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Kim, Y.

Publications and source records attributed to Kim, Y..

At least 91 records · Page 5Linked to original sources

Template-based RNA structure prediction advanced through a blind code competition

Automatically predicting RNA 3D structure from sequence remains an unsolved challenge in biology and biotechnology. Here, we describe a Kaggle code competition engaging over 1700 teams and 43 previously unreleased structures to tackle this challenge. The top three submitted algorithms achieved scores within statistical error of the winners of the recent CASP16 competition. Unexpectedly, the top Kaggle strategy involved a pipeline for discovering 3D templates, without the use of deep learning. We integrated this template-modeling pipeline and other Kaggle strategies to develop a single model RNAPro that retrospectively outperformed individual Kaggle models on the same test set. These results suggest a growing importance of template-based modeling in RNA structure prediction.

biophysics↗

Urolithin A Restores Mitochondrial Function and Reverses Cardiac Remodeling in Heart Failure with Preserved Ejection Fraction

BackgroundHeart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases; however, mechanism-based therapies targeting cellular dysfunction remain absent. Emerging evidence suggests that mitochondrial dysfunction and impaired quality control, particularly defective mitophagy, are central to the pathogenesis of HFpEF. Urolithin A (UA), a gut microbiome-derived postbiotic metabolite, has shown promise as a mitophagy activator in preclinical models; however, its therapeutic efficacy in HFpEF remains unknown. MethodsWe used a clinically relevant two-hit HFpEF mouse model (high-fat diet (HFD) plus N{omega}-nitro-L-arginine methyl ester (L-NAME)) and co-administered UA during disease progression. The cardiac structure and function were assessed using echocardiography, histology, and transmission electron microscopy. Mitochondrial bioenergetics were evaluated using Seahorse-based respirometry. Mitophagy flux was monitored using mt-Keima assays in H9c2 cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic insights were obtained using immunoblotting, integrated shotgun metagenomic and lipidomic profiling, and single-nucleus RNA sequencing (snRNA-seq). ResultsUA treatment significantly attenuated cardiac remodeling and fibrosis in HFpEF mice while improving diastolic function parameters. Transmission electron microscopy revealed restoration of the mitochondrial ultrastructure, and mitochondrial stress tests demonstrated enhanced oxidative phosphorylation capacity and glycolytic reserves. Immunoblot assays revealed that UA treatment recovered PINK1/Parkin-mediated mitophagy markers (reduced LC3-II and p62/SQSTM1). Mt-Keima assays confirmed enhanced mitophagic flux in H9c2 cells under HFpEF-like stress conditions. Integrated metagenomics and lipidomics revealed significant reductions in cardiovascular risk-associated ceramides. snRNA-seq demonstrated that HFpEF-like stress downregulated contractile, calcium-handling, and mitochondrial mitophagy gene programs. UA treatment restored the mitochondrial quality control signatures and normalized profibrotic and conduction-type cell populations. ConclusionsUrolithin A restored mitochondrial quality control through the activation of mitophagy and reversed cardiac remodeling in HFpEF. These findings establish UA as a mitochondria-targeted therapeutic candidate for HFpEF. Novelty and SignificanceO_ST_ABSWhat is known?C_ST_ABS{checkmark} Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome driven by metabolic stress and myocardial remodeling, for which effective disease-modifying therapies are lacking. {checkmark}Mitochondrial dysfunction and impaired mitophagy have been implicated in HFpEF, but their roles in cardiomyocyte state remodeling and fibrosis remain incompletely defined. {checkmark}Urolithin A, a gut microbiome-derived metabolite, enhances mitophagy in aging and metabolic tissues, but its relevance to HFpEF has not been established. What new information does this article contribute?{checkmark} Urolithin A restores mitochondrial quality control and mitophagic flux in cardiomyocytes, improving diastolic function and attenuating cardiac remodeling in a two-hit HFpEF model. {checkmark}Integrated metagenomic and lipidomic analyses identify suppression of gut microbiome-associated ceramide biosynthesis as a systemic mechanism linked to Urolithin A-mediated cardioprotection. {checkmark}Single-nucleus RNA sequencing reveals that Urolithin A reverses maladaptive cardiomyocyte transcriptional state transitions toward fibrogenic and conduction-like programs.

molecular biology↗

Structural basis of cyclic phytocytokine recognition by the HSL3/NUT receptor

Plant receptor kinases perceive diverse peptide signals to coordinate stress responses and developmental programs. The HAESA-LIKE 3 (HSL3/NUT) receptor recognizes CTNIP/SCREW phytocytokines--disulfide-stabilized cyclic peptides that regulate immune signaling and stress adaptation. However, how HSL3 distinguishes these structurally constrained cyclic peptides from linear signaling molecules remains unknown. Here we report near-atomic resolution cryo-EM structures of HSL3 in apo and CTNIP448-70-bound states at [~]2.6 [A], using Arabidopsis CTNIP4 as a representative family member, revealing distinct mechanisms for cyclic peptide recognition. The conserved CTNIP motif occupies a negatively charged pocket in HSL3s C-terminal region through a combination of polar contacts, hydrogen bonds, salt bridges, and van der Waals interactions. The receptor employs a two-step recognition mechanism--electrostatic steering followed by motif anchoring--that enables rapid ligand capture and release, consistent with the transient nature of stress signaling. Notably, an N-glycan at Asn449 directly contacts the CTNIP4 peptide, establishing glycosylation as an active participant in ligand recognition. Structure-guided mutagenesis combined with reactive oxygen species (ROS) burst assays confirmed the functional importance of key binding interfaces. N-terminal truncation experiments revealed a minimal active fragment: CTNIP451-70 supported both rapid ROS production and sustained seedling growth inhibition, whereas the shorter CTNIP454-70 variant retained ROS activity but failed to trigger long-term seedling growth inhibition. Structure-guided coevolutionary analysis across plant lineages reveals patterns of both conserved and variable receptor-ligand interfaces, highlighting evolutionary flexibility while preserving core features of recognition. These conserved recognition principles, mediated by receptor glycosylation and evolutionary plasticity, enable specificity in peptide signaling with implications for engineering stress-resilient crops.

plant biology↗

A simple, anesthesia-free infusion technique for in vivo metabolic tracing

Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.

biochemistry↗

Drift, selection and convergence in the evolution of a nonribosomal peptide

Nonribosomal peptides play important roles in microbial ecology and medicine, for example as toxins and antibiotics such as penicillin1. Like ordinary proteins, nonribosomal peptides are subject to evolutionary change, which is driven by rampant recombinations of their synthetases2. This makes it difficult to study the evolutionary histories of nonribosomal peptides, because recombination is a serious challenge for phylogenetic inference3. Here we use recombination-aware phylogenetics and ancestral sequence reconstruction to retrace the evolution of GameXPeptides, nonribosomal peptides entomopathogenic bacteria use to kill their insect prey4. By untangling the complex histories of their synthetases, we discover dozens of new GameXPeptides and show striking patterns of structural convergence. In analogy to classic statistical test for natural selection acting on nucleotide mutations, we develop a similar test for whether selection acts to fix recombinations. We provide statistical and experimental evidence of both neutral genetic drift and natural selection in the diversification of GameXPeptides. GameXPeptides variants rapidly evolved highly insect specific toxicities, suggesting that their diversification may be driven by an evolutionary arms race. Our work suggests that small, fast evolving alteration to nonribosomal peptides can overcome host resistance on short timescales, with important implications for the evolution of resistance evading antibiotics.

evolutionary biology↗

Tether-mediated extraction of myelinoid bodies by microglia and astrocytes can maintain myelin integrity

Oligodendrocytes make myelin for the electrical insulation of axons and saltatory impulse conduction. Myelin lipids and proteins undergo a slow turnover, but exactly how the multilamellar and compacted membrane sheaths are remodeled without compromising myelin sheath integrity has remained puzzling, in particular at advanced age when myelin abnormalities increase. Earlier EM studies had suggested myelin membranes are shed and subsequently phagocytosed by microglia. However, the formation of multilamellar myelinoid bodies (MBs), leaving a well-ordered myelin sheath behind, is difficult to reconcile with simple shedding mechanisms. Here, we show by three-dimensional FIB-SEM reconstructions of optic nerves in mice and by two-photon live-imaging of myelinated cortical slices that MBs are initially connected to their parental sheaths by long tethers, which are stretched by trogocytosing microglia and astrocytes. We observe ruptured tethers attached to both MBs and sheaths, suggesting a novel mechanism of tension-driven tether scission. Importantly, the successive fusion of the corresponding innermost myelin membranes in an extended tether can preserve myelin sheath integrity. Thus, the remodeling by tether-mediated MB extraction emerges as a mechanism of physiological maintenance of myelin sheaths in the CNS.

neuroscience↗

Shared neural geometries for bilingual semantic representations

The human brain has the remarkable ability to comprehend and express similar concepts in multiple languages. To understand how it does so, we examined responses of hippocampal neurons during passive listening, directed speaking, and spontaneous conversation, in both English and Spanish, in a small group of balanced bilinguals. We find a small number of putative cross-language neurons, whose responses to equivalent words (e.g., "tierra" and "earth") are correlated. However, neurons semantic tunings differed substantially by language, suggesting language-specific neural implementations. Instead, the crucial driver of translation was a preserved geometric organization of neural responses between the two languages, one that did not depend on neuron level functional overlap. Indeed, that geometry was implemented by a common set of neurons along distinct readout axes; this difference in readout may help prevent cross-language interference. Together, these results suggest that hippocampus encodes a language-independent internal model for meaning.

neuroscience↗

Mechanisms of adaptive interlimb coordination to sudden ground loss: a neuromusculoskeletal modeling study

Mammals exhibit robust walking across diverse environments, a capability largely attributed to central pattern generators (CPGs) in the spinal cord. Afferent feedback modulates CPG output and plays a critical role in adaptive locomotion, yet its specific contributions remain poorly understood. To investigate this, we used a neuromusculoskeletal model to simulate hindlimb locomotion in spinalized cats encountering a hole and experiencing a sudden loss of ground support, as described in prior experimental studies. The model couples a trunk-andhindlimb musculoskeletal system to a pair of two-level, half-center CPGs--one for each hindlimb. The model reproduced the observed adaptive interlimb coordination that allows cats to maintain walking after the sudden loss of ground support. Notably, the adaptive response emerged without re-optimizing parameters, which were tuned for steady walking in an environment without holes. Nullcline analysis based on dynamical systems theory revealed that afferent feedback mechanisms controlling the transitions between fast and slow neuronal dynamics facilitated adaptive interlimb coordination. These findings provide mechanistic insight into how spinal feedback circuits support robust locomotion through dynamic interactions between the nervous system, the musculoskeletal system, and the environment.

neuroscience↗

Ventral tegmental area dopamine controls timing variability

Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinsons disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start-related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine-depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.

neuroscience↗

AI-based supervised treatment response prediction from tumor transcriptomics: A large-scale pan-cancer study

Precision oncology aims to guide treatment decisions using biomarkers. While DNA-based panels are increasingly applied, RNA transcriptomics remain underused due to limited datasets and the absence of robust models. We assembled the largest transcriptomic resource for drug response prediction to date, spanning 91 cohorts, 5,675 patients, nine cancer types, and six frontline therapies: anti-PD-1/PD-L1 immune-checkpoint inhibitors, trastuzumab, bevacizumab, BRAF inhibitors, paclitaxel, and FAC/FEC (Fluorouracil-Adriamycin-Cyclophosphamide/Fluorouracil-Epirubicin-Cyclophosphamide) chemotherapy. We developed EXPRESSO (EXpression-Profile-RESponSe-Optimizer), a supervised machine-learning framework that predicts treatment response from pre-treatment transcriptomes by integrating drug targets and context-specific biomarkers. EXPRESSO achieves mean ROC-AUCs of 0.62-0.73 and median odds ratios of 2.4-4.6 across therapies, outperforming 20 published transcriptomic signatures and other machine learning methods. Prospective validation on 22 independent cohorts confirms that performance generalizes beyond cross-validation. The EXPRESSO signature additionally stratifies progression-free survival in immune checkpoint blockade-treated cohorts, demonstrating prognostic value beyond binary response prediction. Robustness analysis reveals that predictive performance plateaued for some therapies with increasing training cohorts but continued to improve for others. These findings suggest inherent limits of supervised brute-force learning for certain treatments, but additional data and deeper mechanistic modeling may further enhance transcriptomics-based predictors. SIGNIFICANCEEXPRESSO forms the next step in studying the feasibility of harnessing bulk transcriptomic data to inform therapeutic decision-making, advancing the role of transcriptomics from exploratory biomarker discovery to actionable predictive modeling.

cancer biology↗

Engineering HIV antibodies with enhanced breadth and potency of neutralization through multistate affinity maturation

Broadly neutralizing antibodies (bnAbs) against HIV hold promise as therapeutic and prophylactic agents, but realizing this potential requires antibodies that function across the antigenic heterogeneity of the HIV envelope glycoprotein (Env). Although numerous bnAbs have been isolated from infected individuals, their breadth and potency may not be sufficient to tackle global viral diversity, motivating efforts to further improve their neutralization capacity. Here, we address this challenge using a multistate antibody engineering approach integrating deep mutational scanning with combinatorial library screening across diverse Env variants. This strategy enables identification of mutation patterns that confer improved binding across antigenically distinct targets. Starting from one of the best-in-class CD4-binding site bnAbs, we performed iterative optimization to increase binding affinity across diverse Env variants. The resulting lead candidate exhibited improved breadth and up to 100-fold higher potency against pseudoviruses from large cross-clade historical and contemporary panels while maintaining biophysical and pharmacokinetic profiles conducive to clinical development. Structural and molecular dynamics analyses revealed a unique tri-tyrosine aromatic triad and reinforced electrostatic contacts that stabilized the bnAb/Env interface. These findings demonstrate that systematic in vitro engineering can generate bnAbs with enhanced breadth and potency, providing a generalizable strategy for developing therapeutic antibodies against highly diverse pathogens.

bioengineering↗

TET CpG sequence context specific DNA demeth-ylation shapes progression of IDH-mutant gliomas

BackgroundTreatment decisions in IDH-mutant oligodendrogliomas are shaped by tumor aggressiveness, underscoring the need for objective grading of these malignant brain tumors. Material and MethodsWe collected 302 primary and recurrent resections from oligodendrogliomas and performed Ki-67 staining, proteomics and DNA methylation profiling. Results & conclusionDuring tumor progression, DNA methylation of oligodendrogliomas changed along a continuum. This continuum is linked to increased epigenetic aging, methylation of transcription factors and Ki-67+ cell density, and to large scale DNA demethylation. Demethylation was correlated with CpGs flanking sequences preferred by TET enzymes. We confirmed these findings in previously profiled astrocytomas, indicating IDH-mutant gliomas progress along a shared epigenetic axis. We developed an objective DNA methylation based prognostic continuous grading coefficient (CGC{psi}) that captured these changes and outperformed WHO grading for oligodendrogliomas. Our findings underscore the potential of DNA methylation-based grading to more accurately reflect tumor biology and inform clinical decision-making in IDH-mutant gliomas.

cancer biology↗

ETV4 restrains the formation of CD74+ cytotoxic exhausted CD8+ T cells

Exhausted CD8+ T (Tex) cells comprise heterogeneous subsets with varying cytotoxic and dysfunctional properties, making inhibitory receptor profiles unreliable indicators of function. Therefore, it is essential to define transcriptional regulators or markers that accurately reflect these states. Here, we identified ETS variant 4 (ETV4) as a transcription factor that restricts cytotoxic Tex differentiation within tumors. ETV4 deficiency promotes the emergence of a CD74+ cytotoxic Tex subset while preserving the progenitor Tex (Tpex) pool. CD74 serves as both a marker and regulator, reinforcing Tpex features and enhancing Tex cytotoxicity. Mechanistically, ETV4 loss derepresses T-bet expression, thereby increasing IFN{gamma} production that induces CD74 expression in a paracrine manner. Single-cell analyses across human cancers revealed that CD74+ Tex cells are enriched for proliferative and metabolic programs and correlate with improved survival. Collectively, we establish the ETV4-CD74 axis as a regulator of Tex fate and promising therapeutic target to augment anti-tumor immunity.

immunology↗

Thick filament molecular interfaces play a critical role in pathogenesis of hypertrophic and dilated cardiomyopathy

Hypertrophic (HCM) and dilated (DCM) cardiomyopathy variants in genes encoding the myosin heavy chain (MYH7), myosin light chains (MYL2 and MYL3), and cardiac myosin binding protein-C (cMyBP-C, MYBPC3) lead to cardiac hypertrophy or dilatation, with abnormal contractility, relaxation, and energy consumption. Here we defined the structural consequences of >200 pathogenic and benign missense variants in these genes by mapping variants onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 31 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the myosin heavy chain, essential and regulatory light chains, and cMyBP-C. Pathogenic DCM missense variants are rare, and altered only interfaces involving the myosin IHM and tails. None of the 21 variants classified as benign were within interfaces. We demonstrate earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within versus outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients. The dissimilar distribution of DCM and HCM variants could explain the different features of the two phenotypes.

biophysics↗

Rapid discovery of antiviral targets through dimensionality reduction of genome-scale metabolic models

The COVID-19 pandemic underscored the urgent need for rapid and broadly applicable strategies to identify antiviral targets against emerging pathogens. Conventional approaches, which rely on detailed viral characterization and large-scale drug screening, are too slow to address this challenge. Here, we introduce a transcriptome-based computational framework that integrates genome-scale metabolic models with dimensionality reduction to uncover host metabolic vulnerabilities that support viral replication. Applying this approach to bulk and single-cell RNA-seq data from HCoV-OC43-infected cells and organoids identified oxidative phosphorylation as a key vulnerability, and pharmacological inhibition of complex I effectively curtailed viral replication. Extending the framework to SARS-CoV-2 and MERS-CoV revealed pyrimidine catabolism as a conserved antiviral pathway, with inhibition of its rate-limiting enzyme DPYD suppressing replication in organoid models. Re-analysis of SARS-CoV-2 patient metabolome data further confirmed elevated DPYD activity, underscoring its clinical relevance. Together, these findings establish a generalizable and rapid strategy for host-directed antiviral discovery, providing a foundation for precision therapeutics and pandemic preparedness. Significance StatementHost-directed antiviral therapies offer several advantages in antiviral research, but identifying key host factors poses a significant challenge. By integrating genome-scale metabolic models with single-gene knockout simulation and dimensionality reduction, we developed a computational framework based on single and bulk RNA-seq data that can systematically pinpoint host pathways whose downregulation is predicted to rewire virus-induced metabolic alterations. Applying this approach to multiple human coronaviruses reveals unique metabolic vulnerabilities, and we experimentally demonstrate that inhibiting these host metabolic pathways reduces viral replication. This framework provides a generalizable antiviral strategy to discern effective targets and can be further extended to investigate virus-host metabolic interactions.

systems biology↗

Why early birds sing early: rebound singing from nighttime suppression can explain dawn chorus

Many birds sing vigorously at dawn, a phenomenon widely known as the "dawn chorus." While its adaptive functions have been extensively studied, the proximate mechanisms underlying this widespread phenomenon have remained largely unexplored. Here, we demonstrate that intense morning singing resembling the dawn chorus is evoked as a rebound from singing suppression prior to dawn in captive zebra finches. Our findings indicate that when birds become hormonally aroused in darkness well before dawn, the suppression of spontaneous singing by darkness enhances their intrinsic motivation to sing. This elevated motivation subsequently triggers a rebound of intense singing immediately upon an increase in ambient light. These results reveal mechanisms by which intense morning singing arises from the interaction between the birds arousal state and ambient light, providing a plausible mechanistic explanation for the dawn chorus. Additionally, we found that rebound morning singing accelerates morning changes in song structure, supporting the existing hypothesis that the dawn chorus functions as a vocal warm-up to rapidly optimize song performance following nighttime silence. Together, our findings provide both mechanistic and functional insights into the dawn chorus and other diel vocal patterns in songbirds.

animal behavior and cognition↗

Retrospective attention reveals a decaying theta rhythm in conscious access to a preceeding stimulus

Conscious perception is often presumed to arise immediately upon external stimulation. However, the phenomenon of retroperception-conscious access to a stimulus after it has disappeared-challenges this view by demonstrating that awareness can emerge retrospectively. The fine-grained temporal dynamics governing this process, however, remain unknown. Here, we tested three competing models for the temporal architecture of retroperception: a monotonic decay, a sustained oscillation, and a damped oscillation. We implemented an established retro-cue paradigm and densely sampled behavioral reports. Through spectral analysis and computational modeling, we revealed that both behavioral accuracy and subjective visibility exhibited damped oscillations in the theta-band, superimposed on a time-dependent decay. Furthermore, we demonstrated that these oscillations in accuracy and visibility were temporally aligned, advocating a functional interplay between attention and perception in the post-stimulus period. These results reveal a rhythmically structured and temporally constrained window for conscious reactivation, redefining the limits of when and how the mind can become aware of the past.

neuroscience↗

Mining thermophile photosynthesis genes: a synthetic operon expressing Chloroflexota species reaction center genes in Rhodobacter sphaeroides

Photosynthesis is the foundation of the vast majority of life systems, and therefore the most important bioenergetic process on earth, and the greatest diversity in photosynthetic systems are found in microorganisms. However, understanding of the biophysical and biochemical processes that transduce light to chemical energy has derived from the relatively small subset of proteins from microbes that are amenable to cultivation, in contrast to the huge number of microbial DNA sequences encoding proteins that catalyze the initial photochemical reactions that has been deposited in databases, such as from metagenomics. We describe the use of a Rhodobacter sphaeroides laboratory strain for expression of heterologous photosynthesis genes to demonstrate the feasibility of mining this resource, focusing on hot spring Chloroflexota gene sequences. Using a synthetic operon of genes, we produced a photochemically active complex of reaction center proteins in our biological system. We also present bioinformatic analyses of anoxygenic type II reaction center sequences from metagenomic samples collected from hot (42-90{degrees} C) springs available through the JGI IMG database, to generate a resource of diverse sequences that potentially are adapted to photosynthesis at such temperatures. These data provide a view into the natural diversity of anoxygenic photosynthesis, through a lens focused on high-temperature environments. The approach we took to express such genes can be applied for potential biotechnology purposes as well as for studies of fundamental catalytic properties of these heretofore inaccessible protein complexes.

microbiology↗