Biology subjects

Yoon, S. H.

Publications and source records attributed to Yoon, S. H..

8 recordsLinked to original sources

bioRxiv2026

A Bayesian Network-Based Framework for Causal Cancer Drug Target Discovery Integrating Patient and Cell Line Data

Current approaches to cancer drug target discovery face two key limitations: poor translation of cell line-derived targets to patient tumors, and the lack of causal explanation of the regulatory mechanisms underlying target prioritization. Here we present BayesTx (Bayesian Therapeutics target discovery), a Bayesian network framework that integrates patient transcriptomics data with cell line data to identify causal therapeutic targets in cancer. BayesTx projects both data domains into a shared biological space of pathway and transcription factor activities, learns domain-specific causal graphs, and merges them through weighted edge aggregation with bootstrap consensus filtering. Do-simulation on the consensus network quantifies the causal effect of each transcription factor on cancer cell viability. Applied to breast cancer using TCGA-BRCA (The Cancer Genome Atlas breast cancer cohort) and DepMap (Cancer Dependency Map) datasets, the framework ranked 47 transcription factors by predicted causal impact, with gene-level targets further derived through regulon-based propagation. Top-ranked transcription factor (TF) targets were independently supported by survival analysis in external cohort data and pharmacogenomic drug response associations. Overall, BayesTx demonstrates that cross-domain Bayesian network modeling can bridge patient and cell line data to systematically identify causal therapeutic targets in cancer.

bioinformatics↗

bioRxiv2026

Comparison of Automated White Matter Lesion Segmentation Approaches for Use in Large, Multi-Site Data Analyses in Parkinson's Disease

BackgroundParkinsons disease (PD) is the second most common neurodegenerative disorder. PD currently lacks effective disease-modifying treatments, likely due to its diverse clinical features and underlying neuropathology. The vascular role in PD is emerging, with vascular mechanisms increasingly implicated, yet the literature remains conflicted, motivating large-data analyses with greater statistical power. White matter lesions (WML) are an accepted imaging marker of small vessel disease. Accurate automated WML segmentation techniques are crucial for large-scale studies in PD due to the impracticality of manual segmentation for extensive datasets and to ensure consistency. Evaluation of the optimum approach in PD for large-scale analysis is lacking. This study aimed to evaluate various automated WML segmentation algorithms to determine the most accurate and reliable method, among those selected, for assessing WML for multi-site large data analysis in PD. MethodsWe assessed whole-brain volumetric T1-weighted and FLAIR images from 201 PD patients (mean age, 66.6 {+/-} 7.86 years) and 64 healthy controls (HC; mean age, 66.3 {+/-} 8.67) across three datasets: the Parkinsons Progression Markers Initiative (PPMI), the University of Pennsylvania (UPenn) and the Montreal Neurological Institute Biobank: Clinical Biological Imaging and Genetic Repository (C-BIG). The sample included different scanners, imaging parameters and lesion loads, as would be expected for multi-site data. WML were manually segmented to provide the gold standard, and four freely available automated algorithms were evaluated: FSLs BIANCA, FreeSurfer, SPMs LST-LPA and U-Net-pgs using the performance metrics: Dice score, Hausdorff distance, recall, precision, F1 score, log absolute volume difference (LOGAVD) and intraclass correlation coefficient (ICC). Subgroup analyses were performed based on lesion load and lobar regions. The associations of data from these automated approaches with age, and with Fazekas and Wahlund visual rating scales, were assessed through partial correlation analysis. ResultsU-Net-pgs performed best overall, with the highest Dice score (PD: 0.46 {+/-} 0.21; HC: 0.39 {+/-} 0.21), recall (PD: 0.76 {+/-} 0.25; HC: 0.62 {+/-} 0.31), precision (PD: 0.49 {+/-} 0.25; HC: 0.63 {+/-} 0.27), F1 score (PD: 0.54 {+/-} 0.22; HC: 0.56 {+/-} 0.22) and ICC (PD: 0.965; HC: 0.967) and lowest Hausdorff distance (PD: 8.89 {+/-} 3.96; HC: 6.33 {+/-} 2.91). U-Net-pgs achieved the lowest LOGAVD in the PD group (0.31 {+/-} 0.31) whereas BIANCA-LOO with a threshold of 0.9 was lowest in HC (0.27 {+/-} 0.30). U-Net also showed superior performances in all lesion loads for PD and overall across various brain regions in both PD and HC. ConclusionOverall, U-Net-pgs emerged as the best performing automated method, of those we evaluated, for WML segmentation in PD and HC within a dataset collected with various scanner and image acquisition parameters. U-Net-pgs consistently outperformed other automated approaches across lesion loads and brain regions, for most metrics. The accuracy and reliability of U-Net-pgs make it a promising tool for large-scale analyses, facilitating future research investigating WML in PD.

neuroscience↗

bioRxiv2024

Hyperactive GluN2B impairs neuroplasticity and cognition in phenylketonuria

Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanism by which elevated Phe levels causes cognitive impairment remains unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. L-Phe exhibited dose-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in an activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment of GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed impaired learning in the PahEnu2 PKU model. Collectively, these results suggest that the concentration of Phe in the cerebrospinal fluid of patients with PKU perturbs extrasynaptic NMDAR and synaptic plasticity, and that suppression of GluN2B may be a therapeutic strategy for improving cognitive function in patients with PKU.

neuroscience↗

bioRxiv2023

Activation of a Vibrio cholerae CBASS anti-phage system by quorum sensing and folate depletion

A major challenge faced by bacteria is infection by bacteriophage (phage). Abortive infection is one strategy for combating phage in which an infected cell kills itself to limit phage replication, thus protecting neighboring kin. One class of abortive infection systems is the cyclic oligonucleotide based anti-phage signaling system (CBASS) which relies on two core enzymatic activities; an oligo-nucleotide cyclase that is activated following phage infection and a cyclic-oligo-nucleotide sensitive effector whose activity kills the infected cell. However, the mechanisms behind the deployment and activation of these lethal CBASS systems prior-to and following infection have largely remained a mystery. While exploring unique genomic features of the current pandemic Vibrio cholerae biotype El Tor for clues underlying its pandemic success we found its CBASS was spuriously activated by the folate biosynthesis inhibitor sulfamethoxazole, but only after the population had reached a high-cell density. This population density dependent activity revealed that transcription of both the oligo-nucleotide cyclase, dncV, and the CBASS phospholipase effector, capV, is enhanced at high-cell density by quorum sensing. Together, these results demonstrate that the V. cholerae CBASS is deployed when the environment is densely populated and activated in response to a perturbation in folate biosynthesis. SignificanceTo counteract infection with phage, bacteria have evolved a myriad of molecular defense systems. Some of these systems initiate a process called abortive infection, in which the infected cell kills itself to prevent phage propagation. However, such systems must be inhibited in the absence of phage infection to prevent spurious death of the host. Here we show that the cyclic oligonucleotide based anti-phage signaling system (CBASS) accomplishes this by sensing intracellular folate molecules and only expressing this system in a group. These results enhance our understanding of the evolution of the 7th V. cholerae pandemic and more broadly how bacteria defend themselves against phage infection.

microbiology↗

bioRxiv2022

Caulobacter requires anionic sphingolipids and deactivation of fur to lose lipid A

Lipid A, the membrane-anchored portion of lipopolysaccharide, is an essential component of the outer membrane (OM) of nearly all Gram-negative bacteria. Here, we identify regulatory and structural factors that together permit Caulobacter crescentus to eliminate lipid A from its OM. Mutations in the ferric uptake regulator fur allow Caulobacter to survive in the absence of either LpxC, which catalyzes an early step of lipid A synthesis, or CtpA, a tyrosine phosphatase homolog which we find is needed for wild-type lipid A structure and abundance. Alterations in Fur-regulated processes, rather than iron status per se, underlie the ability to eliminate lipid A. Fitness of lipid A-deficient Caulobacter requires a previously uncharacterized anionic sphingolipid, ceramide phosphoglycerate (CPG), which also mediates sensitivity to the antibiotic colistin. Our results demonstrate that, in an altered regulatory landscape, anionic sphingolipids can support the integrity of a lipid A-deficient OM.

microbiology↗

bioRxiv2020

Hippocampal GABA-inhibitory circuitry regulates despair-like behavior in mice

Despair is a common human feeling characterized by the loss of hope and is a core symptom of depressive disorders. However, little is known regarding neural circuits mediating despair and their modulation by antidepressants. Here we show that alterations in inhibitory synaptic transmission in the hippocampus affect behavioral despair in mice. Reduced interneuron density, knockdown of GABAA receptor gamma 2 subunit gene (Gabrg2) or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Similarly, a low dose of pentylenetetrazol, a GABAAR antagonist, induced transient anti-despair-like behaviors, with rapid eukaryotic elongation factor 2 (eEF2) activation in the hippocampus. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons induced despair-like behaviors. The antidepressant ketamine rapidly increased c-Fos expression in CA1 neurons and induced anti-despair-like behaviors. These results suggest that the enhanced hippocampal CA1 neuron activity induces anti-despair-like behaviors and contributes to the antidepressant effects of ketamine.

neuroscience↗

bioRxiv2019

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of the patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M-line disassembly that is similar to the pathological changes found in HCM. Positional cloning revealed a missense mutation in an immunoglobulin (Ig) domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. In vitro studies revealed that the mutations found in both medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

developmental biology↗

bioRxiv2017

Enhancing Multiplex Genome Editing by Natural Transformation (MuGENT) via inactivation of ssDNA exonucleases

Recently, we described a method for multiplex genome editing by natural transformation (MuGENT). Mutant constructs for MuGENT require large arms of homology (>2000 bp) surrounding each genome edit, which necessitates laborious in vitro DNA splicing. In Vibrio cholerae, we uncover that this requirement is due to cytoplasmic ssDNA exonucleases, which inhibit natural transformation. In ssDNA exonuclease mutants, one arm of homology can be reduced to as little as 40 bp while still promoting integration of genome edits at rates of ~50% without selection in cis. Consequently, editing constructs are generated in a single PCR reaction where one homology arm is oligonucleotide encoded. To further enhance editing efficiencies, we also developed a strain for transient inactivation of the mismatch repair system. As a proof-of-concept, we used these advances to rapidly mutate 10 high-affinity binding sites for the nucleoid occlusion protein SlmA and generated a duodecuple mutant of 12 diguanylate cyclases in V. cholerae. Whole genome sequencing revealed little to no off-target mutations in these strains. Finally, we show that ssDNA exonucleases inhibit natural transformation in Acinetobacter baylyi. Thus, rational removal of ssDNA exonucleases may be broadly applicable for enhancing the efficacy and ease of MuGENT in diverse naturally transformable species.

microbiology↗