Biology subjects

Shin, W.

Publications and source records attributed to Shin, W..

12 recordsLinked to original sources

bioRxiv2026

Structural insights into MBOAT2 catalysis, product retention, and ligand exchange

MBOAT2 suppresses ferroptosis independently of GPX4 and FSP1 by transferring monounsaturated acyl chains from acyl-CoA donors to lysophospholipid acceptors, but the structural basis of its catalytic cycle remains unclear. Here, we report the first cryo-EM structures of human MBOAT2, capturing endogenous and substrate-induced ligand-bound states. Unexpectedly, as-purified MBOAT2 contains a co-purified phospholipid-like density consistent with a retained product, together with a second density at a putative acyl-donor entry site. Oleoyl-CoA addition reduces the ordered product-like density and reveals donor density, whereas LPE addition increases local heterogeneity near the archway. The inactive H373A mutant contains endogenous donor- and acceptor-like densities along the two access pathways, consistent with substrate preloading. Together, these structures define the catalytic architecture of MBOAT2, support a product-retained, donor-primed working model, and provide templates for structure-guided ligand discovery.

biophysics↗

bioRxiv2026

Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease

AbstractNeuroinflammation, along with amyloid beta (A{beta}) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimers disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in nai ve T killer cells and phospho-PLC{gamma}2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-nai ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/716122v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@f5060corg.highwire.dtl.DTLVardef@600ba7org.highwire.dtl.DTLVardef@19d281dorg.highwire.dtl.DTLVardef@b4a36a_HPS_FORMAT_FIGEXP M_FIG Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimers disease. C_FIG

neuroscience↗

bioRxiv2024

Morphological and Molecular Phylogenetic Characterization of Three New Marine Goniomonad Species

Goniomonads are commonly found heterotrophic biflagellates in both marine and freshwater environments. Despite the high genetic diversity inferred from 18S rDNA data, many goniomonad species remain undescribed. In this study, we established a total of 21 marine goniomonad culture strains, and from these, describe three new species by using light microscopy, electron microscopy, and 18S rDNA phylogeny. Molecular sequence analyses suggest the presence of several distinct sub-lineages within the marine goniomonad clade. Two of these are Goniomonas ulleungensis sp. nov. and G. lingua sp. nov., which are similar in size, flagellar length, appendage & orientation and by having a tongue-like protrusion at the anterior. The two species can be differentiated by the periplast plate pattern with G. ulleungensis displaying one additional plate on the right side. G. duplex sp. nov. differed from these two species by having two unequal flagella with the longer one trailing posteriorly and having the opposite cell orientation when skidding. Comparative analyses of five marine goniomonad species showed that genetically distinct goniomonad groups can be delineated by morphological data as well, and of several morphological features that are of taxonomic utility, the periplast plate pattern, observable by SEM, is particularly informative in goniomonad taxonomy.

evolutionary biology↗

bioRxiv2024

O-glycosylation contributes to mammalian glycoRNA biogenesis

There is an increasing appreciation for the role of cell surface glycans in modulating interactions with extracellular ligands and participating in intercellular communication. We recently reported the existence of sialoglycoRNAs, where mammalian small RNAs are covalently linked to N-glycans through the modified base acp3U and trafficked to the cell surface. However, little is currently known about the role for O-glycosylation, another major class of carbohydrate polymer modifications. Here, we use parallel genetic, enzymatic, and mass spectrometry approaches to demonstrate that O-linked glycan biosynthesis is responsible for the majority of sialoglycoRNA levels. By examining the O-glycans associated with RNA from cell lines and colon organoids we find known and previously unreported O-linked glycan structures. Further, we find that O-linked glycans released from small RNA from organoids derived from ulcerative colitis patients exhibit higher levels of sialylation than glycans from healthy organoids. Together, our work provides flexible tools to interrogate O-linked glycoRNAs (O-glycoRNA) and suggests that they may be modulated in human disease.

molecular biology↗

bioRxiv2023

An Automated Model Annotation System (AMAS) for SBML Models

MotivationAnnotations of biochemical models provide details of chemical species, documentation of chemical reactions, and other essential information. Unfortunately, the vast majority of biochemical models have few, if any, annotations, or the annotations provide insufficient detail to understand the limitations of the model. The quality and quantity of annotations can be improved by developing tools that recommend annotations. For example, recommender tools have been developed for annotations of genes. Although annotating genes is conceptually similar to annotating biochemical models, there are important technical differences that make it difficult to directly apply this prior work. ResultsWe present AMAS, a system that predicts annotations for elements of models represented in the Systems Biology Markup Language (SBML) community standard. We provide a general framework for predicting model annotations for a query element based on a database of annotated reference elements and a match score function that calculates the similarity between the query element and reference elements. The framework is instantiated to specific element types (e.g., species, reactions) by specifying the reference database (e.g., ChEBI for species) and the match score function (e.g., string similarity). We analyze the computational efficiency and prediction quality of AMAS for species and reactions in BiGG and BioModels and find that it has sub-second response times and accuracy between 80% and 95% depending on specifics of what is predicted. We have incorporated AMAS into an open-source, pip-installable Python package that can run as a command-line tool that predicts and adds annotations to species and reactions to an SBML model. AvailabilityOur project is hosted at https://github.com/sys-bio/AMAS, where we provide examples, documentation, and source code files. Our source code is licensed under the MIT open-source license. Contacthsauro@uw.edu Supplementary informationSupplementary data are available online.

systems biology↗

bioRxiv2023

Integrative analysis of CAKUT multi-omics data

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood end-stage renal disease and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. Multi-omics experiments, including amniotic fluid miRNome, peptidome, and proteome analyses, can shed light on foetal kidney development in non-severe CAKUT patients compared to severe CAKUT cases. We performed FAIRification of these omics data sets to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.

systems biology↗

bioRxiv2022

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations in GRIN2A, encoding a subunit of the NMDA (N-methyl-d-aspartate) receptor, greatly increase the risk of schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that heterozygous Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes, oligodendrocytes); (ii) evidence of reduced activity in prefrontal cortex and increased activity in hippocampus and striatum; (iii) elevated dopamine signaling in striatum; (iv) altered cholesterol biosynthesis in astrocytes; (v) reduction of glutamatergic receptor signalin g proteins in the synapse; (iv) heightened gamma oscillation power in EEG; (vi) aberrant locomotor behavioral pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of schizophrenia, and underscore the utility of Grin2a-deficient mice as a new genetic model of schizophrenia.

neuroscience↗

bioRxiv2022

Molecular mechanics underlying flat-to-round membrane budding in live secretory cells

Membrane budding entails forces to transform flat membrane into vesicles essential for cell survival. Accumulated studies have identified coat-proteins (e.g., clathrin) as potential budding factors. However, forces mediating many non-coated membrane buddings remain unclear. By visualizing proteins in mediating endocytic budding in live neuroendocrine cells, performing in vitro protein reconstitution and physical modelling, we discovered how non-coated-membrane budding is mediated: actin filaments and dynamin generate a pulling force transforming flat membrane into {Lambda}-shape; subsequently, dynamin helices surround and constrict {Lambda}-profiles base, transforming {Lambda}- to {Omega}-profile, and then constrict {Omega}-profiles pore, converting {Omega}-profiles to vesicles. These mechanisms control budding speed, vesicle size and number, generating diverse endocytic modes differing in these parameters. Their impact is widespread beyond secretory cells, as the unexpectedly powerful functions of dynamin and actin, previously thought to mediate fission and overcome tension, respectively, may contribute to many dynamin/actin-dependent non- coated-membrane buddings, coated-membrane buddings, and other membrane remodelling processes.

cell biology↗

bioRxiv2021

SBMate: A Framework for Evaluating Quality of Annotations in Systems Biology Models

The interests in repurposing and reusing systems biology models have been growing in recent years. Semantic annotations play an important role for this, as they provide crucial information on the meanings and functions of models. However, there are a limited number of tools that evaluate the existence or quality of such annotations. In this paper, we introduce SBMate, a python package that would serve as a framework for evaluating the quality of annotations in systems biology models. Three default metrics are provided: coverage, consistency, and specificity. Coverage checks whether annotations exist in a model. Consistency tests if the annotations are appropriate for the given model element. Finally, specificity represents how detailed the annotations are. We analyzed 1,000 curated models from the BioModels repository using the three metrics and discussed the results. Additional metrics can be easily added to extend the current version of SBMate.

systems biology↗

bioRxiv2021

Single-cell transcriptomics elucidates in vitro reprogramming of human intestinal epithelium cultured in a physiodynamic gut-on-a-chip

The microphysiological human gut-on-a-chip has demonstrated in vivo-relevant cellular fidelity of intestinal epithelium compared to its cultures in a static condition1, 2. Microfluidic control of morphogen gradients and mechanical cues robustly induced morphological histogenesis with villi-like three-dimensional (3D) microarchitecture, lineage-associated cytodifferentiation, and physiological functions of a human intestinal Caco-2 epithelium3, 4. However, transcriptomic dynamics that orchestrates morphological and functional reprogramming of the epithelium in a microphysiological culture remains elusive. Single-cell transcriptomic analysis revealed that a gut-on-a-chip culture that offers physiological motions and flow drives three distinctive subclusters that offer distinct gene expression and unique spatial representation in 3D epithelial layers. The pseudotemporal trajectory of individual cells visualized the evolutionary transition from ancestral genotypes in static cultures into more heterogeneous phenotypes in physiodynamic cultures on cell cycles, differentiation, and intestinal functions including digestion, absorption, drug transport, and metabolism of xenobiotics. Furthermore, the inversed transcriptomic signature of oncogenes and tumor-suppressor genes of Caco-2 cells verified that a gut-on-a-chip culture drives a postmitotic reprogramming of cancer-associated phenotypes. Thus, we discovered that a physiodynamic on-chip culture is necessary and sufficient for a cancer cell line to be reprogrammed to elicit in vivo-relevant heterogeneous cell populations with restored normal physiological signatures.

bioengineering↗

bioRxiv2021

Visualizing sequential compound fusion and kiss-and-run in live excitable cells

Vesicle fusion is assumed to occur at flat membrane of excitable cells. In live neuroendocrine cells, we visualized vesicle fusion at {Omega}-shape membrane generated by preceding fusion, termed sequential compound fusion, which may be followed by fusion pore closure, termed compound kiss-and-run. These novel fusion modes contribute to vesicle docking, multi-vesicular release, asynchronous release, and endocytosis. We suggest modifying current models of exo-endocytosis to include these new fusion modes.

cell biology↗

bioRxiv2019

Detecting and Isolating Mass Balance Errors in Reaction Based Models in Systems Biology

MotivationThe growing complexity of reaction-based models necessitates early detection and resolution of model errors. This paper addresses mass balance errors, discrepancies between the mass of reactants and products in reaction specifications. One approach to detection is atomic mass analysis, which uses meta-data to expose atomic formulas of chemical species. Atomic mass analysis isolates errors to individual reactions. However, this approach burdens modelers with expressing model meta-data and writing excessively detailed reactions that include implicit chemical species (e.g., water). Moreover, atomic mass analysis has the shortcoming of not being applicable to large molecules because of the limitations of current annotation techniques. The second approach, Linear Programming (LP) analysis, avoids using model meta-data by checking for a weaker condition, stoichiometric inconsistency. But this approach suffers from false negatives and has large isolation sets (the set of reactions implicated in the stoichiometric inconsistency).\n\nResultsWe propose alternatives to both approaches. Our alternative to atomic mass analysis is moiety analysis. Moiety analysis uses model meta-data in the form of moieties present in chemical species. Moiety analysis avoids excessively detailed reaction specifications, and can be used with large molecules. Our alternative to LP analysis is Graphical Analysis of Mass Equivalence Sets (GAMES). GAMES has a slightly higher false negative rate than LP analysis, but it provides much better error isolation. In our studies of the BioModels Repository, the average size of isolation sets for LP analysis is 55.5; for GAMES, it is 5.4. We have created open source codes for moiety analysis and GAMES.\n\nAvailability and ImplementationOur project is hosted at https://github.com/ModelEngineering/ SBMLLint, which contains examples, documentation, source code files, and build scripts used to create SBMLLint. Our source code is licensed under the MIT open source license.\n\nContact: jlheller@uw.edu\n\nSupplementary information: None.

systems biology↗