Biology subjects

Dai, Z.

Publications and source records attributed to Dai, Z..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Age-related seroprevalence trajectories of seasonal coronaviruses in children

Four seasonal coronaviruses, including HCoV-NL63 and HCoV-229E, HCoV-OC43 and HCoV-HKU1 cause approximately 15-30% of common colds in adults. However, the frequency and timing of early infection with four seasonal coronaviruses in the infant are still not well studied. Here, we evaluated the serological response to four seasonal coronaviruses in 1886 children under 18-year-old to construct the viral infection rates. The antibody levels were also determined from the plasma samples of 485 pairs postpartum women and their newborn babies. This passive immunity waned at one year after birth and the resurgence of the IgGs were found thereafter with the increase of the age. Taken together, our results show the age-related seroprevalence trajectories of seasonal coronaviruses in children and provide useful information for deciding vaccine strategy for coronaviruses in the future.

immunology↗

bioRxiv2022

Intestinal Epithelial Heat Shock Protein 25/27 integrates host and microbial drivers of mucosal restitution following inflammatory injury

Mucosal healing following inflammatory injury is poorly understood and often neglected, despite being the best indicator of long-term outcomes in inflammatory bowel diseases. We report here that the enigmatic small molecular weight heat shock protein, Hsp25 (the human form is Hsp27), plays a vital role in converging microbial and host factors to promote pSTAT3-mediated mucosal healing. In wild type mice, the proximal-to-distal gradient of intestinal epithelial cell (IEC) Hsp25 expression is dependent on microbial cues. Patients with left-sided ulcerative colitis, however, show reduced levels of Hsp27 expression in both uninvolved and involved areas compared to normal colons of non-IBD patients. In mice with global or IEC-specific Hsp25 gene-targeted deletion, impaired mucosal healing with development of hallmarks of chronic disease are observed following DSS-induced or TNBS-induced colitis, whereas mucosal restitution is accelerated in IEC-specific overexpressing Hsp25 transgenic mice. In colonic IECs derived from these murine lines, Hsp25 binds and stabilizes a phospho-STAT3/YAP nuclear complex stimulated by IL-22 to sustain its wound healing gene programming. Thus, our findings provide insight into the mechanism of action of IEC Hsp25/27 in integrating host and microbial drivers of mucosal restitution, which can be leveraged to develop novel approaches for achieving and maintaining remission in complex immune disorders like IBD.

pathology↗

bioRxiv2022

Small cytosolic dsDNAs repress cGAS activation and induce autophagy

Cyclic GMP-AMP (cGAMP) synthase (cGAS), a major cytosolic DNA sensor, activates innate immune responses by producing cGAMP, which activates stimulator of interferon genes (STING)1. Cytosolic DNA induces autophagy in a cGAS-dependent manner to avoid persistent immune stimulation. Although dsDNAs < 20 bp can bind to cGAS, robust cGAS activation requires dsDNAs > 45 bp 2-4. However, whether cytosolic dsDNAs < 45 bp exist in mammalian cells remains unclear. Here, we identified a class of small cytosolic DNAs (scDNAs) of [~]20-40 bp in human and mouse cell lines. scDNAs competed with herring testis DNA (HT-DNA, [~]200-1500 bp) for binding to cGAS, and repressing HT-DNA-induced cGAS activation and the associated interferon {beta} (IFN{beta}) production. Moreover, scDNAs promoted cGAS and Beclin-1 interaction, triggering the release of Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3)5,6, from the Beclin-1-PI3KC3 complex, activating PI3KC3 and inducing autophagy. DNA damage decreased and autophagy inducers increased scDNA levels. scDNA transfection or autophagy induction attenuated DNA damage-induced cGAS-STING activation and IFN{beta} expression. Thus, scDNAs acted as molecular brakes of cGAS activation, preventing excessive inflammatory cytokine production following DNA damage. Our findings lay foundations for understanding the physiological and pathological functions of scDNAs.

molecular biology↗

bioRxiv2022

Distinct Single-cell Immune Ecosystems Distinguish True and De Novo HBV-related Hepatocellular Carcinoma Recurrences

Revealing differential tumor immune microenvironment (TIME) characteristics between true versus de novo hepatocellular carcinoma (HCC) recurrence could help optimal development and use of immunotherapies. Here, we studied the TIME of recurrent HBV-related HCCs by 5and VDJ single-cell and bulk RNA-sequencing, flow cytometry, and multiplexed immunofluorescence. Analyses of mutational profiles, evolutionary trajectories, and clonal architecture using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The TIME of truly recurrent HCCs was characterized by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed an upregulated GDF15 expression level on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited anti-tumor immunity in the TIME of truly recurrent lesions. In contrast, we found that myeloid cells crosstalk with T cells mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCC. In conclusion, our results support genomic diagnosis and immune profiling for guiding immunotherapy implementation based on the type of HCC recurrence and TIME. HighlightsO_LITruly recurrent lesions are seeded before primary tumor diagnosis, and that de novo cancer can occur earlier than the clinically used 2-year limit. C_LIO_LIScRNA-seq unravels distinct immune ecosystems in true versus de novo HCC recurrences, highlighting the need for different immunotherapy strategies for two types of HCC recurrence. C_LIO_LICD8+ T cells in de novo recurrence displayed cytotoxic and exhausted phenotypes while those in truly recurrent lesions showed a memory phenotype with weak cytotoxicity. C_LIO_LIHCC cells expressing the inhibitory molecule GDF15 were in the proximity of DCs only in truly recurrent lesions. C_LIO_LIHigh GDF15 expression level was associated with truly recurrent HCC and worse prognosis. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/494526v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1b76bf0org.highwire.dtl.DTLVardef@10f889aorg.highwire.dtl.DTLVardef@d16b52org.highwire.dtl.DTLVardef@dceb7a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

MCIBox: A Toolkit for Single-molecule Multi-way Chromatin Interaction Visualization and Micro-Domains Identification

The emerging ligation-free three-dimensional (3D) genome mapping technologies can identify multiplex chromatin interactions with single-molecule precision. These technologies offer new insight into high-dimensional chromatin organization and gene regulation, but also introduce new challenges in data visualization and analysis. To overcome these challenges, we developed MCIBox, a toolkit for Multi-way Chromatin Interaction (MCI) analysis, including a visualization tool and a platform for identifying micro-domains with clustered single-molecule chromatin complexes. MCIBox is based on various clustering algorithms integrated with dimensionality reduction methods that can display multiplex chromatin interactions at single-molecule level, allowing users to explore chromatin extrusion patterns and super-enhancers regulation modes in transcription, and to identify single-molecule chromatin complexes that are clustered into micro-domains. Furthermore, MCIBox incorporates a two-dimensional kernel density estimation algorithm to identify micro-domains boundaries automatically. These micro-domains were stratified with distinctive signatures of transcription activity and contained different cell cycle associated genes. MCIBox could potentially distinguish the specificity of single-molecule chromatin interaction patterns in various phases of a cell cycle or cell types.

genomics↗

bioRxiv2022

A high-throughput yeast display approach to profile pathogen proteomes for MHC-II binding

T cells play a critical role in the adaptive immune response, recognizing peptide antigens presented on the cell surface by Major Histocompatibility Complex (MHC) proteins. While assessing peptides for MHC binding is an important component of probing these interactions, traditional assays for testing peptides of interest for MHC binding are limited in throughput. Here we present a yeast display-based platform for assessing the binding of tens of thousands of user-defined peptides in a high throughput manner. We apply this approach to assess a tiled library covering the SARS-CoV-2 proteome and four dengue virus serotypes for binding to human class II MHCs, including HLA-DR401, -DR402, and -DR404. This approach identifies binders missed by computational prediction, highlighting the potential for systemic computational errors given even state-of-the-art training data, and underlines design considerations for epitope identification experiments. This platform serves as a framework for examining relationships between viral conservation and MHC binding, and can be used to identify potentially high-interest peptide binders from viral proteins. These results demonstrate the utility of this approach for determining high-confidence peptide-MHC binding.

immunology↗

bioRxiv2022

Ultra high diversity factorizable libraries for efficient therapeutic discovery

The successful discovery of novel biological therapeutics by selection requires highly diverse libraries of candidate sequences that contain a high proportion of desirable candidates. Here we propose the use of computationally designed factorizable libraries made of concatenated segment libraries as a method of creating large libraries that meet an objective function at low cost. We show that factorizable libraries can be designed efficiently by representing objective functions that describe sequence optimality as an inner product of feature vectors, which we use to design an optimization method we call Stochastically Annealed Product Spaces (SAPS). We then use this approach to design diverse and efficient libraries of antibody CDR-H3 sequences with various optimized characteristics.

bioengineering↗

bioRxiv2021

The grape MYB24 mediates the coordination of light-induced terpene and flavonol accumulation in response to berry anthocyanin sunscreen depletion

The presence of naturally-occurring color mutants in plants has permitted the identification of many regulatory genes implicated in the synthesis of discrete metabolic compounds, mostly anthocyanins and carotenoids. Conversely, transcription factors that coordinate more than one specialized metabolic pathway seem challenging to screen from a forward genetics perspective. We explored the relationship between different branches of the phenylpropanoid and isoprenoid pathways while examining an infrequent berry skin color variegation in grapevine. Red and white berry skin sections were compared at the genetic, transcriptomic and metabolomic levels showing that, as in most cultivated white grape varieties, the uncolored skin section convened the non-functional alleles of the anthocyanin regulators MYBA1 and MYBA2, explaining the lack of pigments. In contrast, light-responsive flavonols and monoterpenes increased in anthocyanin-depleted areas. We disclosed an enrichment of the flavonol, terpene and carotenoid pathways among up-regulated genes from white-skin sections, accompanied by increased expressions of flavonol regulators and the still uncharacterized MYB24 gene. We used DAP-seq to examine the in vitro binding of affinity-purified MYB24 protein to genomic DNA and demonstrated its binding in the promoter regions of terpene (22) and carotenoid (6) genes, in addition to more than 30 photosynthesis and light-response genes, including the flavonol-regulator HY5 homologue (HYH). We confirmed the activation of TPS35 and HYH promoter:luciferase reporters in the presence of MYB24 and the grape bHLH MYC2, all of which correlate in their higher expression in white skin variegated sections. The integration of several datasets allowed to define a list of high confidence targets, suggesting MYB24 as a modulator of light responses including the synthesis of flavonoids (flavonols) and isoprenoids (terpenes, and putatively carotenoids). The correspondence between MYB24 and monoterpenes in all conditions surveyed implies that this regulatory network is broadly triggered towards berry ripening, and that the absence of anthocyanin sunscreens accelerates its activation most likely in a dose-dependent manner due to increased radiation exposure.

plant biology↗

bioRxiv2021

A Hybrid Communication Pattern in Brain Structural Network Revealed by Evolutionary Computation

The human brain functional connectivity network (FCN) is constrained and shaped by the communication processes in the structural connectivity network (SCN). The underlying communication mechanism thus becomes a critical issue for understanding the formation and organization of the FCN. A number of communication models supported by different routing strategies have been proposed, with shortest path (SP), random diffusion (DIF), and spatial navigation (NAV) as the most typical, respectively requiring network global knowledge, local knowledge, and both for path seeking. Yet these models all assumed every brain region to use one routing strategy uniformly, ignoring convergent evidence that supports the regional heterogeneity in both terms of biological substrates and functional roles. In this regard, the current study developed a hybrid communication model that allowed each brain region to choose a routing strategy from SP, DIF, and NAV independently. A genetic algorithm was designed to uncover the underlying region-wise hybrid routing strategy (namely HYB). The HYB was found to outperform the three typical routing strategies in predicting FCN and facilitating robust communication. Analyses on HYB further revealed that brain regions in lower-order functional modules inclined to route signals using global knowledge, while those in higher-order functional modules preferred DIF that requires only local knowledge. Compared to regions that used global knowledge for routing, regions using DIF had denser structural connections, participated in more functional modules, but played a less dominant role within modules. Together, our findings further evidenced that hybrid routing underpins efficient SCN communication and locally heterogeneous structure-function coupling.

neuroscience↗

bioRxiv2021

The overlapping modular organization of human brain functional networks across the adult lifespan

Previous lifespan studies have demonstrated that the brain functional modular organization would change along with the adult lifespan. Yet, they assumed mutual exclusion among functional modules, ignoring convergent evidence for the existence of modular overlap. To reveal how age affects the overlapping functional modular organization, this study applied a detection algorithm requiring no prior knowledge of the resting-state fMRI data of a healthy cohort (N = 570, 18-88 years). Age-related regression analyses found a linear decrease in the overlapping modularity and the similarity of modular structure and overlapping node (i.e., region involved in multiple modules) distribution. The number of overlapping nodes increased with age, but the increment was distributed unevenly. In addition, across the adult lifespan and within each age group, the nodal overlapping probability consistently exhibited positive correlations with both functional gradient and flexibility. Further, we showed that the influence of age on memory-related cognitive performance might be explained by the change in the overlapping functional modular organization. Together, our results revealed age-related decreased segregation from the perspective of brain functional overlapping modular organization, providing new insight into the adult lifespan change in brain function and its influence on cognitive performance.

neuroscience↗

bioRxiv2021

Dysconnectivity between auditory-cognitive network associated with auditory GABA and glutamate levels in presbycusis patients

Accumulating studies suggest an interaction between presbycusis (PC) and cognitive impairment, which may be explained by the cognitive-ear link to a large extent. However, the neurophysiological mechanisms underlying this link are largely unknown. Here, 51 PC patients and 51 well-matched healthy controls were recruited. We combined resting-state functional MRI and edited magnetic resonance spectroscopy to investigate changes of intra- and inter-network functional connectivity and their relationships with auditory gamma-aminobutyric acid (GABA) and glutamate (Glu) levels and cognitive impairment in PC. Our study confirmed the plastic model of cognitive-ear link at the level of the large-scale brain network, including the dysconnectivity within high-order cognitive networks and between the auditory-cognitive network and overactivation between cognitive networks dependent on hearing loss, which was closely related to the cognitive impairment of PC patients. Moreover, GABA and Glu levels in the central auditory processing were abnormal in patients with PC. Importantly, reduction of GABA-mediated inhibition plays a crucial role in a dysconnectivity between the auditory-cognitive network, which may be neurochemical underpinnings of functional remodeling of cognitive-ear link in PC. Modulation of GABA neurotransmission may enable the development of new therapeutic strategies for the cognitive impairment of PC patients.

neuroscience↗

bioRxiv2021

A Snapshot of the Global Drinking Water Virome: Diversity and Metabolic Potential Vary with Residual Disinfectant Use

Viruses are important drivers of microbial community ecology and evolution, influencing microbial mortality, metabolism, and horizontal gene transfer. However, the effects of viruses remain largely unknown in many environments, including in drinking water systems. Drinking water metagenomic studies have offered a whole community perspective of bacterial impacts on water quality, but have not yet considered the influences of viruses. In this study, we address this gap by mining viral DNA sequences from publicly available drinking water metagenomes from distribution systems in six countries around the world. These datasets provide a snapshot of the taxonomic diversity and metabolic potential of the global drinking water virome; and provide an opportunity to investigate the effects of geography, climate, and drinking water treatment practices on viral diversity. Both environmental conditions and differences in sample processing were found to influence the viral composition. Using free chlorine as the residual disinfectant was associated with clear differences in viral taxonomic diversity and metabolic potential, with significantly fewer viral populations and less even viral community structures than observed in distribution systems without residual disinfectant. Additionally, drinking water viruses carry antibiotic resistance genes (ARGs), as well as genes to survive oxidative stress and nitrogen limitation. Through this study, we have demonstrated that viral communities are diverse across drinking water systems and vary with the use of residual disinfectant. Our findings offer directions for future research to develop a more robust understanding of how virus-bacteria interactions in drinking water distribution systems affect water quality.

microbiology↗

bioRxiv2021

Comammox Nitrospira bacteria outnumber canonical nitrifiers irrespective of electron donor mode and availability

Complete ammonia oxidizing bacteria coexist with canonical ammonia and nitrite oxidizing bacteria in a wide range of environments. Whether this is due to competitive or cooperative interactions, or a result of niche separation is not yet clear. Understanding the factors driving coexistence of nitrifiers is critical to manage nitrification processes occurring in engineered and natural ecosystems. In this study, microcosm-based experiments were used to investigate the impact of nitrogen source and loading on the population dynamics of nitrifiers in drinking water biofilter media. Shotgun sequencing of DNA followed by co-assembly and reconstruction of metagenome assembled genomes revealed clade A2 comammox bacteria were likely the primary nitrifiers within microcosms and increased in abundance over Nitrsomonas-like ammonia and Nitrospira-like nitrite oxidizing bacteria irrespective of nitrogen source type or loading. Changes in comammox bacterial abundance did not correlate with either ammonia or nitrite oxidizing bacterial abundance in urea amended systems where metabolic reconstruction indicated potential for cross feeding between ammonia and nitrite oxidizing bacteria. In contrast, comammox bacterial abundance demonstrated a negative correlation with nitrite oxidizers in ammonia amended systems. This suggests potentially weaker synergistic relationships between ammonia and nitrite oxidizers might enable comammox bacteria to displace nitrite oxidizers from complex nitrifying communities.

ecology↗

bioRxiv2021

Endothelial PHD2 Deficiency Induces Nitrative Stress via Suppression of Caveolin-1 in Pulmonary Arterial Hypertension

Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 [PHD2]) with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP, also known as a peroxynitrite scavenger) treatment inhibited obliterative pulmonary vascular remodeling and attenuated severe PAH in Egln1Tie2Cre mice. Genetic restoration of endothelial Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PAH and improved right heart function. These data suggest that suppression of endothelial Cav1 expression secondary to PHD2 deficiency augments nitrative stress, which contributes to obliterative vascular remodeling and severe PAH. Thus, reactive oxygen/nitrogen species scavenger might have great therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.

physiology↗

bioRxiv2021

Stable Flow-induced Expression of KLK10 Inhibits Endothelial Inflammation and Atherosclerosis

IntroductionAtherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow (d-flow), while regions exposed to stable flow (s-flow) are protected. The proatherogenic and atheroprotective effects of d-flow and s-flow are mediated in part by the global changes in endothelial cell gene expression, which regulates endothelial dysfunction, inflammation, and atherosclerosis. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10, a secreted serine protease) as a flow-sensitive gene in arterial endothelial cells, but its role in endothelial biology and atherosclerosis was unknown. Methods and ResultsHere, we show that KLK10 is upregulated under s-flow conditions and downregulated under d-flow conditions using in vivo mouse models and in vitro studies with cultured endothelial cells (ECs). Single-cell RNA sequencing (scRNAseq) and scATAC sequencing (scATACseq) study using the partial carotid ligation mouse model showed flow-regulated KLK10 expression at the epigenomic and transcription levels. Functionally, KLK10 protected against d-flow-induced inflammation and permeability dysfunction in human artery ECs (HAECs). Further, treatment of mice in vivo with rKLK10 decreased arterial endothelial inflammation in d-flow regions. Additionally, rKLK10 injection or ultrasound-mediated transfection of KLK10-expressing plasmids inhibited atherosclerosis in ApoE-/- mice. Studies using pharmacological inhibitors and siRNAs revealed that the anti-inflammatory effects of KLK10 were mediated by a Protease Activated Receptors (PAR1/2)-dependent manner. However, unexpectedly, KLK10 did not cleave the PARs. Through a proteomics study, we identified HTRA1 (High-temperature requirement A serine peptidase 1), which bound and cleaved KLK10. Further, siRNA knockdown of HTRA1 prevented KLK10s anti-inflammatory and barrier protective function in HAECs, suggesting that HTRA1 regulates KLK10 function. Moreover, KLK10 expression was significantly reduced in human coronary arteries with advanced atherosclerotic plaques compared to those with less severe plaques. ConclusionKLK10 is a flow-sensitive endothelial protein and, in collaboration with HTRA1, serves as an anti-inflammatory, barrier-protective, and anti-atherogenic factor.

cell biology↗

bioRxiv2021

Evaluating de novo assembly and binning strategies for time-series drinking water metagenomes.

Reconstructing microbial genomes from metagenomic short-read data can be challenging due to the unknown and uneven complexity of microbial communities. This complexity encompasses highly diverse populations which often includes strain variants. Reconstructing high-quality genomes is a crucial part of the metagenomic workflow as subsequent ecological and metabolic inferences depend on their accuracy, quality, and completeness. In contrast to microbial communities in other ecosystems, there has been no systematic assessment of genome-centric metagenomic workflows for drinking water microbiomes. In this study, we assessed the performance of a combination of assembly and binning strategies for time-series drinking water metagenomes that were collected over a period of 6 months. The goal of this study was to identify the combination of assembly and binning approaches that results in high quality and quantity metagenome-assembled genomes (MAGs), representing most of the sequenced metagenome. Our findings suggest that the metaSPAdes co-assembly strategies had the best performance as they resulted in larger and less fragmented assemblies with at least 85% of the sequence data mapping to contigs greater than 1kbp. Furthermore, a combination of metaSPAdes co-assembly strategies and MetaBAT2 produced the highest number of medium-quality MAGs while capturing at least 70% of the metagenomes based on read recruitment. Utilizing different assembly/binning approaches also assist in the reconstruction of unique MAGs from closely related species that would have otherwise collapsed into a single MAG using a single workflow. Overall, our study suggests that leveraging multiple binning approaches with different metaSPAdes co-assembly strategies may be required to maximize the recovery of good-quality MAGs, which more accurately capture the microbial diversity of drinking water samples.

genomics↗

bioRxiv2021

Amino acid variability, tradeoffs and optimality in human diet

While the quality of fat (e.g. saturated/unsaturated) and carbohydrate (e.g. whole grain/simple sugars) intake has been of great interest, less attention has been made to the type of protein and resulting amino acid intake profiles in human diets. Studies at the molecular level however demonstrate that dietary amino acid intake produces substantial effects on health and disease such as cancer by modulating metabolism. How these effects may manifest in human food consumption and dietary patterns is unknown. We developed a series of algorithms to map, characterize and model the landscape of amino acid content in human food, dietary patterns, and individual consumption including relations to health status, covering over 2,000 foods, ten dietary patterns, and over 30,000 dietary records. We found that the type of amino acids contained in foods and human consumption is highly dynamic with variability far exceeding that of fat and carbohydrate. Some amino acids positively associate with diseases such as obesity while others contained in the same food negatively link to disease. Using linear programming and machine learning, we show that these health trade-offs among can be accounted to satisfy biochemical constraints in food and human eating patterns to construct a Pareto front in dietary practice, a means of achieving optimality in the face of tradeoffs that are commonly considered in economic and evolutionary theories. Thus this study may enable the design of human protein quality intake guidelines based on a quantitative framework.

systems biology↗

bioRxiv2021

Gene Expression Associated with Individual Variability in Intrinsic Functional Connectivity

It has been revealed that intersubject variability (ISV) in intrinsic functional connectivity (FC) is associated with a wide variety of cognitive and behavioral performances. However, the underlying organizational principle of ISV in FC and its related gene transcriptional profiles remain unclear. Using resting-state fMRI data from the Human Connectome Project (299 participants) and microarray gene expression data from the Allen Human Brain Atlas, we conducted a transcription-neuroimaging association study to investigate the spatial configurations of ISV in intrinsic FC and their associations with gene transcriptional profiles. We found that the multimodal association cortices showed the greatest ISV in FC, while the unimodal cortices and subcortical areas showed the least ISV. Importantly, partial least squares regression analysis revealed that the transcriptional profiles of genes associated with human accelerated regions (HARs) could explain 31.29% of the variation in the spatial distribution of ISV in FC. The top-related genes in the transcriptional profiles were enriched for the development of the central nervous system, neurogenesis and the cellular components of synapse. Moreover, we observed that the effect of gene expression profile on the heterogeneous distribution of ISV in FC was significantly mediated by the cerebral blood flow configuration. These findings highlighted the spatial arrangement of ISV in FC and their coupling with variations in transcriptional profiles and cerebral blood flow supply.

neuroscience↗