Biology subjects

Qiao, F.

Publications and source records attributed to Qiao, F..

11 recordsLinked to original sources

bioRxiv2026

Integrative Proteomic Analysis Implicates Inhibition of Intracellular Protein Trafficking in Therapy-Induced Migrastasis in Prostate Cancer

BackgroundDysregulated cell migration leading to metastasis remains the primary cause of cancer-related mortality. It has been challenging to understand how cells regulate migration. We have previously created the first selective inhibitor of cell migration, KBU2046. Here, we use it as a probe to identify regulatory processes. MethodsMetastatic and primary human prostate cancer cells were treated for different times and at different concentrations with KBU2046. Immunofluorescent microscopy examined protein localization in cells. Label-free mass spectrometry (MS) was performed on total cell proteins, Tandem Mass Tag (TMT) labeling MS was used on membrane fractions, and temporal phosphoproteomic profiling. Results were analyzed with a suite of bioinformatic tools. ResultsKBU2046-induced migrastasis is associated with the accumulation of activated integrin {beta}1 into focal adhesions. Whole-cell proteomics demonstrated suppression of processes that mediate intracellular protein trafficking and increases in mitochondrial energy-generation signatures. Evaluation of the membrane fraction identified increases in membrane repair and maintenance processes and decreases in those that drive motility. Temporal- and concentration-dependent phosphoproteomic profiling revealed that KBU2046 initiates a dynamic, cascading sequence of transient signaling waves rather than a static block. ConclusionsKBU2046-induced migrastasis appears to operate through spatial decoupling rather than structural degradation. By restricting the intracellular trafficking machinery required for receptor recycling, KBU2046 limits focal adhesion turnover, providing a correlative framework to inhibit metastatic dissemination independent of direct cytotoxicity. O_FIG O_LINKSMALLFIG WIDTH=122 HEIGHT=200 SRC="FIGDIR/small/736165v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1efd74dorg.highwire.dtl.DTLVardef@1202106org.highwire.dtl.DTLVardef@581ed3org.highwire.dtl.DTLVardef@14fdcfb_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG

cancer biology↗

bioRxiv2026

Forward processing of spatiotemporal maps across hippocampal subfields in common marmosets

Episodic memory requires distinguishing similar events occurring at the same location but at different times. While the hippocampus integrates "where" and "when," the specific roles of the primate dentate gyrus (DG) and CA3 remain elusive. We recorded single-unit activity from freely moving marmosets navigating a spatial maze in a visually impoverished environment. Both hippocampal subfields robustly encoded self-position via neurons selective for stationary epochs at platforms and movement along trajectories, whereas gaze-related coding was minimal. While DG signaled stationary and dynamic self-positions independently, CA3 integrated these elements into conjunctive representations. Critically, only CA3 neurons exhibited strong temporal-order modulation. These findings reveal a feedforward disambiguation process in which CA3 transforms discrete spatial inputs from DG into the integrated spatiotemporal maps essential for episodic memory.

neuroscience↗

bioRxiv2025

A Sequence Motif Enables Widespread Use of Non-Canonical Redox Cofactors in Natural Enzymes

Non-canonical redox cofactors (NRCs) are promising alternatives to nicotinamide adenine dinucleotide (phosphate) (NAD(P)+) for biomanufacturing due to low cost and exquisite electron delivery control, yet their adoption is limited by the scarcity of compatible enzymes. Here, we screened the aldehyde dehydrogenase (ALDH) protein family and identified a conserved RH/QxxR sequence motif that enables widespread NRC activity among natural enzymes. Bos taurus ALDH3a1 and Pseudanabaena biceps ALDH exhibit unprecedented turnover with nicotinamide mononucleotide (NMN+), with kcat values matching or exceeding that of NAD+ and surpassing most engineered NRC-active enzymes by 10 to 105-fold, based on the relative NRC to native activity. Structural and dynamic analyses reveal this motif reinforces cofactor positioning and pre-organizes the active site without dependence on the adenosine monophosphate moiety of NAD+. When introduced into diverse ALDH scaffolds, the RH/QxxR motif enhances NMN+ activity up to 60-fold. In addition to NMN+, this motif also supports activity across multiple non-nucleotide, simple synthetic NRCs such as 1-(2-carbamoylmethyl)nicotinamide (AmNA+). These findings elucidate Natures solution to the engineering challenge of obtaining NRC-active enzymes and offers a blueprint to mine latent evolutionary plasticity in natural enzymes that serve as superior engineering starting points.

synthetic biology↗

bioRxiv2025

A New Class of Precision Therapeutics that Inhibit Prostate Cancer Mediated Bone Destruction

Cancer mediated bone destruction remains a common cause of morbidity and mortality. Here we couple an inhibitor of cell movement to bone trophic bisphosphonates, forming heterobifunctional compounds termed Dual Acting Bone Defender agents (DABDs). DABDs inhibit prostate cancer cell motility and osteoclast mediated bone destruction in vitro. Our lead compound, BTE-EN1, inhibits circulating human prostate cancer cells from forming bone destructive lesions in mice and prolongs life in a dose-dependent fashion. In mice with established metastatic lesions, BTE-EN1 significantly decreases bone destruction by over 60% compared to the control. Mechanistically, BTE-EN1 binds hydroxyapatite, inhibits prenylation of Rap1A, induces apoptosis in osteoclasts, and inhibits Raf1 activation and formation of bone resorptive cavities in osteoclasts, thus retaining the function of its constituent chemicals. BTE-EN1 is not toxic to mice at doses 4,000-fold over those required for efficacy, exhibits anti-cell motility activity across other bone-destructive cancer cell types, and does not interfere with standard-of-care hormone therapy or chemotherapy. BTE-EN1 is a new class of highly active therapeutics that inhibit cancer mediated bone destruction and holds high potential for translation into humans.

cancer biology↗

bioRxiv2024

Protein Structure Inspired Drug Discovery

Drug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface. As protein structure determines function, we hypothesized that unique 3D structural motifs represent primary information denoting unique function that can drive discovery of novel agents. Using a physics-based protein structure analysis platform developed by us, designed to conduct computationally intensive analysis at supercomputing speeds, we probed a high-resolution protein x-ray crystallographic library developed by us. We selected 3D structural motifs whose function was not otherwise established, that offered environments supporting binding of drug-like chemicals and were present on proteins that were not established therapeutic targets. For each of eight potential binding pockets on six different proteins we accessed a 60 million compound library and used our analysis platform to evaluate binding. Using eight-day colony formation assays acquired compounds were screened for efficacy against human breast, prostate, colon and lung cancer cells and toxicity against human bone marrow stem cells. Compounds selectively inhibiting cancer growth segregated to two pockets on separate proteins. The compound, Dxr2-017, exhibited selective activity against human melanoma cells in the NCI-60 cell line screen, had an IC50 of 19 nM against human melanoma M14 cells in our eight-day assay, while over 2100-fold higher concentrations inhibited stem cells by less than 30%. We show that Dxr2-017 induces anoikis, a unique form of programmed cell death in need of targeted therapeutics. The predicted target protein for Dxr2-017 is expressed in bacteria, not in humans. This supports our strategy of focusing on unique 3D structural motifs. It is known that functionally important 3D structures are evolutionarily conserved. Here we demonstrate proof-of-concept that protein structure represents high value primary data to support discovery of novel therapeutics. This approach is widely applicable. Author summaryWe introduce the concept that protein 3D structure represents primary information which can support downstream investigations, in this instance leading to the discovery of novel anticancer therapeutics.

cancer biology↗

bioRxiv2024

Systematic Identification of UBE2C As a Prognostic Biomarker and Correlated with Immunosuppression and Invasiveness in Glioma

Glioma is one of the common tumors of the central nervous system, which presents difficulties in clinical diagnosis and treatment due to its characteristics of immunosuppression and cell invasion phenotypes. If the condition and prognosis of glioma can be predicted during the process of diagnosis and treatment, it will be more conducive to timely intervention or evaluation of glioma. Therefore, we still need to search for more valuable tumor markers. The differential/risk genes and enrichment analysis based on glioma samples (The Cancer Genome Atlas, TCGA). Target gene UBE2C were obtained by the expression correlation and differential expression analysis for the enrichment results. UBE2C were evaluated by clinical grading, survival prognosis and cell experiments. The correlation of UBE2C with immune invasion, immune checkpoint, network analysis and cell invasiveness of gliomas was analyzed by TCGA-glioma data and STRING, respectively. The results suggests that the high expression and risk of UBE2C in gliomas may be a factor that promotes malignant phenotype of tumor cells. The immune phenotype shows that IL6 and IL10 may be the key nodes affecting the immunosuppressive phenotype of glioma. Further, the tumor cells aggressive genes from the MMP family can be correlated with immunosuppressive phenotypes via UBE2C-IL6/IL10 axis, especially displayed by MMP2/MMP9. The UBE2C may systemic effects the malignant phenotype, immunosuppression and cell invasiveness of tumors systematically, which reflects UBE2C as a potential biomarker of glioma and therapeutic target for this tumor.

cancer biology↗

bioRxiv2023

Pan-genome and Haplotype Map of Cultivars and Their Wild Ancestors Provides Insights into Adaptive Evolution of Cassava (Manihot esculenta Crantz)

Cassava is the most important starch sources, a tropical model crop. We constructed nearly T2T genomes of cultivar AM560, wild ancestors FLA4047 and W14, pan-genome of 24 representatives and a clarified evolutionary tree with 486 accessions. Comparison of SVs and SNVs between the ancestors and cultivated cassavas revealed predominant expansion, contraction of genes and gene families. Significantly selective sweeping occurred in the cassava genomes in 122 footprints with 1,519 candidate domestication genes. We identified selective mutations in MeCSK and MeFNR3 promoting photoreaction associated with MeNADP-ME of C4 assimilation in modern cassava. Co-evolved retardation of floral primordia and initiation of storage roots arose from MeCOL5 mutants with altered bindings to MeFT1, MeFT2 and MeTFL2. MebHLHs evolved to regulate the biosynthesis, transport and endogenous remobilization of cyanogenic glucosides, with new functionalities of MeMATE1, MeGTR in selected sweet cassava. These findings enhanced comprehensive knowledge and database on the evolution and breeding of cassava. HIGHLIGHTSO_LIThree nearly T2T cassava genomes of cultivar AM560 and its wild ancestors FLA4047 and W14. C_LIO_LIA species-level cassava panSV haplotype map across 346,322 structural variations over 31,362 gene families and 96,032,008 SNPs and InDels variations globally and a clarified evolutionary tree with 486 accessions. C_LIO_LISelective mutations in MeCSK and MeFNR3 promoted photoreaction associated with MeNADP-ME of C4 assimilation shaped the C3-C4 intermediate photosynthesis of modern cassava. C_LIO_LICoevolution of floral primordia contrary to initiated storage root is pivotal for the domestication of cassava, and arose from MeCOL5 mutants altered the binding with MeFT1, MeFT2 (SP6A), and MeTFL2. C_LI

systems biology↗

bioRxiv2023

The anti-cancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery

JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2- mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3' processing machinery.

molecular biology↗

bioRxiv2022

Complex genetic architecture underlying the plasticity of maize agronomic traits

Phenotypic plasticity is the property of a given genotype to produce multiple phenotypes in response to changing environmental conditions. Understanding the genetic basis of phenotypic plasticity and establishing a predictive model is highly relevant for future agriculture under changing climate. Here, we report findings on the genetic basis of phenotypic plasticity for 23 complex traits using a maize diverse population, planted at five sites with distinct environmental conditions and genotyped with ~ 6.60 million SNPs. We found that altitude-related environmental factors were main drivers for across site variation in flowering time traits but not plant architecture and yield traits. For 23 traits, we detected 109 QTLs, of which 29 was for mean, 66 was for plasticity, and 14 for both parameters, besides, 80% of the QTLs were interreacted with the environment. The effects of several QTLs changed in magnitude or sign, driving variation in phenotype plasticity, and we further experimentally validated one plastic gene ZmTPS14.1 whose effect was likely mediated by the compensation effect of ZmSPL6 which was from the downstream pathway probably. By integrating genetic diversity, environmental variation, and their interaction in a joint model, we could provide site-specific predictions with increased accuracy by as much as 15.5%, 3.8%, and 4.4% for DTT, PH, and EW, respectively. Overall, we revealed a complex genetic architecture involving multiallelic, pleiotropy, and genotype by environment interaction underlying maize complex trait mean and plasticity variation. Our study thus provided novel insights into the dynamic genetic architectures of agronomic traits in response to changing environments, paving a practical route to precision agriculture.

genetics↗

bioRxiv2021

Ketogenesis Impact on Liver Metabolism Revealed by Proteomics of Lysine β-hydroxybutyrylation

Ketone bodies are evolutionarily conserved metabolites that function as energy substrates, signaling molecules and epigenetic regulators. {beta}-hydroxybutyrate ({beta}-OHB) is utilized in lysine {beta}-hydroxybutyrylation (Kbhb) of histones, which associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke {beta}-OHB. Mass spectrometry analysis of the {beta}-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification and 1-carbon metabolic pathways. Kbhb of S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, results in inhibition of enzymatic activity. Our results illuminate the role of Kbhb on hepatic metabolism under ketogenic conditions and demonstrate the functional consequence of this modification on a central metabolic enzyme.

molecular biology↗

bioRxiv2020

The cooperative assembly of shelterin bridge provides a kinetic gateway that controls telomere length homeostasis

Shelterin is a six-proteins complex that coats chromosome ends to ensure their proper protection and maintenance. Similar to the human shelterin, fission yeast shelterin is composed of telomeric double- and single-stranded DNA-binding proteins, Taz1 and Pot1, respectively, bridged by Rap1, Poz1, and Tpz1. The assembly of the proteinaceous Tpz1-Poz1-Rap1 complex occurs cooperatively and disruption of this shelterin bridge leads to unregulated telomere elongation. However, how this biophysical property of bridge assembly is integrated into shelterin function is not known. Here, utilizing synthetic bridges with a range of binding properties, we find that synthetic shelterin bridge lacking cooperativity requires a linker pair that matches the native bridge in complex lifespan but has dramatically higher affinity. We find that cooperative assembly confers kinetic properties on the shelterin bridge allowing disassembly to function as a molecular timer, regulating the duration of the telomere open state, and consequently telomere lengthening to achieve a defined species-specific length range.

molecular biology↗