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Tong, Y.

Publications and source records attributed to Tong, Y..

At least 55 records · Page 3Linked to original sources
bioRxiv2024

Dynamin 1-mediated endocytic recycling of glycosylated N-cadherin sustains the plastic mesenchymal state to promote ovarian cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is a key process that confers metastatic plasticity to ovarian cancer cells, enabling them to disseminate aggressively throughout the peritoneal cavity and contributing to poor clinical outcomes for patients. However, a pharmacologically exploitable driver of EMT in ovarian cancer has yet to be identified. To address this, we utilized a master regulators algorithm to prioritize EMT regulators from a dataset of over 8,000 patient samples, including multidimensional omics data from more than 20 cancer types in TCGA. Further analysis identified dynamin-1 (DNM1), an endocytic regulator, as a novel master regulator of EMT in ovarian cancer. Clinically, DNM1 overexpression was found to be associated with the mesenchymal subtype and advanced/metastatic stages of ovarian carcinomas. Molecular assays revealed that DNM1 upregulates N-cadherin, a hallmark mesenchymal marker, by promoting its endocytosis and recycling, thereby inducing cell polarization and motility. In addition, integration of ATAC-seq and RNA-seq analyses uncovered the repression of beta-1,3-galactosyltransferase (B3GALT1), a glycosyltransferase, in metastatic cells. B3GALT1-mediated glycosylation hindered the recycling of N-cadherin. Functional studies demonstrated that depletion of DNM1 or pharmacological inhibition of endocytic recycling significantly impaired cell polarity, migration, and also cancer stemness. Importantly, in vivo experiments showed that the loss of DNM1 significantly suppressed peritoneal metastatic colonization. Interestingly, metastatic cells with elevated DNM1-mediated endocytosis showed increased susceptibility to nanoparticle delivery. Collectively, these results establish the DNM1-N-cadherin axis as an important regulator of EMT-associated ovarian cancer metastasis and suggest its potential as a biomarker for targeted nanodrug therapy.

cancer biology↗
bioRxiv2024

IsRNAcirc: 3D structure prediction of circular RNAs based on coarse-grained molecular dynamics simulation

As an emerging class of RNA molecules, circular RNAs play pivotal roles in various biological processes, thereby determining their three-dimensional (3D) structure is crucial for a deep understanding of their biological significances. Similar to linear RNAs, the development of computational methods for circular RNA 3D structure prediction is challenging, especially considering the inherent flexibility and potentially long length of circular RNAs. Here, we introduce an extension of our previous IsRNA2 model, named IsRNAcirc, to enable circular RNA 3D structure predictions through coarse-grained molecular dynamics simulations. The workflow of IsRNAcirc consists of four main steps, including input preparation, end closure, structure prediction, and model refinement. Our results demonstrate that IsRNAcirc can provide reasonable 3D structure predictions for circular RNAs, which significantly reduce the locally irrational elements contained in the initial input. Moreover, for a validation test set comprising 34 circular RNAs, our IsRNAcirc can generate 3D models with better scores than the template-based 3dRNA method. These findings demonstrate that our IsRNAcirc method is a promising tool to explore the structural details along with intricate interactions of circular RNAs. Author SummaryKnowledge of the 3D structure of circular RNA molecules can help us better understand their roles in eukaryotic cells. However, experimental determination of circular RNA 3D structure remains challenging, with currently only one complete circular RNA 3D structure available in the Protein Data Bank. Thus, extending from their linear counterparts, computational methods that can predict circular RNA 3D structure are urgently needed. In particular, physics-based de novo 3D structure prediction methods are promising due to their powerful sampling capability in the conformational space, which avoid the problem of limited available templates in template-based approaches. We have developed IsRNAcirc, a new physics-based method that employs an accurate coarse-grained force field and replica-exchange molecular dynamics simulations to predict the 3D structure of circular RNAs. IsRNAcirc is shown to significantly reduce the number of locally irrational structures in the input trials, which are caused by the lack of suitable templates and the improper assembly of fragments. Furthermore, in the absence of experimental reference structures, the predicted 3D models were validated using the popular scoring functions, such as DFIRE-RNA and rsRNASP, demonstrating that IsRNAcirc outperforms the template-based 3dRNA method in generating low-energy conformations.

biophysics↗
bioRxiv2024

Single-cell analysis of human diversity in circulating immune cells

Lack of diversity and proportionate representation in genomics datasets and databases contributes to inequity in healthcare outcomes globally1,2. The relationships of human diversity with biological and biomedical phenotypes are pervasive3, yet remain understudied, particularly in a single-cell genomics context. Here we present the Asian Immune Diversity Atlas (AIDA), a multi-national single-cell RNA-sequencing (scRNA-seq) healthy reference atlas of human immune cells. AIDA comprises 1,265,624 circulating immune cells from 619 healthy donors and 6 controls, spanning 7 population groups across 5 countries. AIDA is one of the largest healthy blood datasets in terms of number of cells, and also the most diverse in terms of number of population groups. Though population groups are frequently compared at the continental level, we identified a pervasive impact of sub-continental diversity on cellular and molecular properties of immune cells. These included cell populations and genes implicated in disease risk and pathogenesis as well as those relevant for diagnostics. We detected single-cell signatures of human diversity not apparent at the level of cell types, as well as modulation of the effects of age and sex by self-reported ethnicity. We discovered functional genetic variants influencing cell type-specific gene expression, including context-dependent effects, which were under-represented in analyses of non-Asian population groups, and which helped contextualise disease-associated variants. We validated our findings using multiple independent datasets and cohorts. AIDA provides fundamental insights into the relationships of human diversity with immune cell phenotypes, enables analyses of multi-ancestry disease datasets, and facilitates the development of precision medicine efforts in Asia and beyond.

genomics↗
bioRxiv2024

Down regulation of Engase in Caenorhabditis elegans may improve its stresses adaptivity

Endo-beta-N-acetylglucosaminidase (ENGASE) is one of the key enzymes involved in the regulation of structure and function of glycoproteins. It is conserved from prokaryotic to eukaryotic cells. Although their activities in vitro and applications have been well studied, the biological function of ENGASE remains to be illustrated. In this study, we analyzed the molecular and physiological function of Engase from Caenorhabditis elegans homolog eng-1(CeEngase). We found that CeEngase knockout or knockdown increased the environmental stresses adaptability, such as heat stress and osmotic stress. Preliminary glycomics analysis showed that the basement membrane proteins of extracellular matrix may be the main targets of CeENGASE. In addition, CeENGASE may selectively prefer to N2H7 glycans on glycoproteins. In conclusion, our data illustrated that the defection and/or down regulation of CeEngase may provide a beneficially adaptation for stresses.

biochemistry↗
bioRxiv2024

A nanobody-enzyme fusion protein targeting PD-L1 and sialic acid exerts anti-tumor effects by affecting tumor associated macrophages

Cancer cells employ various mechanisms to evade immune surveillance. Their surface features, including a protective "sugar coat" and immune checkpoints like PD-L1 (programmed death ligand 1), can impede immune cell recognition. Sialic acids, which carry negative charges, may hinder cell contact through electrostatic repulsion, while PD-L1 transmits immunosuppressive signals to T cells. Furthermore, cancer cells manipulate macrophages within the tumor microenvironment to facilitate immune escape. Prior research has demonstrated the effectiveness of separately blocking the PD-L1 and sialic acid pathways in eliciting anti-tumor effects. In this study, we investigated the relationship between PD-L1 expression and genes associated with sialic acid in clinical databases. Subsequently, we developed a novel nanobody enzyme fusion protein termed Nb16-Sia to simultaneously target both PD-L1 and sialic acid pathways. In vivo experiments confirmed the anti-tumor activity of Nb16-Sia and highlighted its dependence on macrophages. Further investigations revealed that Nb16-Sia could polarize macrophages towards the M1 phenotype through the C-type lectin pathway in vitro and eliminate tumor-associated macrophages in vivo. In conclusion, our findings demonstrate that the fusion of PD-L1 nanobody with sialidase effectively targets tumor-associated macrophages, resulting in significant anti-tumor effects. This approach holds promise for drug development aimed at enhancing immune responses against cancer.

pharmacology and toxicology↗
bioRxiv2024

Transcriptome-wide mapping of small-molecule RNA-binding sites in live cells

Small molecules targeting RNA can be valuable chemical probes and potential therapeutics. The interactions between small molecules, particularly fragments, and RNA, however, can be difficult to detect due to their modest affinities and short residence times. Here, we describe the procedures for mapping the molecular fingerprints of small molecules in vitro and throughout the human transcriptome in live cells, identifying both the targets bound by the small molecule and the sites of binding therein. For complete details on the use and execution of this protocol, please refer to 1.

biochemistry↗
bioRxiv2024

Mining the biosynthetic landscape of lactic acid bacteria unearths a new family of RiPPs assembled by a novel type of ThiF-like adenylyltransferases

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are chemically diverse natural products of ribosomal origin. These peptides, which frequently act as signals or antimicrobials, are biosynthesized by conserved enzymatic machineries, making genome mining a powerful strategy for unearthing previously uncharacterized members of their class. Herein, we investigate the untapped biosynthetic potential of Lactobacillales (i.e. lactic acid bacteria) - an order of Gram-positive bacteria closely associated with human life, including pathogenic species and industrially-relevent fermenters of dairy products. Through genome mining methods, we systematically explored the distribution and diversity of ThiF-like adenylyltransferases-utilizing RiPP systems in lactic acid bacteria and identified a number of unprecedented biosynthetic gene clusters. In one of these clusters, we found a previously undescribed group of macrocyclic imide biosynthetic pathways containing multiple transporters and may be involved in potential quorum sensing (QS) system. Through in vitro assays, we determined that one such adenylyltranferase specifically catalyzes the intracyclization of its precursor peptide through macrocyclic imide formation. Incubating the enzyme with various primary amines revealed it could effectively amidate the C-terminus of the precursor peptide. This new transformation adds to the growing list of Natures peptide macrocyclization strategies and expands the impressive catalytic repertoire of the adenylyltransferase family. The diverse RiPP systems identified herein represent a vast, unexploited landscape for discovery of novel class of natural products and potential QS systems. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/593846v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1cd3125org.highwire.dtl.DTLVardef@55a546org.highwire.dtl.DTLVardef@d5a325org.highwire.dtl.DTLVardef@1c9e1f3_HPS_FORMAT_FIGEXP M_FIG C_FIG (For Table of Contents use only)

biochemistry↗
bioRxiv2024

The visuomotor transformations underlying defensive behaviors and hunting

The visual system can process diverse stimuli and make the decision to execute appropriate behaviors, but it remains unclear where and how this transformation takes place. We imaged the zebrafish visual system while larvae responded with hunting, freezing, and escape behaviors, and systematically identified visually driven neurons and behaviorally correlated sensorimotor neurons. Our analyses indicate within the optic tectum, broadly tuned sensory neurons are functionally connected to sensorimotor neurons that respond specifically during one behavior, transforming visual information into motor output. We also identified sensorimotor neurons in four other areas downstream of the tectum, and these neurons are also specific for one behavior, indicating that once the decision to behave has been made, the segregation of the pathways continues in later areas. Our findings suggest that the tectum receives visual sensory information and is responsible for selecting a single behavioral outcome, which is then relayed to downstream areas. Significance statementHere, we developed a novel visually-evoked freezing paradigm in zebrafish, and combined this with escape and hunting behaviors to ask how visual stimuli are identified and converted into different behavioral outcomes. We found that the optic tectum contains neurons that detect all three stimuli, as well as sensorimotor neurons for the three behaviors, suggesting that it is a site of sensorimotor transformation, which was supported by our analysis of correlations between the populations. The sensorimotor neurons in the tectum are highly specific for one behavior, and this segregation is maintained in the three downstream areas where we also identified sensorimotor neurons, indicating that the tectum flexibly transforms visual information into a single behavioral output.

neuroscience↗
bioRxiv2024

Virtual Growing Child (VGC): A general normative comparative system via quantitative dynamic MRI for quantifying pediatric regional respiratory anomalies with application in thoracic insufficiency syndrome (TIS)

BackgroundA normative database of regional respiratory structure and function in healthy children does not exist. MethodsVGC provides a database with four categories of regional respiratory measurement parameters including morphological, architectural, dynamic, and developmental. The database has 3,820 3D segmentations (around 100,000 2D slices with segmentations). Age and gender group analysis and comparisons for healthy children were performed using those parameters via two-sided t-testing to compare mean measurements, for left and right sides at end-inspiration (EI) and end-expiration (EE), for different age and gender specific groups. We also apply VGC measurements for comparison with TIS patients via an extrapolation approach to estimate the association between measurement and age via a linear model and to predict measurements for TIS patients. Furthermore, we check the Mahalanobis distance between TIS patients and healthy children of corresponding age. FindingsThe difference between male and female groups (10-12 years) behave differently from that in other age groups which is consistent with physiology/natural growth behavior related to adolescence with higher right lung and right diaphragm tidal volumes for females(p<0.05). The comparison of TIS patients before and after surgery show that the right and left components are not symmetrical, and the left side diaphragm height and tidal volume has been significantly improved after surgery (p <0.05). The left lung volume at EE, and left diaphragm height at EI of TIS patients after surgery are closer to the normal children with a significant smaller Mahalanobis distance (MD) after surgery (p<0.05). InterpretationThe VGC system can serve as a reference standard to quantify regional respiratory abnormalities on dMRI in young patients with various respiratory conditions and facilitate treatment planning and response assessment. FundingThe grant R01HL150147 from the National Institutes of Health (PI Udupa).

bioengineering↗
bioRxiv2024

Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression

ObjectiveGastric intestinal metaplasia (IM) is a pre-cancerous stage spanning a morphological spectrum that is poorly represented by human cell line models. We aim to establish and characterize human IM cell models to better understand IM progression along the cancer spectrum. DesignA large human gastric IM organoid (IMO) cohort (n=28) was established, along with normal gastric organoids (n=42) for comparison, and comprehensive multi-omics profiling and functional characterization were performed. ResultsSingle-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation, and unveiled lineage trajectories that connected different cycling and quiescent stem and progenitors, highlighting their differences in gastric to IM transition. The hybrid IMO cells showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates, and reactivation of a fetal gene program. Cell populations in gastric IM and cancer tissues were found to be highly similar to those derived from IMOs and exhibited fetal signature. Genomically, IMOs showed an elevated mutation burden, frequent chromosome 20 gain, and epigenetic de-regulation of many intestinal and gastric genes. Functionally, IMOs downregulated FGFR2 and became independent of FGF10 for survival. Several IMOs exhibited a cell-matrix adhesion independent (CMi) subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, which could represent the earliest neoplastic precursor of IM-induced gastric cancer. ConclusionsOverall, our IM organoid biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and its neoplastic progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention.

cancer biology↗
bioRxiv2024

An interpretable integration model improving disease-free survival prediction for gastric cancer based on CT images and clinical parameters

Preoperative prediction of disease-free survival of gastric cancer is significantly important in clinical practice. Existing studies showed the potentials of CT images in identifying predicting the disease-free survival of gastric cancer. However, no studies to date have combined deep features with radiomics features and clinical features. In this study, we proposed a model which embedded radiomics features and clinical features into deep learning model for improving the prediction performance. Our models showed a 3%-5% C-index improvement and 10% AUC improvement in predicting DFS and disease event. Interpretation analysis including T-SNE visualization and Grad-CAM visualization revealed that the model extract biologically meaning features, which are potentially useful in predicting disease trajectory and reveal tumor heterogeneity. The embedding of radiomics features and clinical features into deep learning model could guide the deep learning to learn biologically meaningful information and further improve the performance on the DFS prediction of gastric cancer. The proposed model would be extendable to related problems, at least in few-shot medical image learning. Key PointsO_LIAn integration model combining deep features, radiomics features and clinical parameters improved disease-free-survival prediction of gastric cancer by 3%-5% C-index. C_LIO_LIEmbedding radiomics and clinical features into deep learning model through concatenation and loss design improved feature extraction ability of deep network. C_LIO_LIThe model revealed disease progression trajectory and tumor heterogeneity. C_LI

cancer biology↗
bioRxiv2024

Analytical Methods and Platforms for circRNA Vector Engineering to Improve Circularization Efficiency

Circular RNAs (circRNAs) have emerged as pivotal players in RNA therapeutics. Unlike linear counterparts, circRNAs possess a closed-loop structure, conferring them with enhanced stability and resistance to degradation. This resilience makes them promising candidates for diagnostic and therapeutic applications. The ribozyme-based strategy stands out as the predominant method for synthetic circRNA production. In this strategy, ribozymes (catalytic RNA molecules) facilitate the circularization process by precisely cleaving and promoting the formation of a covalent circular structure. In the report, we detail analytical methods for circRNA vector engineering to enhance circularization efficiency. This approach will capture the attention of researchers interested in optimizing RNA circularization efficiency, as well as those focused on exploring key elements for ribozyme catalytic activity.

molecular biology↗
bioRxiv2024

A Novel Dual Probe-based Method for Mutation Detection using Isothermal Amplification

Cost efficient and rapid detection tools to detect mutations especially those linked to drug-resistance are important to address concerns of the rising multi-drug resistance infections. Here we integrated dual probes, namely a calibrator probe and an indicator probe, into isothermal amplification detection system. These two probes are designed to bind distinct regions on the same amplicon to determine the presence or absence of mutation. The calibrator probe signal is used as an internal signal calibrator for indicator probe which detects the presence or absence of the mutation. As an illustrative example, we evaluated the applicability of this dual probe method for detecting mutations associated with rifampicin (RIF) drug resistance at codons 516, 526 and 531 of the rpoB gene in Mycobacterium tuberculosis. In this assessment, we examined 127 artificial samples comprising wild type and mutant target sequences with single or multiple mutations. Our results demonstrated 100% accuracy of both wild type and mutant samples for mutations at codons 526 and 531. As regards to mutations at codon 516, the wild type was identified with 100% accuracy, while the mutant type was identified with 95% accuracy. Moreover, when we extended our evaluation using the Zeptometrix MTB Verification panel, our dual probe method correctly differentiated between the wild type and mutant, and identified the RIF-mutant strain which harbors mutations at codon 531 of the rpoB gene. Our isothermal mutation detection system, relying on dual probes exhibits a versatile approach. With the capability to identify mutations without prior knowledge of their specific mutation direction, our dual-probe method shows significant promise for applications in drug resistance nucleic acid testing, particularly in resource-limited settings.

molecular biology↗
bioRxiv2024

TabHLH27 orchestrates root growth and drought tolerance to enhance water use efficiency in wheat

Cultivating high-yield wheat under limited water resources is essential for sustainable agriculture in semiarid regions. Amid water scarcity, plants activate drought response signaling, yet the delicate balance between drought tolerance and development remains unclear. Through genome-wide-association study (GWAS) and transcriptome profiling, we identified a wheat atypical basic helix-loop-helix (bHLH) transcription factor (TF), TabHLH27-A1, as a promising quantitative trait locus (QTL) candidate for both relative root dry weight (DW.R%) and spikelet number per spike (SPS) in wheat. TabHLH27-A1/B1/D1 knockout reduced wheat drought tolerance, yield, and water use efficiency (WUE). TabHLH27-A1 exhibited rapid induction with PEG treatment, gradually declining over days. It activated stress response genes such as TaCBL8-B1 and TaCPI2-A1 while inhibiting root growth genes like TaSH15-B1 and TaWRKY70-B1 under short-term PEG stimulus. The distinct transcriptional regulation of TabHLH27-A1 involved diverse interacting factors such as TaABI3-D1 and TabZIP62-D1. Natural variations of TabHLH27-A1 influences its transcriptional responses to drought stress, with TabHLH27-A1Hap-II associated with stronger drought tolerance, larger root system, more spikelets, and higher WUE in wheat. Significantly, the elite TabHLH27-A1Hap-II was selected during the breeding process in China, and introgression of TabHLH27-A1Hap-II allele improves drought tolerance and grain yield, especially under water-limited conditions. Our study highlights TabHLH27-A1s role in balancing root growth and drought tolerance, providing a genetic manipulation locus for enhancing WUE in wheat.

genetics↗
bioRxiv2024

Targeted NAD+ Delivery for Intimal Hyperplasia and Re-endothelialization: A Novel Anti-restenotic Therapy Approach

Endovascular interventions often fail due to restenosis, primarily caused by smooth muscle cell (SMC) proliferation, leading to intimal hyperplasia (IH). Current strategies to prevent restenosis are far from perfect and impose significant collateral damage on the fragile endothelial cell (EC), causing profound thrombotic risks. Nicotinamide adenine dinucleotide (NAD+) is a co-enzyme and signaling substrate implicated in redox and metabolic homeostasis, with a pleiotropic role in protecting against cardiovascular diseases. However, a functional link between NAD+ repletion and the delicate duo of IH and EC regeneration has yet to be established. NAD+ repletion has been historically challenging due to its poor cellular uptake and low bioavailability. We have recently invented the first nanocarrier that enables direct intracellular delivery of NAD+ in vivo. Combining the merits of this prototypic NAD+-loaded calcium phosphate (CaP) nanoparticle (NP) and biomimetic surface functionalization, we created a biomimetic P-NAD+-NP with platelet membrane coating, which enabled an injectable modality that targets IH with excellent biocompatibility. Using human cell primary culture, we demonstrated the benefits of NP-assisted NAD+ repletion in selectively inhibiting the excessive proliferation of aortic SMC, while differentially protecting aortic EC from apoptosis. Moreover, in a rat balloon angioplasty model, a single-dose treatment with intravenously injected P-NAD+-NP immediately post angioplasty not only mitigated IH, but also accelerated the regeneration of EC (re-endothelialization) in vivo in comparison to control groups (i.e., saline, free NAD+ solution, empty CaP-NP). Collectively, our current study provides proof-of-concept evidence supporting the role of targeted NAD+ repletion nanotherapy in managing restenosis and improving re-endothelialization.

pathology↗
bioRxiv2023

INHBA/Activin A promotes tumor growth and induces resistance to anti-PD-L1 therapy by suppressing IFN-γ signaling

Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, respectively, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. As evidenced by our RNA-Seq and in vitro results, the interferon-{gamma} (IFN-{gamma}) signaling pathway was significantly down-regulated by tumor intrinsic activin A. Tumor INHBA deficiency led to lower expression of PD-L1 induced by IFN-{gamma}, resulting in poor responsiveness to anti-PD-L1 therapy. On the other hand, decreased secretion of IFN-{gamma}-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment. Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy. Our findings reveal that INHBA/activin A is involved in anti-tumor immunity by inhibiting the IFN-{gamma} signaling pathway and considered to be a potential target to overcome anti-PD-L1 resistance in clinical cancer treatment.

immunology↗
bioRxiv2023

Assessment of the macrovascular contribution to resting-state fMRI functional connectivity at 3 Tesla

In resting-state functional magnetic resonance imaging (rs-fMRI) functional connectivity (FC) mapping, temporal correlation are widely assumed to reflect synchronized neural-related activaty. Although a large number of studies have demonstrated the potential vascular effects on FC, little research has been conducted on FC resulting from macrovascular signal fluctuations. Previously, Tong et al. found (Tong et al., 2019b) a robust anti-correlation between the fMRI signals in the internal carotid artery and the internal jugular vein (and the sagittal sinus). The present study extends the previous study to include all detectable major veins and arteries in the brain in a systematic analysis of the macrovascular contribution to the functional connectivity of the whole-GM. This study demonstrates that: 1) The macrovasculature consistently exhibited strong correlational connectivity among itself, with the sign of the correlations varying between arterial and venous connectivity; 2) GM connectivity was found to have a strong macrovascular contribution, stronger from veins than arteries; 3) functional connectivity originating from the macrovasculature displayed disproportionately high spatial variability compared to across all GM voxels; 4) macrovascular contributions to connectivity were still evident well beyond the confines of the macrovascular space. These findings highlight the extensive contribution to rs-fMRI BOLD and FC predominantly by large veins, but also by large arteries. These findings pave the way for future studies aimed at more comprehensively modeling and thereby removing these macrovascular contributions.

biophysics↗