Biology subjects

Xie, D.

Publications and source records attributed to Xie, D..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

YAP promotes chromosomal instability by transcriptionally activating AJUBA through its super enhancer in breast cancer

Chromosomal instability (CIN) has been proven to be a fundamental property of cancer and a key underlying mechanism of tumorigenesis and progression. Still, relatively few studies have revealed the mechanism of this process. In this research, we identified the core Hippo component, YAP, played a crucial role in CIN formation in breast cancer. Using public ChIP-seq data and bioinformatic analysis, we found YAP could transcriptionally induce spindle assembly checkpoint, AJUBA, via TEAD, then activate AJUBA-AURKA signaling. Abolish AJUBA-AURKA axis could reverse YAP-induced CIN formation and aberrant mitosis. Mechanically, YAP/TEAD complex could accumulate to the super enhancer region of AJUBA, thus significantly induced its expression, and subsequently promoted AURKA auto-phosphorylating. These findings revealed a novel cross-talk between Hippo and AJUBA-AURKA signaling, and provided a new insight in CIN formation in breast cancer.

cancer biology↗

bioRxiv2023

M1 Macrophage-Related Genes Model for NSCLC Immunotherapy Response Prediction

2.Patients diagnosed with non-small cell lung cancer have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for anti-tumor immunity. This study aimed to develop an immunotherapy response evaluation model for NSCLC patients based on transcriptional expression. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy were downloaded from POPLAR and OAK projects. Immune cell infiltration in NSCLC patients has been examined, and thereafter different co-expressed genes were identified. Following that, the impact of M1 macrophage related genes on the prognosis of NSCLC patients was investigated. Six M1 macrophage co-expression genes, namely NKX2-1, CD8A, SFTA3, IL2RB, IDO1, and CXCL9, exhibited a strong association with the prognosis of NSCLC and served as effective predictors for immunotherapy response. A response model was constructed using Cox regression model and Lasso Cox regression analysis. The M1 genes were validated on our previous TD- FOREKNOW NSCLC clinical trial by RT-qPCR. The response model showed excellent immunotherapy response predicting and prognosis evaluating value in advanced stage of NSCLC. The model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

immunology↗

bioRxiv2023

Landscape of Large-Scale Somatic Genomic Insertions in Non-Small Cell Lung Carcinoma Revealed by Nanopore Sequencing

Previous NSCLC genomic studies were mostly based on the next-generation sequencing of short reads, which is an efficient approach for identifying single nucleotide variants and small indels but ineffective for identifying structural variants, especially large-scale insertions. Here, we studied 151 lung adenocarcinoma (LUAD) and 106 lung squamous cell carcinoma (LUSC) samples and paired blood samples using nanopore sequencing technology. We developed a rigorous computational pipeline and characterized the landscape of large-scale somatic insertions in NSCLC. Combining other omics data, we report three findings: 1. we identified an LUSC-enriched somatic simple repeat expansion shared by approximately 40% of LUSC patients that regulates PTPRZ1 gene expression through distal enhancers; 2. the somatic insertion of transposable elements (TEs) in NSCLC were mostly complex TEs consisting of multiple TE elements; and 3. the insertion of short interspersed nuclear elements, especially from the Alu family in young lineages, is a frequent somatic mutation type that shapes the transcriptome of NSCLC through the expression of these elements.

genomics↗

bioRxiv2023

Sclerotic prostate cancer bone metastasis: woven bone lesions with a twist.

Bone metastasis (BM) are the most severe and prevalent consequences of prostate cancer (PC) affecting more than 80% of patients with advanced PC. PCBM generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences of PCBM. Radiographically, PCBM are predominantly osteosclerotic, but the mechanisms of abnormal bone formation, and how this "more and new" bone is related to fractures is unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM samples and 12 from non-PC donors as control. We used -CT to determine three-dimensional organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nano indentation to determine mechanical properties, and we finalize with histological and immunohistochemical analysis of bone structure and composition. We define 4 phenotypes of PCBM, osteolytic, mixed lytic-sclerotic, and two subgroups of osteosclerotic lesions, those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone within the trabeculae surfaces and intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology and orientation. However, we observed no significant difference between this irregular bone and residual trabeculae in terms of mineral content, hardness, and elastic modulus at micron-scale. The collagen matrix of this abnormal bone presents with irregular organization and is accompanied by increased proteoglycan and phosphorylated glycoprotein content. These characteristics suggests the presence of woven bone in PCBM. However, the lack of subsequent bone remodelling, absence of lamellar bone deposition on its surface, absence of markers of matrix vesicles but evidence of alkaline phosphatase dominated mineralization and collagen-III structure, set up differences from woven bone, while the role of PC cells in inducing this irregular bone phenotype remains unclear.

cancer biology↗

bioRxiv2023

Female baboon adrenal zona fasciculata and zona reticularis regulatory and functional proteins decrease across the life course

Debate exists on life-course adrenocortical zonal function trajectories. Rapid, phasic blood steroid concentration changes, such as circadian rhythms and acute stress responses, complicate quantification. To avoid pitfalls and account for life-stage changes in adrenocortical activity indices, we quantified zonae fasciculata (ZF) and reticularis (ZR) across the life-course, by immunohistochemistry of key regulatory and functional proteins. In 28 female baboon adrenals (7.5-22.1 years), we quantified 12 key proteins involved in cell metabolism, division, proliferation, steroidogenesis (including steroid acute regulatory protein, StAR), oxidative stress, and glucocorticoid and mitochondrial function. Life-course abundance of ten ZF proteins decreased with age. Cell cycle inhibitor and oxidative stress markers increased. Seven of the 12 proteins changed in the same direction for ZR and ZF. Importantly, ZF StAR decreased while ZR StAR was unchanged. Findings indicate ZF function decreased, and less markedly ZR function, with age. Causes and aging consequences of these changes remain to be determined.

physiology↗

bioRxiv2023

Frequency-dependent selection of neoantigens fosters tumor immune escape and predicts immunotherapy response

Cancer is an evolutionary process undergoing stringent immune selection. However, recent studies have revealed that certain tumors undergo neutral evolution following the malignant transformation. Here, we propose negative frequency-dependent selection (or NFDS), where the immune response against cancer cells depends on the clonality of neoantigens, can lead to an immunogenic landscape that is similar to neutral evolution. With a stochastic model of NFDS, we demonstrated that NFDS promotes early immune evasion in hypermutable tumors, leading to neutral-like evolutionary dynamics with high antigenic heterogeneity and worse response to immune checkpoint blockade (ICB) therapy. Our model also revealed that NFDS is characterized by a negative association between average clonality and total burden of neoantigens. Indeed, NFDS was validated with whole-exome sequencing datasets (357 tumor samples from 275 patients) from four melanoma cohorts with ICB therapy. Altogether, our study provides the first quantitative evidence supporting the theory of NFDS in immune-driven cancer evolution. These findings highlight the critical role of NFDS theory in devising more efficient and predictive immunotherapies.

cancer biology↗

bioRxiv2023

Fast and flexible joint fine-mapping of multiple traits via the Sum of Single Effects model

We introduce mvSuSiE, a multi-trait fine-mapping method for identifying putative causal variants from genetic association data (individual-level or summary data). mvSuSiE learns patterns of shared genetic effects from data, and exploits these patterns to improve power to identify causal SNPs. Comparisons on simulated data show that mvSuSiE is competitive in speed, power and precision with existing multi-trait methods, and uniformly improves over single-trait fine-mapping (SuSiE) performed separately for each trait. We applied mvSuSiE to jointly finemap 16 blood cell traits using data from the UK Biobank. By jointly analyzing the traits and modeling heterogeneous effect sharing patterns, we discovered a much larger number of causal SNPs (>3,000) compared with single-trait fine-mapping, and with narrower credible sets. mvSuSiE also more comprehensively characterized the ways in which the genetic variants affect one or more blood cell traits; 68% of causal SNPs showed significant effects in more than one blood cell type.

genomics↗

bioRxiv2023

Biosynthesis of plant papanridins -A group of novel oligomeric flavonoids

Discovery of novel flavonoids and their biosynthesis are fundamental to understand their roles in plants and benefits to human and animal health. Herein, we report a new polymerization pathway of a group of novel oligomeric flavonoids in plants. We have engineered red cells for discovering genes of interest involved in the flavonoid pathway and identified a gene that encodes a novel flavanol polymerase (FP) localized in the central vacuole. FP catalyzes the polymerization of flavanols, such as epicatechin and catechin, to produce yellowish dimers or oligomers. Structural elucidation show that these compounds are featured with a novel oligomeric flaven-flavan (FF) skeleton linked by interflavan-flaven and interflaven bonds, which are different from proanthocyanidins and dehydrodicatechins. Detailed chemical and physical characterizations further demonstrate that FFs are novel flavonoids. Mechanistic investigations show that FP polymerizes flavan-3-ols and flav-2-en-3-ol carbocation to form dimeric or oligomeric flaven-4[->]8-flavans, termed as papanridins. Data from transgenic, mutation, metabolic profiling, and phylogenetic analyses demonstrate that the biosynthesis of papanridins is prevalent in cacao, grape, blue berry, corn, rice, Arabidopsis and others in the plant kingdom. Given that these findings are the first report, many questions remain for answers. For instance, what are roles of papanridins in plants and what benefits do they have for human and animal health? We anticipate that these findings will promote investigations across plant, nutritional, and animal sciences to understand papanridins in plants and food products. TeaserPlant flavanol polymerase catalyzes the biosynthesis of novel oligomeric flavonoids in the plant kingdom.

plant biology↗

bioRxiv2022

LinguaPhylo: a probabilistic model specification language for reproducible phylogenetic analyses

Phylogenetic models have become increasingly complex, and phylogenetic data sets have expanded in both size and richness. However, current inference tools lack a model specification language that can concisely describe a complete phylogenetic analysis while remaining independent of implementation details. We introduce a new lightweight and concise model specification language, LPhy, which is designed to be both human and machine-readable. A graphical user interface accompanies LPhy, allowing users to build models, simulate data, and create natural language narratives describing the models. These narratives can serve as the foundation for manuscript method sections. Additionally, we present a command-line interface for converting LPhy-specified models into analysis specification files (in XML format) compatible with the BEAST2 software platform. Collectively, these tools aim to enhance the clarity of descriptions and reporting of probabilistic models in phylogenetic studies, ultimately promoting reproducibility of results.

evolutionary biology↗

bioRxiv2022

Seasonality but not photoperiodism affects susceptibility of the two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae) to pesticides

Understanding how endogenous and exogenous factors such as annual seasonal rhythm and photoperiodism affect the toxicity of pesticides can help design integrated pest management strategies. The two-spotted spider mite Tetranychus urticae Koch (Acari: Tetranychidae), a worldwide phytophagous pest species distributed in areas with different time zones, is a good model to explore how the photoperiodism and seasonality affect the pesticide toxicity. In this study, we conducted a laboratory experiment from March 2017 to November 2018 where spider mites were reared at three photoperiod regimes in environmentally controlled incubators. The toxicities of two acaricides, propargite and diafenthiruon, were measured on T. urticae every month. To determine potential mechanisms underlying the changes in the acaricide toxicity, we measured body size and total GSTs activity with the toxicity measurements in 2018. Our results showed that the toxicities of the two acaricides were not significantly different among the three photoperiod regimes. However, both had a consistent trend along the season which increased in the spring and summer and decreased in the winter in all photoperiod regimes for two consecutive years, suggesting seasonality be an endogenous factor affecting the susceptibility of the spider mites to pesticide. Pearsons correlation analyses showed only the body size had a weak negative correlation with the acaricide toxicities, suggesting a minor contribution to the higher toxicity from the smaller size of T. urticae. Our study is the first to show that seasonality can have an endogenous effect on the pesticide toxicity, and the results can inform practical insights into the pest management strategies.

zoology↗

bioRxiv2022

Introduction of a condensed, reverse tricarboxylic acid cycle for additional CO2 fixation in plants

Plants employ the Calvin-Benson cycle (CBC) to fix atmospheric CO2 for the production of biomass. The flux of carbon through the CBC is limited by the activity and selectivity of ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO). Alternative pathways that do not use RuBisCO to fix CO2 exist but occur only in anaerobic microorganisms. Rather than modifying existing routes of carbon metabolism in plants, we have developed a synthetic carbon fixation cycle that does not exist in nature, but is inspired by metabolisms of bacterial autotrophs. This synthetic cycle uses endogenous plant metabolites to fix CO2 and yield glyoxylate as a product. In this work, we build and characterize a condensed, reverse tricarboxylic acid (crTCA) cycle in vitro and in planta. We demonstrate that a simple, synthetic cycle can be used to fix carbon in vitro under aerobic and mesophilic conditions and that these enzymes retain activity when expressed transiently in planta. We then evaluate stable transgenic lines of Camelina sativa that have both phenotypic and physiologic changes. Transgenic C. sativa are shorter than controls with increased rates of photosynthetic CO2 assimilation and changes in photorespiratory metabolism. This first iteration of a build-test-learn phase of the crTCA cycle provides promising evidence that this pathway can be used to increase photosynthetic capacity in plants.

plant biology↗

bioRxiv2022

Metabolic Engineering of Oleaginous Yeast Rhodotorula toruloides for Overproduction of Triacetic Acid Lactone

The plant-sourced polyketide triacetic acid lactone (TAL) has been recognized as a promising platform chemical for the biorefinery industry. However, its practical application was rather limited due to low natural abundance and inefficient cell factories for biosynthesis. Here we report the metabolic engineering of oleaginous yeast Rhodotorula toruloides for TAL overproduction. We first introduced a 2-pyrone synthase gene from Gerbera hybrida (GhPS) into R. toruloides and investigated the effects of different carbon sources on TAL production. We then systematically employed a variety of metabolic engineering strategies to increase the flux of acetyl-CoA by enhancing its biosynthetic pathways and disrupting its competing pathways. We found that overexpression of citrate lyase (ACL1) improved TAL production by 45% compared to the GhPS overexpressing strain, and additional overexpression of acetyl-CoA carboxylase (ACC1) further increased TAL production by 29%. Finally, we characterized the resulting strain I12-ACL1-ACC1 using fed-batch bioreactor fermentation in glucose or oilcane juice medium with acetate supplementation and achieved a titer of 28 g/L or 23 g/L TAL, respectively. This study demonstrates that R. toruloides is a promising host for production of TAL and other acetyl-CoA-derived polyketides from low-cost carbon sources. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/481788v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@32eb52org.highwire.dtl.DTLVardef@f786dborg.highwire.dtl.DTLVardef@b6d3f5org.highwire.dtl.DTLVardef@115aa67_HPS_FORMAT_FIGEXP M_FIG C_FIG Triacetic acid lactone (TAL) is a promising platform chemical. Cao et al. overexpressed 2-pyrone synthase in oleaginous yeast Rhodotorula toruloides to produce TAL. They systematically evaluated various metabolic gene targets to increase acetyl-CoA and malonyl-CoA levels for TAL production and found that overexpression of both ACL1 and ACC1 led to 28 g/L or 23 g/L of TAL from glucose or oilcane juice with acetate supplementation, respectively, in fed-batch fermentation.

synthetic biology↗

bioRxiv2021

Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2

The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social and economic stability. In this study, we established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus S protein and its host receptor ACE2. This platform is a rapid, sensitive, specific, and high throughput system. With this platform, we screened two compound libraries of 2,864 molecules and identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S-protein and the human cell ACE2 receptor. This data suggests that TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug. SIGNIFICANCEThe ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. In this present study, we screened two compound libraries of 2,864 molecules and identified a potent inhibitor (TS-984) for blocking the coronavirus S-protein and the human cell ACE2 receptor. TS-984 might have the potential to be developed into an effective anti-coronavirus drug for treating COVID-19.

pharmacology and toxicology↗

bioRxiv2021

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

bioRxiv2021

Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis

The chromatin state undergoes global and dynamic changes during spermatogenesis, and is critical to chromosomal synapsis, meiotic recombination, and transcriptional regulation. However, the key regulators involved and the underlying molecular mechanisms remain poorly understood. Herein we report that mouse BEND2, one of the BEN-domain-containing proteins conserved in vertebrates, was specifically expressed in spermatogenic cells within a short time-window spanning meiotic initiation, and that it plays an essential role in the progression of prophase in meiosis I. Bend2 gene knockout in male mice arrested meiosis at the transition from zygonema to pachynema, disrupted synapsis and DNA double-strand break repair, and induced non-homologous chromosomal pairing. BEND2 interacted with a number of chromatin-associated proteins--including ZMYM2, LSD1, CHD4, and ADNP-- which are components of certain transcription-repressor complexes. BEND2-binding sites were identified in diverse chromatin states and enriched in simple sequence repeats. BEND2 contributed to shutting down the mitotic gene-expression program and to the activation of meiotic and post-meiotic gene expression, and it regulated chromatin accessibility as well as the modification of H3K4me3. Therefore, our study identified BEND2 as a novel and key regulator of meiosis, gene expression, and chromatin state during mouse spermatogenesis. TeaserMeiosis is a highly complex yet poorly understood process that involves the concerted actions of an increasing number of regulators, of which the list remains incomplete. Ma et al. identified BEND2 as a novel and key regulator of meiosis and showed that it interacts with critical chromatin modulators and specific genomic elements to control the expression of mitotic and meiotic genes.

developmental biology↗

bioRxiv2021

Inhibition of Kallikrein-related peptidases 7 restrains pancreatic tumor growth through induction of ferroptosis

Pancreatic cancer is one of the most aggressive and lethal malignancies with extremely poor prognosis, and KLK7 was considered as a potential therapeutic target. In this study, we analyzed the expression of KLK7 in TCGA and GTEx databases and found that KLK7 had a negative correlation to long-term survival rate (>1.5 years) of pancreatic cancer patients. Compound 42 is a coumarinic derivative, a suicide substrate inhibitor of KLK7, which has been proved to inhibit the proliferation of PANC-1 cells in vitro effectively in our previous study. In this study, we further investigated the inhibition ability of Compound 42 in tumor formation and development in CDX and PDX tumor models of pancreatic cancer subsequently. Besides, we studied the inhibitory mechanism of Compound 42 and the result showed that Compound 42 arrested the pancreatic cancer cell cycle in G0/G1 phase and induced ferroptosis through down-regulation of GPX4 protein level and accumulation of iron ion. Thus, these experiments demonstrate that Compound 42, suppressing pancreatic cancer in vivo, is expected to become a novel drug for pancreatic cancer treatment.

molecular biology↗

bioRxiv2021

Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E

Since December 2019, the deadly novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 pandemic. To date, vaccines are available in the developed countries to prevent the infection of this virus, however, medicines are necessary to help control COVID-19. Human coronavirus 229E (HCoV-229E) causes the common cold. The main protease (Mpro) is an essential enzyme required for the multiplication of these two viruses in the host cells, and thus is an appropriate candidate to screen potential medicinal compounds. Flavonols and dihydroflavonols are two groups of plant flavonoids. In this study, we report docking simulation with two Mpro enzymes and five flavonols and three dihydroflavonols, in vitro inhibition of the SARS-CoV-2 Mpro, and in vitro inhibition of the HCoV 229E replication. The docking simulation results predicted that (+)-dihydrokaempferol, (+)-dihydroquercetin, (+)-dihydromyricetin, kaempferol, quercetin, myricentin, isoquercetin, and rutin could bind to at least two subsites (S1, S1, S2, and S4) in the binding pocket and inhibit the activity of SARS-CoV-2 Mpro. Their affinity scores ranged from -8.8 to -7.4. Likewise, these compounds were predicted to bind and inhibit the HCoV-229E Mpro activity with affinity scores ranging from -7.1 to -7.8. In vitro inhibition assays showed that seven available compounds effectively inhibited the SARS-CoV-2 Mpro activity and their IC50 values ranged from 0.125 to 12.9 {micro}M. Five compounds inhibited the replication of HCoV-229E in Huh-7 cells. These findings indicate that these antioxidative flavonols and dihydroflavonols are promising candidates for curbing the two viruses.

biochemistry↗

bioRxiv2021

DAB2IP inhibits p53 ubiquitin-mediated degradation by competitively binding to GRP75 and suppresses tumor malignancy in colon cancer

Increasing evidence has shown that DAB2IP acts as a tumor suppressor and plays an inhibition role in many tumors. However, the underlying mechanism is still uncertain. Our study shows that DAB2IP is positively associated with a better prognosis in colon cancer patients with wild-type TP53 expression. In vitro assay shows that DAB2IP elicits potent tumor-suppressive effects on inhibiting cell invasiveness, colony formation and promoting cell apoptosis in wild-type TP53 colon cancer cell lines. Subsequently, DAB2IP is demonstrated to up-regulate the stability of wild-type TP53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner. Using mass spectrometry profiling, we unveil that DAB2IP and p53 could both interact with the ubiquitin ligase-related protein, GRP75. Mechanistically, DAB2IP could competitively bind with GRP75, thus reducing GRP75-mediated p53 ubiquitination and degradation. Finally, animal experiments also reveal that DAB2IP inhibits the tumor progression in vivo. In conclusion, our study presents a novel function of DAB2IP in GRP75-driven wild-type p53 degradation, which provides a new insight in DAB2IP-induced tumor suppression and provides a novel molecular aspect of the p53 pathway.

cancer biology↗