Biology subjects

Kim, M. G.

Publications and source records attributed to Kim, M. G..

5 recordsLinked to original sources

bioRxiv2026

A Hierarchy-aware Gene Exploration Platform for Multi-layered Toxicogenomic Analysis: A Case Study on Acetaminophen-induced Hepatotoxicity

BackgroundThe interpretation of high-dimensional transcriptomic data remains a major challenge in mechanistic toxicology and drug safety assessment. Conventional clustering approaches based solely on expression profiles often fail to capture intrinsic biological relationships among genes, limiting interpretability and downstream analysis. MethodsWe developed a hierarchy-aware gene exploration platform that integrates structured biological knowledge from the HUGO Gene Nomenclature Committee (HGNC). The core of the framework is a similarity kernel based on a single-step hyperdiffusion formulation (HKH{top}), which embeds gene family hierarchy into the similarity space. The platform is implemented as an interactive web application supporting Uniform Manifold Approximation and Projection (UMAP) visualization, Leiden clustering, functional enrichment analysis, and hierarchy-based gene recommendation. ResultsApplied to a transcriptomic dataset of acetaminophen-induced acute liver failure (APAP-ALF), the proposed approach achieved a 33.8-fold improvement in functional coherence compared to an expression-only baseline. The hierarchy-aware embedding produced compact and biologically consistent clusters, enabling identification of key toxicological modules, including disruption of RNA processing, extracellular matrix remodeling, and impairment of lipid transport. In addition, the framework detected small but highly significant regulatory modules associated with epigenetic reprogramming. ConclusionBy incorporating biological hierarchy into gene similarity, the proposed platform enhances the interpretability of transcriptomic analysis and enables structured exploration of functional relationships. This approach provides a practical framework for mechanistic insight generation and supports more transparent and reproducible analysis in toxicogenomics. AvailabilityThe web application is freely available at https://hgncgeneexplorer.streamlit.app/.

bioinformatics↗

bioRxiv2026

Virus-like particle delivery enables orthogonal genome editing in vitro and in vivo

The advent of CRISPR-Cas systems has revolutionized multiple fields, including basic science, biotechnology, and medicine. Central to this versatility is the use of programmable guide RNAs (gRNAs), which enable flexible and specific gene targeting. Building on this principle, various CRISPR-associated tools have been developed, including Cas9, base editors, prime editors, and gene-regulation platforms. However, because most CRISPR modalities share a common gRNA platform, the simultaneous use of multiple tools is constrained by interactions among different gRNAs, limiting orthogonal genome editing. This study presents a method for orthogonal multiplexed gene editing by packaging distinct CRISPR effectors and their corresponding gRNAs into separate virus-like particles (VLPs), thereby virtually eliminating the gRNA crosstalk. Furthermore, we demonstrate that this VLP-based strategy enables orthogonal, multiplexed gene editing in vivo in mouse eyes and ears. This platform expands the CRISPR toolkit by enabling simultaneous, non-interfering genetic manipulations in both cultured cells and living organisms.

genetics↗

bioRxiv2025

Low-intensity transcranial focused ultrasound engages parvalbumin-positive GABAergic interneurons in a humanized mouse model of chronic pain: from electrophysiology to cellular investigation

BackgroundLow-intensity transcranial focused ultrasound (tFUS) offers high spatial specificity and deep brain penetration, showing great promise as a non-invasive stimulation technology for modulating brain activity and behavior. Recent studies show that specific tFUS parameters targeted to pain-processing brain circuits can significantly alter pain-related behaviors in rodent models and humans. However, a comprehensive understanding of how tFUS influences brain networks and cellular mechanisms is essential to optimize efficacy and facilitate safe translation to clinical pain therapies. ObjectiveWe aimed to evaluate the modulation of inhibitory neural circuits induced by tFUS of 40 Hz pulse repetition frequency (PRF) in a humanized mouse model of chronic pain, integrating local and network-level electrophysiological investigations, molecular analyses, and histological assessment to confirm safety. Methods and ResultsWe used a 128-element random array transducer for stimulation, along with a non-invasive and flexible 30-channel electroencephalography (EEG) to assess local evoked responses, topographical brain activity, and global brain dynamics including excitation and inhibition (E/I) balance. To further assess tFUS neuromodulation effects at the cellular level, we performed immunohistochemistry (IHC) analysis and found that tFUS significantly increased the activity of inhibitory neurons as indicated by elevated expression of Glutamate Decarboxylase 67 (GAD67) and Parvalbumin (PV). Finally, safety was evaluated in the same brain samples used for mechanistic analysis, with blinded histological assessment revealing no signs of tissue damage. ConclusionsThese findings provide new evidence that tFUS non-invasively engages PV GABAergic inhibitory circuits in a chronic pain mouse model, supporting its development as a robust neuromodulation strategy. TopicsChronic pain; Transcranial focused ultrasound; Non-invasive brain neuromodulation; GABAergic neural circuit modulation HighlightsO_LIMulti-modal assessment of low-intensity tFUS in a humanized chronic pain model. C_LIO_LI40 Hz tFUS enhances inhibition, mirroring optogenetic PV neuron activation. C_LIO_LIRepeated tFUS restored chronic pain-disrupted E/I balance. C_LIO_LIMulti-session tFUS upregulates GAD67 and PV interneuron expressions. C_LI

bioengineering↗

bioRxiv2024

PAM-flexible adenine base editing rescues hearing loss in a humanized MPZL2 mouse model harboring an East Asian founder mutation

Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identified an East Asia-specific founder mutation, the homozygous c.220C>T mutation in MPZL2, that contributes to a significant proportion of hereditary deafness cases in our cohort study. We found that the disease-causing mutation could be targetable by adenine base editors (ABEs) that enable A{middle dot}T-to-G{middle dot}C base corrections without DNA double-strand breaks. To demonstrate this, we developed a humanized mouse model (hMPZL2Q74X/Q74X) that recapitulates human MPZL2 deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) was packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear of hMPZL2Q74X/Q74X mice and effectively corrected the mutation. This treatment significantly restored hearing function, improved inner ear structural integrity, and reversed altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases of MPZL2 deafness.

genetics↗

bioRxiv2022

Low-intensity transcranial focused ultrasound changes pain-associated behaviors by modulating pain processing brain circuits

There is an urgent and unmet clinical need to develop non-pharmacological interventions for chronic pain management due to the critical side effects of opioids. Low-intensity transcranial focused ultrasound is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly-focused 128-element ultrasound transducer to specifically target small mouse brains, employing dynamic focus steering. We demonstrate that transcranial focused ultrasound stimulation at pain processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (e.g., insula) and multi-session focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitive- and chronic hyperalgesia-associated neural signals following focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting inter-experiment intervals, and investigating effects on age, gender, genotype, and in a head-fixed awake model. Importantly, transcranial focused ultrasound was shown to be safe, causing no adverse effects on motor function and brain neuropathology. In conclusion, the rich experimental evidence validates the ability of novel focused ultrasound neuromodulation to suppress pain, presenting significant translational potential for next-generation chronic pain treatment without adverse effects. Key pointsO_LINovel non-invasive neuromodulation of brains pain processing circuits with submillimeter spatial precision for pain management C_LIO_LITranscranial focused ultrasound significantly modulates pain-related behaviors and brain electrical rhythms of pain in humanized SCD mice C_LI

bioengineering↗