Biology subjects

Heo, J.

Publications and source records attributed to Heo, J..

12 recordsLinked to original sources

bioRxiv2026

Direct electrochemical cortisol detection via transition-resolved interrogation at a defect-engineered graphene interface

Continuous tracking of cortisol is central to understanding human stress physiology, yet direct electrochemical detection without biological receptors remains challenging despite its promise for stable and dynamic sensing. Electrochemical reduction of cortisol typically occurs at highly negative potentials, where parasitic interfacial currents, hydrogen evolution, and substantial capacitive background overlap with the cortisol reduction signal, preventing accurate quantification. We overcome this barrier through an integrated material-measurement strategy combining a defect-engineered graphene interface with a transition-resolved interrogation (TRI) measurement strategy. First, we engineered polybenzimidazole-derived laser-induced graphene containing nitrogen-rich defects while suppressing oxygen-derived functionalities which reduced parasitic background currents within the same cathodic potential regime. Next, we designed TRI to leverage differences in the time-dependent evolution of overlapping cathodic processes to isolate a localized cortisol-associated electrochemical reduction transition. Derivative-domain projection coupled with background estimation enables its reliable quantification. This integrated sensing architecture enables sensitive, selective, and dynamic cortisol detection in both artificial and biological interstitial fluids at low nanomolar concentrations. The response remains reproducible across physiologically relevant variations in pH, ionic strength, temperature, and repeated cycling. Together, these capabilities provide a basis for continuous electrochemical cortisol monitoring for future study of stress physiology.

bioengineering↗

bioRxiv2026

Digoxin Inhibits Bax{triangleup}2-induced Neuronal Cell Death

Pro-death Bax isoform Bax{Delta}2 forms protein aggregates in Alzheimers neurons, triggering stress granule formation and neuronal cell death. In seeking chemical ligands to prevent Bax{Delta}2 monomer aggregation, we performed in silico screening of FDA-approved drugs using computational docking. This screening identified a group of compounds that bind to the hydrophobic pocket of Bax{Delta}2. Subsequent wet-lab testing revealed that digoxin could block neuronal cell death at nanomolar concentrations (50 to 100 nM). Importantly, digoxins protective role is specific to Bax{Delta}2-induced cell death and is independent of its primary cardio-action on Na/K-ATPase. Further investigation suggests that digoxin does not significantly affect the formation of Bax{Delta}2 aggregates but may instead modulate Bax{Delta}2 protein levels. Although the therapeutic use of digoxin for Alzheimers disease is not feasible due to its narrow therapeutic window and toxicity, these findings open the door for chemical modification of digoxin, or development of similar compounds, to prevent Bax{Delta}2-mediated neuronal cell death in Alzheimers disease.

molecular biology↗

bioRxiv2026

Sympathetic innervation regulates metabolic flexibility of skeletal muscle

The sympathetic nervous system (SNS) is recognized for its role in the physiological regulation of organs, such as heart, vasculature and lungs, and has emerged as a potential player in skeletal muscle metabolic and neuromuscular junction (NMJ) health. However, the mechanism through which SNS signaling influences skeletal muscle function and adaptation to exercise remains unclear. Using molecular, electrophysiological, immunohistochemical, and high-resolution respirometry techniques, we tested the role of sympathetic innervation to skeletal muscle in response to exercise. Our findings reveal that sympathetic denervation disrupts the NMJ, reducing motor and sympathetic receptor expression, with concomitant deficits in skeletal muscle function. Mechanistically, these deficits are linked to diminished CPT1 enzyme activity, which impairs long-chain fatty acid-mediated oxidation in skeletal muscle mitochondria. These findings reveal a key role for sympathetic innervation in maintaining mitochondrial metabolic function and by extension, skeletal muscle performance, offering novel insight into the interplay between the SNS, exercise, and muscle mitochondria.

cell biology↗

bioRxiv2025

The SAMM50 rs3761472 causes mitochondrial dysfunction and metabolic dysfunction-associated steatotic liver disease

Genome-wide association studies (GWAS) have identified the SAMM50 rs3761472 single nucleotide polymorphism (SNP) as a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), although its in vivo functions remain unclear. SAMM50 encodes a mitochondrial outer membrane protein critical for maintaining mitochondrial structure. To investigate the biological effects of rs3761472, we generated Samm50-knock-in (KI) mice harboring a D110G substitution using CRISPR/Cas9. This variant impaired mitochondrial integrity by downregulating key regulators of mitochondrial architecture, dynamics, and quality control. This contributed to reduced ATP production and elevated oxidative stress, inflammation, and hepatocyte death. The mutation also induced insulin resistance and glucose intolerance. Samm50-KI mice fed a high-fat diet exhibited pronounced hepatic lipid accumulation and liver injury, highlighting its pathogenic role in MASLD progression. Our findings demonstrate that SAMM50 rs3761472 is a critical driver of mitochondrial dysfunction and MASLD susceptibility, supporting its potential as a therapeutic target and its relevance to precision medicine.

genetics↗

bioRxiv2025

The N-terminal order-disorder transition is a critical determinant for a metamorphosis of IscU

IscU, a key scaffold protein mediating the biogenesis of iron-sulfur (Fe-S) clusters, exhibits metamorphic characteristics crucial for its versatile and efficient function. Previous studies have demonstrated that IscU has two interconverting conformations: the structured state (S-state) and the disordered state (D-state), each contributing to its distinct functionality and interaction network. Despite its physiological importance, the precise mechanism underpinning the maintenance of IscUs unique structural heterogeneity has remained elusive. In this study, we used computational and experimental approaches to reveal that the N-terminal order-disorder plays a critical role in the metamorphic modulation of IscU. We found that the N-terminal region displays greater structural plasticity, which is linked to other regions of IscU through coevolutionary relationships. Moreover, we demonstrated that the degree of orderliness in the N-terminal region correlates positively with the stabilization of IscUs S-state and negatively with its affinity for HscA. This indicates that the flexibility in the N-terminal region is finely tuned to optimize IscUs physiological efficiency and efficacy. Finally, our data suggest that a peptide mimicking the N-terminal motif can modulate IscUs metamorphic properties, suggesting a novel therapeutic potential for related pathogenic processes.

biochemistry↗

bioRxiv2024

Modeling With Uncertainty Quantification Identifies Essential Features of a Non-Canonical Algal Carbon-Concentrating Mechanism

The thermoacidophilic red alga Cyanidioschyzon merolae survives its challenging environment likely in part by operating a carbon-concentrating mechanism (CCM). Here, we demonstrated that C. merolaes cellular affinity for CO2 is stronger than its rubisco affinity for CO2. This provided further evidence that C. merolae operates a CCM while lacking structures and functions characteristic of CCMs in other organisms. To test how such a CCM could function, we created a mathematical compartmental model of a simple CCM distinct from those previously described in detail. The results supported the feasibility of this proposed minimal and non-canonical CCM in C. merolae. To facilitate robust modeling of this process, we incorporated new physiological and enzymatic data into the model, and we additionally trained a surrogate machine-learning model to emulate the mechanistic model and characterized the effects of model parameters on key outputs. This parameter exploration enabled us to identify model features that influenced whether the model met experimentally-derived criteria for functional carbon-concentration and efficient energy usage. Such parameters included cytosolic pH, bicarbonate pumping cost and kinetics, cell radius, carboxylation velocity, number of thylakoid membranes, and CO2 membrane permeability. Our exploration thus suggested that a novel CCM could exist in C. merolae and illuminated essential features necessary for CCMs to function. SignificanceCarbon-concentrating mechanisms (CCMs) are processes which boost photosynthetic efficiency. By developing modeling approaches to robustly describe CCMs in organisms where biochemical data is limited, such as extremophile algae, we can better understand how organisms survive environmental challenges. We demonstrate an interdisciplinary modeling approach which efficiently sampled from large parameter spaces and identified features (e.g., compartment permeability, pH, enzyme characteristics) which determine the function and energy cost of a simple CCM. This approach is new to compartmental photosynthetic modeling, and could facilitate effective use of models to inform experiments and rational engineering. For example, engineering CCMs into crops may improve agricultural productivity, and could benefit from models defining the structural and biochemical features necessary for CCM function.

plant biology↗

bioRxiv2023

Identification and characterization of new structural scaffolds modulating the activity of Mycobacterium tuberculosis dihydroneopterin aldolase (FolB) in vitro

Antifolates were among the first broad-spectrum compounds used as antimycobacterial agents and can still be of use when no other therapeutic options are available. The discovery of compounds targeting this essential pathway could lead to new therapeutic agents to treat tuberculosis (TB). In particular, the enzyme required for the conversion of 7,8-dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) in the folate pathway (MtbFolB, a dihydroneopterin aldolase - DHNA, EC 4.1.2.25), has received little attention as a potential drug target. Here, we conducted a small-scale diversity screening to identify MtbFolB inhibitors using a microplate-based enzyme inhibition assay. About 6,000 compounds were assembled for the screening and 19 hits were identified, spanning 5 independent clusters. These compounds were tested in dose-response studies and active compounds selected for kinetic inhibition and time-dependent inhibition studies, leading to compounds with IC50 values ranging from 2.6 to 47 {micro}M. A preliminary structure activity analysis was performed, revealing that bi-sulfonamide compounds could be explored for further optimizations. Docking studies highlighted two modes of binding for pyrazol-3-one compounds and, for the sulfonamide series, indicated several interactions with the catalytic Tyrosine-54 (Tyr54D) and Lysine-99 (Lys99A) residues of MtbFolB. The sulfonamide compound 13 represents the first identified compound directed against MtbFolB with an antimycobacterial activity.

biochemistry↗

bioRxiv2023

Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by Atf4 following optic nerve injury

Stress signaling is important for determining the fates of neurons following axonal insults. Previously we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here we show that PERK acts primarily through Activating Transcription Factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.

neuroscience↗

bioRxiv2022

The Solanum americanum pangenome and effectoromics reveal new resistance genes against potato late blight

Late blight caused by the oomycete pathogen Phytophthora infestans continues to cause major worldwide losses in potato and tomato. Most accessions of Solanum americanum, a globally distributed, wild Solanaceae plant, are highly resistant to late blight. We generated high-quality reference genomes of four S. americanum accessions, re-sequenced 52 accessions, and we defined variation in the NLR immune receptor genes (the S. americanum NLRome). We further screened for variation in recognition of [~]315 P. infestans RXLR effectors in 52 S. americanum accessions. Using these genotypic and phenotypic data, we cloned three novel NLR-encoding genes Rpi-amr4, Rpi-amr16 and Rpi-amr17, and determined their corresponding RXLR effector genes Avramr4 (PITG_22825), Avramr16 (PITG_02860) and Avramr17 (PITG_04373) from P. infestans. These genomic resources and methodology will support efforts to convert potato into a "nonhost" of late blight and can be applied to diseases of other crops.

plant biology↗

bioRxiv2022

Newly discovered alleles of the tomato antiflorigen gene SELF PRUNING provide a range of plant compactness and yield

In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato breeding for open field production. Heterozygosity for induced mutations in the florigen gene SINGLE FLOWER TRUSS in the background of sp-classic provides a heterosis-like effect by delaying shoot termination, suggesting subtle suppression of determinacy by genetic modification of florigen-antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminate functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.

plant biology↗

bioRxiv2021

Transcriptome-wide Association Study and eQTL colocalization identify potentially causal genes responsible for bone mineral density GWAS associations

Genome-wide association studies (GWASs) for bone mineral density (BMD) have identified over 1,100 associations to date. However, identifying causal genes implicated by such studies has been challenging. Recent advances in the development of transcriptome reference datasets and computational approaches such as transcriptome-wide association studies (TWASs) and expression quantitative trait loci (eQTL) colocalization have proven to be informative in identifying putatively causal genes underlying GWAS associations. Here, we used TWAS/eQTL colocalization in conjunction with transcriptomic data from the Genotype-Tissue Expression (GTEx) project to identify potentially causal genes for the largest BMD GWAS performed to date. Using this approach, we identified 512 genes as significant (Bonferroni <= 0.05) using both TWAS and eQTL colocalization. This set of genes was enriched for regulators of BMD and members of bone relevant biological processes. To investigate the significance of our findings, we selected PPP6R3, the gene with the strongest support from our analysis which was not previously implicated in the regulation of BMD, for further investigation. We observed that Ppp6r3 deletion in mice decreased BMD. In this work, we provide an updated resource of putatively causal BMD genes and demonstrate that PPP6R3 is a putatively causal BMD GWAS gene. These data increase our understanding of the genetics of BMD and provide further evidence for the utility of combined TWAS/colocalization approaches in untangling the genetics of complex traits.

genomics↗

bioRxiv2019

Transcriptome responses associated with carbon and energy flows under high salinity stress suggest the overflow of acetyl-CoA from glycolysis and NADPH co-factor induces high lipid accumulation and halotolerance in Chlorella sp. HS2

Previously, we isolated Chlorella sp. HS2 (referred hereupon HS2) from a local tidal rock pool and demonstrated its halotolerance and relatively high biomass productivity under different salinity conditions. To further understand acclimation responses of this alga against high salinity stress, we performed transcriptome analysis of triplicated culture samples grown in freshwater and marine conditions at both exponential and stationary growth phases. De novo assembly followed by differential expression analysis identified 5907 and 6783 differentially expressed genes (DEGs) respectively at exponential and stationary phases from a total of 52770 transcripts, and the functional enrichment of DEGs with KEGG database resulted in 1445 KEGG Orthology (KO) groups with a defined differential expression. Specifically, the transcripts involved in photosynthesis, TCA and Calvin cycles were downregulated, whereas the upregulation of DNA repair mechanisms and an ABCB subfamily of eukaryotic type ABC transporter was observed at high salinity condition. In addition, while key enzymes associated with glycolysis pathway and triacylglycerol (TAG) synthesis were determined to be upregulated from early growth phase, salinity stress seemed to reduce the carbohydrate content of harvested biomass from 45.6 dw% to 14.7 dw% and nearly triple the total lipid content from 26.0 dw% to 62.0 dw%. These results suggest that the reallocation of storage carbon toward lipids played a significant role in conferring the viability of this alga under high salinity stress, most notably by remediating high level of cellular stress partially caused by ROS generated in oxygen-evolving thylakoids.\n\nSummary StatementRedirection of storage carbon towards the synthesis of lipids played a critical role in conferring the halotolerance of a Chlorella isolate by remediating excess oxidative stress experienced in photosystems.

microbiology↗