Biology subjects

Ko, Y. H.

Publications and source records attributed to Ko, Y. H..

7 recordsLinked to original sources

bioRxiv2025

The anti-metabolite KAT/3BP has in vitro and in vivo anti-tumor activity in lymphoma models

Reprogramming of cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP), a small alkylating agent, acts as an anti-metabolite to vital substrates in cancer metabolism and exhibits antitumor activity across various cancer types, but the unformulated 3BP can cause high toxicity. This study explores the efficacy of the 3BP clinical derivative KAT/3BP, currently in phase 1 for patients with hepatocellular carcinoma, in lymphoma models. In vitro, KAT/3BP demonstrated cytotoxicity across 12 lymphoma cell lines, including diffuse large B-cell lymphoma and mantle cell lymphoma, with a median IC50 of 3.7 M. KAT/3BP was also effective against lymphoma cell lines with acquired resistance to FDA-approved therapies. In vivo, we observed reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration proving most effective. Additionally, KAT/3BP exhibited synergistic activity when combined with lymphoma therapies, including bendamustine and R-CHOP. These findings underscore the potential of KAT/3BP as a novel therapeutic option for a single agent or a combination of lymphomas.

cancer biology↗

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↗

bioRxiv2023

Neural correlates of confidence during decision formation in a perceptual judgment task

When we make a decision, we also estimate the probability that our choice is correct or accurate. This probability estimate is termed our degree of decision confidence. Recent work has reported event-related potential (ERP) correlates of confidence both during decision formation (the centro-parietal positivity component; CPP) and after a decision has been made (the error positivity component; Pe). However, there are several measurement confounds that complicate the interpretation of these findings. More recent studies that overcome these issues have so far produced conflicting results. To better characterise the ERP correlates of confidence we presented participants with a comparative brightness judgment task while recording electroencephalography. Participants judged which of two flickering squares (varying in luminance over time) was brighter on average. Participants then gave confidence ratings ranging from "surely incorrect" to "surely correct". To elicit a range of confidence ratings we manipulated both the mean luminance difference between the brighter and darker squares (relative evidence) and the overall luminance of both squares (absolute evidence). We found larger CPP amplitudes in trials with higher confidence ratings. This association was not simply a by-product of differences in relative evidence (which covaries with confidence) across trials. We did not identify postdecisional ERP correlates of confidence, except when they were artificially produced by pre-response ERP baselines. These results provide further evidence for neural correlates of processes that inform confidence judgments during decision formation.

neuroscience↗

bioRxiv2022

The relationship between response dynamics and the formation of confidence varies across the lifespan

Accurate metacognitive judgements, such as forming a confidence judgement, are crucial for goaldirected behaviour but decline with older age. Besides changes in the sensory processing of stimulus features, there might also be changes in the motoric aspects of giving responses that account for age-related changes in confidence. In order to assess the association between confidence and response parameters across the adult lifespan, we measured response times and peak forces in a four-choice flanker task with subsequent confidence judgements. In 65 healthy adults from 20 to 76 years of age, we showed divergent associations of each measure with confidence, depending on decision accuracy. Participants indicated higher confidence after faster responses in correct but not incorrect trials. They also indicated higher confidence after less forceful responses in errors but not in correct trials. Notably, these associations were age-dependent as the relationship between confidence and response time was more pronounced in older participants, while the relationship between confidence and response force decayed with age. Our results add to the notion that confidence is related to response parameters and demonstrate noteworthy changes in the observed associations across the adult lifespan. These changes potentially constitute an expression of general age-related deficits in performance monitoring or, alternatively, index a failing mechanism in the computation of confidence in older adults.

neuroscience↗

bioRxiv2021

Divergent effects of absolute evidence magnitude on decision accuracy and confidence in perceptual judgements

Whether people change their mind after making a perceptual judgement may depend on how confident they are in their decision. Recently, it was shown that, when making perceptual judgements about stimuli containing high levels of absolute evidence (i.e., the overall magnitude of sensory evidence across choice options), people make less accurate decisions and are also slower to change their mind and correct their mistakes. Here we report two studies that investigated whether high levels of absolute evidence also lead to increased decision confidence. We used a luminance judgment task in which participants decided which of two dynamic, flickering stimuli was brighter. After making a decision, participants rated their confidence. We manipulated relative evidence (i.e., the mean luminance difference between the two stimuli) and absolute evidence (i.e., the summed luminance of the two stimuli). In the first experiment, we found that higher absolute evidence was associated with decreased decision accuracy but increased decision confidence. In the second experiment, we additionally manipulated the degree of luminance variability to assess whether the observed effects were due to differences in perceived evidence variability. We replicated the results of the first experiment but did not find substantial effects of luminance variability on confidence ratings. Our findings support the view that decisions and confidence judgments are based on partly dissociable sources of information, and suggest that decisions initially made with higher confidence may be more resistant to subsequent changes of mind.

neuroscience↗

bioRxiv2021

Neural correlates of metacognition across the adult lifespan

Metacognitive accuracy describes the degree of overlap between the subjective perception of ones decision accuracy (i.e., confidence) and objectively observed performance. With older age, the need for accurate metacognitive evaluation increases; however, error detection rates typically decrease. We investigated the effect of ageing on metacognitive accuracy using event-related potentials (ERPs) reflecting error detection and confidence: the error/correct negativity (Ne/c) and the error/correct positivity (Pe/c). Sixty-five healthy adults (20 to 76 years) completed a complex perceptual task and provided confidence ratings. We found that metacognitive accuracy declined with age beyond the expected decline in task performance, while the adaptive adjustment of behaviour was well preserved. Pe/c amplitudes varied by confidence rating, but they did not mirror the reduction in metacognitive accuracy. Ne/c amplitudes decreased with age except for high confidence correct responses. The results suggest that age-related difficulties in metacognitive evaluation could be related to an impaired integration of decision accuracy and confidence information processing. Ultimately, training the metacognitive evaluation of fundamental decisions in older adults might constitute a promising endeavour.

neuroscience↗

bioRxiv2020

Hormone Receptor-status Prediction in Breast Cancer Using Gene Expression Profiles and Their Macroscopic Landscape

The cost of next-generation sequencing technologies is rapidly declining, making RNA-seq-based gene expression profiling (GEP) an affordable technique for predicting receptor expression status and intrinsic subtypes in breast cancer (BRCA) patients. Based on the expression levels of co-expressed genes, GEP-based receptor-status prediction can classify clinical subtypes more accurately than can immunohistochemistry (IHC). Using data from the cancer genome atlas TCGA BRCA and METABRIC datasets, we identified common predictor genes found in both datasets and performed receptor-status prediction based on these genes. By assessing the survival outcomes of patients classified using GEP- or IHC-based receptor status, we compared the prognostic value of the two methods. We found that GEP-based HR prediction provided higher concordance with the intrinsic subtypes and a stronger association with treatment outcomes than did IHC-based hormone receptor (HR) status. GEP-based prediction improved the identification of patients who could benefit from hormone therapy, even in patients with non-luminal BRCA. We also confirmed that non-matching subgroup classification affected the survival of BRCA patients and that this could be largely overcome by GEP-based receptor-status prediction. In conclusion, GEP-based prediction provides more reliable classification of HR status, improving therapeutic decision making for breast cancer patients.

cancer biology↗