Biology subjects

Muramatsu, K.

Publications and source records attributed to Muramatsu, K..

3 recordsLinked to original sources

bioRxiv2025

Therapeutic Knock-in Genome Editing Using Single AAV Vectors in Mouse Models of Inherited Liver Disease

Gene knock-in therapy has the potential to cure inherited liver diseases but is limited by low efficiency and delivery complexity. Here, we developed a single adeno-associated virus (AAV) vector system comprising a compact CRISPR effector, enAsCas12f, a guide RNA, and a donor template to enable therapeutic genome editing via non-homologous end joining (NHEJ). We targeted the system to the murine Alb locus and applied it to mouse models of hemophilia B, protein C (PC) deficiency, and ornithine transcarbamylase (OTC) deficiency. NHEJ-mediated knock-in showed higher efficiency than homology-directed repair, with successful therapeutic gene insertion in both neonatal and adult mice. The strategy restored plasma factor IX activity in hemophilia B (F9-/-) mice, prolonged survival of PC-deficient (Proc-/-) mice, and prevented hyperammonemia and weight loss in OTC-deficient (Otcspf-ash) mice upon high protein challenge. Importantly, gene integration was restricted to the liver, with no evidence of germline transmission. This compact, all-in-one AAV knock-in platform simplifies vector production, enables efficient delivery, and achieves reliable transgene expression in vivo. Our findings highlight the potential of liver-targeted knock-in genome editing as a transplant-independent treatment for neonatal-onset metabolic diseases, offering a clinically feasible path towards curative gene therapies for a wide range of monogenic liver disorders.

bioengineering↗

bioRxiv2022

Simulation of the effect of the randomness of climbing fiber input on the relationship between motor learning and Focal Task-Specific Dystonia

Focal Task-Specific Dystonia (FTSD) is an intractable neurological disorder with no clear prevention or treatment that affects more than 1% of classical musicians and threatens the active lives of experts due to its task-specific tremor symptoms. In the present study, we focused on the motor learning function of the cerebellum, which has not been the focus of much attention in the past. We numerically simulated the firing of cerebellar Purkinje cells and cerebellar nuclei during eyeblink conditioning as a typical example of cerebellar-related timing motor learning, with the aim to find the principle of the pathogenesis of FTSD at the level of individual neurons. The results showed the sustained firing of cerebellar nuclei after the learning condition in which the climbing fiber input to Purkinje cells was continued randomly. Therefore, the present study claims a suggestive factor regarding the neural mechanism of the cerebellum in the motor learning-induced task-specific tremor, which is a symptom of FTSD. We also proposed a motor learning paradigm, "undesirable motor learning," in which the motor goal is too advanced to be achieved by repetitions alone and converges to a different result than the desired.

neuroscience↗

bioRxiv2022

Plyometric training enhances strength and precision of the finger movements in pianists

Stability of timing and force production in repetitive movements characterizes skillful motor behaviors such as surgery and playing musical instruments. However, even trained individuals such as musicians undergo further extensive training for the improvement of these skills. Previous studies that investigated the lower extremity movements such as jumping and sprinting demonstrated enhancement of the maximum force and rate of force development immediately after the plyometric exercises. However, it remains unknown whether the plyometric exercises enhance the stability of timing and force production of the dexterous finger movements in trained individuals. Here we address this issue by examining the effects of plyometric-like training specialized for finger movements on piano performance by well-trained pianists. The training demonstrated a decrease of the variation in timing and velocity of successive keystrokes, along with a concomitant increase in the rate of force development of the four fingers, but not the thumb, although there was no change in the finger muscular activities through the training. By contrast, such a training effect was not evident following a conventional repetitive piano practice. In addition, a significant increase in the forearm muscle temperature was observed specifically through performing the plyometric exercise with the fingers, implying its association with improved performance. These results indicate effectiveness of the plyometric exercises for improvement of strength, precision, and physiological efficiency of the finger movements even in expert pianists, which implicates a role of ways of practicing in enhancing experts expertise.

physiology↗