Biology subjects

Cheung, E.

Publications and source records attributed to Cheung, E..

11 recordsLinked to original sources

bioRxiv2026

An interoperable research agent network for scientific discovery

Recent advances in agentic systems have enabled the autonomous execution of research tasks across scientific domains. However, the rapid emergence of specialized scientific agents for areas such as computational pathology, microbiome research, gene editing, materials science, organic chemistry, and drug discovery has created a fragmented ecosystem of scientific capabilities. While these agents often demonstrate strong performance within their respective domains, limited interoperability makes it difficult to combine expertise across platforms and coordinate complex interdisciplinary workflows. Here we introduce GUIA (Guided-research Utilizing Intelligent Agents), an interoperable research-agent network built upon a flexible Agent-to-Agent (A2A) communication architecture. GUIA enables both in-house and third-party agents to collaborate within shared workflows, allowing scientific capabilities to accumulate through the integration of complementary expertise. We evaluated GUIA through four assessments spanning baseline benchmarking, third-party single-agent integration, third-party multi-agent integration, and cross-server agent collaboration. Furthermore, we demonstrate its practical utility through real-world applications involving therapeutic target discovery, drug discovery, and spatial proteomics analysis. Together, our results show that interoperable research-agent networks can coordinate specialized expertise across independently developed systems, providing a scalable framework for expanding scientific capabilities through collaboration.

bioinformatics↗

bioRxiv2024

Mapping Plasmodium transitions and interactions in the Anopheles female

The human malaria parasite, Plasmodium falciparum, relies exclusively on Anopheles mosquitoes for transmission. Once ingested during blood feeding, most parasites die in the mosquito midgut lumen or during epithelium traversal1. How surviving ookinetes interact with midgut cells and form oocysts is poorly known, yet these steps are essential to initiate a remarkable growth process culminating in the production of thousands of infectious sporozoites2. Here, using single-cell RNA sequencing of both parasites and mosquito cells across different developmental stages and metabolic conditions, we unveil key transitions and mosquito-parasite interactions occurring in the midgut. Functional analyses uncover processes regulating oocyst growth and identify the transcription factor PfSIP2 as essential for sporozoite infection of human hepatocytes. Combining shared mosquito-parasite barcode analysis with confocal microscopy, we reveal that parasites preferentially interact with midgut progenitor cells during epithelial crossing, potentially using their basal location as an exit landmark. Additionally, we show tight connections between extracellular late oocysts and surrounding muscle cells that may ensure parasites adherence to the midgut. We confirm our major findings in several mosquito-parasite combinations, including field-derived parasites. Our study provides fundamental insight into the molecular events characterizing previously inaccessible biological transitions and mosquito-parasite interactions, and identifies candidates for transmission-blocking strategies.

microbiology↗

bioRxiv2024

Sex-specific chemosensory gene expression in the whitelined sphinx moth (Lepidoptera: Hyles lineata) suggests a role for odorant-binding proteins in host plant choice

The whitelined sphinx moth, Hyles lineata, is a generalist during both the larval and adult stages with a broad geographic range extending across North and Central America. Within the genus Hyles there have been multiple transitions to a narrower host plant range, making Hyles an ideal group to study the evolution and mechanisms of host plant selection. We characterize sex- and appendage-specific chemosensory gene expression in H. lineata, the oldest extant member of the genus. We also describe female-specific gene expression in appendages used to sense plant surfaces as a means of identifying candidate genes involved in host plant choice. Sensilla on these appendages house sensory neurons and support cells that express chemosensory genes, receptors, and small proteins that bind, shuttle, and transport small molecules to allow detection of odorants and other small molecules. We considered genes detected more frequently in the female leg and ovipositor samples to be candidate oviposition-relevant genes. Most chemosensory genes of interest were detected in both sexes, while several odorant receptors were only detected in females. We identified 18 putative chemosensory genes that were specific to female legs, ovipositors, or both body parts. However, most of these genes did not reach statistical criteria to be considered differentially expressed. Instead, a set of OBPs show statistically significant female-biased expression in legs and ovipositors. These genes may serve as candidates for future study of the evolution and mechanisms of oviposition behavior in this species and its relatives. SummaryThe sphinx moth genus Hyles contains both generalist and specialized feeders, making it an ideal system to study the evolution of host plant breadth. The whitelined sphinx moth (Hyles lineata) is a generalist feeder at both adult and larval stages and is the oldest lineage of the genus. In this analysis of sex-specific gene expression, Godfrey and colleagues identify several odorant binding proteins as being more frequently detected in female appendages used to assess host plants. These genes could play a role in host plant selection and can be targets for future mechanistic studies on this species.

evolutionary biology↗

bioRxiv2024

Marsilea: An intuitive generalized visualization paradigm for complex datasets

Contemporary data visualization is challenged by the growing complexity and size of datasets, often comprising numerous interrelated features. Traditional visualization methods struggle to capture these complex relationships fully or are specialized to a domain requiring familiarity with multiple visualization tools. We introduce a novel and intuitive general visualization paradigm, termed "cross-layout visualization", which integrates multiple plot types in a cross-like structure. This paradigm allows for a central main plot surrounded by secondary plots, each capable of layering additional features for enhanced context and understanding. To operationalize this paradigm, we present "Marsilea", a Python library designed for creating complex visualizations with ease. Marsilea is notable for its modularity, diverse plot types, compatibility with various data formats, and is available in a coding-free web-based interface for users of all experience levels. We showcase its versatility and broad applicability by re-creating existing visualizations and creating novel visualizations that include elements such as heatmaps, sequence motifs, and set intersections that are typically beyond the scope of existing general visualization tools. The cross-layout paradigm, exemplified by Marsilea, offers a flexible, customizable, and intuitive approach to complex data visualization, promising to enhance data analysis across scientific domains.

bioinformatics↗

bioRxiv2023

Comprehensive characterization of the integrin family across 32 cancer types

Integrin genes widely involve in tumorigenesis. Yet, a comprehensive characterization of integrin family and their interactome on the pan-cancer level is lacking. Here, we systematically dissect integrin family in nearly 10000 tumors across 32 cancer types. Globally, integrins represent a frequently altered and misexpressed pathway, with alteration and dysregulation overall being protumorigenic. Expression dysregulation, better than mutational landscape, of integrin family successfully identifies a subgroup of aggressive tumors demonstrating a high level of proliferation and stemness. We identify that several molecular mechanisms jointly regulate integrin expression in a context-dependent manner. For potential clinical usage, we construct a weighted score, integrinScore, to measure integrin signaling patterns in individual tumors. Remarkably, integrinScore consistently correlates with predefined molecular subtypes in multiple cancers, with integrinScore high tumors being more aggressive. Importantly, integrinScore is cancer-dependently and closely associated with proliferation, stemness, tumor microenvironment, metastasis, and immune signatures. IntegrinScore also predicts patients response to immunotherapy. By mining drug databases, we unravel an array of compounds that may serve as integrin signaling modulators. Finally, we build a user-friendly database to facilitate researchers to explore integrin-related knowledge. Collectively, we provide a comprehensive characterization of integrins across cancers, which offers gene- and cancer-specific rationales for developing integrin-targeted therapy.

bioinformatics↗

bioRxiv2023

Single cell analyses of cancer cells identified two regulatorily and functionally distinct categories in differentially expressed genes among tumor subclones

To explore the feature of cancer cells and tumor subclones, we analyzed 101,065 single-cell transcriptomes from 12 colorectal cancer (CRC) patients and 92 single cell genomes from one of these patients. We found cancer cells, endothelial cells and stromal cells in tumor tissue expressed much more genes and had stronger cell-cell interactions than their counterparts in normal tissue. We identified copy number variations (CNVs) in each cancer cell and found correlation between gene copy number and expression level in cancer cells at single cell resolution. Analysis of tumor subclones inferred by CNVs showed accumulation of mutations in each tumor subclone along lineage trajectories. We found differentially expressed genes (DEGs) between tumor subclones had two populations: DEGCNV and DEGreg. DEGCNV, showing high CNV-expression correlation and whose expression differences depend on the differences of CNV level, enriched in housekeeping genes and cell adhesion associated genes. DEGreg, showing low CNV-expression correlation and mainly in low CNV variation regions and regions without CNVs, enriched in cytokine signaling genes. Furthermore, cell-cell communication analyses showed that DEGCNV tends to involve in cell-cell contact while DEGreg tends to involve in secreted signaling, which further support that DEGCNV and DEGreg are two regulatorily and functionally distinct categories.

genomics↗

bioRxiv2021

PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrate that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B-cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme in this pathway, leads to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis is a characteristic of germinal center B-cell derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induces apoptosis in lymphoma cells reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

immunology↗

bioRxiv2021

A programmable system to methylate and demethylate m6A on specific mRNAs

RNA N6-Methyladenosine (m6A) is the most abundant mRNA modification, and forms part of an epitranscriptomic system that modulates RNA function. RNA modifications can be reversibly catalyzed by several specific enzymes, and those modifications can be recognized by RNA binding proteins that in turn regulate biological processes. Although there are many reports demonstrating m6A participation in critical biological functions, this exploration has mainly been conducted through the global knockout or knockdown of the writers, erasers, or readers of m6A. Consequently, there is a lack of information about the role of m6A on single transcripts in biological processes, posing a challenge in understanding the biological functions of m6A. Here, we demonstrate a CRISPR/dCas13a-based RNA m6A-editor which can target mRNAs using single crRNA or multiple crRNAs array to methylate or demethylate m6A. We systematically assay its capabilities to enable the targeted rewriting of m6A dynamics, including modulation of circular RNA translation and transcript half-life. Finally, we demonstrate the utility of the system by specifically modulating XIST m6A levels, which can control X chromosome silencing and activation. Based on our editors, m6A on single and multiple transcripts can be modified to allow the exploration of the role of m6A on in biological processes.

cell biology↗

bioRxiv2020

Systematic Chromatin Architecture Analysis in Xenopus tropicalis Reveals Conserved Three-Dimensional Folding Principles of Vertebrate Genomes

Metazoan genomes are folded into 3D structures in interphase nuclei. However, the molecular mechanism remains unknown. Here, we show that topologically associating domains (TADs) form in two waves during Xenopus tropicalis embryogenesis, first at zygotic genome activation and then as the expression of CTCF and Rad21 is elevated. We also found TAD structures continually change for at least three times during development. Surprisingly, the directionality index is preferentially stronger on one side of TADs where orientation-biased CTCF and Rad21 binding are observed, a conserved pattern that is found in human cells as well. Depletion analysis revealed CTCF, Rad21, and RPB1, a component of RNAPII, are required for the establishment of TADs. Overall, our work shows that Xenopus is a powerful model for chromosome architecture analysis. Furthermore, our findings indicate that cohesin-mediated extrusion may anchor at orientation-biased CTCF binding sites, supporting a CTCF-anchored extrusion model as the mechanism for TAD establishment.

genetics↗

bioRxiv2018

Single-cell transcriptome analysis reveals estrogen signaling augments the mitochondrial folate pathway to coordinately fuel purine and polyamine synthesis in breast cancer cells

Estrogen regulates diverse physiological effects and drives breast tumor progression by directly activating estrogen receptor (ER). However, due to the stochastic nature of gene transcription and the resulting heterogeneous cellular response, it is important to investigate estrogen-stimulated gene expression profiles at the single-cell level in order to fully understand how ER regulates transcription in breast cancer cells. In this study, we performed single-cell transcriptome analysis on ER-positive breast cancer cell lines following 17{beta}-estradiol stimulation. Overall, we observed robust gene expression diversity between individual cells. Moreover, we found over two thirds of the genes in breast cancer cells displayed a bimodal expression pattern, which caused averaging artifacts and masked the identification of potential estrogen-regulated genes. We overcame this issue by reconstructing a dynamic estrogen-responsive transcriptional network from discrete time points into a pseudotemporal continuum. Pathway analysis of the differentially expressed genes derived from the pseudotemporal analysis showed an estrogen-stimulated metabolic switch that favored biosynthesis and cell proliferation but reduced estrogen degradation. In addition, we identified folate-mediated one-carbon metabolism as a novel estrogen-regulated pathway in breast cancer cells. Notably, estrogen stimulation reprogramed this pathway through the mitochondrial folate pathway to coordinately fuel polyamine and de novo purine synthesis. Finally, we showed AZIN1 and PPAT, key regulators in the above pathways, are direct ER target genes and essential for breast cancer cell survival and growth. In summary, our single-cell study illustrated a dynamic transcriptional heterogeneity in ER-positive breast cancer cells in response to estrogen stimulation and uncovered a novel mechanism of an estrogen-mediated metabolic switch.

genomics↗

bioRxiv2018

A novel long noncoding RNA LINC00844 regulates prostate cancer cell migration and invasion through androgen receptor signaling

The majority of the human genome is transcribed, yielding a rich repository of non-coding transcripts that are involved in a myriad of biological processes including cancer. However, how non-coding transcripts such as long non-coding RNAs (lncRNAs) function in prostate cancer is still unclear. In this study, we have identified a novel set of clinically relevant androgen-regulated lncRNAs in prostate cancer. Among this group, we showed LINC00844 is a direct androgen-regulated target that is actively transcribed in androgen receptor (AR)-dependent prostate cancer cells. The expression of LINC00844 is higher in normal prostate compared to malignant and metastatic prostate cancer samples and patients with low expression demonstrate poor prognosis and significantly increased biochemical recurrence, suggesting LINC00844 may function in suppressing tumor progression and metastasis. Indeed, in-vitro loss-of-function studies revealed that LINC00844 prevents prostate cancer cell migration and invasion. Moreover, findings from gene expression analysis indicated that LINC00844 functions in trans, affecting global androgen-regulated gene transcription. Mechanistically, we provide evidence to show LINC00844 is important in facilitating AR binding to the chromatin. Finally, we demonstrated LINC00844 mediates its phenotypic effects in part by activating the expression of NDRG1, a crucial cancer metastasis suppressor. Collectively, our findings suggest LINC00844 is a novel coregulator of AR that plays a central role in the androgen transcriptional network and the development and progression of prostate cancer.

cancer biology↗