Biology subjects

Kuo, S.-H.

Publications and source records attributed to Kuo, S.-H..

5 recordsLinked to original sources

bioRxiv2026

Generative Neuromorphic Programming of Mammalian Cells

Cells make decisions through densely interconnected regulatory networks that compute graded, analog responses. Synthetic biology has made cells programmable, but the field's dominant abstractions poorly match the analog nature of cells. Designing analog circuits that work in cells is challenging: predicting how components combine remains difficult, and the vast combinatorial space of parts, weights and topologies exceeds what experiments can explore. Here we establish generative programming of mammalian cells through a neuromorphic framework that compiles desired behavior into DNA. Composable regulatory devices built from RNA-targeting endoribonucleases (ERNs) supply signed weights and nonlinear activation, enabling multi-layer circuits with diverse multi-input analog responses. To predict and design such circuits, we develop biomorphic neural networks (BMNs): a compositional architecture that mirrors biological interactions, in which each basic process (transcription, translation, cleavage) is captured by a reusable neural block learned from the behavior of whole circuits that contain it. Recomposed into architectures absent from training, these models predict responses with errors often comparable to variability between experimental repeats. Inverting this process, our software package, the biocompiler, jointly optimizes topology, parts, and weights to realize specified target behaviors. Challenged with three target behaviors, the biocompiler proposed three previously unseen architectures; we built all three, and each reproduced its target behavior in mammalian cells in a single design pass without manual tuning. Generative neuromorphic programming thus offers a systematic route to engineering the analog computation native to living cells.

synthetic biology↗

bioRxiv2025

CANVAS causing AAGGG repeat expansions cause tissue-specific reduction in RFC1 expression and increase sensitivity to DNA damage

Biallelic AAGGG expansions in Replication Factor Complex Subunit 1 (RFC1) are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and are increasingly recognised as a common cause of adult-onset ataxia and sensory neuropathy. However, the disease-causing mechanisms remain unclear. Here we leveraged in vitro assays, post-mortem brain tissue, patient-derived cell lines and a neuronal Drosophila model to demonstrate that AAGGG expansions are associated with tissue-specific reductions in the expression of RFC1 transcript, along with impaired RFC1 function and increased sensitivity to DNA damage from platinum-based drugs. CRISPR/Cas9 excision of the AAGGG repeat and flanking AluSx3 element normalized RFC1 expression in iPSC-derived neurons and rescued the DNA damage response, providing a framework for future therapeutic strategies. We also show that these biological findings are clinically relevant in heterozygous AAGGG expansion carriers, who display an increased risk and severity of neuropathy with platinum-based chemotherapy.

neuroscience↗

bioRxiv2022

Prostaglandin E2 prevents radiotherapy-induced alopecia by attenuating transit amplifying cell apoptosis through promoting G1 arrest

Growing hair follicles (HFs) harbor actively dividing transit amplifying cells (TACs), rendering them highly sensitive to radiotherapy (RT). Clinically, there is still a lack of effective treatment for radiotherapy-induced alopecia (RIA). We aimed to dissect the effect and mechanism of local prostaglandin E2 (PGE2) pretreatment in RIA prevention. We found that PGE2 pretreatment reduced RIA by preventing premature termination of anagen through enhancing HF self-repair. Mechanistically, PGE2 did not activate HF stem cells, but preserved more TACs for regenerative attempts. Pretreatment of PGE2 lessened radiosensitivity of TACs by transiently arresting them in the G1 phase, thereby reducing TAC apoptosis and mitigating HF dystrophy. The preservation of more TACs accelerated HF self-repair and bypassed RT-induced premature catagen entry. Promoting G1 arrest by systemic administration of palbociclib isethionate (PD0332991), a CDK4/6 inhibitor, offered a similar protective effect against RT. Therefore, PGE2 protects HF TACs from RT by transiently inducing G1 arrest, and the regeneration of HF structures lost from RT is accelerated to resume anagen growth, thus bypassing the long downtime of hair loss. PGE2 has the potential to be repurposed as a preventive treatment for RIA.

cell biology↗

bioRxiv2022

The role of the cerebellum in learning to predict reward: evidence from cerebellar ataxia

Recent findings in animals have challenged the traditional view of the cerebellum solely as the site of motor control, suggesting that the cerebellum may also be important for learning to predict reward from trial-and-error feedback. Yet, evidence for the role of the cerebellum in reward learning in humans is lacking. Moreover, open questions remain about which specific aspects of reward learning the cerebellum may contribute to. Here we address this gap through an investigation of multiple forms of reward learning in individuals with cerebellum dysfunction, represented by cerebellar ataxia cases. Nineteen participants with cerebellar ataxia and 57 age- and sex-matched healthy controls completed two separate tasks that required learning about reward contingencies from trial-and-error. To probe the selectivity of reward learning processes, the tasks differed in their underlying structure: while one task measured incremental reward learning ability alone, the other allowed participants to use an alternative learning strategy based on episodic memory alongside incremental reward learning. We found that individuals with cerebellar ataxia were profoundly impaired at reward learning from trial-and-error feedback on both tasks, but retained the ability to learn to predict reward based on episodic memory. These findings provide evidence from humans for a specific and necessary role for the cerebellum in incremental learning of reward associations based on reinforcement. More broadly, the findings suggest that alongside its role in motor learning, the cerebellum likely operates in concert with the basal ganglia to support reinforcement learning from reward.

neuroscience↗

bioRxiv2017

The Cerebellum Does More Than Sensory-Prediction-Error-Based Learning In Sensorimotor Adaptation Tasks

Individuals with damage to the cerebellum perform poorly in sensorimotor adaptation paradigms. This deficit has been attributed to impairment in sensory-prediction-error-based updating of an internal forward model, a form of implicit learning. These individuals can, however, successfully counter a perturbation when instructed with an explicit aiming strategy. This successful use of an instructed aiming strategy presents a paradox: In adaptation tasks, why dont individuals with cerebellar damage come up with an aiming solution on their own to compensate for their implicit learning deficit? To explore this question, we employed a variant of a visuomotor rotation task in which, prior to executing a movement on each trial, the participants verbally reported their intended aiming location. Compared to healthy controls, participants with spinocerebellar ataxia (SCA) displayed impairments in both implicit learning and aiming. This was observed when the visuomotor rotation was introduced abruptly (Exp. 1) or gradually (Exp. 2). This dual deficit does not appear to be related to the increased movement variance associated with ataxia: Healthy undergraduates showed little change in implicit learning or aiming when their movement feedback was artificially manipulated to produce similar levels of variability (Exp. 3). Taken together the results indicate that a consequence of cerebellar dysfunction is not only impaired sensory-prediction-error-based learning, but also a difficulty in developing and/or maintaining an aiming solution in response to a visuomotor perturbation. We suggest that this dual deficit can be explained by the cerebellum forming part of a network that learns and maintains action-outcome associations across trials.\n\nNew and noteworthyIndividuals with cerebellar pathology are impaired in sensorimotor adaptation. This deficit has been attributed to an impairment in error-based learning, specifically, from a deficit in using sensory prediction errors to update an internal model. Here, we show that these individuals also have difficulty in discovering an aiming solution to overcome their adaptation deficit, suggesting a new role for the cerebellum in sensorimotor adaptation tasks.

neuroscience↗