Biology subjects

Yao, M.

Publications and source records attributed to Yao, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Discovery of a Novel Chemotype as DYRK1A Inhibitors against Alzheimer's disease: Computational Modeling and Biological Evaluation

Dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) plays an essential role in tau and A{beta} pathology closely related to Alzheimers disease (AD). Accumulative evidence has demonstrated DYRK1A inhibition is able to reduce the pathological features of AD. Nevertheless, there is no approved DYRK1A inhibitors for clinical use as anti-AD drugs. This is somewhat the lack of effective and safe chemotypes of DYRK1A inhibitors. To address this issue, we carried out in silico screening, in vitro assays and in vivo efficacy evaluation with the aim to discover a new class of DYRK1A inhibitors for potential treatment of AD. By in silico screening, we selected and purchased 16 potential DYRK1A inhibitors from the Specs chemical library. Among them, compound Q17 (Specs ID: AO-476/40829177) potently inhibited DYRK1A. The hydrogen bonds between compound Q17 and each of three amino acid residues named GLU239, LEU241 and LYS188, were uncovered by molecular docking and molecular dynamics simulation. The cell-based assays showed that compound Q17 could protect SH-SY5Y cells from okadaic acid (OA)-induced injury by targeting DYRK1A. More importantly, compound Q17 significantly improved cognitive dysfunction in 3xTg-AD mice, ameliorated pathological changes, and reduced the expression of DYRK1A, GSK-3{beta} and GSK-3{beta} (pSer9), attenuated tau hyperphosphorylation and A{beta} deposition as well. In summary, our computational modeling strategy is effective to identify novel chemotypes of DYRK1A inhibitors with great potential to treat AD, and the identified compound Q17 in this study is worthy of further study. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/565431v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@75abecorg.highwire.dtl.DTLVardef@16a3611org.highwire.dtl.DTLVardef@39aeborg.highwire.dtl.DTLVardef@afc8ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

The role of immune inflammatory response and inflammatory infiltrates in major depression disorder and atopic dermatitis: new insights from machine learning

BackgroundMajor depression disorder (MDD) and atopic dermatitis (AD) are distinct disorders involving immune inflammatory responses. This study aimed to investigate the comorbid relationship between AD and MDD and to identify possible common mechanisms. MethodsWe obtained AD and MDD data from the Gene Expression Omnibus (GEO) database. Differential expression analysis and the Genecard database were employed to identify shared genes associated with inflammatory diseases. These shared genes were then subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Hub genes were selected based on the protein-protein interactions using CytoHubba, and key regulatory genes were identified through enrichment analysis. Subsequently, we conducted immune infiltration and correlation analyses of the shared genes in AD. Finally, we employed three machine learning models to predict the significance of shared genes. ResultsA total of 17 shared genes were identified in the AD_Inflammatory_MDD dataset (S100A9, PTGER2, PI3, SNCA, DAB2, PDGFA, FSTL1, CALD1, XK, UTS2, DHRS9, PARD3, NFIB,TMEM158, LIPH, RAB27B, and SH3BRL2). These genes were associated with biological processes such as the regulation of mesenchymal cell proliferation, mesenchymal cell proliferation, and glial cell differentiation. The neuroactive ligand-receptor interaction, IL-17 signaling, and Rap1 signaling pathways were significantly enriched in KEGG analysis. SNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as hub genes contributing to comorbid AD and MDD development. The three machine learning models consistently identified SNCA and PARD3 as important biomarkers. ConclusionSNCA, S100A9, SH3BGRL2, RAB27B, TMEM158, DAB2, FSTL1, CALD1, and XK were identified as significant genes contributing to the development of AD and MDD comorbidities. Immune infiltration analysis showed a notable increase in the infiltration of various subtypes of CD4+ T cells, suggesting a potential association between the development of skin inflammation and the immune response. Across different machine learning models, SNCA and PARD3 consistently emerged as important biomarkers.

genetics↗

bioRxiv2023

Elasticity of adhesion bonds determines multistable mechanosensitive behaviour of living cells.

The ability of cells to sense the mechanical properties of their microenvironment is essential to many physiological processes. The molecular clutch theory has played an important role in explaining many mechanosensitive cell behaviors. However, its current implementations have limited ability to understand how molecular heterogeneity, such as adhesion molecules with different elasticities, regulates the mechanical response of cell adhesion. In this study, we developed a model incorporating the experimentally measured elastic properties of such proteins to investigate their influence on cell adhesion. It was found that the model not only could accurately fit previous experimental measurements of cell traction force and retrograde actin flow, but also predicted multistablility of cell adhesion as well as a feedback loop between the densities of the extracellular matrix proteins and contractile myosin II motors in living cells. The existence of such a feedback loop was successfully confirmed in experiments. Taken together, our study provides a theoretical framework for understanding how the mechanical properties of adaptor proteins, local substrate deformations and myosin II contractility affect cell adhesion across different cell types and physiological conditions.

biophysics↗

bioRxiv2023

In-situ Single-Molecule Investigations of the Impacts of Biochemical Perturbations on Conformational Intermediates of Monomeric α-Synuclein

-Synuclein aggregation is a common trait in synucleinopathies, including Parkinsons disease. Being an unstructured protein, -synuclein exists in several distinct conformational intermediates, contributing to both its function and pathogenesis. However, the regulation of these monomer conformations by biochemical factors and potential drugs has remained elusive. In this study, we devised an in-situ single-molecule manipulation approach to pinpoint kinetically stable conformational intermediates of monomeric -synuclein and explore the effects of various biochemical factors and drugs. We uncovered a partially folded conformation located in the non-amyloid-{beta} component (NAC) region of monomeric -synuclein, which is regulated by preNAC region. This conformational intermediate is sensitive to biochemical perturbations and small-molecule drugs that influencing -synucleins aggregation tendency. Our findings reveal that this partially folded intermediate may play a role in -synuclein aggregation, offering fresh perspectives for potential treatments aimed at the initial stage of higher-order -synuclein aggregation. The single-molecule approach developed here can be broadly applied to the study of disease-related intrinsically disordered proteins.

biophysics↗

bioRxiv2023

Structural basis of EHEP-mediated offense against phlorotannin-induced defense from brown algae to protect akuBGL activity

The defensive-offensive associations between algae and herbivores determine marine ecology. Brown algae utilize phlorotannin as their chemical defense against the predator Aplysia kurodai, which uses {beta}-glucosidase (akuBGL) to digest the laminarin in algae to glucose. Moreover, A. kurodai employs Eisenia hydrolysis-enhancing protein (EHEP) as an offense to protect akuBGL activity from phlorotannin inhibition by precipitating phlorotannin. To underpin the molecular mechanism of this digestive-defensive-offensive system, we determined the structures of apo and tannic-acid (TNA, a phlorotannin-analog) bound form of EHEP, as well as apo akuBGL. EHEP consisted of three peritrophin-A domains formed in a triangle and bound TNA in the center without significant conformational changes. Structural comparison between EHEP and EHEP-TNA led us to find that EHEP can be resolubilized from phlorotannin-precipitation at an alkaline pH, which reflects a requirement in the digestive tract. akuBGL contained two GH1 domains, only one of which conserved the active site. Combining docking analysis, we propose the mechanisms by which phlorotannin inhibits akuBGL by occupying the substrate-binding pocket, and EHEP protects akuBGL against the inhibition by binding with phlorotannin to free the akuBGL pocket.

biochemistry↗

bioRxiv2023

The mechanical response of vinculin

Vinculin is a mechanosensitive adapter protein that links the actin network to cell-extracellular matrix adhesions and cell-cell adhesions. It is perhaps the best characterized mechanoeffector, as it is recruited to sites of adhesion in response to force on the mechanotransducers talin and alpha-catenin. Here we examined the mechanical properties of vinculin to assess its potential role as a mechanotransducer. We find that at physiological loading rates, the structural domains of vinculin unfold at forces in the 5-15 pN range and rapidly refold when forces are reduced back to 1 pN. Thus, vinculin domains also have the potential to act as force dependent molecular switches, akin to those in talin and alpha-catenin. As with the force dependent switches in talin, the unfolding of these domains in vinculin introduces large extension changes in the vinculin cytoskeletal linkage up to 150 nm with 20-30 nm steps of unfolding. Modelling of the tension-dependent interactions of the unstructured vinculin linker region with a model protein containing two SH3 domains indicated that even unstructured protein regions can mediate force-dependent interactions with ligands, where the binding of a dual-SH3 model protein is predicted to be significantly suppressed by forces greater than 10 pN. Together, these findings suggest that vinculin has a complex mechanical response with force-dependent interaction sites, suggesting it also acts as a mechanotransducer, recruiting partners in response to force.

biophysics↗

bioRxiv2023

Engrailed-1 Promotes Pancreatic Cancer Metastasis

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

cancer biology↗

bioRxiv2023

MORE IS DIFFERENT: DRUG PROPERTY ANALYSIS ON CELLULAR HIGH-CONTENT IMAGES USING DEEP LEARNING

High-content analysis (HCA) holds enormous potential for drug discovery and research, but widely used methods can be cumbersome and yield inaccurate results. Noise and high similarity in cell images impede the accuracy of deep learning-based image analysis. To address these issues, we introduce More Is Different (MID), a novel HCA method that combines cellular experiments, image processing, and deep learning modeling. MID effectively combines the convolutional neural network and Transformer to encode high-content images, effectively filtering out noisy signals and characterizing cell phenotypes with high precision. In comparative tests on drug-induced cardiotoxicity and mitochondrial toxicity classification, as well as compound classification, MID outperformed both DeepProfiler and CellProfiler, which are two highly recognized methods in HCA. We believe that our results demonstrate the utility and versatility of MID and anticipate its widespread adoption in HCA for advancing drug development and disease research.

pharmacology and toxicology↗

bioRxiv2023

Evolution of the Telencephalon Anterior-Posterior Patterning by Core Endogenous Network Bifurcation

How did the complex structure of telencephalon evolve? Existing explanations are based on phenomena and lack the first principle. The Darwinian dynamics and the endogenous network theory established a few years ago provide a mathematical and theoretical framework of a dynamical structure, and a general constitutive structure for theory-experiment coupling, respectively, for answering this question from the first principle perspective. By revisiting a gene network that explains the anterior-posterior patterning of the vertebrate telencephalon, we found that with the increase of the cooperative effect in this network, the fixed points gradually evolve, accompanied by the occurrence of two bifurcations. The dynamic behavior of this network consists with the knowledge obtained from experiments on telencephalon evolution. Furtherly, our work drew an answer quantitatively of how the telencephalon anterior-posterior patterning evolved from the pre-vertebrate chordate to the vertebrate and gave a series of verifiable predictions in a first principle manner. Figure Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

systems biology↗

bioRxiv2023

Plasma cells in human pancreatic ductal adenocarcinoma secrete antibodies to self-antigens

Intratumoral B cell responses are associated with more favorable clinical outcomes in human pancreatic ductal adenocarcinoma (PDAC). However, the antigens driving these B cell responses are largely unknown. We sought to discover these antigens by using single-cell RNA sequencing (scRNA-Seq) and immunoglobulin (Ig) sequencing of tumor-infiltrating immune cells from seven primary PDAC samples. We identified activated T and B cell responses and evidence of germinal center reactions. Ig sequencing identified plasma cell (PC) clones expressing isotype-switched and hyper-mutated Igs, suggesting the occurrence of T cell-dependent B cell responses. We assessed the reactivity of 41 recombinant antibodies that represented the products of 235 PCs and 12 B cells toward multiple cell lines and PDAC tissues, and observed frequent staining of intracellular self-antigens. Three of these antigens were identified: the filamentous actin (F-actin), the nucleic protein, RUVBL2, and the mitochondrial protein, HSPD1. Antibody titers to F-actin and HSPD1 were elevated in the plasma of PDAC patients, and also detectable in healthy donors. Thus, PCs in PDAC produce auto-antibodies reacting with intracellular self-antigens, which may result from promotion of pre-existing, autoreactive B cell responses. These observations indicate that the chronic inflammatory microenvironment of PDAC can support the adaptive immune response.

cancer biology↗

bioRxiv2023

A new microphysiological system shows hypoxia primes human ISCs for interleukin-dependent rescue of stem cell activity

Background & AimsHypoxia in the intestinal epithelium can be caused by acute ischemic events or conditions like Inflammatory Bowel Disease (IBD) where immune cell infiltration produces inflammatory hypoxia, a chronic condition that starves the mucosa of oxygen. Epithelial regeneration after ischemia and IBD suggests intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of acute and chronic hypoxia on human ISC (hISC) properties have not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs isolated from healthy human tissues. We then test the hypothesis that some inflammation-associated interleukins protect hISCs during prolonged hypoxia. MethodshISCs were exposed to <1.0% oxygen in the MPS for 6-, 24-, 48- & 72hrs. Viability, HIF1 response, transcriptomics, cell cycle dynamics, and hISC response to cytokines were evaluated. ResultsThe novel MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs remain viable until 72hrs and exhibit peak HIF1 at 24hrs. hISCs lose stem cell activity at 24hrs that recovers at 48hrs of hypoxia. Hypoxia increases the proportion of hISCs in G1 and regulates hISC capacity to respond to multiple inflammatory signals. Hypoxia induces hISCs to upregulate many interleukin receptors and hISCs demonstrate hypoxia-dependent cell cycle regulation and increased organoid forming efficiency when treated with specific interleukins ConclusionsHypoxia primes hISCs to respond differently to interleukins than hISCs in normoxia through a transcriptional response. hISCs slow cell cycle progression and increase hISC activity when treated with hypoxia and specific interleukins. These findings have important implications for epithelial regeneration in the gut during inflammatory events.

cell biology↗

bioRxiv2022

Flaver: mining transcription factors in genome-wide transcriptome profiling data using weighted rank correlation statistics

BackgroundMining key transcription factors (TFs) in genome-wide transcriptome profiling data has been an active research area for many years and it has been partially solved by mathematically modelling the ranking orders of genes in the target gene-set for the TF of interest in the gene-list ranked by expression values, called gene-set enrichment analysis (GSEA). However, in some application scenarios the gene-set itself also has a rank attribute, such as the putative target gene-set predicted by the Grit software and other alternatives like FIMO and Pscan. New algorithms must be developed to analyze these data properly. Methodology/Principal FindingsBy implementing the weighted Kendalls tau statistic, we proposed a method for genome-wide transcriptome profiling data mining that can identify the key TFs orchestrating a profile. Theoretical properties of the proposed method were established, and its advantages over the GSEA approach were demonstrated when analyzing the RNA-Atlas datasets. The results showed that the top-rated TFs by our method always have experimentally supported evidences in the literatures. Benchmarking using gene ontology (GO) annotations in the AmiGO database indicated that the geometry performance (SQR_P) of our method is higher than GSEA in more than 14% of the cases. SignificanceThe developed method is suitable for analyzing the significance of overrepresentation of ranked gene-sets in a ranked gene-list. A software implementing the method, called "Flaver", was developed and is publicly available at http://www.thua45.cn/flaver under an academic free license. Author SummaryIdentification of the regulation roles of TFs in the transcriptome is fundamental in understanding various biological processes. Improve the performance of the prediction tools is important because accurate TF-mining in transcriptome data can finely improve the efficiency of wet-lab experiments. Also, genome wide TF-mining can provide new target genes for transcriptome regulation analysis in system biology perspective. This study developed a new TF-mining tool based on weighted rank correlation statistical method. The tool has better performance in analyzing ranked gene-set and ranked gene-list than its competitor, the GSEA tool. It can help the researchers in identification of the most important TFs in transcriptional data.

bioinformatics↗

bioRxiv2022

CoxMKF: A Knockoff Filter for High-Dimensional Mediation Analysis with a Survival Outcome in Epigenetic Studies

MotivationIt is of scientific interest to identify DNA methylation CpG sites that might mediate the effect of an environmental exposure on a survival outcome in high-dimensional mediation analysis. However, there is a lack of powerful statistical methods that can provide a guarantee of false discovery rate (FDR) control in finite-sample settings. ResultsIn this article, we propose a novel method called CoxMKF, which applies aggregation of multiple knockoffs to a Cox proportional hazards model for a survival outcome with high-dimensional mediators. The proposed CoxMKF can achieve FDR control even in finite-sample settings, which is particularly advantageous when the sample size is not large. Moreover, our proposed CoxMKF can overcome the randomness of the unstable model-X knockoffs. Our simulation results show that CoxMKF controls FDR well in finite samples. We further apply CoxMKF to a lung cancer data set from The Cancer Genome Atlas (TCGA) project with 754 subjects and 365 306 DNA methylation CpG sites, and identify four DNA methylation CpG sites that might mediate the effect of smoking on the overall survival among lung cancer patients. AvailabilityThe R package CoxMKF is publicly available at https://github.com/MinhaoYaooo/CoxMKF. Contactzl2509@cumc.columbia.edu.

bioinformatics↗

bioRxiv2022

Dynamic interaction of bacterial cellulose synthase subunit D (BcsD) in type I bacterial cellulose synthase

Cellulose is a promising biological material for supporting sustainable human life. This natural polymer is synthesized by cellulose synthase, a protein complex in the cell membrane. Cellulose synthase in bacteria is a hetero-subunit complex, and its subunit organization varies widely depending on the species. In the type I bacterial cellulose synthase complex, the BcsD (bacterial cellulose synthase D) protein is believed to play an important role in producing cellulose with long slender fiber morphology and high crystallinity, given the phenotype of the bcsD-deficient mutant and the specific existence of the type I operon in bacterial species synthesizing crystalline cellulose microfibrils such as Acetobacter. In this study, we successfully established a heterogeneously expressed Bcs protein in Escherichia coli as an experimental model and conducted biochemical studies for the BcsD protein and the other three major subunits of bacterial cellulose synthase, BcsA, BcsB, and BcsC. It has been shown that the BcsD protein interacts with the functionally required minimal subunits of the BcsAB complex, as well as the BcsC protein. Furthermore, it was shown that BcsD interacts with the BcsAB complex in two modes: direct protein-protein interactions and indirect interactions through the product cellulose. The former and latter modes represent the basal and active states of the type I bacterial cellulose synthase, respectively. This dynamic behavior of the BcsD protein is important for the type I bacterial cellulose synthase complex to regulate the crystallization process of cellulose.

biochemistry↗

bioRxiv2022

Tension Gauge Tethers as tension-dependent lifetime sensors

Mechanotransduction of cells relies on responding to tension transmitted along various supramolecular linkages. Tension gauge tethers (TGTs), short double-stranded DNA (dsDNA) fragments that undergo irreversible tension-dependent dissociation under shear-stretching mode, have been widely applied in live cell experiments to provide critical insights into the mechanotransduction activities of cells. However, the current physical understanding of the mechanical responses of TGTs remains limited, which restricts the range of information that can be extracted from experimental observations. In order to provide quantitative in-depth understanding and interpretation of experimental observations, in this work, we quantified the tension-dependent lifetime of TGTs from which the mechanical stability of TGTs under various physiologically relevant stretching conditions can be derived. Applications of the determined mechanical stability of TGTs to cell studies strongly suggest revisiting the previous interpretations of several reported experimental observations.

biophysics↗

bioRxiv2021

Identification of upstream transcription factor binding sites in orthologous genes using mixed Student's t-test statistics

BackgroundTranscription factor (TF) regulates the transcription of DNA to messenger RNA by binding to upstream sequence motifs. Identifying the locations of known motifs in whole genomes is computationally intensive. Methodology/Principal FindingsThis study presents a computational tool, named "Grit", for screening TF-binding sites (TFBS) by coordinating transcription factors to their promoter sequences in orthologous genes. This tool employs a newly developed mixed Students t-test statistical method that detects high-scoring conserved and non-conserved binding sites among species. The program performs sequence scanning at a rate of 3.2 Mb/s on a quad-core Amazon server and has been benchmarked by the well-established ChIP-Seq datasets, putting Grit amongst the top-ranked TFBS predictors. It marginally outperforms the well-known transcription factor motif scanning tools, Pscan (4.8%) and FIMO (17.8%), in analyzing well-documented ChIP-Atlas human genome Chip-Seq datasets. SignificanceGrit is a good alternative to current available motif scanning tools and is publicly available at http://www.thua45.cn/grit under an academic free license. Author SummaryLocating transcription factor-binding (TF-binding) site in the genome and identification their function is fundamental in understanding various biological processes. Improve the performance of the prediction tools is important because accurate TF-binding site prediction can save cost and time for wet-lab experiments. Also, genome wide TF-binding site prediction can provide new insights for transcriptome regulation in system biology perspective. This study developed a new TF-binding site prediction tool based on mixed Students t-test statistical method. The tool is amongst the top-ranked TF-binding site predictors, as such, it can help the researchers in TF-binding site identification and transcriptional regulation mechanism interpretation of genes.

bioinformatics↗

bioRxiv2021

Transcriptome analysis of SARS-CoV-2 naive and recovered individuals vaccinated with inactivated vaccine

The urgent approval of the use of the inactivated COVID-19 vaccine is essential to reduce the threat and burden of the epidemic on global public health, however, our current understanding of the host immune response to inactivated vaccine remains limited. Herein, we performed serum IgG antibody detection and transcriptomics analysis on 20 SARS-CoV-2 naive individuals who received multiple doses of inactivated vaccine and 5 SARS-CoV-2 recovered individuals who received single dose of inactivated vaccine. Our research revealed the important role of many innate immune pathways after vaccination, identified a significant correlation with the third dose of booster vaccine and proteasome-related genes, and found that SARS-CoV-2 recovered individuals can produces a strong immune response to a single dose of inactivated vaccine. These results help us understand the reaction mechanism of the hosts molecular immune system to the inactivated vaccine, and provide a basis for the choice of vaccination strategy.

microbiology↗

bioRxiv2021

Force-dependent interactions between talin and full-length vinculin

Talin and vinculin are part of a multi-component system involved in mechanosensing in cell-matrix adhesions. Both exist in auto-inhibited forms, and activation of vinculin requires binding to mechanically activated talin, yet how forces affect talins interaction with vinculin has not been investigated. Here by quantifying the force-dependent talin-vinculin interactions and kinetics using single-molecule analysis, we show that mechanical exposure of a single vinculin binding site (VBS) in talin is sufficient to relieve the autoinhibition of vinculin resulting in high-affinity binding. We provide evidence that the vinculin undergoes dynamic fluctuations between an auto-inhibited closed conformation and an open conformation that is stabilized upon binding to the VBS. Furthermore, we discover an additional level of regulation in which the mechanically exposed VBS binds vinculin significantly more tightly than the isolated VBS alone. Molecular dynamics simulations reveal the basis of this new regulatory mechanism, identifying a sensitive force-dependent change in the conformation of an exposed VBS that modulates binding. Together, these results provide a comprehensive understanding of how the interplay between force and autoinhibition provides exquisite complexity within this major mechanosensing axis.

biophysics↗