Biology subjects

Ryu, B.

Publications and source records attributed to Ryu, B..

7 recordsLinked to original sources

bioRxiv2026

Mechanism of Renal Cyst Initiation and Progression Through ETV Transcription Factors and Hedgehog Signaling

Renal cysts are categorized as non-pathogenic simple cysts and pathogenic malignant cysts based on their pathophysiological status. Cyst formation is divided by cyst initiation and cyst progression/promotion. Pathogenic cysts are thought to be developed through continuous initiation followed by progression until pathogenic status is achieved. Although many genetic and environmental factors are identified to cause pathogenic cyst formation, the mechanisms that discriminate cyst initiation and progression are poorly understood. Using genetic mutation models of ETV transcription factors, ETV1, ETV4, and ETV5, and a pharmacological inhibitor of hedgehog signaling, cyclopamine, we identified one of the mechanisms regulating cyst initiation and progression. Nephron specific deletion of ETV4 and ETV5 initiated cyst formation. However, cyst initiation did not continue as animals grow, and a limited number of the initial cysts underwent further growth. Additional deletion of ETV1 was required for continuous initiation in addition to promotion of cyst growth. Furthermore, administration of cyclopamine attenuated promotion of cyst progression but had little effect on cyst initiation. Therefore, we provide evidence that cyst initiation and progression is genetically and molecularly distinct and can be modulated. This information provides new insight into how to control renal cyst initiation and progression and can be used to suppress pathogenic cyst growth.

developmental biology↗

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2026

AI-Accelerated Structure Elucidation of Boavistamides A-C, Cyclic Depsipeptides from a Marine Filamentous Cyanobacterium Collected in Cabo Verde

Boavistamide A (1), a new alkyne-containing cyclic depsipeptide featuring the rare 3-amino-2-methyl-7-octynoic acid (AMOYA) moiety, was discovered along with two structurally related analogs, boavistamides B and C (2 and 3), from a filamentous marine cyanobacterium collected on Boa Vista Island, Cabo Verde. Their isolation was guided by antiplasmodial activity, GNPS MS/MS molecular networking, LC-MS profiling, and dereplication using the MarinLit database. The planar structures of boavistamides A-C (1-3) were elucidated through comprehensive HRMS and 1D/2D NMR analyses, with annotation support from AI-based tools SMART-NMR 2.1 and DeepSAT. The absolute configurations were established using Marfeys analysis and L-Phe-OMe coupling, complemented by NMR-based conformational studies. Boavistamides A and B exhibited moderate antiplasmodial activity with no mammalian cell cytotoxicity. Microscopic observations and metagenomic binning identified the producer strain as belonging to the genus Okeania (Microcoleaceae). These results expand the chemical diversity of AMOYA-containing cyanobacterial metabolites and highlight the utility of integrated metabolomics and AI-assisted workflows for natural product discovery from environmental samples. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/732064v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@6577feorg.highwire.dtl.DTLVardef@1a8d656org.highwire.dtl.DTLVardef@18fc299org.highwire.dtl.DTLVardef@130d3d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Heartbeat-like dynamics drives oxygen activation in methane monooxygenase

Soluble methane monooxygenase (sMMO) is an enzyme that hydroxylates methane (CH4), a potent greenhouse gas, at non-heme di-iron active sites under atmospheric conditions. The regulatory component (MMOB) is essential for the catalytic activity of hydroxylase (MMOH) as it induces conformational changes in the active site and facilitating substrate ingress. Recent advances in cryogenic electron microscopy (cryo-EM) have enabled us to elucidate the high resolution picture of sMMO catalytic mechanism. We describe the 2.85 [A] cryo-EM structure of MMOH-MMOB, with one equivalent of MMOB bound to MMOH (H-1B), which is in contrast with previously solved crystal structures. MMOB allosterically regulates the MMOH protomer ({beta}{gamma}) and induces conformational changes that propagate from the surface to the di-iron coordination site. The N-terminal region of the MMOH {beta}-subunit (NT-H{beta}) stabilizes helices essential for iron coordination and oxygen activation. The MMOB-bound protomer (HBA, {beta}{gamma}B) presents the first structural report of a 2.7 [A] Fe{middle dot}{middle dot}{middle dot}Fe distance, while the non-MMOB-bound protomer (HBB, {beta}{gamma}) and MMOH display a 3.1 [A] distance. The coordination of Fe-ligands is maintained by the structural stabilization provided by the {beta}- and {gamma}-subunits of MMOH. This novel cryo-EM structure reveals new coordination environments, offering crucial mechanistic insights into sMMO catalysis.

biochemistry↗

bioRxiv2024

The CoREST-complex regulates MYC stability and promotes post-transcriptional mRNA splicing in melanoma

The CoREST complex is a multi-subunit epigenetic regulator implicated in histone modification and transcriptional repression, but its role in tumorigenesis is not well-defined. Here, we show that the CoREST complex directly interacts with and stabilizes the MYC oncoprotein in cancer cells through site-specific deacetylation of lysine residues, primarily mediated by HDAC1/2. These modifications protect MYC from proteasomal degradation independently of transcriptional regulation, maintaining high MYC protein levels in cancer cells. Transcriptomic analysis reveals that the CoREST-mediated MYC stabilization activates transcription of genes critical for DNA replication and mitotic chromosome segregation, and enhances melanoma cell viability. These findings suggest that the CoREST complex maintains cancer cell genome stability and promotes survival by sustaining MYC oncogenic activity, highlighting it as a potential therapeutic target in MYC-driven malignancies.

cancer biology↗

bioRxiv2024

Journey to the center of the phage; revealing the ejectosome of Pectobacterium bacteriophage {Phi}M1

Podophages that infect gram-negative bacteria, such as Pectobacterium pathogen {Phi}M1, encode tail assemblies too short to extend across the complex gram-negative cell wall. To overcome this, podophages encode a large protein complex (ejectosome) packaged inside the viral capsid and correspondingly ejected during infection to form a transient channel that spans the periplasmic space. Here we describe the ejectosome of bacteriophage {Phi}M1 to a resolution of 3.32 [A] by single particle cryo-EM. The core consists of tetrameric and octameric ejection proteins which form a [~]1.5 MDa ejectosome that must transition through the [~]30 [A] aperture created by the short tail nozzle assembly that acts as the conduit for the passage of DNA during infection. The ejectosome forms several grooves into which coils of genomic DNA are fit before the DNA sharply turns and goes down the tunnel and into the portal. In addition, we reconstructed the icosahedral capsid and hybrid tail apparatus to resolutions between 3.04 [A] and 3.23 [A], and note an uncommon fold adopted by the dimerized decoration proteins which further emphasize the structural diversity of podophages. These reconstructions have allowed the generation of a complete atomic model of the {Phi}M1, uncovering two distinct decoration proteins and highlighting the exquisite structural diversity of tailed bacteriophages. Significance StatementThis study resolves the cryo-EM structure of bacteriophage {Phi}M1, which possesses several unique and interesting structural elements, including a pair of distinct decoration proteins that are underreported in tailed DNA phages. Significantly, we also report the internal ejectosome proteins of {Phi}M1, which are highly non-conserved with previously solved proteins to date and demonstrate the structural diversity of ejection proteins. The ejectosome reveals a DNA spooling phenomenon whereby the viral genome wraps around the ejectosome within the capsid, which has never been reported before. We provide a clear, step-by-step method for the technically challenging reconstruction of ejectosomes using standard, open-source software.

microbiology↗

bioRxiv2019

Development and Validation of Phenotype Classifiers across Multiple Sites in the Observational Health Sciences and Informatics (OHDSI) Network

ObjectiveAccurate electronic phenotyping is essential to support collaborative observational research. Supervised machine learning methods can be used to train phenotype classifiers in a high-throughput manner using imperfectly labeled data. We developed ten phenotype classifiers using this approach and evaluated performance across multiple sites within the Observational Health Sciences and Informatics (OHDSI) network.\n\nMaterials and MethodsWe constructed classifiers using the Automated PHenotype Routine for Observational Definition, Identification, Training and Evaluation (APHRODITE) R-package, an open-source framework for learning phenotype classifiers using datasets in the OMOP CDM. We labeled training data based on the presence of multiple mentions of disease-specific codes. Performance was evaluated on cohorts derived using rule-based definitions and real-world disease prevalence. Classifiers were developed and evaluated across three medical centers, including one international site.\n\nResultsCompared to the multiple mentions labeling heuristic, classifiers showed a mean recall boost of 0.43 with a mean precision loss of 0.17. Performance decreased slightly when classifiers were shared across medical centers, with mean recall and precision decreasing by 0.08 and 0.01, respectively, at a site within the USA, and by 0.18 and 0.10, respectively, at an international site.\n\nDiscussion and ConclusionWe demonstrate a high-throughput pipeline for constructing and sharing phenotype classifiers across multiple sites within the OHDSI network using APHRODITE. Classifiers exhibit good portability between sites within the USA, however limited portability internationally, indicating that classifier generalizability may have geographic limitations, and consequently, sharing the classifier-building recipe, rather than the pre-trained classifiers, may be more useful for facilitating collaborative observational research.

bioinformatics↗