Biology subjects

Manabe, Y.

Publications and source records attributed to Manabe, Y..

5 recordsLinked to original sources

bioRxiv2026

FUT8 mediated core fucosylation modulates growth related functions of LRP1 in liver cancer cells

Fucosylation is a cancer-associated glycosylation change, and core fucosylation of N-glycans catalyzed by the 1,6-fucosyltransferase FUT8, has been closely linked to tumor progression, metastasis, drug resistance, and poor prognosis. However, the core-fucosylated proteins that directly support hepatocarcinogenesis are not fully defined. In a KRAS-G12D-driven mouse liver cancer model, we observed increased fucosylation and FUT8 upregulation, and glycoproteomic analysis of fucose-enriched fractions identified low-density lipoprotein receptor-related protein 1 (LRP1) as a prominent core-fucosylated protein in tumor tissue. In immortalized mouse hepatocytes, genetic or pharmacological inhibition of FUT8 markedly increased Lrp1 mRNA and protein, indicating that loss of core fucosylation is accompanied by robust upregulation of LRP1. In human HepG2 cells, LRP1 knockout suppressed cell proliferation and markedly altered colony morphology, leading to compact rounded clusters instead of the typical polygonal pattern. It also reduced EGFR protein and further inhibited proliferation of HepG2 cell. These findings identify LRP1 as a FUT8-dependent core-fucosylated receptor in experimental hepatocarcinogenesis and suggest that the FUT8-LRP1 axis contributes to the maintenance of proliferative signaling in hepatoma cells.

cancer biology↗

bioRxiv2025

Challenging the Diffusion Barrier Paradigm: Biofilms Promote Flavin-mediated Electron Shuttling in Shewanella oneidensis

Flavins are ubiquitous diffusible redox mediators that are crucial in enabling extracellular electron transfer (EET) in electroactive bacteria that often form biofilms in both natural and engineered environments. However, the behavior of flavin diffusion within biofilms remains poorly understood. In this study, we developed a colony-based electrochemical platform using interdigitated electrode arrays to quantify the diffusion coefficients of flavins within bacterial biofilms. We found that flavin diffusivity was about 11-fold enhanced in Shewanella oneidensis MR-1 biofilms than in the bulk solution. However, this enhancement was abolished in the gene deletion mutant that lacked the membrane-associated flavin-binding c-type cytochrome OmcA, which suggests that the flavin-OmcA interaction on cell surfaces facilitates flavin diffusion within the biofilm. Notably, the diffusion coefficients of other redox molecules, such as methylene blue and safranin, scarcely improved in biofilms, which validates the inference that flavin-specific interaction-accelerated diffusion occurs in biofilm environments. These findings uncover a phenomenon promoting long-range electron transfer, overturning the prevailing assumption that shuttling-based EET is hindered by slow molecular diffusion in biofilms. Our study highlights the functional importance of cell-surface cytochromes in overcoming the kinetic limitation of diffusion-based electron transfer, thereby shaping the bioenergetics in biofilms.

microbiology↗

bioRxiv2025

Combined stimuli of elasticity and microgrooves form aligned myotubes that characterize slow-twitch muscles

Skeletal muscles are classified into slow-twitch muscles composed primarily of type I and IIa fibers with high oxidative metabolism, and fast-twitch muscles composed of type IIx and IIb fibers with high glycolytic metabolism. Fiber-type shifts occur during development and aging; however, the stimuli that shift these types remain unclear. We analyzed the role of mechanical stimuli in myotube formation and shift to the characteristics of each fiber type using crosslinked gelatin gels with tunable elasticity (10-230 kPa) and microgrooves (3-50 {micro}m). C2C12 myotubes on 10 kPa gel increased the expression of marker genes for type I and IIa fibers (MYH7 and MYH2) and oxidative metabolism (GLUT4 and myoglobin) than those on stiffer gels. Upregulation of PGC-1 on soft gel induced a shift toward slow-twitch muscle genetic characteristics. Microgrooves (3-10 {micro}m) enhanced myoblast fusion and myotube orientation, without affecting the gene expressions characterizing fiber types. This study demonstrated an approach to create highly oriented slow-twitch muscle models by controlling the elasticity and microgrooves.

cell biology↗

bioRxiv2022

Mycobacterium tuberculosis disease associates with higher HIV-1-specific antibody responses

Mycobacterium tuberculosis (Mtb) can enhance immune responses against unrelated pathogens. Although Mtb is the most common co-infection in people living with HIV (PWH), there has been no examination of its impact on HIV-1 immune responses. Plasma neutralization and antibody dependent cellular cytotoxicity (ADCC) was compared among PWH and Mtb disease (PWH/Active Mtb) and PWH/No Mtb both prior to and after antiretroviral treatment (ART) and completion of Mtb therapy. We assessed HIV-1 sequences, total antibody quantities and isotypes, and plasma cytokine levels to ascertain mechanisms that affect humoral responses. HIV-1 neutralizing antibodies (nAbs) were broader and more potent in PWH/Active Mtb as compared to PWH/No Mtb, and nAbs increased among PWH who developed Mtb after ART initiation. ADCC was also higher in the PWH who had Mtb disease after starting ART. PWH/Active Mtb as compared to PWH/No Mtb had unique HIV-1 envelope sequence motifs associated with neutralization resistance further implying differences in humoral selection. The Mtb-linked antibody augmentation associated with elevated plasma cytokine levels important for B cells and antibody production, namely interleukin-6, a proliferation-inducing ligand (APRIL), and B-cell activating factor (BAFF). Increased plasma virus levels, greater HIV-1 envelope diversity, higher levels of all antibodies, and cross-reactive responses did not explain the enhanced HIV-1 humoral responses in those with Mtb. Mtb disease enhances HIV-1 humoral responses likely by perturbing pathways important for antibody production in lymphoid tissue that has both pathogens. These findings have implications for using antibody-based therapies and inducing optimal HIV-1 antibody responses. Author SummaryMycobacterium tuberculosis (Mtb) is the most common infection among people with HIV (PWH) in the world. Mtb infection can enhance immune responses against unrelated pathogens. Previous studies have not examined the impact of Mtb disease on HIV antibodies in PWH. This information has importance for future strategies aimed at enhancing HIV antibody responses in naive individuals or PWH. We show that HIV neutralizing antibodies and antibody-dependent cellular cytotoxicity are broader and more potent in PWH in the presence as compared to the absence of Mtb disease. PWH and Mtb disease as compared to those without Mtb also harbor unique HIV envelope sequences, which further indicates that there is differential antibody selection pressure. The Mtb linked HIV antibody enhancement associated with specific mediators important for B cell and antibody development. Importantly, the Mtb mediated HIV antibody augmentation was not due to cross-reactivity, a generalized increase in all antibodies, or a higher level, more diverse, or longer duration of antigen exposure. We speculate that more potent HIV antibodies arise in lymphatic tissue that harbors both Mtb and HIV. Our findings have implications for both future uses of HIV antibodies as prophylaxis or treatment and strategies aimed inducing better HIV antibody responses.

microbiology↗

bioRxiv2019

Single-cell information analysis reveals small intra- and large intercellular variations increase cellular information capacity

Cells transmit information about extracellular stimulation through signaling pathways to control cellular function. A signaling pathway can be regarded as a communication channel. In the analysis of channels of cell populations, intercellular variation is considered noise. However, intercellular variation enables individual cells to encode different information. Therefore, at the single-cell level, each cell can be regarded as an independent channel. Thus, we propose that responses of cells of the same type in tissues, such as the fibers in a skeletal muscle, should be regarded as a multiple-cell channel composed of single-cell channels, in which intercellular variation contains information. Here, we applied electrical pulses to individual myotubes from cultured C2C12 cells or dissociated skeletal muscle fibers and measured Ca2+ responses or contraction, respectively, to estimate information capacity in a biological system. For each muscle cell system, we found that a single-cell channel transmitted more information than did a cell-population channel, indicating that the cellular response is consistent with each cell (low intracellular variation) but different among individual cells (high intercellular variation). As cell number and thus the number of single-cell channels increased, a multiple-cell channel transmitted more information by incorporating the differences among individual cells. Thus, a tissue with small intracellular and large intercellular variations has the capacity to distinguish differences in stimulation intensity to precisely control physiological function.\n\nOne Sentence SummarySmall intracellular and large intercellular variations increase information transmission for precise control of tissue function.

systems biology↗