Biology subjects

Murakami, R.

Publications and source records attributed to Murakami, R..

6 recordsLinked to original sources

bioRxiv2026

Leucine Aminopeptidase 3 Regulates Skeletal Muscle Mitochondrial Homeostasis with Sex-Dependent Metabolic Consequences

Skeletal muscle homeostasis depends on the coordinated regulation of protein turnover and mitochondrial quality control; however, the molecular mechanisms linking these processes remain unclear. In this study, we examined the physiological role of leucine aminopeptidase 3 (LAP3), a post-proteolytic aminopeptidase, using constitutive LAP3-deficient mice. LAP3 deficiency preferentially affected skeletal muscle, causing reduced muscle mass and mitochondrial enlargement in both sexes. Female LAP3-deficient mice also showed reduced myofiber size, impaired endurance capacity, increased energy expenditure, elevated lipid oxidation, and lipid droplet accumulation adjacent to the mitochondria. Proteomic analyses revealed remodeling of pathways related to lipid metabolism and protein homeostasis. Consistent with these findings, LAP3 deficiency increased the expression of Pink1 and Tax1bp1 and promoted the accumulation of ubiquitinated proteins, suggesting alterations in mitochondrial quality control and proteostatic regulation. In cultured myogenic cells, LAP3 localized to mitochondrial fractions, and both LAP3 knockdown and overexpression altered mitochondrial morphology. Taken together, these results identify LAP3 as a regulator of skeletal muscle homeostasis and support a role for LAP3 in linking intracellular peptide turnover to mitochondrial homeostasis, with female skeletal muscle showing greater susceptibility to LAP3 deficiency.

physiology↗

bioRxiv2025

Adaptation of an herbivorous arthropod to green tea plants by overcoming catechin defenses

Green tea catechins are known antioxidants that benefit human health and protect tea plants from biotic stressors. However, some herbivores can counteract catechin defenses and can use tea plants as a host. Among herbivorous mites, an extreme generalist Tetranychus urticae has not been reported as a tea pest. Instead, T. kanzawai, another generalist, has some populations that thrive on tea plants. Here, we investigated the mechanism of the adaptation of these mites to tea plants. Comparative study of the intra- and inter-specific variations in mite performances uncovered differences in their behavioral and xenobiotic responsiveness to green tea catechins. We showed that green tea catechins exert complex defensive roles. They were repellent and toxic to T. urticae and tea non-adapted T. kanzawai mites. In addition, they had an antifeedant effect on tea non-adapted T. kanzawai mites. Matching the catechin structure, we identified an intradiol ring-cleavage dioxygenase DOG15, a gene horizontally transferred from fungi, as one required for the adaptation of T. kanzawai mites to tea plants. The DOG15 gene has an enhanced inducible expression in tea-adapted T. kanzawai mites, with mRNA and protein levels up to 31.6 and 12.1 times higher than in T. urticae mites fed on tea plants. Furthermore, we identified two amino acid substitutions in DOG15 between Tetranychus species leading to the increased efficacy of the T. kanzawai encoded enzyme toward cleavage of green tea catechins. Thus, we showed that mite adaptation to tea plants occurred in a two-step process. The amino acid substitutions in DOG15 predispose T. kanzawai but not T. urticae for the adaptation to tea plants. Further increased expression of modified DOG15 enables T. kanzawai mites to efficiently detoxify green tea catechins, leading to intra- and inter-specific differences in mites ability to use tea plants as a host. Our findings reveal how a horizontally transferred gene can be co-opted through structural and regulatory changes to overcome plant chemical defenses, with implications for herbivore host adaptation and tea pest management.

evolutionary biology↗

bioRxiv2025

Chemotherapy Induces an IL1β-dependent Neutrophil Recruitment that Promotes Chemoresistance in Metastatic Ovarian Cancer

High-grade serous carcinoma (HGSC) of the ovary acquires chemoresistance through diverse cancer cell-intrinsic and-extrinsic mechanisms, culminating in treatment-refractory intraperitoneal metastasis. How chemotherapy-induced remodeling of the tumor microenvironment modulates drug sensitivity remains unclear. In this study, we demonstrate that chemotherapy induced IL1{beta}-dependent neutrophil accumulation in tumors, driving chemoresistance in HGSC. Using patient samples, bulk transcriptomic profiling before and after chemotherapy revealed post-treatment upregulation of IL1B, and single-cell RNA sequencing identified myeloid cells as its principal source. In a chemoresistant murine metastatic ovarian cancer model, chemotherapy increased neutrophils and neutrophil extracellular traps (NETs) in omentum tumors; these increases were abrogated in IL1{beta}-deficient mice, with expansion of activated CD8+ T cells and tumor control. Neutrophil depletion in wild-type mice recapitulated the chemosensitive phenotype of IL1{beta}-deficient mice. In vitro, IL1{beta} did not alter cancer cell-intrinsic chemosensitivity, whereas NETs reduced the chemosensitivity of cancer cells. Additionally, the dominant IL1{beta} receptor (IL1R1) was predominantly expressed in tumor-associated fibroblasts in humans and mice. Consistently, IL1R1-deficient mice exhibited chemosensitivity with decreased neutrophil accumulation and increased IFN{gamma}TNFCD8 T cells. We also found that chemotherapy upregulated CXCL2 in patients and that ablating IL1{beta}-IL1R1 axis decreased CXCL2 expression in tumor-associated fibroblasts in mice. Finally, residual human HGSC tumor after chemotherapy showed increased neutrophils and a trend toward more NETs. Collectively, these findings illuminate a paradoxical, cancer cell-extrinsic mechanism in HGSC whereby chemotherapy itself amplifies chemoresistance and suggest that targeting chemotherapy-induced inflammation may help overcome treatment resistance.

immunology↗

bioRxiv2025

Foxp3 and BATF cooperatively direct cis-regulatory programs and gene expression for functional differentiation of Treg cells

Mechanisms by which diverse transcription factors (TFs) shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. By investigating interactions between BATF and Foxp3 TFs, we discovered their cooperative roles in directing cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis regulatory and transcriptional landscape critical for functional Treg cell differentiation.

immunology↗

bioRxiv2024

Intraoperative Ablation Control Based on Real-time Necrosis Monitoring Feedback: Numerical Evaluation

Ablation therapy is a type of minimally invasive treatment, utilized for various organs including the brain, heart, and kidneys. The accuracy of the ablation process is critically important to avoid both insufficient and excessive ablation, which may result in compromised efficacy or complications. The thermal ablation is formulated by two theoretical models: the heat transfer (HT) and necrosis formation (NF) models. In modern medical practices, feed-forward (FF) and temperature feedback (TFB) controls are primarily used as ablation control methodologies. FF involves pre-therapy procedure planning based on previous experiences and theoretical knowledge without monitoring the intraoperative tissue response, hence, it cant compensate for discrepancies in the assumed HT or NF models. These discrepancies can arise due to individual patients tissue characteristic differences and specific environmental conditions. Conversely, TFB control is based on the intraoperative temperature profile. It estimates the resulting heat damage based on the monitored temperature distribution and assumed NF model. Therefore, TFB can make necessary adjustments even if there is an error in the assumed HT model. TFB is thus seen as a more robust control method against modeling errors in the HT model. Still, TFB is limited as it assumes a fixed NF model, irrespective of the patient or the ablation technique used. An ideal solution to these limitations would be to actively monitor heat damage to the tissue during the operation and utilize this data to control ablation. This strategy is defined as necrosis feedback (NFB) in this study. Such real-time necrosis monitoring modalities making NFB possible are emerging, however, there is an absence of a generalized study that discusses the integration and quantifies the significance of the real-time necrosis monitor techniques for ablation therapy. Such an investigation is expected to clarify the universal principles of how these techniques would improve ablation therapy. In this study, we examine the potential of NFB in suppressing errors associated with the NF model as NFB is theoretically capable of monitoring and suppressing the errors associated with the NF models in its closed control loop. We simulate and compare the performances of TFB and NFB with artificially generated modeling errors using the finite element method (FEM). The results show that NFB provides more accurate ablation control than TFB when NF-oriented errors are applied, indicating NFBs potential to improve the ablation control accuracy and highlighting the value of the ongoing research to make real-time necrosis monitoring a clinically viable option.

bioengineering↗

bioRxiv2023

In-bore MRI-compatible Transrectal Ultrasound and Photoacoustic Imaging

Prostate cancer (PCa) is known as one of the most prevalent and fatal cancer types. This report describes an MRI-compatible photoacoustic/ultrasound (PA/US) imaging platform to improve the diagnosis of PCa. In the proposed solution, PA imaging, which offers real-time, non-ionizing imaging with high sensitivity and specificity, is combined with MRI, aiming to overcome PAs limited field of view (FOV) and make PA scalable for translation to clinical settings. Central to the design of the system is a reflector-based transrectal probing mechanism composed of MRI-compatible materials. The linear transducer with a center hole for optical fiber delivery can be mechanically actuated to form a multi-angled scan, allowing PA/US imaging from varied cross-sectional views. Performance assessment was carried out in phantom and ex-vivo settings. We confirmed the MRI compatibility of the system and demonstrated the feasibility of its tri-modal imaging capability by visualizing a tubing phantom containing contrast agents. The ex-vivo evaluation of targeted tumor imaging capability was performed with a mouse liver sample expressing PSMA-positive tumors, affirming the systems compatibility in spectroscopic PA (sPA) imaging with biological tissue. These results support the feasibility of the in-bore MRI-compatible transrectal PA and US and the potential clinical adaptability.

bioengineering↗