Biology subjects

Kim, C. Y.

Publications and source records attributed to Kim, C. Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Convergent biosynthesis of insect molting hormones in plants

Insect herbivores have driven plants to evolve complex chemical defenses, including mimics of the arthropod molting hormone 20-hydroxyecdysone (20E). Many distantly related plants produce 20E, suggesting multiple, independent evolutionary origins. However, despite the prevalence of 20E in arthropods and plants, complete biosynthetic pathways have remained elusive. Here, we combine genomics, gene co-expression, and enzyme characterization to discover convergent 20E biosynthetic pathways from spinach and quinoa (amaranth family) and Ajuga species (mint family). We reveal that these families use distinct biosynthetic gene clusters to produce 20E and related phytoecdysteroids, highlighting both biochemical and genetic convergence of 20E biosynthesis in plants. Our work establishes the first complete 20E pathways in any organism and provides foundational insight into the evolution of this animal hormone across kingdoms of life.

biochemistry↗

bioRxiv2026

Planetary structure and drivers of diazotroph communities reveal key reservoirs of nitrogen-fixation potential

Biological nitrogen fixation sustains productivity across Earths ecosystems, yet the diversity, distribution and ecological drivers of nitrogen-fixing prokaryotes (diazotrophs) remain incompletely resolved. Here we screened approximately 40 billion genes to generate a catalogue of 21,157 diazotroph genomes. Using this catalogue, we quantified diazotroph diversity and abundance across 9,163 metagenomes spanning diverse environments. Diazotrophy was distributed across the prokaryotic tree of life, but both gene diversity and metagenomic abundance were dominated by heterotrophic lineages. Freshwater and sedimentary ecosystems emerged as major reservoirs of nitrogen-fixation potential beyond the environments that have historically anchored the field. Diazotroph-rich assemblages were associated with nitrogen and phosphorus limitation together with carbohydrate-rich metabolic regimes, revealing distinct nutrient and energy niches for cyanobacterial and heterotrophic diazotrophs. Together, this framework unifies disparate views of diazotroph diversity, abundance and ecology, providing a foundation for improved prediction of biological nitrogen fixation across Earths ecosystems.

microbiology↗

bioRxiv2026

Ancient origins of alkaloid biosynthesis in medicinal clubmosses

The plant kingdom is rich with medicinal natural products that are complex and difficult to access. Discovering how plants build these molecules can be challenging, especially for biosynthetic pathways that have unusual chemical transformations or require intricate coordination among cellular compartments. Here, we leveraged 300 million years of metabolic conservation to uncover how medicinal clubmosses organize extracellular and intracellular alkaloid biosynthesis to produce the Alzheimers disease therapeutic huperzine A (HupA). We reveal not only scaffold-forming enzymes that form key precursors to hundreds of clubmoss alkaloids, but also an essential transporter that connects metabolism across the plasma membrane to enable complete HupA biosynthesis. Our results demonstrate how ancient evolutionary conservation can be used to identify cryptic biosynthetic components and unexpected cellular organization in plant specialized metabolism.

biochemistry↗

bioRxiv2025

Plasmodium falciparum exploits NUAK1 to establish infection in human erythrocytes

The malaria parasite Plasmodium falciparum continues to demonstrate growing drug resistance, raising the need for innovative treatments. Host-directed therapeutics are emerging as a promising approach for many infectious diseases, but knowledge of critical host factors for malaria is limited. P. falciparum is an obligate intracellular parasite of human erythrocytes, suggesting it has evolved to exploit specific host pathways to establish infection. Here, we report that the AMPK-related kinase NUAK1 is a critical host factor for P. falciparum in erythrocytes and has potential as a therapeutic target. We show that NUAK1 is present in human erythrocytes and undergoes increased phosphorylation in P. falciparum-infected cells. Two highly selective NUAK1 inhibitors, HTH-01-015 and WZ4003, inhibited P. falciparum growth throughout its asexual life cycle, including during erythrocyte invasion. Chemoproteomic profiling confirmed the inhibitors selectivity for human NUAK1. We further show that treatment with the inhibitors reduces phosphorylation of the well-characterized NUAK1 substrate MYPT1 in erythroid cells. Moreover, we find that genetic overexpression of NUAK1 in erythroid cells partially rescues both the signaling and invasion phenotypes elicited by the small molecule inhibitors. These results establish a critical role for the NUAK1 signaling pathway in P. falciparum-infected erythrocytes and highlight its potential as a vulnerable target for host-directed malaria control.

microbiology↗

bioRxiv2025

Planetary microbiome structure and generalist-driven gene flow across disparate habitats

Microbes are ubiquitous on Earth, forming microbiomes that sustain macroscopic life and biogeochemical cycles. Microbial dispersion, driven by natural processes and human activities, interconnects microbiomes across habitats, yet most comparative studies focused on specific ecosystems. To study planetary microbiome structure, function, and inter-habitat interactions, we systematically integrated 85,604 public metagenomes spanning diverse habitats worldwide. Using species-based unsupervised clustering and parameter modeling, we delineated 40 habitat clusters and quantified their ecological similarity. Our framework identified key drivers shaping microbiome structure, such as ocean temperature and host lifestyle. Regardless of biogeography, microbiomes were structured primarily by host-associated or environmental conditions, also reflected in genomic and functional traits inferred from 2,065,975 genomes. Generalists emerged as vehicles thriving and facilitating gene flow across ecologically disparate habitat types, illustrated by generalist-mediated horizontal transfer of an antibiotic resistance island across human gut and wastewater, further dispersing to other habitats, exemplifying human impact on the planetary microbiome.

microbiology↗

bioRxiv2024

Trehalose dimycolate inhibits phagosome maturation and promotes intracellular M. tuberculosis growth via noncanonical SNARE interaction

Mycobacterial cell envelopes are rich in unusual lipids and glycans that play key roles during infection and vaccination. The most abundant envelope glycolipid is trehalose dimycolate (TDM). TDM compromises the host response to mycobacterial species via multiple mechanisms, including inhibition of phagosome maturation. The molecular mechanism by which TDM inhibits phagosome maturation has been elusive. We find that a clickable, photoaffinity TDM probe recapitulates key phenotypes of native TDM in macrophage host cells and binds several host SNARE proteins, including VTI1B, STX8, and VAMP2. VTI1B and STX8 normally promote endosome fusion by forming a complex with VAMP8. However, in the presence of Mycobacterium tuberculosis, VTI1B and STX8 complex with VAMP2, which in turn decreases VAMP8 binding. VAMP2 acts together with mycolate structure to inhibit phagosome maturation and promotes intracellular M. tuberculosis replication. Thus one mechanism by which TDM constrains the innate immune response to M. tuberculosis is via non-canonical SNARE complexation. Significance StatementGlycolipids from the Mycobacterium tuberculosis cell envelope, particularly trehalose dimycolate (TDM), play major roles in subverting the immune response to this intracellular pathogen. How subversion occurs is often unclear because glycans and lipids are technically challenging to study in cells. We discovered that a TDM-mimicking chemical probe interacts with three host SNARE proteins, including two that regulate endosome fusion and one that does not. The presence of TDM or M. tuberculosis triggers abnormal binding of these SNAREs, which in turn inhibits the fusion of M. tuberculosis-containing phagosomes with lysosomes and promotes M. tuberculosis replication. Our work provides an unusual example of a bacterial pathogen restricting the immune response via glycolipid-SNARE interactions.

microbiology↗

bioRxiv2024

Tracing the stepwise Darwinian evolution of a plant halogenase

Halogenation chemistry is rare in plant metabolism, with the chloroalkaloid acutumine produced by Menispermaceae species being the only well characterized example, involving a specialized dechloroacutumine halogenase (DAH) from the iron(II)- and 2-oxoglutarate-dependent dioxygenase (2ODD) superfamily. While DAH is presumed to have evolved from an ancestral 2ODD enzyme, the broader question of how new enzymes arise through Darwinian processes, such as the birth of DAH in Menispermaceae, remains a fundamental challenge in understanding metabolic evolution. Here, we investigate DAHs evolutionary trajectory using the chromosomal-level genome assembly of Menispermum canadense. By analyzing the genomic context of DAH in M. canadense and syntenic regions in related plants, we show that DAH evolved through tandem duplication of an ancestral flavonol synthase (FLS) gene, followed by a series of neofunctionalization and gene loss events. Through structural modeling, molecular dynamics simulations, and site-directed mutagenesis, we identify residue changes enabling the transition from FLS to DAH. This functional switch required traversing a complex evolutionary landscape where adaptive peaks were separated by deep fitness valleys. Our work illustrates how new enzymatic functions can arise through lineage-specific evolutionary pathways that gradually reshape the active site architecture through permissive mutations, ultimately enabling mechanism-switching mutations that establish novel catalytic activities.

biochemistry↗

bioRxiv2024

Exclusive cataloging of near-complete genomes unveils novel functional insights into the human gut microbiome

Understanding the human gut microbiome requires comprehensive genomic catalogues, yet many lack geographic diversity and contain medium-quality metagenome-assembled genomes (MAGs) missing up to 50% of genomic regions, potentially distorting functional insights. Here, we describe an enhanced Human Reference Gut Microbiome (HRGM2) resource, a catalogue of near-complete MAGs ([≥]90% completeness, [≤]5% contamination) and isolate genomes. HRGM2 comprises 155,211 non-redundant near-complete genomes from 4,824 prokaryotic species across 41 countries, representing a 66% increase in genome count and a 50% boost in species diversity compared to the Unified Human Gastrointestinal Genome catalogue. It enabled improved DNA-based species profiling, resolution of strain heterogeneity, and survey of human gut resistome. The exclusive use of these genomes improved metabolic capacity assessment enabling high-confidence, automated genome-scale metabolic models (GEMs) of the entire microbiota, revealing disease-associated microbial metabolic interactions. This resource will facilitate reliable functional insights into gut microbiomes.

microbiology↗

bioRxiv2024

A genetically encoded fluorescent reporter for polyamines

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinsons disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinsons disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.

cell biology↗

bioRxiv2024

Refined Enterotyping Reveals Dysbiosis in Global Fecal Metagenomes

BackgroundEnterotypes describe human fecal microbiomes grouped by similarity into clusters of microbial community composition, often associated with disease, medications, diet, and lifestyle. Numbers and determinants of enterotypes have been derived by diverse frameworks and applied to cohorts that often lack diversity or inter-cohort comparability. ResultsTo overcome these limitations, we selected 16,772 fecal metagenomes collected from 38 countries to revisit the enterotypes using state-of-the-art fuzzy clustering and found robust clustering regardless of underlying taxonomy, consistent with previous findings. Quantifying the strength of enterotype classifications enriched the enterotype landscape, also reflecting some continuity of microbial compositions. As the classification strength was associated with the patients health status, we established an "Enterotype Dysbiosis Score" (EDS) as a latent covariate for various diseases. ConclusionThis global study confirms the enterotypes, reveals a dysbiosis signal within the enterotype landscape, and enables robust classification of metagenomes with an online "Enterotyper" tool, allowing reproducible analysis in future studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/607711v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1611a2org.highwire.dtl.DTLVardef@dfbb57org.highwire.dtl.DTLVardef@848ac0org.highwire.dtl.DTLVardef@1b15808_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

MRGM: An enhanced catalog of mouse gut microbial genomes substantially broadening taxonomic and functional landscapes

Mouse gut microbiome research is pivotal for understanding the human gut microbiome, providing insights into disease modeling, host-microbe interactions, and the dietary influence on the gut microbiome. To enhance the translational value of mouse gut microbiome studies, we need detailed and high-quality catalogs of mouse gut microbial genomes. We introduce the Mouse Reference Gut Microbiome (MRGM), a comprehensive catalog with 42,245 non-redundant mouse gut bacterial genomes across 1,524 species. MRGM marks a 40% increase in the known taxonomic diversity of mouse gut microbes, capturing previously underrepresented lineages through refined genome quality assessment techniques. MRGM not only broadens the taxonomic landscape but also enriches the functional landscape of the mouse gut microbiome. Using deep learning, we have elevated the Gene Ontology annotation rate for mouse gut microbial proteins from 3.2% with orthology to 60%, marking an over 18-fold increase. MRGM supports both DNA- and marker-based taxonomic profiling by providing custom databases, surpassing previous catalogs in performance. Finally, taxonomic and functional comparisons between human and mouse gut microbiota reveal diet-driven divergences in their taxonomic composition and functional enrichment. Overall, our study highlights the value of high-quality microbial genome catalogs in advancing our understanding of the co-evolution between gut microbes and their host.

microbiology↗

bioRxiv2023

Diffusion time-related structure-function coupling reveals differential association with inter-individual variations in body mass index

Body mass index (BMI) is an indicator of obesity, and recent neuroimaging studies have demonstrated inter-individual variations in BMI to be associated with altered brain structure and function. However, how the structure-function correspondence is altered according to BMI is under-investigated. In this study, we combined structural and functional connectivity using Riemannian optimization with varying diffusion time parameters and assessed their association with BMI. First, we simulated functional connectivity from structural connectivity and generated low-dimensional principal gradients of the simulated functional connectivity across diffusion times, where low and high diffusion times indirectly reflected mono- and polysynaptic communication. We found the most apparent cortical hierarchical organization differentiating between low-level sensory and higher-order transmodal regions in the middle of the diffusion time, indicating that the hierarchical organization of the brain may reflect the intermediate mechanisms of mono- and polysynaptic communications. Associations between the simulated gradients and BMI revealed the strongest relationship when the hierarchical structure was most evident. Moreover, the functional gradient-BMI association map showed significant correlations with the cytoarchitectonic measures of the microstructural gradient and moment features, indicating that BMI-related functional connectome alterations were remarkable in higher-order cognitive control-related brain regions. Finally, transcriptomic association analysis provided potential biological underpinnings, specifying gene enrichment in the striatum, hypothalamus, and cortical cells. Our findings provide evidence that structure-function correspondence is strongly coupled with BMI when hierarchical organization is most apparent, and the associations are related to the multiscale properties of the brain, leading to an advanced understanding of the neural mechanisms related to BMI.

neuroscience↗

bioRxiv2023

The CD4 transmembrane GGXXG and juxtamembrane (C/F)CV+C motifs mediate pMHCII-specific signaling independently of CD4-Lck interactions

CD4+ T cell activation is driven by 5-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3{gamma}{varepsilon}, CD3{delta}{varepsilon}, and CD3{zeta}{zeta}) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee, et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3{zeta}, ZAP70, and PLC{gamma}1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.

immunology↗

bioRxiv2023

GAN-MAT: Generative Adversarial Network-based Microstructural Profile Covariance Analysis Toolbox

AO_SCPLOWBSTRACTC_SCPLOWMultimodal magnetic resonance imaging (MRI) provides complementary information for investigating brain structure and function; for example, an in vivo microstructure-sensitive proxy can be estimated using the ratio between T1- and T2-weighted structural MRI. However, acquiring multiple imaging modalities is challenging in patients with inattentive disorders. In this study, we proposed a comprehensive framework to provide multiple imaging features related to the brain microstructure using only T1-weighted MRI. Our toolbox consists of (i) synthesizing T2-weighted MRI from T1-weighted MRI using a conditional generative adversarial network; (ii) estimating microstructural features, including intracortical covariance and moment features of cortical layer-wise microstructural profiles; and (iii) generating a microstructural gradient, which is a low-dimensional representation of the intracortical microstructure profile. We trained and tested our toolbox using T1- and T2-weighted MRI scans of 1,104 healthy young adults obtained from the Human Connectome Project database. We found that the synthesized T2-weighted MRI was very similar to the actual image and that the synthesized data successfully reproduced the microstructural features. The toolbox was validated using an independent dataset containing healthy controls and patients with episodic migraine as well as the atypical developmental condition of autism spectrum disorder. Our toolbox may provide a new paradigm for analyzing multimodal structural MRI in the neuroscience community, and is openly accessible at https://github.com/CAMIN-neuro/GAN-MAT.

neuroscience↗

bioRxiv2023

Plasmodium falciparum exploits CD44 as a co-receptor for erythrocyte invasion

The malaria parasite Plasmodium falciparum invades and replicates asexually within human erythrocytes. CD44 expressed on erythrocytes was previously identified as an important host factor for P. falciparum infection through a forward genetic screen, but little is known about its regulation or function in these cells, nor how it may be utilized by the parasite. We found that CD44 can be efficiently deleted from primary human hematopoietic stem cells using CRISPR/Cas9 genome editing, and that the efficiency of ex-vivo erythropoiesis to enucleated cultured red blood cells (cRBCs) is not impacted by lack of CD44. However, the rate of P. falciparum invasion was substantially reduced in CD44-null cRBCs relative to isogenic wild-type (WT) control cells, validating CD44 as an important host factor for this parasite. We identified two P. falciparum invasion ligands as binding partners for CD44, Erythrocyte Binding Antigen-175 (EBA-175) and EBA-140, and demonstrated that their ability to bind to human erythrocytes relies primarily on their canonical receptors-glycophorin A and glycophorin C, respectively. We further show that EBA-175 induces phosphorylation of erythrocyte cytoskeletal proteins in a CD44-dependent manner. Our findings support a model where P. falciparum exploits CD44 as a co-receptor during invasion of human erythrocytes, stimulating CD44-dependent phosphorylation of host cytoskeletal proteins that alter host cell deformability and facilitate parasite entry.

microbiology↗

bioRxiv2023

Reticulocytes in donor RBC units enhance RBC alloimmunization

Although red blood cell (RBC) transfusions save lives, some patients develop clinically-significant alloantibodies against donor blood group antigens, which then have adverse effects in multiple clinical settings. Few effective measures exist to prevent RBC alloimmunization and/or eliminate alloantibodies in sensitized patients. Donor-related factors may influence alloimmunization; thus, there is an unmet clinical need to identify which RBC units are immunogenic. Repeat volunteer blood donors and donors on iron supplements have elevated reticulocyte counts compared to healthy non-donors. Early reticulocytes retain mitochondria and other components, which may act as danger signals in immune responses. Herein, we tested whether reticulocytes in donor RBC units could enhance RBC alloimmunization. Using a murine model, we demonstrate that transfusing donor RBC units with increased reticulocyte frequencies dose-dependently increase RBC alloimmunization rates and alloantibody levels. Transfusing reticulocyte-rich RBC units was associated with increased RBC clearance from the circulation and a robust proinflammatory cytokine response. As compared to previously reported post-transfusion RBC consumption patterns, erythrophagocytosis from reticulocyte-rich units was increasingly performed by splenic B cells. These data suggest that reticulocytes in a donated RBC unit impact the quality of blood transfused, are targeted to a distinct compartment, and may be an underappreciated risk factor for RBC alloimmunization.

immunology↗

bioRxiv2022

Social context modulates multibrain broadband dynamics and functional brain-to-brain coupling in the group of mice

Although mice are social animals, studies that explore the simultaneously recorded neural activities of multiple mice, especially in a social setting, are still lacking. In this study, we simultaneously recorded local field potential (LFP) signals in the dorsomedial prefrontal cortex (dmPFC) from up to four mice. The brain activities of the mice were measured in two contradicting conditions - freely interacting in a group or being individually separated. We found that social context and the locomotive states predominately modulate the entire LFP structure. Power spectral density (PSD) estimate and spectrogram of LFP signals showed a broadband modulation; lower frequency bands--delta (<4Hz), theta (4-7Hz), and alpha (8-12Hz) power were highly correlated to each other and anti-correlated with gamma and high gamma (>30Hz) power. We calculated the high-to-low-power ratio (HLR) and found that HLR was higher when the mice were in a group than were separated. The HLR was also higher when they were active--whether or not they were moving. The mice in the group showed higher HLR in any locomotive states. We then analyzed whether social context can be divided into sub-contexts. Notably, the aggregation of animals, called huddling, decreased social context-induced increase in HLR. Multibrain analyses of HLR indicated that the mice in the group displayed high cross-correlation to each other, indicating interbrain synchrony. Then we examined whether there is any directional relationship between HLR from pairs of mice. A majority of dyad selected within the group of mice showed unilateral precedence of HLR by Granger causality analysis, comprising a hierarchical social structure based on a directionality of influence. Overall, this study shows the importance of the social environment in brain dynamics and emphasizes the value of simultaneous multibrain recording for researching social behaviors and their neural correlates. One-sentence summaryCoexistence modulates overall brain activities with unilateral causal relationship.

neuroscience↗

bioRxiv2022

Cryogenic electron tomography reveals novel structures in the apical complex of Plasmodium falciparum

Intracellular infectious agents, like the malaria parasite, Plasmodium falciparum, face the daunting challenge of how to invade a host cell. This problem may be even harder when the host cell in question is the enucleated red blood cell. Evolution has provided P. falciparum and related single-celled parasites within the phylum Apicomplexa with a collection of organelles at their apical end that mediate invasion. This apical complex includes at least two sets of secretory organelles, micronemes and rhoptries, and several structural features like apical rings and a putative pore through which proteins may be introduced into the host cell during invasion. In this paper, we perform cryogenic electron tomography (cryo-ET) on isolated merozoites to visualize the apical machinery. Through tomography reconstruction of cellular compartments, we see new details of known structures like the rhoptry tip interacting directly with a rosette resembling the recently described rhoptry-secretory-apparatus (RSA), or with an apical vesicle docked beneath the RSA. Subtomogram averaging reveals that the apical rings have a fixed number of repeating units, each of which is similar in overall size and shape to the units in the apical rings of tachyzoites of Toxoplasma gondii. Comparison of these polar rings in Plasmodium and Toxoplasma parasites also reveals them to have a structurally conserved assembly patterning. These results provide new insight into the essential features of this remarkable machinery used by apicomplexan parasites to invade their respective host cells.

cell biology↗