Biology subjects

Yang, C.

Publications and source records attributed to Yang, C..

At least 253 records · Page 14Linked to original sources

bioRxiv2023

Integrin beta4 promotes DNA damage drug resistance in triple-negative breast cancer via TNFAIP2/IQGAP1/Rac1

Anti-tumor drug resistance is a challenge for human triple-negative breast cancer treatment. Our previous work demonstrated that TNFAIP2 activates RAC1 to promote triple-negative breast cancer cell proliferation and migration. However, the mechanism by which TNFAIP2 activates RAC1 is unknown. In this study, we found that TNFAIP2 interacts with IQGAP1 and Integrin {beta}4. Integrin {beta}4 activates RAC1 through TNFAIP2 and IQGAP1 and confers DNA damage-related drug resistance in triple-negative breast cancer. These results indicate that the Integrin {beta}4/TNFAIP2/IQGAP1/RAC1 axis provides potential therapeutic targets to overcome DNA damage-related drug resistance in triple-negative breast cancer.

cancer biology↗

bioRxiv2023

Progranulin inhibits phospholipase sPLA2-IIA to control neuroinflammation

Withdrawal StatementThe authors have withdrawn this manuscript because more work is needed to fully define the role of sPLA2-IIA. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗

bioRxiv2023

Characterization of mitotic phenotypes associated with a MYC synthetic lethal compound

Therapeutic targeting of MYC directly has proven difficult, but several means to target MYC indirectly using a synthetic lethal drug approach have been proposed. Synthetic lethal approaches for MYC have sought to take advantage of vulnerabilities MYC imposes related to either metabolic reprogramming, apoptotic signaling or the cycling of cancer cells. Here, we describe in detail the cell division phenotypes induced by a MYC synthetic lethal compound, dimethylfasudil (diMF). DiMF is a known ROCK inhibitor, but structurally related ROCK inhibitors are not synthetic lethal with MYC, so the activity of diMF is not related to blockade of this family of kinases. Instead, this compound induced multiple cell cycle-related liabilities. These included the early mitotic arrest of cycling cells followed by mitotic catastrophe-induced death and the induction of polyploidy in cells that do manage to pass through mitosis. As early as prometaphase, we noted diminished staining for BUB1 kinase, which binds to kinetochores and regulates the mitotic spindle checkpoint and chromosome congression. Kinetochore proteins, such as CENP-F, failed to localize at the metaphase plate, confirming a deficit in centromere assembly. This, presumably, contributed to the development of segregation anomalies in diMF-treated cells. In anaphase cells, the protein regulator of cytokinesis 1 (PRC1), failed to be recruited to the midzone, leading to a cascade of defects that included failed recruitment of the chromosomal passenger protein complex, the centralspindlin complex and polo-like-kinase 1 (PLK1). These observations correlate well with the cell death phenotypes induced by diMF, which may serve as a prototype MYC synthetic lethal compound to explore synthetic lethal therapy or as a scaffold upon which to build superior compounds. The phenotypes described here serve as examples of MYC synthetic lethal drug effects that can be used to explore and maximize drug discovery programs.

cancer biology↗

bioRxiv2023

XMAP: Cross-population fine-mapping by leveraging genetic diversity and accounting for confounding bias

Fine-mapping prioritizes risk variants identified by genome-wide association studies (GWASs), serving as a critical step to uncover biological mechanisms underlying complex traits. However, several major challenges still remain for existing fine-mapping methods. First, the strong linkage disequilibrium among variants can limit the statistical power and resolution of fine-mapping. Second, it is computationally expensive to simultaneously search for multiple causal variants. Third, the confounding bias hidden in GWAS summary statistics can produce spurious signals. To address these challenges, we develop a statistical method for cross-population fine-mapping (XMAP) by leveraging genetic diversity and accounting for confounding bias. By using cross-population GWAS summary statistics from global biobanks and genomic consortia, we show that XMAP can achieve greater statistical power, better control of false positive rate, and substantially higher computational efficiency for identifying multiple causal signals, compared to existing methods. Importantly, we show that the output of XMAP can be integrated with single-cell datasets, which greatly improves the interpretation of putative causal variants in their cellular context at single-cell resolution.

genetics↗

bioRxiv2023

High-level production of nervonic acid in the oleaginous yeast Yarrowia lipolytica by systematic metabolic engineering

Brain and neurological diseases are influencing more than one billion worlds people. Nervonic acid (cis-15-tetracosenoic acid, C24:1 {Delta}15) benefits the treatment of neurological diseases and the health of brain. Currently, the sources of nervonic acid are limited to the seeds of a couple of plants. In this study, we employed the oleaginous yeast Yarrowia lipolytica to overproduce nervonic acid oil by systematic metabolic engineering. First, engineering the fatty acid elongation (FAE) pathway by expressing a heterologous {beta}-ketoacyl-CoA synthase gene CgKCS enabled the production of nervonic acid in Y. lipolytica. Second, modulation of endogenous pathways by expressing a C16:0-acyl-CoA preferred fatty acid elongase gELOVL6 together with a C18:0-acyl-CoA preferred fatty acid desaturase MaOLE2 increased the content of nervonic acid in total fatty acids (TFA). Third, iterative expression of CgKCS, gELOVL6 and MaOLE2 at the genomic loci of rDNA, FAD2, TGL4, GSY1 and SNF1 dramatically improved the production of nervonic acid. Fourth, the biosynthesis of both nervonic acid and lipids were further enhanced by expression of the MaOLE2-CgKCS fusion protein and glycerol-3-phosphate acyltransferases (GPAT) and diacylglycerol acyltransferases (DGAT) from Malania oleifera in the endoplasmic reticulum (ER) membrane. Fifth, an ER structure regulator YlINO2 was identified in Y. lipolytica and the overexpression of YlINO2 led to a 39.3% increase in lipid production. Next, pilot-scale fermentation in 50-L reactor using the strain YLNA9 exhibited a lipid titer of 96.7 g/L and a nervonic acid titer of 17.3 g/L, the highest reported titer to date for de novo nervonic acid production. We also found that disruption of the AMP-activated S/T protein kinase SNF1 increased the ratio of nervonic acid (C24:1) to lignoceric acid (C24:0) by 61.6% and a ratio of 3.5:1 (nervonic acid to lignoceric acid) was achieved in the strain YLNA10. Finally, a proof-of-concept purification and separation of nervonic acid were performed and the purity of it reached 98.7%. This study suggested that oleaginous yeasts are attractive hosts for the cost-efficient production of nervonic acid and possibly other very long-chain fatty acids (VLCFAs).

bioengineering↗

bioRxiv2023

Multiple cancer types rapidly escape from multiple MAPK inhibitors to generate mutagenesis-prone subpopulations

Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway and many targeted inhibitors now exist for clinical use, but drug resistance remains a major issue. We recently showed that BRAF-driven melanoma cells treated with BRAF inhibitors can non-genetically adapt to drug within 3-4 days to escape quiescence and resume slow proliferation. Here we show that this phenomenon is not unique to melanomas treated with BRAF inhibitors but rather is widespread across many clinical MAPK inhibitors and cancer types driven by EGFR, KRAS, and BRAF mutations. In all treatment contexts examined, a subset of cells can escape drug-induced quiescence within four days to resume proliferation. These escapee cells broadly experience aberrant DNA replication, accumulate DNA lesions, spend longer in G2-M cell cycle phases, and mount an ATR-dependent stress response. We further identify the Fanconi anemia (FA) DNA repair pathway as critical for successful mitotic completion in escapees. Long-term cultures, patient samples, and clinical data demonstrate a broad dependency on ATR- and FA-mediated stress tolerance. Together, these results highlight the pervasiveness with which MAPK-mutant cancers are able to rapidly escape drug and the importance of suppressing early stress tolerance pathways to potentially achieve more durable clinical responses to targeted MAPK pathway inhibitors.

cancer biology↗

bioRxiv2023

SpatialScope: A unified approach for integrating spatial and single-cell transcriptomics data using deep generative models

The rapid emergence of spatial transcriptomics (ST) technologies are revolutionizing our under-standing of tissue spatial architecture and their biology. Current ST technologies based on either next generation sequencing (seq-based approaches) or fluorescence in situ hybridization (image-based approaches), while providing hugely informative insights, remain unable to provide spatial characterization at transcriptome-wide single-cell resolution, limiting their usage in resolving detailed tissue structure and detecting cellular communications. To overcome these limitations, we developed SpatialScope, a unified approach to integrating scRNA-seq reference data and ST data that leverages deep generative models. With innovation in model and algorithm designs, SpatialScope not only enhances seq-based ST data to achieve single-cell resolution, but also accurately infers transcriptome-wide expression levels for image-based ST data. We demonstrate the utility of SpatialScope through comprehensive simulation studies and then apply it to real data from both seq-based and image-based ST approaches. SpatialScope provides a spatial characterization of tissue structures at transcriptome-wide single-cell resolution, greatly facilitating the downstream analysis of ST data, such as detection of cellular communication by identifying ligand-receptor interactions from seq-based ST data, localization of cellular subtypes, and detection of spatially differently expressed genes.

bioinformatics↗

bioRxiv2023

Epithelial galectin-3 induces mitochondrial complex inhibition and cell cycle arrest of CD8+ T Cells in severe/critical ill COVID-19

Several studies have identified the presence of functionally depleted CD8+ T cells in COVID-19 patients, and particularly abnormally reduced CD8+ T cells in severe/critical patients, which may be a major cause of disease progression and poor prognosis. In this study, a proliferating-depleted CD8+ T cell phenotype was observed in severe/critical COVID-19 patients through scRNA-seq and scTCR-seq analysis. These CD8+ T cells were subsequently found to be characterized by cell cycle arrest and downregulation of mitochondrial biogenesis and respiratory chain complex genes. Cellchat analysis revealed that the Galectin signaling pathways between infected lung epithelial cells and CD8+ T cells play the key role in inducing CD8+ T cell reduction and dysfunction in severe/critical COVID-19. We used SARS-COV-2 ORF3a to transfect A549 epithelial cells, and co-cultured with CD8+ T cells. The ex vivo experiments confirmed that galectin-3 inhibited the transcription of mitochondrial respiratory chain complex III/IV genes in CD8+ T cells by suppressing the nuclear translocation of nuclear respiratory factor 1 (NRF1). In addition, the regulatory effect of galectin-3 was correlated with the activation of ERK signaling and/or the inhibition of Akt signaling. Galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, and enhanced mitochondrial respiratory chain complex III/IV gene expression and mitochondrial biogenesis, then restore the expansion ability of CD8+ T cells. Our study improved the understanding the immunopathogenesis and provided new target for the prevention and treatment of severe/critical COVID-19.

immunology↗

bioRxiv2023

Inhibition mechanism and antiviral activity of an α-ketoamide based SARS-CoV-2 main protease inhibitor

SARS-CoV-2 has demonstrated extraordinary ability to evade antibody immunity by antigenic drift. Small molecule drugs may provide effective therapy while being part of a solution to circumvent SARS-CoV-2 immune escape. In this study we report an -ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), RAY1216. Enzyme inhibition kinetic analysis established that RAY1216 is a slow-tight inhibitor with a Ki of 8.6 nM; RAY1216 has a drug-target residence time of 104 min compared to 9 min of PF-07321332 (nirmatrelvir), the antiviral component in Paxlovid, suggesting that RAY1216 is approximately 12 times slower to dissociate from the protease-inhibitor complex compared to PF-07321332. Crystal structure of SARS-CoV-2 Mpro:RAY1216 complex demonstrates that RAY1216 is covalently attached to the catalytic Cys145 through the -ketoamide warhead; more extensive interactions are identified between bound RAY1216 and Mpro active site compared to PF-07321332, consistent with a more stable acyl-enzyme inhibition complex for RAY1216. In cell culture and human ACE2 transgenic mouse models, RAY1216 demonstrates comparable antiviral activities towards different SARS-CoV-2 virus variants compared to PF-07321332. Improvement in pharmacokinetics has been observed for RAY1216 over PF-07321332 in various animal models, which may allow RAY1216 to be used without ritonavir. RAY1216 is currently undergoing phase III clinical trials (https://clinicaltrials.gov/ct2/show/NCT05620160) to test real-world therapeutic efficacy against COVID-19.

biochemistry↗

bioRxiv2023

Scalable Solar-Driven Chemical Production by Semiconductor Biohybrids Synthesized from Wastewater Pollutants

Semiconductors biohybrids integrate the best of biological catalysts and semiconductor nanomaterials for solar-to-chemical conversion. To realize the potential of hybrid systems at the commercial level, it remains an urgent need for cost-competitive and environmentally friendly approaches to scaling up. Here, we successfully tackle this challenge through developing biohybrid route that co-utilize multi-pollutants in wastewater to produce semiconductor biohybrids in-situ for solar-to-chemical production. To achieve cost-effective biohybrid production, we introduced an aerobic sulfate reduction pathway into Vibrio natriegens to enable the direct utilization of the heavy metal ions (i.e., Cd2+), sulfate, and organics in the wastewater to biosynthesize functional semiconductor nanoparticles in living V. natriegens. Furthermore, 2,3-butanediol biosynthetic pathway was introduced into the V. natriegens hybrid to couple the solar energy for enhanced bioproduction. We demonstrated the scalability of this system in a 5-L illuminated fermenter using wastewater as the feedstock, which resulted in production of 13 g/L of 2,3-butanediol. Life cycle analysis showed this specific biohybrid route had a significantly lower cost and reduced CO2 emission compared to both pure sugars fermentation and fossil-based routes. In addition to providing a promising step toward sustainable commercializing semiconductor biohybrids for biomanufacturing, our work may lead to hybrid living matter toward future waste to wealth conversion.

synthetic biology↗

bioRxiv2023

ABI5-FLZ13 Module Transcriptionally Represses Growth-related Genes to Delay Seed Germination in Response to ABA

The bZIP transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) is a master regulator determining seed germination and postgerminative growth in response to abscisic acid (ABA), but the detailed molecular mechanism underlying the repression function of ABI5 in plant growth remains to be characterized. In this study, we used proximity labeling (PL) to map the neighboring proteome of ABI5 and identified FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13) as an up-to-now unknown ABI5-interacting partner. Phenotypic analysis of flz13 mutants and FLZ13-overexpressing lines demonstrated that FLZ13 acts as a positive regulator of ABA signaling. Interestingly, transcriptomic analysis showed that ABI5 and FLZ13 co-downregulate the expression of ABA-repressed and growth-related genes involved in chlorophyll biosynthesis, photosynthesis and cell wall organization, thereby repressing seed germination and seedling establishment in response to ABA. Further genetic analysis proved that FLZ13 works synergistically with ABI5 to regulate seed germination. Collectively, our study reveals a previously uncharacterized transcriptional regulatory mechanism regarding ABA-inhibited seed germination and seedling establishment.

plant biology↗

bioRxiv2023

Construction of a 3D whole organism spatial atlas by joint modeling of multiple slices

Spatial transcriptomics (ST) technologies are revolutionizing the way that researchers explore the spatial architecture of tissues. Currently, ST data analysis is often restricted to 2D space within a single tissue slice, limiting our capacity to understand biological processes that take place in 3D space. Here, we present STitch3D, a unified computational framework that integrates multiple 2D tissue slices to reconstruct 3D cellular structures from the tissue level to the whole organism level. By jointly modeling multiple 2D tissue slices and integrating them with cell-type-specific expression profiles derived from single-cell RNA-sequencing data, STitch3D simultaneously identifies 3D spatial regions with coherent gene expression levels and reveals 3D distributions of cell types. STitch3D distinguishes biological variation among slices from batch effects, and effectively borrows shared information across slices to assemble powerful 3D models of tissues. Through comprehensive experiments using diverse datasets, we demonstrate the performance of STitch3D in building comprehensive 3D tissue architectures of the mouse brain, the human heart, and the Drosophila embryo, which allow 3D analysis in the entire tissue region or even the whole organism. To gain deeper biological insights, the outputs of STitch3D can be used for downstream tasks, such as inference of spatial trajectories, identification of spatially variable genes enriched in tissue regions or subregions, denoising or imputation of spatial gene expressions, as well as generation of virtual tissue slices.

bioinformatics↗

bioRxiv2023

An orally bioavailable 4-phenoxy-quinoline compound as a potent AURKB relocation blocker for cancer treatment

We investigated a novel 4-phenoxy-quinoline-based scaffold that mislocalizes the essential mitotic kinase, AURKB. Here, we evaluated the impact of halogen substitutions (F, Cl, Br, I) on this scaffold with respect to various drug parameters. Br-substituted LXY18 was found to be a potent and orally bioavailable disruptor of cell division, at sub-nanomolar concentrations. LXY18 prevents cytokinesis by blocking AURKB relocalization in mitosis and exhibits broad-spectrum antimitotic activity in vitro. With a favorable PK profile, it shows widespread tissue distribution including the blood-brain barrier penetrance and effective accumulation in tumor tissues. More importantly, it markedly suppresses tumor growth. The novel mode of action of LXY18 may eliminate some drawbacks of direct catalytic inhibition of AURKs. Successful development of LXY18 as a clinical candidate for cancer treatment could enable a new, less toxic means of antimitotic attack that avoids drug resistance mechanisms.

cancer biology↗

bioRxiv2023

Endogenous inflammatory mediators produced by injury activate TRPV1 and TRPA1 nociceptors to induce sexually dimorphic cold pain that is dependent on TRPM8 and GFRalpha3

The detection of environmental temperatures is critical for survival, yet inappropriate responses to thermal stimuli can have a negative impact on overall health. The physiological effect of cold is distinct among somatosensory modalities in that it is soothing and analgesic, but also agonizing in the context of tissue damage. Inflammatory mediators produced during injury activate nociceptors to release neuropeptides, such as CGRP and substance P, inducing neurogenic inflammation which further exasperates pain. Many inflammatory mediators induce sensitization to heat and mechanical stimuli but, conversely, inhibit cold responsiveness, and the identity of molecules inducing cold pain peripherally is enigmatic, as are the cellular and molecular mechanisms altering cold sensitivity. Here, we asked if inflammatory mediators that induce neurogenic inflammation via the nociceptive ion channels TRPV1 and TRPA1 lead to cold pain in mice. Specifically, we tested cold sensitivity in mice after intraplantar injection of lysophosphatidic acid (LPA) or 4-hydroxy-2-nonenal (4HNE), finding each induces cold pain that is dependent on the cold-gated channel TRPM8. Inhibition of either CGRP, substance P, or toll-like receptor 4 (TLR4) signaling attenuates this phenotype, and each neuropeptide produces TRPM8-dependent cold pain directly. Further, the inhibition of CGRP or TLR4 signaling alleviates cold allodynia differentially by sex. Lastly, we find that cold pain induced by inflammatory mediators and neuropeptides requires the neurotrophin artemin and its receptor GFR3. These results demonstrate that tissue damage alters cold sensitivity via neurogenic inflammation, likely leading to localized artemin release that induces cold pain via GFR3 and TRPM8. Significance StatementThe cellular and molecular mechanisms that generate pain are complex with a diverse array of pain-producing molecules generated during injury that act to sensitize peripheral sensory neurons, thereby inducing pain. Here we identify a specific neuroinflammatory pathway involving the ion channel TRPM8 and the neurotrophin receptor GFR3 that leads to cold pain, providing select targets for potential therapies for this pain modality.

neuroscience↗

bioRxiv2023

The effects of excess salt intake on the kidney metabolism in Sprague-Dawley rats

In the present study, novel methods were developed which allowed continuous (24/7) measurement of blood pressure (BP) and renal blood flow (RBF) in freely moving rats and the intermittent collection of arterial and renal venous blood to estimate kidney metabolic fluxes of O2 and metabolites. The study determined the effects of a high salt (HS) diet upon whole kidney O2 consumption and the metabolomic profiles of normal Sprague Dawley (SD) rats. A separate group of rats was studied to determine changes in the cortex (Cx) and outer medulla (OM) tissue metabolomic and mRNAseq profiles before and following the switch from a 0.4% to a 4.0% NaCl diet. Significant changes in the metabolomic and transcriptomic profiles occurred with feeding of the HS diet. A progressive increase of kidney O2 consumption was found despite a reduction in expression of most of the mRNA encoding enzymes of TCA cycle. Increased glycolysis was evident with the elevation of mRNA expression encoding key glycolytic enzymes and release of pyruvate and lactate from the kidney in the renal venous blood. Glycolytic production of NADH is used in either the production of lactate or oxidized via the malate aspartate shuttle. Aerobic glycolysis (e.g., Warburg-effect) may account for the needed increase in cellular energy. The study provides evidence that kidney metabolism responds to a HS diet enabling enhanced energy production while protecting from oxidate stress and injury.

physiology↗

bioRxiv2022

A unified classification system for HIV-1 5' long terminal repeats

The HIV-1 provirus mainly consists of internal coding region flanked by the 2 same long terminal repeats (LTRs) at each terminus. The LTRs play important roles in HIV-1 reverse transcription, integration, and transcription by the association with host factors. However, despite of the significant study advances of the internal coding regions of HIV-1 by using definite reference classification, there are no systematic classifications for HIV-1 5 LTRs, which hinders our elaboration on 5 LTR and a better understanding of the viral origin, spread and therapy. Here, by analyzing all available resources of 5 LTR sequences in public databases following 4 recognized principles for the reference classification, 83 representatives and 14 consensus sequences were identified as representatives of 2 groups, 6 subtypes, 6 sub-subtypes, and 9 CRFs. To test the reliability of our established classification system, the constructed references were applied to identify the 5 LTR assignment of the 22 clinical isolates in China. The results revealed that 16 out of 22 tested strains showed a consistent subtype classification with the previous LTR-independent classification system. However, 6 strains, for which recombination events within 5 LTR were demonstrated, unexpectedly showed a different subtype classification, leading a significant change of binding sites for important transcription factors including SP1, p53, and NF-{kappa}B. The binding change of these transcriptional factors would probably affect the transcriptional activity of 5 LTR. This study established a unified classification system for HIV-1 5 LTRs, which will facilitate HIV-1 characterization and be helpful for both basic and clinical research fields. IMPORTANCEHere, a scientific, reliable, and usable classification system based on the 5 LTR sequences was established, which will allow us to effectively facilitate the precise typing of HIV-1 strains. This classification system was applied to 22 HIV-1 strains circulating in China, we found that 6 out of 22 strains analyzed, belonged to a different subtype when our results were compared to those obtained with the previous LTR-independent classification system. Thus, these data demonstrated that our classification method could greatly improve the HIV-1 subtype classification. We found that 6 5 LTR sequences showed recombination events, leading to a significant exchange of the binding sites of transcriptional factors. Thus, this work established a comprehensive HIV-1 5 LTR classification system, which will help the scientific community to precisely characterize HIV-1 variants, and better understand the origin and spread of HIV-1 strains, and it also may be helpful for pathogenicity and transmissibility evaluation studies.

microbiology↗

bioRxiv2022

Running ahead of evolution - AI based simulation for predicting future high-risk SARS-CoV-2 variants

The never-ending emergence of SARS-CoV-2 variations of concern (VOCs) has challenged the whole world for pandemic control. In order to develop effective drugs and vaccines, one needs to efficiently simulate SARS-CoV-2 spike receptor binding domain (RBD) mutations and identify high-risk variants. We pretrain a large protein language model with approximately 408 million protein sequences and construct a high-throughput screening for the prediction of binding affinity and antibody escape. As the first work on SARS-CoV-2 RBD mutation simulation, we successfully identify mutations in the RBD regions of 5 VOCs and can screen millions of potential variants in seconds. Our workflow scales to 4096 NPUs with 96.5% scalability and 493.9x speedup in mixed precision computing, while achieving a peak performance of 366.8 PFLOPS (reaching 34.9% theoretical peak) on Pengcheng Cloudbrain-II. Our method paves the way for simulating coronavirus evolution in order to prepare for a future pandemic that will inevitably take place. Our models are released at https://github.com/ZhiweiNiepku/SARS-CoV-2_mutation_simulation to facilitate future related work. JustificationWe develop a novel multi-constraint variation prediction framework to simulate SARS-CoV-2 RBD mutations, reaching a peak performance of 366.8 PFLOPS with 96.5% scalability and achieving 493.9x speedup. Our method facilitates the prediction and prioritization of future high-risk variants for the early deployment of drugs and vaccines. Performance attributes O_TBL View this table: org.highwire.dtl.DTLVardef@1b1873aorg.highwire.dtl.DTLVardef@25314eorg.highwire.dtl.DTLVardef@1c80130org.highwire.dtl.DTLVardef@1c61b21org.highwire.dtl.DTLVardef@11f21c5_HPS_FORMAT_FIGEXP M_TBL C_TBL Overview of the problemCoronavirus Disease 2019 (COVID-19) has spread rapidly to more than 200 countries or regions since December 2019. Due to its high infectivity, there have been over 645 million confirmed cases, including approximately 6.6 million deaths, reported by the World Health Organization (WHO) as of December 20221. In addition to being a serious threat to human health, COVID-19 has had a catastrophic impact on the global economy.

bioinformatics↗

bioRxiv2022

Regulation of adventitial interstitial fluid circulation by heartbeat and respiration

Converging studies showed interstitial fluid (ISF) adjacent to blood vessels flows along adventitia of vasculature into heart and lungs. We aim to reveal circulatory pathways and regulatory mechanism of such adventitial ISF flow in rat model. By MRI, real-time fluorescent imaging, micro-CT and histological analysis, ISF was found to flow in adventitial matrix surrounded by fascia and along systemic vessels into heart, then flow into lungs via pulmonary arteries and back to heart via pulmonary veins, which was neither perivascular tissues nor blood or lymphatic vessels. Under physiological conditions, speckle-like adventitial ISF flow rate was positively correlated with heart rate, increased when holding breath, became pulsative during heavy breathing. During cardiac or respiratory cycle, each dilation or contraction of heart or lungs can generate to-and-fro adventitial ISF flow along femoral veins. Discovered regulatory mechanisms of adventitial ISF flow along vasculature by heart and lungs will revolutionize understanding of cardiovascular system. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/512678v3_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@1d29c16org.highwire.dtl.DTLVardef@583f5org.highwire.dtl.DTLVardef@1a551eorg.highwire.dtl.DTLVardef@ca4780_HPS_FORMAT_FIGEXP M_FIG Graphic abstract of adventitial interstitial fluid cycle by heartbeat and respiration.The heart and lungs can work together to regulate the ISF (green arrow) adjacent to blood vessels to flow centripetally in an adventitial pathway along the major arteries and veins of the systemic vasculature to the epicardium and myocardium, then flow into the lungs via the pulmonary arteries and back to the heart via the pulmonary veins, forming an adventitial ISF circulatory network. Under physiological conditions, the speckle-like adventitial ISF flow rate was positively correlated with heart rate, increased when holding breath, and became pulsative during heavy breathing. During respiratory cycle, each expansion of the lungs during inflation generates a centrifugal flow of adventitial ISF along the systemic veins, while each contraction of the lungs during deflation generates a centripetal adventitial ISF flow. During cardiac cycle, each dilation of atria or ventricles generates a centripetal flow of adventitial ISF along the systemic veins, while each contraction of atria or ventricles generates a centrifugal adventitial ISF flow. C_FIG

physiology↗