Biology subjects

Yoo, S.

Publications and source records attributed to Yoo, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

Signaling and transcriptional networks governing late synovial joint development

BackgroundDuring synovial joint development, cavitation marks the end of the emergence of new cell types and the onset of the consolidation of cell type specific programs. However, the transcriptional programs that regulate this crucial stage prior to joint maturation are incompletely characterized. Gdf5-lineage cells give rise to the majority of joint constituents such as articular cartilage, meniscus, ligament, and tendon. Therefore, to explore pre-maturation of the synovial joint, we performed single cell RNA-Seq analysis of 1,306 Gdf5-lineage cells from the murine knee joint at E17.5. ResultsUsing computational analytics and in situ hybridization, we identified nine sub-states contributing to articular cartilage, meniscus, cruciate ligament, synovium, lining, and surrounding fibrous tissue. We identified a common progenitor population that is predicted to give rise to ligamentaocytes, articular chondrocytes, and lining cells. We further found that while a large number of signaling pathways orchestrate the differentiation of this progenitor to either ligamentocytes or to lining cells, only continued FGF signaling guides these cells to a default chondrocyte fate. ConclusionsOur single cell transcriptional atlas is a resource that can be used to better understand and further study synovial joint development and the reactivation of embryonic programs in diseases such as osteoarthritis.

developmental biology↗

bioRxiv2020

Regions of Highly Recurrent Electrogram Morphology at Sites of Low Cycle Length Accurately Reflect Arrhythmogenic Substrate for Atrial Fibrillation - Implications For a New, Mechanism Guided Therapeutic Approach for Atrial Fibrillation

BackgroundAlthough atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation. MethodsPersistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannons Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified. ResultsRec% was greatest in the appendages, and CLR was lowest in the posterior left atrium. Rec%/CLR correlated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLR response to atropine. ConclusionEMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLR may therefore be a viable therapeutic target in persistent AF.

physiology↗

bioRxiv2020

Control of neurogenic competence in mammalian hypothalamic tanycytes.

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we demonstrate that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA- and ATAC-Seq analysis reveals that NFI factors repress Shh and Wnt signaling in tanycytes, and small molecule modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. We show that Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, integrate into hypothalamic synaptic circuitry, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, suggesting a new therapeutic approach to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

neuroscience↗

bioRxiv2020

Transcriptional Profiling of Identified Neurons in Leech

While leeches in the genus Hirudo have long been models for neurobiology, the molecular underpinnings of nervous system structure and function in this group remain largely unknown. To begin to bridge this gap, we performed RNASeq on pools of identified neurons of the central nervous system (CNS): sensory T (touch), P (pressure) and N (nociception) neurons; neurosecretory Retzius cells; and ganglia from which these four cell types had been removed. Bioinformatic analyses identified 2,812 putative genes whose expression differed significantly among the samples. These genes clustered into 7 groups which could be associated with one or more of the identified cell types. We verified predicted expression patterns through in situ hybridization on whole CNS ganglia, and found that orthologous genes were for the most part similarly expressed in a divergent leech genus, suggesting evolutionarily conserved roles for these genes. Transcriptional profiling allowed us to identify candidate phenotype-defining genes from expanded gene families. Thus, we identified one of eight hyperpolarization-activated cyclic-nucleotide gated (HCN) channels as a candidate for mediating the prominent sag current in P neurons, and found that one of five inositol triphosphate receptors (IP3Rs), representing a sub-family of IP3Rs absent from vertebrate genomes, is expressed with high specificity in T cells. We also identified one of two piezo genes, two of ~65 deg/enac genes, and one of at least 16 transient receptor potential (trp) genes as prime candidates for involvement in sensory transduction in the three distinct classes of leech mechanosensory neurons.

neuroscience↗

bioRxiv2020

DreamAI: algorithm for the imputation of proteomics data

Deep proteomics profiling using labeled LC-MS/MS experiments has been proven to be powerful to study complex diseases. However, due to the dynamic nature of the discovery mass spectrometry, the generated data contain a substantial fraction of missing values. This poses great challenges for data analyses, as many tools, especially those for high dimensional data, cannot deal with missing values directly. To address this problem, the NCI-CPTAC Proteogenomics DREAM Challenge was carried out to develop effective imputation algorithms for labeled LC-MS/MS proteomics data through crowd learning. The final resulting algorithm, DreamAI, is based on an ensemble of six different imputation methods. The imputation accuracy of DreamAI, as measured by Pearson correlation, is about 15%-50% greater than existing tools among less abundant proteins, which are more vulnerable to be missed in proteomics data sets. This new tool notably enhances data analysis capabilities in proteomics research.

bioinformatics↗

bioRxiv2020

Focused ultrasound excites neurons via mechanosensitive calcium accumulation and ion channel amplification

Ultrasonic neuromodulation has the unique potential to provide non-invasive control of neural activity in deep brain regions with high spatial precision and without chemical or genetic modification. However, the biomolecular and cellular mechanisms by which focused ultrasound excites mammalian neurons have remained unclear, posing significant challenges for the use of this technology in research and potential clinical applications. Here, we show that focused ultrasound excites neurons through a primarily mechanical mechanism mediated by specific calcium-selective mechanosensitive ion channels. The activation of these channels results in a gradual build-up of calcium, which is amplified by calcium- and voltage-gated channels, generating a burst firing response. Cavitation, temperature changes, large-scale deformation, and synaptic transmission are not required for this excitation to occur. Pharmacological and genetic inhibition of specific ion channels leads to reduced responses to ultrasound, while over-expressing these channels results in stronger ultrasonic stimulation. These findings provide a critical missing explanation for the effect of ultrasound on neurons and facilitate the further development of ultrasonic neuromodulation and sonogenetics as unique tools for neuroscience research.

neuroscience↗

bioRxiv2020

Reliable data collection in participatory trials to assess digital healthcare apps.

The number of digital healthcare mobile apps on the market is increasing exponentially owing to the development of the mobile network and widespread usage of smartphones. However, only a few of these apps have undergone adequate validation. As with many mobile apps, healthcare apps are generally considered safe to use, making them easy for developers and end-users to exchange them in the marketplace. The existing platforms are not suitable to collect reliable data for evaluating the effectiveness of the apps. Moreover, these platforms only reflect the perspectives of developers and experts, not of end-users. For instance, data collection methods typical of clinical trials are not appropriate for participant-driven assessment of healthcare apps because of their complexity and high cost. Thus, we identified a need for a participant-driven data collection platform for end-users that is interpretable, systematic, and sustainable --as a first step to validate the effectiveness of the apps. To collect reliable data in the participatory trial format, we defined distinct stages for data preparation, storage, and sharing. Interpretable data preparation consists of a protocol database system and semantic feature retrieval method to create a protocol without professional knowledge. Collected data reliability weight calculation belongs to the systematic data storage stage. For sustainable data collection, we integrated the weight method and the future reward distribution function. We validated the methods through statistical tests conducted on 718 human participants. The validation results demonstrate that the methods have significant differences in the comparative experiment and prove that the choice of the right method is essential for reliable data collection. Furthermore, we created a web-based system for our pilot platform to collect reliable data in an integrated pipeline. We validate the platform features with existing clinical and pragmatic trial data collection platforms. In conclusion, we show that the method and platform support reliable data collection, forging a path to effectiveness validation of digital healthcare apps.

bioinformatics↗

bioRxiv2020

Molecular and cellular heterogeneity of gastric cancer explained by methylation-driven key regulators

Gastric cancer (GC) is a heterogeneous disease of diverse genetic, genomic, and epigenetic alterations. Tumor microenvironment (TME) also contributes to the heterogeneity of GC. To investigate GC heterogeneity, we developed an Integrative Sequential Causality Test (ISCT) to identify key regulators of GC by integrating DNA methylation, copy number variation, and transcriptomic data. Applying ISCT to three GC cohorts containing methylation, CNV and transcriptomic data, 11 common methylation-driven key regulators (ADHFE1, CDO1, CRYAB, FSTL1, GPT, PKP3, PTPRCAP, RAB25, RHOH, SFN, and SORD) were identified. Based on these 11 genes, gastric tumors were clustered into 3 clusters which were associated with known molecular subtypes, Lauren classification, tumor stage, and patient survival, suggesting significance of the methylation-driven key regulators in molecular and histological heterogeneity of GC. We further showed that chemotherapy benefit was different in the 3 GC clusters and varied depending on the tumor stage. Both immune/stromal proportions in TME and tumor cell genomic variations contributed to expression variations of the 11 methylation-driven key regulators and to the GC heterogeneity.

genomics↗

bioRxiv2019

Repression of LKB1 by miR-17~92 sensitizes MYC-dependent lymphoma to biguanide treatment

Cancer cells display metabolic plasticity to survive metabolic and energetic stresses in the tumor microenvironment, prompting the need for tools to target tumor metabolism. Cellular adaptation to energetic stress is coordinated in part by signaling through the Liver Kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Reducing LKB1-AMPK signaling exposes metabolic vulnerabilities in tumor cells with potential for therapeutic targeting. Here we describe that miRNA-mediated silencing of LKB1 (mediated by the oncogenic miRNA cluster miR-17[~]92) confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and novel (IM156) biguanides, we demonstrate that Myc+ lymphoma cells with elevated miR-17[~]92 expression display increased sensitivity to biguanide treatment both in cell viability assays in vitro and tumor growth assays in vivo. This increased biguanide sensitivity is driven by miR-17-dependent silencing of LKB1, which results in reduced AMPK activation in response to bioenergetic stress. Mechanistically, biguanide treatment inhibits TCA cycle metabolism and mitochondrial respiration in miR-17[~]92-expressing tumor cells, targeting their metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17[~]92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17[~]92 expression as a potential biomarker for biguanide sensitivity in hematological malignancies and solid tumors. One Sentence SummarymiR-17[~]92 expression in Myc+ tumors sensitizes cancer cells to biguanide treatment by disrupting bioenergetic stability in lymphoma cells.

cancer biology↗

bioRxiv2019

Integrative genomic and epigenomic analyses identify a distinct role of c-Myc and L-Myc for lineage determination in small cell lung cancer

Comprehensive genomic analyses of small cell lung cancer (SCLC), the most aggressive form of lung cancer, have revealed near universal loss of tumor suppressors (RB1 and TP53) and frequent genomic amplification of all three MYC family members. The amplification of each Myc family member is mutually exclusive; hence it had been long suggested that they are functionally equivalent. However, their expression has more recently been associated with specific neuroendocrine markers and distinct histopathology. In this study, we explored a novel role of c-Myc and L-Myc as lineage determining factors contributing to SCLC molecular subtypes and histology. Integrated analyses of a gene regulatory network generated from mRNA expression of primary SCLC tumor and chromatin state profiling of SCLC cell lines showed that Myc family members impart distinct transcriptional programs associated with lineage state; wherein the L-Myc signature was enriched for neuronal pathways while the c-Myc signature was enriched for Notch signaling and epithelial-to-mesenchymal transition. We investigated the functional redundancy and distinction of c-Myc and L-Myc, and noted the insufficiency of L-Myc to induce lineage switch in contrast to the potential of c-Myc to induce trans-differentiation. c-Myc rewires the Myc-accessible landscape and activates neuron al repressor, Rest to mediate transition from ASCL1-SCLC to NeuroD1-SCLC characterized by distinct LCNEC-like histopathology. Collectively, our findings reveal a previously undescribed role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular subtypes as well as histological subclasses.

cancer biology↗

bioRxiv2019

An interactive retrieval system for clinical trial studies with context-dependent protocol elements

A clinical trial protocol defines the procedures that should be performed during a clinical trial. Every clinical trial begins with the design of its protocol. While designing the protocol, most researchers refer to electronic databases and extract protocol elements using a keyword search. However, state-of-the-art retrieval systems only offer text-based searches for user-entered keywords. In this study, we present an interactive retrieval system with a context-dependent and protocol-element-selection function for successfully designing a clinical trial protocol. To do this, we first introduce a database for a protocol retrieval system constructed from individual protocol data extracted from 184,634 clinical trials and 13,210 frame structures of clinical trial protocols. The database contains various semantic information that enables the protocols to be filtered during the search operation. Based on the database, we developed a web application called the clinical trial protocol database system (CLIPS; available at https://corus.kaist.edu/clips), which enables an interactive search by utilizing protocol elements. CLIPS provides the options to select the next element according to the previous element in the form of a connected tree, thus enabling an interactive search for combinations of protocol elements. The validation results show that our method achieves better performance than existing databases in predicting phenotypic features.

bioinformatics↗

bioRxiv2019

Disruption of NOX2-dependent Oxidative Injury with a Targeted Gene-Therapy Approach Prevents Atrial Fibrillation in a Canine Model

Atrial fibrillation is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. In this study, we demonstrated using a novel gene-based strategy in a clinically relevant large animal of AF that oxidative injury is a key mechanism underlying the onset and perpetuation of AF. First, we demonstrated that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NADPH oxidase 2 (NOX2) and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulating a constitutively active form of acetylcholine-dependent K+ current (IKACh) - called IKH - by a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKC{varepsilon}). To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA in atria of normal dogs followed by rapid atrial pacing. The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, with attenuated activation of PKC{varepsilon}, a likely molecular mechanism underlying this beneficial electrophysiological remodeling. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.\n\nOne Sentence SummaryTargeted disruption of NOX2-dependent oxidative injury with a novel gene therapy approach prevents onset as well as perpetuation of atrial fibrillation.

physiology↗

bioRxiv2019

Comparative transcriptomic and epigenomic analysis identifies key regulators of injury response and neurogenic competence in retinal glia

Injury induces retinal Muller glia of cold-blooded, but not mammalian, vertebrates to regenerate neurons. To identify gene regulatory networks that control neuronal reprogramming in retinal glia, we comprehensively profiled injury-dependent changes in gene expression and chromatin accessibility in Muller glia from zebrafish, chick and mice using bulk RNA-Seq and ATAC-Seq, as well as single-cell RNA-Seq. Cross-species integrative analysis of these data, together with functional validation, identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, gliosis and neurogenesis. In zebrafish and chick, transition from the resting state to gliosis is essential for initiation of retinal regeneration, while in mice a dedicated network suppresses neurogenic competence and restores quiescence. Selective disruption of NFI family transcription factors, which maintain and restore quiescence, enables Muller glia to proliferate and generate neurons in adult mice following retinal injury. These findings may aid in the design of cell-based therapies aimed at restoring retinal neurons lost to degenerative disease. Summary sentenceThis study identifies gene regulatory networks controlling proliferative and neurogenic competence in retinal Muller glia.

neuroscience↗

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↗

bioRxiv2019

Cooperating lineage factors SOX2 and BRN2 govern the transcriptional program of the neural subtype of lung squamous cell carcinoma

Molecular characterization of lung squamous cell carcinoma (LUSC), a major subtype of lung cancer, has not sufficiently improved its non-stratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution, and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed neural subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic co-occupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the neural LUSC. Forced expression of p63 downregulated Brn2 in the neural LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted.

cancer biology↗

bioRxiv2019

Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice.

Tanycytes are radial glial cells located in the mediobasal hypothalamus. Recent studies have proposed that tanycytes play an important role in hypothalamic control of energy homeostasis, although this has not been directly tested. Here, we report the phenotype of mice in which tanycytes of the arcuate nucleus and median eminence were conditionally ablated. Although the CSF-hypothalamic barrier was rendered more permeable, the blood-hypothalamic barrier was not altered. The metabolic effects of tanycyte ablation were likewise moderate. However, we consistently observed a significant increase in visceral fat distribution accompanying insulin insensitivity, but only in male mice, and without an effect on either body weight or food intake. A high-fat diet accelerated overall body weight gain in tanycyte-ablated mice, but the development of visceral adiposity and insulin insensitivity was attenuated. These results clarify the extent to which tanycytes regulate energy metabolism, and indicate a role for tanycytes in controlling body adiposity.

physiology↗

bioRxiv2019

Electronic Health Records Based Prediction of Future Incidence of Alzheimers Disease Using Machine Learning

Nationwide population-based cohort provides a new opportunity to build a completely automated risk prediction model based on individuals history of health and healthcare beyond existing risk prediction models. We tested the possibility of machine learning models to predict future incidence of Alzheimers disease (AD) using large-scale administrative health data. From the Korean National Health Insurance Service database between 2002 and 2010, we obtained de-identified health data in elders above 65 years (N=40,736) containing 4,894 unique clinical features including ICD-10 codes, medication codes, laboratory values, history of personal and family illness, and socio-demographics. To define incident AD two operational definitions were considered: "definite AD" with diagnostic codes and dementia medication (n=614) and "probable AD" with only diagnosis (n=2,026). We trained and validated a random forest, support vector machine, and logistic regression to predict incident AD in 1,2,3, and 4 subsequent years. For predicting future incidence of AD in balanced samples (bootstrapping), the machine learning models showed reasonable performance in 1-year prediction with AUC of 0.775 and 0.759, based on "definite AD" and "probable AD" outcomes, respectively; in 2-year, 0.730 and 0.693; in 3-year, 0.677 and 0.644; in 4-year, 0.725 and 0.683. The results were similar when the entire (unbalanced) samples were used. Important clinical features selected in logistic regression included hemoglobin level, age, and urine protein level. This study may shed a light on the utility of the data-driven machine learning model based on large-scale administrative health data in AD risk prediction, which may enable better selection of individuals at risk for AD in clinical trials or early detection in clinical settings.

bioinformatics↗

bioRxiv2019

Acoustically Detonated Biomolecules for Genetically Encodable Inertial Cavitation

Recent advances in molecular engineering and synthetic biology have made it possible for biomolecular and cell-based therapies to provide highly specific disease treatment. However, both the ability to spatially target the action of such therapies, and their range of effects on the target tissue remain limited. Here we show that biomolecules and cells can be engineered to deliver potent mechanical effects at specific locations inside the body under the direction of focused ultrasound. This capability is based on gas vesicles, a unique class of air-filled protein nanostructures derived from buoyant photosynthetic microbes. We show that low-frequency ultrasound can convert these nanoscale biomolecules into micron-scale cavitating bubbles, as demonstrated with acoustic measurements and ultrafast optical microscopy. This allows gas vesicles targeted to cell-surface receptors to serve as remotely detonated cell-killing agents. In addition, it allows cells genetically engineered to express gas vesicles to be triggered with ultrasound to lyse and release therapeutic payloads. We demonstrate these capabilities in vitro, in cellulo, and in vivo. This technology equips biomolecular and cellular therapeutics with unique capabilities for spatiotemporal control and mechanical action.

bioengineering↗