnine-sensitive pentameric Glycine Receptor (GlyR) mediates fast inhibitory neurotransmission in the mammalian nervous system. Only heteromeric GlyRs mediate synaptic transmission, since they contain the {beta} subunit that permits clustering at the synapse through its interaction with scaffolding proteins. Here we show that 2 and {beta} subunits assemble with an unexpected 4:1 stoichiometry to produce GlyR with native electrophysiological properties. We determined structures in multiple functional states at 3.6 - 3.8 [A] resolutions and show 2{beta} GlyR assembly mechanism. Furthermore, we show that one single {beta} subunit in each GlyR gives rise to the characteristic electrophysiological properties of heteromeric GlyR, while more {beta} subunits renders GlyR non-conductive. A single {beta} subunit ensures a univalent GlyR-scaffold linkage, which means the scaffold alone regulates the cluster properties.

biophysics↗

bioRxiv2021

Dual origin and multiple neuropeptidergic trajectories of hypothalamic POMC progenitors revealed by developmental single-cell transcriptomics

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential to regulate food intake and energy balance. However, the ontogenetic transcriptional programs that specify the identity and functioning of these neurons are poorly understood. Here, we use scRNAseq to define the transcriptomes characterizing POMC progenitors in the developing hypothalamus and TRAP-seq to analyze the subsequent translatomes of mature POMC neurons. Our data show that Pomc-expressing neurons originate from multiple developmental pathways expressing distinct combinations of transcription factors. The predominant cluster, featured by high levels of Pomc and Prdm12 transcripts represents the precursor of canonical arcuate POMC neurons. Additional clusters of progenitors expressing lower levels of Pomc mature into different neuronal phenotypes characterized by distinct combinations of transcription factors, neuropeptides, processing enzymes, cell surface and nuclear receptors. We conclude that the genetic programs specifying the identity and differentiation of arcuate POMC neurons are diverse and generate a heterogeneous repertoire of neuronal phenotypes early in development that continue to evolve postnatally.

neuroscience↗

bioRxiv2021

Imaging the ultrastructures and dynamics of live erythrocyte membranes at the single-molecule level with a far-red probe on a microfluidic platform

Both the ultrastructures and dynamics of living erythrocyte membranes provide critical criteria for clinical diagnostics. However, it is challenging to simultaneously visualize these features at the single-molecule level due to the rigid photophysical requirements of different single-molecule imaging techniques. Herein, we rationally developed a far-red boron dipyrromethene membrane (BDP-Mem) probe that not only retained consistent and intensive single-molecule emission but also possessed the capability to photoswitch on cellular membranes. We also constructed a microfluidic platform for the noninvasive trapping and long-term imaging of nonadherent erythrocytes. By combining these advantageous technologies, super-resolution reconstruction and single-molecule tracking of living human RBC membranes were achieved at the molecular scale in a high-throughput fashion. Our integrated paradigm defines a quantitative approach for analyzing living RBC membranes under physiological and pathological conditions, improving imaging precisions and revealing new perspectives for future disease diagnostic approaches.

biophysics↗

bioRxiv2021

SENSV: Detecting Structural Variations with Precise Breakpoints using Low-Depth WGS Data from a Single Oxford Nanopore MinION Flowcell

Structural variation (SV) is a major cause of genetic disorders. In this paper, we show that low-depth (specifically, 4x) whole-genome sequencing using a single Oxford Nanopore MinION flow cell suffices to support sensitive detection of SV, in particular, pathogenic SV for supporting clinical diagnosis. Existing SV calling software, when using 4x ONT WGS data, often fails to detect pathogenic SV especially in the form of long deletion, terminal deletion, duplication, and unbalanced translocation. Our new SV calling software SENSV is able to achieve high sensitivity for all types of SV and a breakpoint precision typically {+/-}100 bp, both features are important for clinical concerns. The improvement achieved by SENSV stems from several new algorithms. We evaluated SENSV and other software using both real and simulated data. The former was based on 24 patient samples, each diagnosed with a genetic disorder. SENSV found the pathogenic SV in 22 out of 24 cases (all heterozygous, size from hundreds of Kbp to a few Mbp), reporting breakpoints within 100 bp of the true answers. No existing software can detect the pathogenic SV in more than 10 out of 24 cases, even when the breakpoint requirement is relaxed to {+/-}2,000 bp.

bioinformatics↗

bioRxiv2021

The Expression of Angiopoietin-1 and -2 in the Osteogenesis of Mesenchymal Stem Cells

ObjectiveThe objectives of this study are to clarify whether rat bone marrow derived Mesenchymal stem cells (MSCs) express Ang1 and Ang2 and their expression in the process of osteogenesis in vitro. Material and MethodsMSCs were cultured from rat tibia bone marrow cells and the hemopoietic stem cells were deplete by consistently replacement of the culture medium. The MSCs were induced osteogenesis with mineralization conditional medium and Immunohistochemical and immunofluorescent staining were performed to assess the expression of Ang1 and Ang2. ResultsThe method used to expand rat MSCs in vitro was applicable, and the cell morphology is spindle-like shape that is consistent with the privous reports. The immunohistochemical staining results showed that both Ang1 and Ang2 were expressed by rat MSCs. Both Ang1 and Ang2 were up-regulated in the process of osteogenesis of rat MSCs. ConclusionRat MSCs express both Ang1 and Ang2 which might play critical roles in the osteogenesis in vitro.

cell biology↗

bioRxiv2021

A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimers disease (AD). PGRN is highly expressed in the microglia near A{beta} plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and A{beta} levels in the young male but not female mice. PGRN deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, Galectin-3, TREM2 and GPNMB, specifically near A{beta} plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to A{beta} fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on amyloid metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia, which may contribute to the disease mechanism associated with PGRN polymorphisms in AD.

neuroscience↗

bioRxiv2021

Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we generated a de novo genome assembly of the black rat, 67 ancient black rat mitogenomes and 36 ancient nuclear genomes from sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of mitochondrial DNA confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.

evolutionary biology↗

bioRxiv2021

Quantatitive Analysis of Conserved Sites on the SARS-CoV-2 Receptor-Binding Domain to Promote Development of Universal SARS-Like Coronavirus Vaccines

Although vaccines have been successfully developed and approved against SARS-CoV-2, it is still valuable to perform studies on conserved antigenic sites for preventing possible pandemic-risk of other SARS-like coronavirus in the future and prevalent SARS-CoV-2 variants. By antibodies obtained from convalescent COVID-19 individuals, receptor binding domain (RBD) were identified as immunodominant neutralizing domain that efficiently elicits neutralizing antibody response with on-going affinity mature. Moreover, we succeeded to define a quantitative antigenic map of neutralizing sites within SARS-CoV-2 RBD, and found that sites S2, S3 and S4 (new-found site) are conserved sites and determined as subimmunodominant sites, putatively due to their less accessibility than SARS-CoV-2 unique sites. P10-6G3, P07-4D10 and P05-6H7, respectively targeting S2, S3 and S4, are relatively rare antibodies that also potently neutralizes SARS-CoV, and the last mAbs performing neutralization without blocking S protein binding to receptor. Further, we have tried to design some RBDs to improve the immunogenicity of conserved sites. Our studies, focusing on conserved antigenic sites of SARS-CoV-2 and SARS-CoV, provide insights for promoting development of universal SARS-like coronavirus vaccines therefore enhancing our pandemic preparedness.

immunology↗

bioRxiv2021

Unbalanced dietary patterns contribute to the pathogenesis of precocious puberty by affecting gut microbiota and host metabolites

Precocious puberty (PP) mostly stems from endocrine disorders. However, its triggering factors, especially for the early onset of partial PP, and the associated pathogenic mechanisms remain ambiguous. In this study, a systematic analysis in the form of a questionnaire of lifestyles, gut microbiome, and serum metabolome data was carried out to examine the pathogenesis of PP in a cohort comprised of 200 girls, with or without PP. The analysis revealed substantial alterations in gut microbiota, serum metabolites, as well as lifestyle patterns in the PP group, which were characterized by an elevated abundance of {beta}-glucuronidase-producing and butyrate-producing bacteria, and excessive lipid concentration with decreased levels of organic nitrogen compounds in the serum of the participants. These differential microbes and metabolites tend to be reliable non-invasive diagnostic biomarkers aiding the early diagnosis of PP and exhibit a strong discriminative power (AUC = 0.93 and AUC = 0.97, respectively). Furthermore, the microbial biomarkers were confirmed in an independent validation cohort (n = 83, AUC = 0.85). Moreover, structural equation modeling revealed that unhealthy dietary habits were the primary contributors for the alteration of gut microbiota and serum metabolites, triggering the imbalance in the host hormones that leads to premature physical development. Our study determines a causal relationship among the gut microbiota, host metabolites, diet, and clinical characteristics of preadolescent girls who experienced early onset of PP, and formulates non-invasive diagnostic tools demonstrating excellent performance for the early detection of PP.

microbiology↗

bioRxiv2021

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

BackgroundDementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. MethodsIn this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimers disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. ResultsWe found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. ConclusionOur results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.

systems biology↗