Biology subjects

Hirao, A.

Publications and source records attributed to Hirao, A..

5 recordsLinked to original sources

bioRxiv2026

MHC class II in dopaminergic neurons prunes GABAergic synapses in neurodevelopmental disorders

Although the brain was traditionally considered immune-privileged, recent studies show immune factors play key roles in brain function. Dysfunction of these factors is linked to neurodevelopmental disorders, but mechanisms remain unclear. Using a maternal immune activation (MIA) mouse model, we investigated immune-related genes in neurodevelopmental disorder pathogenesis. MIA mice showed increased locomotor activity and disrupted prepulse inhibition. RNA-seq and qPCR analyses revealed persistent increases in major histocompatibility complex class II (MHCII) expression and persistent decreases in GABAergic synapse-related gene expression, particularly glutamate decarboxylase (Gad) expression, in dopaminergic regions. These expressions were negatively correlated, and immunohistochemistry showed MHCII at postsynaptic GABAergic synapses on dopaminergic neurons. Patch-clamp recordings confirmed reduced mIPSC frequency in MIA mice. MHCII knockout mice showed opposite phenotypes, while MHCII overexpression in dopaminergic neurons decreased Gad expression. These results suggest MIA-induced MHCII upregulation enhances pruning of GABAergic synapses on dopaminergic neurons, leading to behavioral deficits.

neuroscience↗

bioRxiv2025

The rhythmic bimodal sensory stimulation in synchronous manner entrains the network oscillation in basolateral amygdala

The state of neural oscillation is important for various brain functions. In the basolateral nucleus of amygdala (BA), the oscillation frequency is accelerated in retrieval of conditioned fear memory. The amygdala receives sensory inputs from associated cortex and thalamus. Therefore, we tried to apply the bimodal sensory stimulation at slow frequency (5 Hz, functional frequency in behavioral context) for the entrainment of the BA oscillation. Young adult rats (P24-30) were stimulated by LED illuminator and acoustic speaker at 1 or 5 Hz for 1 hour. Immediately after the stimulus was finished, BA slices were prepared and whole-cell recording was applied to projection neuron. The slow (0.5-2 Hz) rhythmic IPSCs obtained from the pyramidal neuron was accelerated at [~]4 Hz by synchronous opto-acoustic stimulation at 5 Hz. However, the frequency of the neuron at the later recording did not change in the same slice, suggesting that this induced entrainment is transient and reversible phenomenon. As a result, the power distribution was shifted from 0.1-2 to 2-6 Hz by synchronous bimodal 5 Hz stimulation. The regularity of the interval between IPSCs, quantified by rhythm index and the concentration of power around peak frequency in the power spectrum, was not changed by rhythmic sensory stimulation. These results suggest that synchronous bimodal sensory stimuli control the neuronal oscillation frequency by applying with rhythmicity.

neuroscience↗

bioRxiv2021

SMURF2 phosphorylation at Thr249 modifies the stemness and tumorigenicity of glioma stem cells by regulating TGF-β receptor stability

Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr249 (SMURF2Thr249) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2Thr249 phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity. SMURF2 silencing augmented the self-renewal potential and tumorgenicity of patient-derived GSCs. The SMURF2Thr249 phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the SMURF2T249A mutant resulted in increased stemness and tumorgenicity of GSCs, recapitulating the SMURF2 silencing. Moreover, the inactivation of SMURF2Thr249 phosphorylation increases TGF-{beta} receptor (TGFBR) protein stability. Indeed, TGFBR1 knockdown markedly counteracted the GSC phenotypes by SMURF2T249A mutant. These findings highlight the importance of SMURF2Thr249 phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy.

cancer biology↗

bioRxiv2020

Therapeutic Efficacy and Safety of Lenvatinib for Unresectable Hepatocellular Carcinoma Beyond Progression with Sorafenib

Background & AimsThe efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line treatment of LEN, investigated the sensitivity of SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and their signal transduction pathway by protein array analysis. MethodsWe retrospectively enrolled 57 unresectable HCC patients. Radiologic responses in 53 patients were evaluated by modified Response Evaluation Criteria in Solid Tumors. Active signal transduction pathways in cells were identified by protein array analysis, including 1205 proteins. ResultsPatients comprised 34 tyrosine kinase inhibitor (TKI)-naive (first-line), nine SOR-intolerant (second-line), and ten resistant to regorafenib (third-line). Objective response rates (ORRs) were 61.8% (21/34) in TKI-naive, 33.3% (3/9) in second-line, and 20.0% (2/10) in third-line groups. The overall survival (OS) and the progression free survival (PFS) in the first-line was significantly longer than those in third-line group (p<0.05). Patients with better liver functional reserve (Child score, ALBI grade) exhibited higher ORR and longer OS. LEN was well-tolerated as second/third-line treatment. The IC50 value of LEN against PLC/PRF5-R2 cells (30 M) was significantly higher than that against PLC/PRF5 cells (6.4 M). LEN inhibited significantly more signal transduction pathways related to FRS2, a crucial FGFR downstream molecule, in PLC/PRF5 than PLC/PRF5-R2 cells. ConclusionsLEN was active and safe as a second/third-line treatment for unresectable HCC. LEN seems to be more effective for HCC patients with better hepatic reserve function or before TKI-resistance is acquired because of partial cross-resistance to SOR.

molecular biology↗

bioRxiv2019

Experimental and field data support habitat expansion of the allopolyploid Arabidopsis kamchatica owing to parental legacy of heavy metal hyperaccumulation

Little empirical evidence is available whether allopolyploid species combine or merge adaptations of parental species. The allopolyploid species Arabidopsis kamchatica is a natural hybrid of the diploid parents A. halleri, a heavy metal hyperaccumulator, and A. lyrata, a non-hyperaccumulating species. Zinc and cadmium were measured in native soils and leaf tissues in natural populations, and in hydroponic cultures of A. kamchatica and A. halleri. Pyrosequencing was used to estimate homeolog expression ratios. Soils from human modified sites showed significantly higher Zn concentrations than non-modified sites. Leaf samples of A. kamchatica collected from 40 field localities had > 1,000 {micro}g g-1 Zn in over half of the populations, with significantly higher amounts of Zn concentrations in plants from human modified sites. In addition, serpentine soils were found in two populations. Most genotypes accumulated >3000 {micro}g g-1 of Zn in hydroponic culture with high variability among them. Genes involved in hyperaccumulation showed a bias in the halleri-derived homeolog. A. kamchatica has retained constitutive hyperaccumulation ability inherited from A. halleri. Our field and experimental data provides a compelling example in which the inheritance of genetic toolkits for soil adaptations likely contributed to the habitat expansion of an allopolyploid species.

evolutionary biology↗