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Qiao, B.

Publications and source records attributed to Qiao, B..

13 recordsLinked to original sources
bioRxiv2026

How Phosphorylation of How Phosphorylation of alpha/beta-Tubulin Perturbs Microtubule Structure: A Computational Study

Microtubules are cytoskeletal structures composed of polymers of /{beta}-tubulin heterodimers that enable cell division and motility by a process of alternating episodes of polymerization and depolymerization (dynamic instability). Transition from a polymerizing to a depolymerizing microtubule is triggered at the interdimer interface by Glu254 in -tubulin (:Glu254), which hydrolyzes GTP bound to {beta}-tubulin ({beta}:GTP). The process is regulated by phosphorylation of -tubulin (Ser165) or {beta}-tubulin (Ser172) via signaling protein kinases (PKC, CDK1). All-atom molecular dynamics simulations of /{beta}-tubulin 6-mer systems are used to screen the cryo-EM structure of a microtubule (PDB 3J6E) for structural responses to phosphorylation of each tubulin subunit. In terms of global structure, microtubules with phosphorylated -tubulin have a straight conformation attributed to a growing microtubule, whereas MTs with phosphorylated {beta}-tubulin are curved, characteristic of a disassembling MT. Phospho--tubulin initiates displacement of key secondary structures (helix H8, loop T5) at the inter-dimer interface, shifts the {beta}:GTP nucleotide by 5 [A], and immobilizes the {gamma}-phosphate of {beta}:GTP through increased H-bonding with {beta}-tubulin. Phospho-{beta}-tubulin produces fewer structural effects and has a more flexible {beta}:GTP. For {beta}:GTP hydrolysis, the phospho-{beta}-tubulin system displays an extensive network of water molecules between :Glu254 and the {gamma}-phosphate of {beta}:GTP, facilitating its hydrolysis. In contrast, phospho--tubulin displays a discontinuous network of water molecules that predicts a diminished capacity for {beta}:GTP hydrolysis. These findings provide a detailed framework for understanding how phosphorylation of each tubulin subunit restructures the inter-dimer interface to modulate {beta}:GTP hydrolysis, global structure, and dynamic instability in response to key signaling protein kinases.

biochemistry↗
bioRxiv2025

Nanoplastics Penetration Across the Blood-Brain Barrier

Microplastics and nanoplastics (MNPs), originating from plastic degradation, have arisen to be a threat to ecology and human health. Alarmingly, the penetration of MNPs across the highly selective blood-brain barrier (BBB) poses an emerging and urgent risk, yet its molecular mechanism remains unexplored. In this work, using long-time-scale (over 27 s) all-atom explicit solvent steered molecular dynamics, we examine the free energy of the passive permeation of four polymer nanoparticles: polyethylene, polypropylene, polystyrene, and polyethylene terephthalate. Polyethylene and polypropylene nanoparticles exhibited a remarkable preference for entering the BBB, attributed to their high hydrophobicity. Our study reveals that polymers can enter the BBB as polymerized nanoplastics and exit as dispersed polymer chains as the nanoparticles dissolve within the BBB. Further, the crystalline structure of polyethylene nanoparticles is found to adopt varying orientations. Our work advances the knowledge about the mechanism of nanoplastic penetration across the BBB, which could aid in the rational design of therapeutics for nanoplastic penetration inhibitors. TOC Graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/675462v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1b20796org.highwire.dtl.DTLVardef@1102985org.highwire.dtl.DTLVardef@15fc22org.highwire.dtl.DTLVardef@15c2260_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗
bioRxiv2025

Protein-Like Polymer for Inhibition of Tau Fibril Propagation in Human-Derived Models of Neurodegeneration

The misfolding, aggregation, and spread of tau protein fibrils underlie tauopathies, a diverse class of neurodegenerative diseases for which effective treatments remain elusive. Among these are corticobasal dementia (CBD) and progressive supranuclear palsy (PSP), canonical examples of 4-repeat (4R) tauopathies characterized by tau isoforms exclusively with four microtubule-binding repeat domains. We target this 4R tau isoform-specific mechanism by focusing on misfolded taus distinctive stem-loop-stem structural motif formed by the junction of the 4R-defining alternatively spliced exon and the adjacent constitutive exon. A synthetic peptide based on this stem-loop-stem sequence can induce aggregation and spread in an isoform-specific manner. Here, we develop a protein-like polymer (PLP) in which multiple copies of this synthetic peptide form a brush-like structure capable of preventing tau aggregation by binding and capping fibril ends in vitro, in human brain organoids, and in cellular models with an EC50 of 105 {+/-} 14 nM. PLPs demonstrate robust activity against fibrils derived from CBD and PSP patient brains and a PS19 mouse tauopathy model. Previous tau-targeted treatments have primarily focused on broad tau clearance, aggregation inhibition, or microtubule stabilization, often lacking isoform specificity and precision. In contrast, this approach targets the 4R tau isoforms unique structural motif, offering a tailored therapeutic intervention for diseases like CBD and PSP. Supported by prior studies showing blood-brain barrier penetrance and safety profiles, this tau-binding PLP offers a promising translational path toward clinical applications in tauopathy treatment.

neuroscience↗
bioRxiv2024

Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

cancer biology↗
bioRxiv2023

ZHX2 alleviates vascular remodeling and smooth muscle cell proliferation by transcriptional regulation of GADD45G

ObjectiveThis study explores the role of ZHX2 in vascular remodeling, specifically focusing on its effects on VSMC proliferation, migration, and neointima formation following vascular injury. Methods and Results: Data from both human atherosclerotic samples and a mouse carotid injury model indicated a decrease in ZHX2 levels. In vivo, ZHX2 overexpression reduced neointima formation in mice subjected to carotid artery ligation. In vitro, ZHX2 inhibited the proliferation and migration of primary VSMCs. Conversely, specific knockout of ZHX2 in SMCs in vivo or knockdown of ZHX2 in primary VSMCs had opposite effects. RNA- seq analysis revealed that ZHX2 overexpression significantly affected the expression of cell cycle-related genes. Using Chromatin Immunoprecipitation Sequencing (ChIP-seq) and luciferase reporter assays, we demonstrated that ZHX2 plays a crucial role in the transcriptional regulation of GADD45G, identifying GADD45G as the downstream target responsible for ZHX2-mediated effects. Conclusions: ZHX2 emerges as a key player in pathological vascular remodeling, suppressing VSMC proliferation and migration through its regulatory impact on GADD45G transcription and cell cycle-related gene expression.

molecular biology↗
bioRxiv2023

Comprehensive Analysis of Molecular Characteristics, Clinical Signifificance, and Cancer Immune Interactions of Patients by Anoikis-Related Genes in LUAD Combined with Single-cell Data

BackgroundLung adenocarcinoma(LUAD) is the most prevalent subtype of lung cancer today. There is a close relationship between Anoikis related genes(ARGs) and tumor prognosis, drug susceptibility, and tumor microenvironment(TME). MethodWe calculated differential expression genes using downloaded Anoikis genes and selected genes of prognostic value. Consensus clustering analysis was used and characterized between different clusters. Differences between the different groups were also explored. Risk scores and Nomogram with predictive prognostic functions were established. Immune status and drug sensitivity were also assessed between different risk groups. Single-cell data were downloaded to compare the expression profiles of selected genes, and immunohistochemical results of selected genes were also downloaded to corroborate the reliability of the manuscript. ResultTwo clusters were identified on the basis of related gene expression. We analyzed the survival time, functional enrichment between the two groups and found significant differences between the two clusters. Significant relationships were found between the different clusters and clinical variables. group B had a significantly lower KM curve than group A, as well as a significant enrichment in multiple tumor functions. A risk score with prognostic value was established. The risk score was found to have a high predictive value for prognosis and was an independent prognostic factor. Combined with clinical variables, a Nomogram was established and found to be an accurate predictor of patient prognosis. There were significant differences in immune status between the different risk groups. Patients in the low-risk group were significantly better treated than those in the high-risk group. Finally single cell data confirmed the expression of the selected genes. Also, the immunohistochemical results helped us to confirm the selected genes have increased expression in tumor tissue. ConclusionIn conclusion, this paper reveals the role of ARGs and immune status, drug susceptibility, and prediction of prognosis in LUAD. Also, an accurate prognostic prediction model was established based on genetic.

bioinformatics↗
bioRxiv2022

Genome-scale mRNA transcriptomic insights into the mature growth dynamic of Cigar tobacco leaves

The harvest time is a key factor for cigar leaves with high quality, which varies greatly depending on the environment. Here, we performed a genome-scale mRNA transcriptomic analysis on the cigar cultivar CX-26 (Nicotiana tabacum L.) to evaluate the relationship between gene expression and growth state. The leaves were harvested with 67 (T1), 71(T2) and 75 (T3)-day growth. A total of 80,502 genes were detected in the CX-26 leaves, of which 64,611 genes were annotated on the reference genome. Principal component analysis showed that T1 and T2 leaves had a high overlapping pattern, while T3 leaves were distinct. Indeed, T1 and T2 leaves had fewer differential expressing genes (DEGs), while T3 leaves had 26,456 DGEs from T2 leaves, supporting the distinct growth of T3 leaves. GO annotations mainly enriched the photosynthesis-related metabolic process, catalytic activity and binding biological processes. KEEG analysis identified the key pathways including photosynthesisantenna proteins, plant hormone/MAPK signaling pathway and plant-pathogen interaction. The maturity regulation and defense response-associated hormones abscisic acid and jasmonate acid were higher in the T3 leaves than that in T1 and T2 leaves confirming the KEEG analysis. Furthermore, several photosynthesis-related enzymes and a transcription factor were highlighted in the gene regulatory network, which might regulate the dynamics of carbohydrate metabolism, lipid metabolism and energy metabolism. In summary, our study provides insight into the growth state of CX-26 cigar leaves.

plant biology↗
bioRxiv2020

Protein Surface Printer for Exploring Protein Domains

The surface of proteins is vital in determining protein functions. Herein, a program, Protein Surface Printer(PSP), is built that performs multiple functions in quantifying protein surface domains. Two proteins, PETase and cytochrome P450, are used to validate that the program supports atomistic simulations with different combinations of programs and force fields. A case study is conducted on the structural analysis of the spike proteins of SARS-CoV-2 and SARS-CoV, and the human cell receptor ACE2. Although the surface domains of both spike proteins are highly similar, their receptor binding domains(RBDs) and the O-linked glycan domains are structurally different. Statistically, the outer surface of ACE2 displays less correlation with the RBD of SARS-CoV-2 than that of SARS-CoV. The O-linked glycan domain of SARS-CoV-2 is highly positively charged, which may promote binding to negatively charged human cells. Our program paves the way for an accurate understanding of protein binding for aggregation and ligand recognition.

bioinformatics↗
bioRxiv2020

The Distal Polybasic Cleavage Sites of SARS-CoV-2 Spike Protein Enhance Spike Protein-ACE2 Binding

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY TOC: The SARS-CoV-2 spike protein-ACE2 complex showing the polybasic cleavage sites C_FIG_DISPLAY

biophysics↗
bioRxiv2019

Pathway engineering in yeast for synthesizing the complex polyketide bikaverin

Fungal polyketides display remarkable structural diversity and bioactivity, and therefore the biosynthesis and engineering of this large class of molecules is therapeutically significant. Here, we successfully recoded, constructed and characterized the biosynthetic pathway of the formation of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We used a green fluorescent protein (GFP) tagging strategy to identify the low expression of Bik1 (polyketide synthase) as the bottleneck step in the pathway, and a promoter exchange strategy to increase expression of Bik1 and bikaverin yield. To further increase product yield, we used an enzyme-fusion strategy to couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to a dramatic improvement of Bikaverin yield of nearly 60-fold. This study demonstrates that the biosynthesis of complex polyketides biosynthesis can be established and efficiently engineered in S. cerevisiae, highlighting the great potential for natural product synthesis and large-scale fermentation in yeast.

synthetic biology↗
bioRxiv2018

Using composite phenotypes to reveal heterogeneity and model SpO2 of altitude acclimatization

Altitude acclimatization is the physiological process of the human body adjusting to the decreased availability of oxygen. Since several physiological processes are involved and the relation among them is complicated, analyses of single-traits is insufficient in revealing the complex mechanism of altitude acclimatization. In this study, we examined whether these physiological responses could be studied as composite phenotypes which are represented by a linear combination of physiological traits. We developed a strategy which combines both spectral clustering and PLSPM to define composite phenotypes. We captured 14 composite phenotypes from 28 physiological traits of altitude acclimatization. Using these composite phenotypes, we applied k-means to reveal hidden physiological heterogeneity in altitude acclimatization. Furthermore, we employed linear regression to systematically model oxygen saturation (SpO2) changes in altitude acclimatization and evaluated the model fitness performance. And composite phenotypes based Model 2 has better fitness than single-traits based Model 1 in all measurement indices. Therefore, this new strategy of defining and applying composite phenotypes can be considered as a general strategy of complex traits.

systems biology↗
bioRxiv2017

Automated analysis of internally programmed grooming behavior in Drosophila using a k-nearest neighbors classifier

Despite being pervasive, the control of programmed grooming is poorly understood. We have addressed this gap in knowledge by developing a high-throughput platform that allows long-term detection of grooming in the fruit fly Drosophila melanogaster. Automatic classification of daily behavior shows flies spend 30% of their active time grooming. We show that a large proportion of this behavior is driven by two major internal programs. One of these programs is the circadian clock that modulates rhythms in daily grooming. The second program depends on cycle and clock and regulates the amount of time flies spend grooming. This emerging dual control model of programmed grooming in which one regulator controls the timing and another controls the duration, resembles the well-established two-process regulatory model of fly sleep. Together, our quantitative approach in Drosophila has revealed that grooming is an important internally driven behavior under the control of two regulatory programs.

bioinformatics↗