Biology subjects

Yuan, X.

Publications and source records attributed to Yuan, X..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Mitigating Cellular Dysfunction by Addressing Contaminants in Synthetic circRNA

Synthetic circular RNA (circRNA) shows great potential in biomedical research and therapies, but impurities introduced during its synthesis can undermine circRNA efficacy. This study investigated the immunogenic potential of byproducts generated during its production. We found that trace amounts of double-stranded RNA in high molecular weight impurities, 5 triphosphates of uncircularized RNA or small intron fragments, and hydrolyzed RNA fragments significantly impact the functionality of circRNA by activating innate immune responses through the sensory molecules involved in RNA sensing. To address this, we developed a novel multi-step purification process that employs enzymatic treatments and cellulose-based filtration to selectively remove these detrimental contaminants. This tailored approach minimizes cellular immune reactions and substantially improves circRNA yields with up to more than 10 times increase. Our findings underscore the critical impact of precise contaminant management in enhancing the expression and potential therapeutic utility of circRNA. This suggests a new direction for optimizing their production for both research and clinical applications.

bioengineering↗

bioRxiv2024

Immune Cell Influence on Diffuse Large B-Cell Lymphoma: A Mendelian Randomization Analysis

ObjectiveTo elucidate the causal relationship between immune cells and diffuse large B-cell lymphoma (DLBCL), we conducted a Mendelian randomization analysis. MethodsMendelian randomization (MR) leverages genetic variants as instruments to infer causal effects from observational data. Here, we performed a two-sample MR analysis to assess the causal impact of 731 immune cell types on DLBCL. We employed various MR techniques, including the weighted median estimator (WME) and inverse variance weighting (IVW), and conducted sensitivity analyses to ensure result robustness. Additionally, reverse MR analysis was performed to explore the potential causal relationship between DLBCL and immune cells. ResultsWe identified seventeen immune features with causal links to DLBCL, categorized across various cellular groups: four in B cells, two in T cell maturation stages, six in Tregs, four in the TBNK group, and one in dendritic cells (DCs). Sensitivity analyses confirmed the absence of heterogeneity, horizontal pleiotropy, and bias in our findings. Reverse causal analysis revealed a causal association between DLBCL and one of the seventeen immune cell types identified. ConclusionsOur MR analysis of seventeen immune cell types uncovers the complex interactions between the immune system and DLBCL, providing crucial insights into the tumor microenvironment and potential avenues for targeted immunotherapy.

immunology↗

bioRxiv2024

Androgen deprivation-mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion

TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor (AR) regulated TMPRSS2 expression. T:E fusion is associated with PTEN loss, and is highly associated with decreased INPP4B expression, which together may compensate for ERG-mediated suppression of AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses IRS2 and AKT activation. In contrast, ERG downregulation did not increase INPP4B, suggesting its decrease is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression is decreased in PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a nonredundant function. As ERG in T:E fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in T:E fusion tumors. A T:E fusion positive PDX had increased AKT activity in vivo and response to AKT inhibition in vitro after androgen deprivation. Moreover, two clinical trials of neoadjuvant AR inhibition prior to radical prostatectomy showed greater increases in AKT activation in the T:E fusion positive versus negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR targeted therapy in T:E fusion PCa, and that these patients may most benefit from combination therapy targeting AR and AKT.

cancer biology↗

bioRxiv2024

Shared and Unique Neural Codes for Biological Motion Perception in Humans and Macaque Monkeys

Throughout evolution, living organisms have honed the ability to swiftly recognize biological motion (BM) across species. However, how the brain processes within- and cross-species BM, and the evolutionary progression of these processes, remain unclear. To investigate these questions, we examined brain activity in the lateral temporal areas of humans and monkeys as they passively observed upright and inverted human and macaque BM stimuli. In humans, the middle temporal area (hMT+) responded to both human and macaque BM stimuli, while the right posterior superior temporal sulcus (pSTS) exhibited selective responses to human BM stimuli. This selectivity was evidenced by an increased feedforward connection from hMT+ to pSTS during the processing of human BM stimuli. In monkeys, the MT region processed BM stimuli from both species, but no subregion in the STS anterior to MT was specific to conspecific BM stimuli. A comparison of these findings suggests that upstream brain regions (i.e., MT) may retain homologous functions across species, while downstream brain regions (i.e., STS) may have undergone differentiation and specialization throughout evolution. These results provide insights into the commonalities and differences in the specialized visual pathway engaged in processing within- and cross-species BMs, as well as their functional divergence during evolution.

neuroscience↗

bioRxiv2024

Unveiling Fine-scale Spatial Structures and Amplifying Gene Expression Signals in Ultra-Large ST slices with HERGAST

We propose HERGAST, a system for spatial structure identification and signal amplification in ultra-large-scale and ultra-high-resolution spatial transcriptomics data. To handle ultra-large ST data, we consider the divide and conquer strategy and devise a Divide-Iterate-Conque framework specially for spatial transcriptomics data analysis, which can also be adopted by other computational methods for extending to ultra-large-scale ST data analysis. To tackle the potential oversmoothing problem arising from data splitting, we construct a heterogeneous graph network to incorporate both local and global spatial relationships. In simulation, HERGAST consistently outperformed other methods across all settings with more than 10% average gaining. In real-world data, HERGASTs high-precision spatial clustering enabled finding SPP1+ macrophages intermingled in tumors in colorectal cancer, while the enhanced gene expression signal enabled discovering unique spatial expression pattern of key genes in breast cancer.

bioinformatics↗

bioRxiv2024

3D histology reveals that immune response to pancreatic precancers is heterogeneous and depends on global pancreas structure

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer for which few effective therapies exist. Immunotherapies specifically are ineffective in pancreatic cancer, in part due to its unique stromal and immune microenvironment. Pancreatic intraepithelial neoplasia, or PanIN, is the main precursor lesion to PDAC. Recently it was discovered that PanINs are remarkably abundant in the grossly normal pancreas, suggesting that the vast majority will never progress to cancer. Here, through construction of 48 samples of cm3-sized human pancreas tissue, we profiled the immune microenvironment of 1,476 PanINs in 3D and at single-cell resolution to better understand the early evolution of the pancreatic tumor microenvironment and to determine how inflammation may play a role in cancer progression. We found that bulk pancreatic inflammation strongly correlates to PanIN cell fraction. We found that the immune response around PanINs is highly heterogeneous, with distinct immune hotspots and cold spots that appear and disappear in a span of tens of microns. Immune hotspots generally mark locations of higher grade of dysplasia or locations near acinar atrophy. The immune composition at these hotspots is dominated by naive, cytotoxic, and regulatory T cells, cancer associated fibroblasts, and tumor associated macrophages, with little similarity to the immune composition around less-inflamed PanINs. By mapping FOXP3+ cells in 3D, we found that regulatory T cells are present at higher density in larger PanIN lesions compared to smaller PanINs, suggesting that the early initiation of PanINs may not exhibit an immunosuppressive response. This analysis demonstrates that while PanINs are common in the pancreases of most individuals, inflammation may play a pivotal role, both at the bulk and the microscopic scale, in demarcating regions of significance in cancer progression.

cancer biology↗

bioRxiv2024

FuncFetch: An LLM-assisted workflow enables mining thousands of enzyme-substrate interactions from published manuscripts

MotivationThousands of genomes are publicly available, however, most genes in those genomes have poorly defined functions. This is partly due to a gap between previously published, experimentally-characterized protein activities and activities deposited in databases. This activity deposition is bottlenecked by the time-consuming biocuration process. The emergence of large language models (LLMs) presents an opportunity to speed up text-mining of protein activities for biocuration. ResultsWe developed FuncFetch -- a workflow that integrates NCBI E-Utilities, OpenAIs GPT-4 and Zotero -- to screen thousands of manuscripts and extract enzyme activities. Extensive validation revealed high precision and recall of GPT-4 in determining whether the abstract of a given paper indicates presence of a characterized enzyme activity in that paper. Provided the manuscript, FuncFetch extracted data such as species information, enzyme names, sequence identifiers, substrates and products, which were subjected to extensive quality analyses. Comparison of this workflow against a manually curated dataset of BAHD acyltransferase activities demonstrated a precision/recall of 0.86/0.64 in extracting substrates. We further deployed FuncFetch on nine large plant enzyme families. Screening 27,120 papers, FuncFetch retrieved 32,605 entries from 5547 selected papers. We also identified multiple extraction errors including incorrect associations, non-target enzymes, and hallucinations, which highlight the need for further manual curation. The BAHD activities were verified, resulting in a comprehensive functional fingerprint of this family and revealing that [~]70% of the experimentally characterized enzymes are uncurated in the public domain. FuncFetch represents an advance in biocuration and lays the groundwork for predicting functions of uncharacterized enzymes. Availability and ImplementationCode and minimally-curated activities available at: https://github.com/moghelab/funcfetch and https://tools.moghelab.org/funczymedb

bioinformatics↗

bioRxiv2024

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate specific neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the telencephalic interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic interneurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

neuroscience↗

bioRxiv2024

A foundation model for generalizable cancer diagnosis and survival prediction from histopathological images

Computational pathology, utilizing whole slide image (WSI) for pathological diagnosis, has advanced the development of intelligent healthcare. However, the scarcity of annotated data and histological differences hinder the general application of existing methods. Extensive histopathological data and the robustness of self-supervised models in small-scale data demonstrate promising prospects for developing foundation pathology models. Due to the need for deployment, lightweight foundation models also need to be developed. In this work, we propose the BEPH (BEiT-based model Pre-training on Histopathological images), a general lightweight foundation model that leverages self-supervised learning to learn meaningful representations from 11 million unlabeled histopathological images. These representations are then efficiently adapted to various tasks, including 2 cancer patch-level recognition tasks, 3 cancer WSI-level classification tasks, and 6 cancer subtypes survival prediction tasks. Experimental results demonstrate that our model consistently outperforms several comparative models with similar parameters, even with limited training data reduced to 50%. Especially when the downstream structure is the same, the model can improve ResNet and DINO by up to a maximum increase of 8.8% and 7.2% (WSI level classification), and 6.44% and 3.28% on average (survival prediction), respectively. Therefore, BEPH offers a universal solution to enhance model performance, reduce the burden of expert annotations, and enable widespread clinical applications of artificial intelligence. The code and models can be obtained at https://github.com/Zhcyoung/BEPH. And currently, online fine-tuning of WSI classification tasks is available for use on http://yulab-sjtu.natapp1.cc/BEPH.

pathology↗

bioRxiv2024

A duplexed CRISPRi-based approach to predict synergistic antibiotic targets in Escherichia coli.

Co-repressing drug targets with CRISPR interference (CRISPRi) has the potential to predict both synergistic and additive drug combinations. In a screen experiment with Escherichia coli, pairwise gene co-repression assays correctly predicted the interaction type observed for 36 antibiotic pairs in checkerboard assays. Furthermore, we used this approach to identify promising synergistic interactions with a gene currently not targeted by clinical antibiotics. CRISPRi can systematically test the impact of gene inhibitions and identify novel drug targets.

microbiology↗

bioRxiv2024

Hypergraph Cortical Cytoarchitectonic Parcellation with Multimodal Canine Brain Atlas

Brain atlases are vital tools in exploring the brain structure-function relationship. The burgeoning cross-species atlases have significantly accelerated our understanding of human brain development, evolution, function, and diseases. However, the existing coarse-grained macroscopic canine brain atlases greatly constrain their utility as an animal model for neurocognition research. Finer-grained brain atlas and partitions are crucial for decoding brain spatial heterogeneity and topology at different scales. Therefore, we conduct macroscopic and microscopic brain imaging to construct an interactive online dataset of multimodal canine brain atlas. Additionally, we develop a pioneering method for cortical cytoarchitectonic partitioning based on hypergraph learning. By integrating high-dimensional cytoarchitectonic features and spatial connections between cortical columns, the method leads to fine-grained partitioning patterns. This innovative approach aims to decode the biological heterogeneity of cortical microstructures, contributing to the structural annotation of canine atlas as well as public human brain atlases. The study not only offers valuable resources but also presents a novel zonation approach to investigate the cellular organization pattern and topology of the cortex.

neuroscience↗

bioRxiv2024

siRNADesign: A Graph Neural Network for siRNA Efficacy Prediction via Deep RNA Sequence Analysis

The clinical adoption of small interfering RNAs (siRNAs) has prompted the development of various computational strategies for siRNA design, from traditional data analysis to advanced machine learning techniques. However, previous studies have inadequately considered the full complexity of the siRNA silencing mechanism, neglecting critical elements such as siRNA positioning on mRNA, RNA base-pairing probabilities, and RNA-AGO2 interactions, thereby limiting the insight and accuracy of existing models. Here, we introduce siRNADesign, a Graph Neural Network (GNN) framework that leverages both non-empirical and empirical rules-based features of siRNA and mRNA to effectively capture the complex dynamics of gene silencing. In multiple internal datasets, siRNADesign achieves state-of-the-art performance. Significantly, siRNADesign also outperforms existing methodologies in in vitro wet lab experiments and an externally validated dataset. Additionally, we develop a new data-splitting methodology that addresses the data leakage issue, a frequently overlooked issue in previous studies, ensuring the robustness and stability of our model under various experimental settings. Through rigorous testing, siRNADesign has demonstrated remarkable predictive accuracy and robustness, making significant contributions to the field of gene silencing. Furthermore, our approach in redefining data-splitting standards aims to set new benchmarks for future research in the domain of predictive biological modeling for siRNA.

bioinformatics↗

bioRxiv2024

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC. SummaryIn neutrophil-enriched triple-negative breast cancer (TNBC) models, CREB binding protein (CBP)/P300 bromodomain (BRD) inhibition reduces tumor growth and systemic neutrophil accumulation while stimulating an antitumor immune response. This improves standard-of-care therapies, suggesting a potential therapeutic benefit of CBP/P300 BRD inhibitors for neutrophil-enriched TNBC.

cancer biology↗

bioRxiv2024

Identification of Glucosidase II that regulates STIM1 activation dynamics

The ubiquitous presence of stromal interaction molecule (STIM), endoplasmic reticulum (ER) Ca2+ sensors, plays a crucial role for maintaining Ca2+ homeostasis and signaling in mammalian cells by linking ER Ca2+ depletion with extracellular Ca2+ influx. Although recent advancements have shed light on glycosylation in STIM proteins, further exploration of deglycosylation enzyme modification and its role remains limited by methodological constraints. In this study, leveraging the miniTurbo-driven proximal biotinylation labeling method, we were able to screen for weak and transiently binding protein molecules within specific environments like ER lumina. Herein, we unveil glucosidase II, comprising GANAB and PRKCSH, as a novel partner of the STIM1 complex. Through investigations into Glucosidase IIs (Glu II) regulation of STIM1s Ca2+ affinities both in cellulo and in situ, alongside its impact on store-operated Ca2+ entry (SOCE), we propose a novel mechanism wherein Glu II governs STIM1 activation by modulating Ca2+ binding affinity, thereby adjusting the level of activated STIM1 in response to physiological stimulation.

cell biology↗

bioRxiv2024

A conserved genetic basis for commensal-host specificity through live imaging of colonization dynamics

Animals throughout the metazoa selectively acquire specific symbiotic gut bacteria from their environment that aid host fitness. Current models of colonization suggest these bacteria use weakly specific receptors to stick to host tissues and that colonization results when they stick in a region of the host gut that overlaps with their nutritional niche. An alternative model is that unique receptor-ligand binding interactions provide specificity for target niches. Here we use live imaging of individual symbiotic bacterial cells colonizing the gut of living Drosophila melanogaster to show that Lactiplantibacillus plantarum specifically recognizes a distinct physical niche in the host gut. We find that recognition is controlled by a colonization island that is widely conserved in commensals and pathogens from the Lactobacillales to the Clostridia. Our findings indicate a genetic mechanism of host specificity that is broadly conserved. One-Sentence SummaryHost-symbiont specificity is encoded by a conserved colonization island that provides molecular precision to host niche access.

microbiology↗

bioRxiv2024

A single-nucleus RNA sequencing atlas of the postnatal retina of the shark Scyliorhinus canicula

The retina, whose basic cellular structure is highly conserved across vertebrates, constitutes an accessible system for studying the central nervous system. In recent years, single-cell RNA-sequencing studies have uncovered cellular diversity in the retina of a variety of species, providing new insights on retinal evolution and development. However, similar data in cartilaginous fishes, the sister group to all other extant jawed vertebrates, are still lacking. Here, we present a single-nucleus RNA-sequencing atlas of the postnatal retina of the catshark Scyliorhinus canicula, consisting of the expression profiles for 17,438 individual cells from three female, juvenile catshark specimens. Unsupervised clustering revealed 22 distinct cell types comprising all major retinal cell classes, as well as retinal progenitor cells (whose presence reflects the persistence of proliferative activity in postnatal stages in sharks) and oligodendrocytes. Thus, our dataset serves as a foundation for further studies on the development and function of the catshark retina. Moreover, integration of our atlas with data from other species will allow for a better understanding of vertebrate retinal evolution.

neuroscience↗

bioRxiv2024

Mapping the breast tumor microenvironment: proximity analysis reveals spatial relationships between macrophage subtypes and metastasis-initiating cancer cells

The development of metastasis, responsible for the majority of cancer-related fatalities, is the most dangerous aspect of breast cancer, the predominant malignancy affecting women. We previously identified specific cancer cell populations responsible for metastatic events which are cytokeratin-14 (CK14) and E-cadherin positive in luminal tumors, and E-cadherin and vimentin positive in triple-negative tumors. Since cancer cells evolve within a complex ecosystem comprised of immune cells and stromal cells, we sought to decipher the spatial interactions of these aggressive cancer cell populations within the tumor microenvironment (TME). We used imaging mass cytometry to detect 36 proteins in tumor microarrays containing paired primary and metastatic lesions from luminal or triple-negative breast cancers (TNBC), resulting in a dataset of 1,477,337 annotated cells. Focusing on metastasis-initiating cell populations, we observed close proximity to specific fibroblast and macrophage subtypes, a relationship maintained between primary and metastatic tumors. Notably, high CK14 in luminal cancer cells and high vimentin in TNBC cells correlated with close proximity to specific macrophage subtypes (CD163intCD206intPDL1intHLA-DR+ or PDL1highARG1high). Our in-depth spatial analysis elucidates that metastasis-initiating cancer cells exhibit with distinct cell populations within the TME, implicating the role of these cell-cell interactions in promoting metastasis.

cancer biology↗

bioRxiv2024

Integrated multi-omics analysis of Klebsiella pneumoniae revealed the discrepancy in flavonoid effect against strain growth between Rutin and Luteolin

The emergence of drug resistant pathogenic bacteria is increasingly challenging conventional antibiotics. Plant derived flavonoids are always considered as potential alternatives to antibiotics due to their antimicrobial properties. However, the molecular mechanisms by which flavonoids inhibit pathogenic microorganisms growth are not fully understood. In order to better understand the inhibitory mechanism of flavonoids, two flavonoids were used to incubate Klebsiella pneumoniae ATCC700603. After incubation for 4 hours, both the metabolomic and transcriptomic analysis were performed. In present study, 5,483 genes and 882 metabolites were measured. Compared to wild control, the Rutin and Luteolin induced 507 and 374 differentially expressed genes (DEGs), respectively. However, the number of differential abundant metabolites (DAMs) were the same. The correlation between DEGs and DAMs were studied. The top 10 correlated DEGs and DAMs were identified in each comparative groups. Our results showed that, compared to Luteolin, Rutin induced the accumulation of metabolites and suppressed genes expression. Our results provided an explanation for the disparate effects of two flavonoids and demonstrated the inhibitory mechanism of Rutin on strain growth.

bioinformatics↗