Biology subjects

Cui, Y.

Publications and source records attributed to Cui, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2022

Macaque Brainnetome Atlas with Fine-grained Parcellations and Reliable Connections

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas that identifies anatomically and functionally distinct regions is fundamental to biomedical and evolutionary research. However, even though connectivity information is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were comprehensively evaluated with multi-contrast MRI, invasive neuronal-tracing, and Nissl-stained images collected from a single subject and with open-access datasets from other cohorts. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, block-face, and section images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

neuroscience↗

bioRxiv2022

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors

Cells selectively remove damaged or excessive mitochondria through mitophagy, a specialized form of autophagy, to maintain mitochondrial quality and quantity. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation, and mitochondrial damage. However, the mechanisms by which cells remove specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F-box protein ubiquitin ligase complex, localizes to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that, unlike wild-type FBXL4, pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13), do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism that actively suppresses mitophagy via preventing NIX and BNIP3 accumulation and propose that excessive basal mitophagy in the FBXL4-associated mtDNA depletion syndrome is caused by dysregulation of NIX and BNIP3 turnover. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/511867v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c97f6org.highwire.dtl.DTLVardef@1bca5a3org.highwire.dtl.DTLVardef@1e9419org.highwire.dtl.DTLVardef@18d28a9_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Deep transfer learning provides a Pareto improvement for multiethnic genomic prediction of diseases

Accurate genomic predisposition assessment is essential for the prevention and early detection of diseases. Polygenic scores and machine learning models have been developed for disease prediction based on genetic variants and other risk factors. However, over 80% of existing genomic data were acquired from individuals of European descent. As a result, clinico-genomic risk prediction is less accurate for non-European populations. Here we employ a transfer learning strategy to improve the clinico-genomic prediction of disease occurrence for the data-disadvantaged populations. Our multi-ancestral machine learning experiments on clinico-genomic datasets of cancers and Alzheimers disease and synthetic datasets with built-in data inequality and subpopulation shift show that transfer learning can significantly improve disease prediction accuracy for data-disadvantaged populations. Under the transfer learning scheme, the prediction accuracy for the data-disadvantaged populations can be improved without compromising the prediction accuracy for other populations. Therefore, transfer learning provides a Pareto improvement toward equitable machine learning for genomic medicine.

bioinformatics↗

bioRxiv2022

Genetic, clinical underpinnings of subtle early brain change along Alzheimer's dimensions

Alzheimers disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE {varepsilon}4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE {varepsilon}4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction - driven by genes different from APOE - which may collectively contribute to the early pathogenesis of AD.

bioengineering↗

bioRxiv2022

Endogenous Plasmids and Reductive Genome Evolution in Host-Associated Bacteria

Reductive genome evolution is commonly observed among host-associated bacteria including many important pathogens, such as Mycobacterium leprae but its molecular mechanism is not well understood 1-5. One of the most widely accepted hypotheses to explain bacterial genome reduction is Mullers ratchet, in which the associated bacteria tend to accumulate deleterious mutations for reduction in the absence of chromosomal recombination inside the eukaryotic host organism 1,2. Cardinium species belong to the family Amoebophilaceae of the CFB group bacteria, which are a group of endosymbiont bacteria widely distributed among arthropods, that along with Wolbachia can cause cytoplasmic incompatibility 6,7. In this study, we explored bacterial reductive evolution within the de novo assembled genomes of Cardinium endosymbionts in two astigmatic mites 8,9. Our results shed light on the reduction mechanism driven by endogenous plasmids and their encoded enzymes.

microbiology↗

bioRxiv2022

Asymmetric Reconstruction of the Aquareovirus Core at Near-Atomic Resolution and Mechanism of Transcriptional Initiation

The Reoviridae family of dsRNA viruses is characterized by its members capacity for endogenous transcription of their multipartite genomes within proteinaceous capsids of 1 to 3 layers. These viruses share inner core particles (ICPs) that conform to icosahedral, T=2*, symmetry, but differ in two major respects: first, the presence or absence of RNA-capping turrets at each icosahedral vertex; second, the number of additional host-specific capsid layers that are often lost upon cell entry. While the role of these additional layers in host infection is generally understood, the absence of asymmetric ICP structures from turreted, multilayered reoviruses has obfuscated our understanding of how successive removal of these external layers impact the structural organization of the ICP and transcription initiation. Here, we present the 3.3 [A] resolution structure of the aquareovirus (ARV) ICP, and atomic models of the capsid proteins VP3 and VP6, transcriptional enzymatic complex (TEC) subunits VP2 and VP4, and RNA-capping turret protein VP1. These structures reveal significant differences when compared to those of the coated ARV, as well as their counterparts in single-layered cytoplasmic polyhedrosis virus (CPV). Compared to the double-layered ARV virion and infectious subvirion particle structures, the ARV ICP undergoes significant capsid expansion and widening of the nucleotide processing channels in its TEC and turret. Thus, the loss of outer capsid layers may regulate transcription initiation in ARV, unlike CPV which relies solely on allosteric regulation by binding transcriptional cofactors. These results shed new light on the mechanism of transcription initiation amongst turreted, multilayered members of Reoviridae.

molecular biology↗

bioRxiv2022

A lone spike in blood glucose can enhance the thrombo-inflammatory response in cortical venules

How transient hyperglycemia contributes to cerebro-vascular disease has been a challenge to study under controlled conditions. We present an approach to model luminal vessel thrombo-inflammation using amplified, ultrashort laser-pulses to physically disrupt brain-venule endothelium. Vessel disruption in conjunction with transient hyperglycemia from a single injection of metabolically active D-glucose results in real-time responses to venule damage that include rapid serum extravasation, platelet aggregation, and neutrophil recruitment, in normal mice. In contrast, vessel thrombo-inflammation following laser-induced vessel disruption is significantly reduced in mice injected with metabolically inert L-glucose. Thrombo-inflammation is pharmacologically ameliorated by a platelet inhibitor, by a scavenger of reactive oxygen species, or by a nitric oxide donor. For comparison, in diabetic mice injured vessel thrombo-inflammatory responses are also reduced by restoration of normo-glycemia. Our approach provides a controlled method to probe synergies of transient metabolic and physical vascular perturbations and reveals new aspects of brain pathophysiology.

neuroscience↗

bioRxiv2022

Neutralization of Omicron BA.4/BA.5 and BA.2.75 by Booster Vaccination or BA.2 Breakthrough Infection Sera

Many new Omicron sub-lineages have been reported to evade neutralizing antibody response, including BA.2, BA.2.12.1, BA.4 and BA.5. Most recently, another emerging sub-lineage BA.2.75 has been reported in multiple countries. In this study, we constructed a comprehensive panel of pseudoviruses (PsVs), including wild-type, Delta, BA.1, BA.1.1, BA.2, BA.3, BA.2.3.1, BA.2.10.1, BA.2.12.1, BA.2.13, BA.2.75 and BA.4/BA.5, with accumulate coverage reached 91% according to the proportion of sequences deposited in GISAID database since Jan 1st, 2022. We collected serum samples from healthy adults at day14 post homologous booster with BBIBP-CorV, or heterologous booster with ZF2001, primed with two doses of BBIBP-CorV, or from convalescents immunized with three-dose inactivated vaccines prior to infection with Omicron BA.2, and tested their neutralization activity on this panel of PsVs. Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection could remarkably elevated neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages.

immunology↗

bioRxiv2022

A Multifunctional Anchor for Multimodal Expansion Microscopy

In situ imaging of biomolecular location with nanoscale resolution enables mapping of the building blocks of life throughout biological systems in normal and disease states. Expansion microscopy (ExM), by physically enlarging specimens in an isotropic fashion, enables nanoimaging on standard light microscopes. Key to ExM is the equipping of different kinds of molecule, with different kinds of anchoring moiety, so they can all be pulled apart by polymer swelling. Here we present a multifunctional anchor, an acrylate epoxide, that enables multiple kinds of molecules (e.g., proteins and RNAs) to be equipped with anchors in a single experimental step. This reagent simplifies ExM protocols and greatly reduces cost (by 2-10 fold for a typical multiplexed ExM experiment) compared to previous strategies for equipping RNAs with anchors. We show that this unified ExM (uniExM) protocol can be used to preserve and visualize RNA transcripts, proteins in biologically relevant ultrastructure, and sets of RNA transcripts in patient-derived xenograft (PDX) cancer tissues, and can support the visualization of other kinds of biomolecular species as well. Thus, uniExM may find many uses in the simple, multimodal nanoscale analysis of cells and tissues.

bioengineering↗

bioRxiv2022

Thinking like a structural biologist: A pocket-based 3D molecule generative model fueled by electron density

We report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets including kinase (HPK1), protease (Covid19-3CL), and nuclear receptor (VDR), and evaluated with a reference dataset composed of over 8,000 compounds that have their activities reported in the literature. The evaluation examined the chemical validity, chemical space distribution-based diversity, and similarity with reference active compounds concerning the molecular structure and pocket-binding mode. Our model can reproduce classical active compounds and can also generate novel molecules with similar binding modes as active compounds, making it a promising tool for library generation supporting high-throughput virtual screening. Our model is available as an online service to academic users via https://edmg.stonewise.cn/#/create.

bioinformatics↗

bioRxiv2022

Single-Cell RNA-Seq Uncovers Dynamic Processes Orchestrated by RNA-Binding Protein DDX43 in Chromatin Remodeling during Spermiogenesis

Advances in single-cell RNA sequencing (scRNA-seq) have allowed for elucidating biological mechanisms at cell state level. Mammalian spermatogenic process showcases dynamic switches of gene expression pattern with delicate morphological and functional alterations of germ cells, but it is unclear how such dynamics is genetically controlled. Here we demonstrate that mouse testis-enriched RNA helicase DDX43, as well as its ATP hydrolysis site, is required for spermiogenesis. Genetic mutation of Ddx43 renders spermatids heterogeneously defective in multiple steps of chromatin remodeling, resulting in incomplete substitution of transition protein by protamine and less condensed sperm nucleus. Through scRNA-seq analyses of testicular cells derived from adult wild-type and Ddx43 mutant testes in mice, we reveal that the DDX43 deficiency-elicited perturbation in the dynamic RNA regulatory processes underlies the differentiation deficiency of spermatids. Further, focused analyses on early-stage spermatids combined with enhanced CLIP sequencing (eCLIP-seq) identify Elfn2 as DDX43-targeted hub gene, whose in vivo knockdown shows similar phenotypic defects as Ddx43 mutant. Our study illustrates an essential role for DDX43 in post-meiotic chromatin remodeling and highlights the single cell-based strategy for a refined dissection of stage-specific regulation of germline differentiation.

developmental biology↗

bioRxiv2022

Development and application of an uncapped mRNA platform

A novel uncapped mRNA platform was developed. Five lipid nanoparticle (LNP)-encapsulated mRNA constructs were made to evaluate several aspects of our platform, including transfection efficiency and durability in vitro and in vivo and the activation of humoral and cellular immunity in several animal models. The constructs were eGFP-mRNA-LNP (for enhanced green fluorescence mRNA), Fluc-mRNA-LNP (for firefly luciferase mRNA), S{delta}T-mRNA-LNP (for Delta strain SARS-CoV-2 spike protein trimer mRNA), gDED-mRNA-LNP (for truncated glycoprotein D mRNA coding ectodomain from herpes simplex virus type 2 (HSV2)) and gDFR-mRNA-LNP (for truncated HSV2 glycoprotein D mRNA coding amino acids 1[~]400). Quantifiable target protein expression was achieved in vitro and in vivo with eGFP-and Fluc-mRNA-LNP. S{delta}T-mRNA-LNP, gDED-mRNA-LNP and gDFR-mRNA-LNP induced both humoral and cellular immune responses comparable to those obtained by previously reported capped mRNA-LNP constructs. Notably, S{delta}T-mRNA-LNP elicited neutralizing antibodies in hamsters against the Omicron and Delta strains. Additionally, gDED-mRNA-LNP and gDFR-mRNA-LNP induced potent neutralizing antibodies in rabbits and mice. The mRNA constructs with uridine triphosphate (UTP) outperformed those with N1-methylpseudouridine triphosphate (N1m{psi}TP) in the induction of antibodies via S{delta}T-mRNA-LNP. Our uncapped, process-simplified, and economical mRNA platform may have broad utility in vaccines and protein replacement drugs.

bioengineering↗

bioRxiv2022

O-GlcNAc transferase contributes to sex-specific placental deregulation in gestational diabetes

Fetal sex has been known to be associated with differential risks for adverse perinatal outcomes. Recently it has been highlighted as a risk factor for gestational diabetes (GDM), which carries short- and long-term cardiometabolic implications for the pregnant women and their offspring. Understanding the molecular mechanisms through which fetal sex can modulate placenta physiology can help identify novel molecular targets for future clinical applications. In this study, we investigated the nutrient-sensing O-GlcNAc pathway as a potential mediator of sex-driven placenta dysfunction due to the unique location of the O-GlcNAc transferase (OGT) enzyme on the X chromosome. Using banked placenta tissues, we demonstrated that placenta OGT is downregulated in women with GDM, especially when carrying a male offspring. We modeled our observation in vitro using male placenta trophoblast BeWo cells in which OGT was knocked down. A comprehensive transcriptomic profile via RNA sequencing demonstrated changes in hormonal, inflammatory and immunologic markers, toward GDM-like transcriptional signatures. Altogether, this study suggests that OGT deserves important consideration for sexual dimorphism observed in GDM and highlights the importance of O-GlcNAcylation in placenta endocrine physiology.

biochemistry↗

bioRxiv2022

Microfluidic chemostatic bioreactor for high-throughput screening and sustainable co-harvesting of biomass and biodiesel in microalgae

As a renewable and sustainable source for energy, environment, and biomedical applications, microalgae and microalgal biodiesel have attracted great attention. However, their applications are confined due to the cost-efficiency of microalgal mass production. One-step strategy and continuous culturing systems could be solutions. However, current studies for optimization throughout microalgae-based biofuel production pipelines are generally derived from the batch culture process. Better tools are needed to study algal growth kinetics in continuous systems. A microfluidics chemostatic bioreactor array was presented, providing low-adhesion cultivation for algae in the gas, nutrition, and temperature (GNT) well-controlled environment with high throughput. The chip wasused to mimic the continuous culture environment of bioreactors. It allowed simultaneously studying of 8x8 different chemostatic conditions on algal growth and oil production in parallel on a 7x7 cm2 footprint. On-chip experiments of batch and continuous cultures of Chlorella. sp. were performed to study growth and lipid accumulation under different nitrogen concentrations. The results demonstrated that microalgal cultures can be regulated to grow and accumulate lipids concurrently, thus enhancing lipid productivity in one step. The developed on-chip culturing condition screening, which was more suitable for continuous bioreactor, was achieved at a half shorter time, 64-times higher throughput, and less reagent consumption. It could be used to establish chemostat cultures in continuous bioreactors which can dramatically accelerate the development of renewable and sustainable algal for CO2 fixation and biosynthesis and related systems for advanced sustainable energy, food, pharmacy, and agriculture with enormous social and ecological benefits. TEASERSustainable microfluidic bioreactor for 64 times higher-throughput screening CO2 fixation and biomass and biodiesel production in microalgae.

bioengineering↗

bioRxiv2022

Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace

Tissues are highly complicated with spatial heterogeneity in gene expression. However, the cutting-edge single-cell RNA-seq technology eliminates the spatial information of individual cells, which contributes to the characterization of cell identities. Herein, we propose single-cell spatial position associated co-embeddings (scSpace), an integrative algorithm to distinguish spatially variable cell subclusters by reconstructing cells onto a pseudo-space with spatial transcriptome references (Visium, STARmap, Slide-seq, etc.). We demonstrated that scSpace can define biologically meaningful cell subpopulations neglected by single-cell RNA-seq or spatially resolved transcriptomics. The use of scSpace to uncover the spatial association within single-cell data, reproduced, the hierarchical distribution of cells in the brain cortex and liver lobules, and the regional variation of cells in heart ventricles and the intestinal villus. scSpace identified cell subclusters in intratelencephalic neurons, which were confirmed by their biomarkers. The application of scSpace in melanoma and Covid-19 exhibited a broad prospect in the discovery of spatial therapeutic markers.

bioinformatics↗

bioRxiv2022

A microfluidic droplet array demonstrating high-throughput screening in individual lipid-producing microalgae

Microalgae are a group of photoautotrophic microorganisms which could use carbon dioxide for autosynthesis. They have been envisioned as one of the most prospective feedstock for renewable oil. However, great endeavors will still be needed to increase their economic feasibility; the screening of competitive species and suitable culture conditions are such issues. To greatly accelerate these rather laborious steps and also improve their experimental lump-sum-manner, we developed a microfluidic droplet-based 2x103 resolution "identification card", which allowed high throughput real-time monitoring of individual algae among population. A novel fluid-blocking-based droplet generating and trapping performance were integrated in the platform which made it excellent in operational simplicity, rapidity and stability and full of the potentials in single-cell-isolation/screening. The developed platform was successfully used to screen three unicellular algae, namely, Isochrysis zhanjiangensis, Platymonas subcordiformis and Platymonas helgolandica var. tsingtaoensis. In situ bioassays of the lipid accumulation and cell proliferation at single cell level for interspecies comparison were possible. Nitrogen stress condition can be indentified that induce positive-skewed frequency distribution of lipid content.

bioengineering↗

bioRxiv2022

The radio-protective effects of (-)-Epigallocatechin-3-gallate (EGCG): regulating macrophage function in radiation-induced intestinal injury.

Accidental and medical radiation exposure may cause radiation-induced intestinal injury (RIII), a catastrophic disease requiring efficient therapies. (-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea, has been shown to have potent biological activity as well as strong anti-inflammation effects. Here, we demonstrate that EGCG treatment not only protects mice against total body irradiation (TBI)-induced toxicity and weight loss but also alleviates whole abdominal irradiation (WAI)-induced intestinal injury. EGCG promotes proliferation and survival of intestinal stem cells, inhibits radiation-induced apoptosis and inflammation. At the same time, EGCG preserves the composition of the gut microbiota in WAI mice. In vitro, we demonstrate that EGCG regulates the release of radiation-induced inflammatory factors by inhibiting inflammatory pathways such as toll-like receptor signaling pathway in peritoneal macrophages. Mechanistically, the radioprotective effect of EGCG was likely attributable to its preservation on macrophages and the colonized gut microbiota composition, thus relieving the intestinal inflammation. EGCG provides a novel strategy to mitigate RIII and improve the prognosis of patients after radiotherapy.

cell biology↗

bioRxiv2022

Metformin decreases Cyp26a1 to prevent hepatocarcinogenesis through down- regulating CD8+ T cells

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, which limits the selectivity of prevention and treatment. Preclinical and clinical studies suggested that in patients with diabetes, prolonged use of metformin, the AMPK activator, was associated with a reduction of HCC incidence. This association promotes us to investigate the possible functions and mechanisms of metformin in HCC without diabetes backgrounds. Here, we found that several unique pathways that changed during chronic liver injury of Fah-/- mice, including glucose metabolic process and retinol metabolism. Further, metformin suppressed the tumor formation in chronic liver injury of Fah-/- mice. RNA sequencing, in vivo and in vitro experiments showed that metformin suppressed Cyp26a1 gene expression of hepatocyte. Moreover, the down-regulation of Cyp26a1 leads to the increased level of all-trans-retinoic acid (atRA), which could suppress the tumor formation in our model. On the other hand, flow multicolor analysis showed that the cell number and proportion of cancer promoting (pro-tumor) CD8+ T cells increased significantly during chronic liver injury in Fah-/- mice, and both metformin and atRA treatment could reduce the number and proportion of pro-tumor CD8+ T cells. We also found metformin decreased the Cyp26a1 expression through the AMPK/JNK/c-Jun pathway. In short, the association between the metformin and atRA may explain the commonness of their anti-tumor activities. Our findings highlight the importance of targeting the precancerous microenvironment for the prognosis, prevention and treatment of HCC.

cancer biology↗