Biology subjects

Hwang, K.

Publications and source records attributed to Hwang, K..

17 recordsLinked to original sources

bioRxiv2026

PredIDR3: A new output-encoding scheme and abundant negative source provide more information for deep learning-based protein intrinsic disorder prediction

Many computational methods to predict intrinsic disordered regions (IDRs) in proteins have been developed and their performances are blindly evaluated in community-driven assessment, Critical Assessment of protein Intrinsic Disorder (CAID). In this study, we developed PredIDR3 series, an updated version of PredIDR2 tested in CAID3 to accurately predict IDRs from protein sequences. It includes two methods depending on ensemble way. The performances of PredIDR3 series (AUC_ROC=0.953) are remarkably better than our previous PredIDR2 (AUC_ROC=0.936) on Disorder-PDB dataset of CAID3, which is thought to be mainly attributed to the use of more information for intrinsic disorder prediction based on deep convolutional neural network. In details, we introduced a new output-encoding scheme permitting a large sliding window (size=91) for the first time and extracted negative samples of the training set from non-IDRs of both PDB and DisProt databases, allowing to use more information for prediction of intrinsic disorder. PredIDR3 achieved comparable performance to the top-ranking methods of CAID3 in all criteria measured. PredIDR3 series can be freely available through the CAID Prediction Portal at https://caid.idpcentral.org/portal or downloaded as a Singularity container from https://biocomputingup.it/shared/caid-predictors/.

bioinformatics↗

bioRxiv2026

Estimating trial-wise modulation of functional connectivity using event-related fMRI

Understanding the neural basis of human cognition requires measuring not only localized brain activity but also how functional interactions between brain regions change in response to different cognitive demands. Event-related fMRI is an efficient design for linking trial-wise behavioral and computational variables to brain activity, but comparable methods for examining their effects on functional connectivity remain limited. Here, we develop beta-PPI (beta-series psychophysiological interaction), a method that leverages single-trial response estimates from even-related fMRI to quantify how trial-wise variables modulate functional connectivity. This task-based functional connectivity method provides a flexible approach for studying functional connectivity for event-related fMRI designs. We evaluated beta-PPI using comprehensive simulations across several experimental conditions and signal qualities. Beta-PPI can sensitively detect ground-truth effects and exhibited good parameter recovery. Compared with generalized psychophysiological interaction, beta-PPI achieved comparable performance across most conditions while demonstrating improved statistical power under lower signal-to-noise conditions. We further validated beta-PPI using empirical event-related fMRI data. Distinct trial-wise cognitive variables selectively modulated functional connectivity during their corresponding trial epochs, demonstrating the temporal specificity and flexibility of the approach. By testing how trial-wise variables modulate functional connectivity, beta-PPI extends task-based connectivity analysis to model-based fMRI and provides a common single-trial framework that could facilitate the integration of connectivity, activation, and representational analyses in event-related fMRI.

neuroscience↗

bioRxiv2026

Specialized outputs and behavioral contributions of Purkinje cell subtypes

Purkinje cells (PCs), the sole outputs of the cerebellar cortex, transform granule cell firing patterns into appropriate outputs to drive learning and behavior. Two major PC classes (typically defined by Aldoc expression) can be further subdivided into nine molecularly distinct PC subtypes, suggesting that each subtype might be specialized for distinct categories of cerebellar processing. This has been difficult to test due to limited tools to target PC subtypes. We therefore developed intersectional tools to target PC subtypes, specifically Kcng4+ PCs (primarily Aldoc-) and Gpr176+ PCs (Aldoc1). We mapped their distributions within the cerebellar cortex and quantitatively characterized their outputs onto different types of cerebellar nuclei (CbN) neurons. Although projections by PC subtypes defined by Kcng4 and Gpr176 are regionally segregated within the CbN, each PC subtype synapses onto many types of CbN neurons, and individual CbN neurons often receive convergent inputs from multiple PC subtypes. We also selectively silenced PC subtype outputs and found that silencing Kcng4+ PC outputs impaired motor behaviors while sparing emotional and social behaviors, whereas silencing Gpr176+ PC outputs selectively increased exploratory behavior and reduced anxiety without affecting motor and social behaviors. These findings demonstrate that molecularly defined PC subtypes differentially regulate specific behaviors and establish a versatile framework for uncovering how cerebellar circuits are specialized to control diverse behaviors.

neuroscience↗

bioRxiv2026

Frontoparietal Hub Connectivity Integrates Information from Multiple Sources

Frontoparietal connector hubs are thought to support information integration across the brain, but this role has largely been inferred from static connectivity, leaving unclear how computational processes shape inter-regional connectivity during behavior. Here, we address this question using a model-based functional connectivity approach in human fMRI data. Thirty-Eight participants (males and females) performed a task requiring the integration of sensory evidence with an internally maintained state belief to guide behavior. We developed a computational model that combines these information sources into an integrated representation and generates distinct variables at successive stages of integration: uncertainty before choice (entropy), the inferred task representation guiding action (task belief), and feedback-driven updating (task inference error). We then tested how these variables modulate the connectivity of frontoparietal connector hubs. Entropy increased coupling between hubs and regions encoding task-relevant inputs and outputs during cue processing, suggesting enhanced communication under uncertainty. During task selection, task belief selectively modulated hub connectivity with motor regions according to the selected task. During feedback, task inference errors increased coupling with regions supporting task-relevant inputs and internal state, while reducing coupling with motor regions, consistent with updating internal representations. Together, our findings show that frontoparietal connector hubs implement integrative control by using an integrated representation to generate distinct computational signals that selectively and dynamically reconfigure inter-regional communication. SignificanceFlexible behavior depends on combining different kinds of information, but how the brain coordinates this integration remains unclear. The frontoparietal cortex is well positioned to support this process because it is broadly connected with many other systems. Here, we combined a computational model with functional MRI to test how integrating information changes patterns of functional connectivity. We find that a common set of signals is associated with dissociable changes in how frontoparietal regions couple with systems involved in perception, action, and internal updating. These findings reveal that integration generates multiple control signals that dynamically reconfigure brain-wide interactions to support goal-directed behavior.

neuroscience↗

bioRxiv2026

Hierarchical Reconfiguration of Neurocognitive Task Set Representations Mediates Cognitive Flexibility

Cognitive control organizes abstract contexts, stimuli, and actions into hierarchically structured representations. This organization supports flexible behavior but requires updating at multiple levels of the hierarchy, a process reflected in task switch costs. However, it remains unclear how updating differs across levels of abstraction and how these differences relate to behavior and neural representations. Here, we investigated the behavioral and neural sources of switch costs using fMRI and behavioral data from healthy adult participants (male and female). We employed a hierarchical control task that dissociates abstract context reconfiguration from more concrete task-set reconfiguration of stimulus-response mappings. We predicted that task sets, which incorporate sensory-motor mappings, would be more strongly influenced by feedforward inputs than higher-level contextual goals, which are more abstracted from immediate perceptual and motor demands. As predicted, subordinate rule switches were faster and were more strongly influenced by task-irrelevant perceptual changes, whereas context switches were slower and relatively insensitive to such interference. To characterize the neural basis of these effects, we quantified trial-to-trial reconfiguration of multivoxel activity patterns. Across the brain, larger pattern shifts predicted larger RT switch costs, linking representational reorganization to behavioral performance. Importantly, representational reconfiguration differed across hierarchical levels and anatomical systems. Subordinate rule updating was modulated by task-irrelevant perceptual features and expressed in distributed perceptual and motor networks, whereas context reconfiguration engaged the mid-lateral frontal cortex and was comparatively insulated from interference. Our results reveal how the hierarchical structure of neural representations supports flexible updating with interference-shielded contextual representations subserving behavioral control. SignificanceDaily activities often require simultaneously updating different tasks and thoughts. Driving requires maintaining a stable destination goal while rapidly updating motor plans (brake, accelerate, turn, etc.) in response to changing perceptual information (traffic lights, pedestrians, etc.). Although people perform such tasks with ease, it remains unclear how neural and cognitive representations are structured to respond to these flexibility demands. The present study suggests that sensory-motor plans prioritize flexibility by allowing greater influence from sensory inputs, which can create interference across brain networks when that input is task-irrelevant. Contextual information is insulated from this interference by representing contexts as distinctly as possible in the lateral prefrontal cortex, resulting in slower but more stable context switching.

neuroscience↗

bioRxiv2025

How Task Representations Integrate Information from Multiple Sources

Adaptive behavior requires integrating information from multiple sources. These sources can originate from distinct channels, such as internally maintained latent cognitive representations or externally presented sensory cues. Because these signals are often stochastic and carry inherent uncertainty, integration is challenging. However, the neural and computational mechanisms that support the integration of such stochastic information remain unknown. We introduce a computational neuroimaging framework to elucidate how brain systems integrate internally maintained and externally cued stochastic information to guide behavior. Neuroimaging data were collected from healthy adult human participants (both male and female). Our computational model estimates trial-by-trial beliefs about internally maintained latent states and externally presented perceptual cues, then integrates them into a unified joint probability distribution. The entropy of this joint distribution quantifies overall uncertainty, which enables continuous tracking of probabilistic task beliefs, prediction errors, and updating dynamics. Results showed that latent state beliefs are encoded in distinct regions from perceptual beliefs. Latent-state beliefs were encoded in the anterior middle frontal gyrus, mediodorsal thalamus, and inferior parietal lobule, whereas perceptual beliefs were encoded in spatially distinct regions including lateral temporo-occipital areas, intraparietal sulcus, and precentral sulcus. The integrated joint probability and its entropy converged in frontoparietal hub areas, notably middle frontal gyrus and intraparietal sulcus. These findings suggest that frontoparietal hubs read out and resolve distributed uncertainty to flexibly guide behavior, revealing how frontoparietal systems implement cognitive integration. SignificanceFlexible human behavior often depends on integrating information from multiple sources, such as memory and perception, each of which can be corrupted by noise. For example, a driver must integrate traffic signals (external cues) with their destination plan (internal goals) to decide when to turn. This study reveals how the human brain integrates multiple information sources to guide flexible behavior. More specifically, distinct brain regions encode internal beliefs and external sensory representations, while frontoparietal regions integrate this information in response to input noise. These findings provide a complete account of how the brain encodes and integrates multiple inputs to guide adaptive behavior.

neuroscience↗

bioRxiv2024

Thalamocortical contributions to hierarchical cognitive control

Cognitive flexibility relies on hierarchically structured task representations that organize task contexts, relevant environmental features, and subordinate decisions. Despite ongoing interest in the human thalamus, its role in cognitive control has been understudied. This study explored thalamic representation and thalamocortical interactions that contribute to hierarchical cognitive control in humans. We found that several thalamic nuclei, including the anterior, mediodorsal, ventrolateral, and pulvinar nuclei, exhibited stronger evoked responses when subjects switch between task contexts. Decoding analysis revealed that thalamic activity encodes task contexts within the hierarchical task representations. To determine how thalamocortical interactions contribute to task representations, we developed a thalamocortical functional interaction model to predict task-related cortical representation. This data-driven model outperformed comparison models, particularly in predicting activity patterns in cortical regions that encode context representations. Collectively, our findings highlight the significant contribution of thalamic activity and thalamocortical interactions for contextually guided hierarchical cognitive control.

neuroscience↗

bioRxiv2024

Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer.

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancer types, either dependent or independent of its m6A methyl transferase activity. We have designed proteolysis-targeting chimeras (PROTACs) targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes more than 80% degradation of METTL3 with a half-maximal degradation concentration (DC50) of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 reverses differentiation and possesses anti-proliferative effects surpassing the reported inhibitors in MOLM-13 cells. Furthermore, KH12 significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effect of KH12 was further confirmed in patient-derived organoids (PDOs). This study highlights the therapeutic potential of targeted degradation of epitranscriptomic writer METTL3 as an anti-cancer strategy.

biochemistry↗

bioRxiv2023

Reinforcement-based option competition in human dorsal stream during exploration/exploitation of a continuous space

Primates exploring and exploiting a continuous sensorimotor space rely on maps in the dorsal stream that guide visual search, locomotion, and grasp. For example, an animal swinging from one tree limb to the next uses rapidly evolving sensorimotor representations to decide when to harvest a reward. We show that such exploration/exploitation depends on dynamic maps of competing option values in the human dorsal stream. Using a reinforcement learning (RL) model capable of rapid learning and efficient exploration and exploitation, we show that preferred options are selectively maintained on the map while the values of spatiotemporally distant alternatives are compressed. Consistent with biophysical models of cortical option competition, dorsal stream BOLD signal increased and posterior cortical {beta}1/ oscillations desynchronized as the number of potentially valuable options grew, matching predictions of information-compressing RL rather than traditional RL that caches long-term values. BOLD and {beta}1/ responses were correlated and predicted the successful transition from exploration to exploitation. These option competition dynamics were observed across parietal and frontal dorsal stream regions, but not in the occipito-temporal MT+ sensitive to the average reward rate. Our results also illustrate that models diverging predictions about information dynamics can help to adjudicate between them based on population activity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/541828v1_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@155b3c8org.highwire.dtl.DTLVardef@18e28c5org.highwire.dtl.DTLVardef@16d7c1org.highwire.dtl.DTLVardef@1aed684_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase

Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves induced proximity between the cellular ubiquitin conjugation machinery and the target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-Like Homology Domain Containing protein 2 (KLHDC2), a substrate adaptor protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of new peptide-based ligands useful for this purpose.

biochemistry↗

bioRxiv2022

Thalamocortical contribution to cognitive task activity

Thalamocortical interaction is a ubiquitous functional motif in the mammalian brain. Previously (Hwang et al., 2021), we reported that lesions to network hubs in the human thalamus are associated with multi-domain behavioral impairments in language, memory, and executive functions. Here we show how task-evoked thalamic activity and thalamocortical interactions are organized to support these broad cognitive abilities. To address this question, we analyzed functional MRI data from human subjects that performed 127 tasks encompassing a broad range of cognitive representations. We first investigated the spatial organization of task-evoked activity and found that multi-task thalamic activity converged onto a low-dimensional structure, through which a basis set of activity patterns are evoked to support processing needs of each task. Specifically, the anterior, medial, and posterior-medial thalamus exhibit hub-like activity profiles that are suggestive of broad functional participation. These thalamic task hubs overlapped with network hubs interlinking cortical systems. To further determine the cognitive relevance of thalamocortical interactions, we built a data-driven thalamocortical interaction model to test whether thalamocortical functional connectivity transformed thalamic activity to cortical task activity. The thalamocortical model predicted task-specific cortical activity patterns, and outperformed comparison models built on cortical, hippocampal, and striatal regions. Simulated lesions to low-dimensional, multi-task thalamic hub regions impaired task activity prediction. This simulation result was further supported by profiles of neuropsychological impairments in human patients with focal thalamic lesions. In summary, our results suggest a general organizational principle of how thalamocortical interactions support cognitive task activity. Impact StatementHuman thalamic activity transformed via thalamocortical functional connectivity to support task representations across functional domains.

neuroscience↗

bioRxiv2021

Neuropsychological evidence of multi-domain network hubs in the human thalamus

Hubs in the human brain support behaviors that arise from brain network interactions. Previous studies have identified hub regions in the human thalamus that are connected with multiple functional networks. However, the behavioral significance of thalamic hubs has yet to be established. Our framework predicts that thalamic subregions with strong hub properties are broadly involved in functions across multiple cognitive domains. To test this prediction, we studied human patients with focal thalamic lesions in conjunction with network analyses of the human thalamocortical functional connectome. In support of our prediction, lesions to thalamic subregions with stronger hub properties were associated with widespread deficits in executive, language, and memory functions, whereas lesions to thalamic subregions with weaker hub properties were associated with more limited deficits. These results highlight how a large-scale network model can broaden our understanding of thalamic function for human cognition.

neuroscience↗

bioRxiv2020

Efficient population modification gene-drive rescue system in the malaria mosquito Anopheles stephensi

The development of Cas9/gRNA-mediated gene-drive systems has bolstered the advancement of genetic technologies for controlling vector-borne pathogen transmission. These include population suppression approaches, genetic analogs of insecticidal techniques that reduce the number of vector insects, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. We developed a recoded gene-drive rescue system for population modification in the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and a functional resistant allele does not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with [≥]95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.

genetics↗

bioRxiv2019

GV1001 prevents ovarian follicle loss triggered by an anti-VEGF monoclonal antibody targeting non-small cell lung carcinoma xenografts in mice

Premature ovarian failure (POF) that could result from chemotherapy applied to young female cancer patients is a significant challenge in reproductive biology. It is widely believed that the hyperactivation of dormant primordial follicles following chemotherapy is a leading cause of POF, but it remains unclear how therapeutic cues are generated and transduced into follicular activation. Here, we provide evidence that supports that GV1001, an immunotherapeutic peptide targeting telomerase, plays a role in the deterrence of POF in mice. In vivo non-small cell lung carcinoma (NSCLC) tumor xenografts were produced by inoculating NSCLC cells into the flank of BALB/c female athymic mice and then subjected to cancer chemotherapy with GV1001 and bevacizumab, an anti-cancer antibody drug, humanized anti-VEGF monoclonal antibody. Bevacizumab when administered at the dosage of 5 mg/kg for three weeks was effective in inhibiting growth of NSCLC tumor xenografts, and its anti-cancer efficacy was not interfered by the presence of GV1001. As expected, bevacizumab induced follicular loss by accelerating primordial follicle growth into primary or secondary follicles concomitant with a decline of serum antimullerian hormone (AMH) level and deactivation of Foxo3 signaling as evidenced by immunohistochemical and immunofluorescent assessment. However, bevacizumab-induced follicle stimulating effects were mitigated by GV1001 co-administration as evidenced by the analysis of follicular count, serum AMH level, and Foxo3a expression. From this study, we propose that a combinatorial administration of GV1001 and bevacizumab could deter POF of young female cancer patients without hampering the anti-cancer effectiveness of bevacizumab.

pharmacology and toxicology↗

bioRxiv2018

Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

immunology↗

bioRxiv2018

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficiency phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signalling in metabolic homeostasis.

developmental biology↗

bioRxiv2017

Fronto-Parietal Interactions With Task-Evoked Functional Connectivity During Cognitive Control

Flexible interaction between brain regions enables neural systems to transfer and process information adaptively for goal-directed behaviors. In the current study, we investigated neural substrates that interact with task-evoked functional connectivity during cognitive control. We conducted a human fMRI study where participants selectively attended to a category of visual stimuli in the presence of competing distractors from another stimulus category. To study flexible interactions between brain regions, we performed a dynamic functional connectivity analysis to estimate temporal changes in connectivity strength between brain regions under different levels of cognitive control. Consistent with theoretical predictions, we found that cognitive control selectively enhances functional connectivity for prioritizing the processing of task-relevant information. By regressing temporal changes in connectivity strength against activity patterns elsewhere in the brain, we localized frontal and parietal regions that potentially provide top-down biasing signals for influencing, or reading information out from, task-evoked functional connectivity. Our results suggest that in addition to modulating local activity, fronto-parietal regions could also exert top-down biasing signals to influence functional connectivity between distributed brain regions.

neuroscience↗