Kumamoto University

Kuyama N., Izumiya Y., Takashio S., Usuku H., Tabira A., Oguni T., Yamamoto M., Hirakawa K., Ishii M., Tabata N., Hoshiyama T., Kanazawa H., Hanatani S., Kidoh M., Oda S., et. al.

Koyano K., Atsukawa M., Tsubota A., Kondo C., Miwa T., Namisaki T., Hiraoka A., Toyoda H., Tada T., Kobayashi Y., Kawata K., Matsuura K., Mikami S., Kawabe N., Oikawa T., et. al.

Background/Objective: Recently, there has been an increasing need to implement the diagnosis of the presence of covert hepatic encephalopathy (CHE) in patients with cirrhosis. The aim of this study was to identify novel factors associated with CHE in clinical practice. Methods: This retrospective study enrolled a total of 402 patients with cirrhosis at 17 institutions. The Stroop test was performed to diagnose CHE at each center. Results: The patients comprised 233 males and 169 females, with a median age of 69 (IQR, 61–75) years. The median albumin and 25(OH)D3 levels were 3.9 (3.5–4.3) g/dL and 15.4 (11.0–21.0) ng/mL, respectively. This cohort included 181 patients with esophageal varices (EV). Multivariate analysis revealed that low 25(OH)D3 (p < 0.05) and EV (p < 0.05) were independent risk factors for CHE. When limited to only laboratory factors, low albumin (p < 0.01) and low 25(OH)D3 (p < 0.05) were independent factors for CHE. The optimal cut-off values of albumin and 25(OH)D3 for predicting CHE were 3.7 g/dL and 16.5 ng/mL, respectively. The prevalence of CHE was 59.2% for 25(OH)D3 < 16.5 ng/mL and EV, 53.8% for albumin < 3.7 g/dL and 25(OH)D3 < 16.5 ng/mL, and 66.7% for albumin < 3.7 g/dL, EV, and 25(OH)D3 < 16.5 ng/mL. Conclusions: Low 25(OH)D3 and albumin levels, and the EV were positively associated with CHE in patients with cirrhosis. Specifically, the prevalence of CHE increased with a decrease in 25(OH)D3 levels. Patients with such risk factors should be actively and carefully examined for the presence of CHE.

Kiyama M., Amagasaki M., Okamoto T.

With increasing incidents due to congestion at events, effective pedestrian guidance has become a critical safety concern. Recent research has explored the application of reinforcement learning to crowd simulation, where agents learn optimal actions through trial and error to maximize rewards based on environmental states. This study investigates the use of reinforcement learning and simulation techniques to mitigate pedestrian congestion through improved guidance systems. We employ the Multi-Agent Deep Deterministic Policy Gradient (MA-DDPG), a multi-agent reinforcement learning approach, and propose an enhanced method for learning the Q-function for actors within the MA-DDPG framework. Using the Mojiko Fireworks Festival dataset as a case study, we evaluated the effectiveness of our proposed method by comparing congestion levels with existing approaches. The results demonstrate that our method successfully reduces congestion, with agents exhibiting superior cooperation in managing crowd flow. This improvement in agent coordination suggests the potential for practical applications in real-world crowd management scenarios.

Harada S., Teraoka R., Kuroda N., Teramoto W.

It is well known that aging affects fundamental perceptual functions. Numerous studies have investigated age-related changes in visual motion perception and demonstrated that aging impairs motion processing. However, limited studies have explored age-related changes in auditory motion perception, and whether aging influences auditory motion perception based on interaural level differences remains unknown. This study examined age-related differences in the discrimination of auditory motion direction based on interaural level differences. We conducted two experiments to estimate the signal-to-noise ratio and motion coherence thresholds required to discriminate auditory motion and visual motion directions, respectively, in younger and older adults. Results showed that age significantly impairs visual motion discrimination; however, it does not impair auditory motion discrimination. These findings suggest that aging does not affect auditory motion perception based on interaural level differences, at least with the broadband noise used in this experiment.

Asigbee T.W., Nakamura-Hoshi M., Kuse N., Ishii H., Ishikawa K., Kawana-Tachikawa A., Horibe E., Nakashima M., Yamano Y., Uchimaru K., Matano T.

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) induces chronic long-term latent infection that can cause fatal diseases, including adult T-cell leukemia. HTLV-1 production is poor and undetectable during the asymptomatic phase of infection. Virus-host immune interaction in latent infection has not been fully determined. In the present study, virus-specific antibody and T-cell responses in asymptomatic HTLV-1 carriers ( n = 77) were investigated. Neutralizing antibody responses were significantly higher in individuals with higher anti-Env SU (gp46) antibody levels and positively correlated with proviral loads. Overnight ex vivo culture of peripheral blood mononuclear cells resulted in detectable HTLV-1 Gag antigen (p19) expression in CD4 + T cells and interferon-γ (IFN-γ) induction in CD8 + T cells. Frequencies of these p19-expressing CD4 + T cells and non-specific IFN-γ-induced CD8 + T cells were positively correlated with proviral loads, respectively. Tax-specific CD8 + T-cell frequencies were not associated with proviral loads but inversely correlated with the ratios of p19-expressing CD4 + T-cell frequencies to proviral loads, implying the involvement of Tax-specific CD8 + T cells in the control of HTLV-1 replication. These results provide insights into the elucidation of the virus-host immune interaction in latent HTLV-1 infection. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) can cause fatal diseases, including adult T-cell leukemia in humans after long-term asymptomatic infection. In asymptomatic HTLV-1 carriers, substantial proviruses are detectable in lymphocytes, and the association of a higher proviral load with a higher risk of disease progression has been observed. However, viral replication is controlled and HTLV-1 production is poor in asymptomatic carriers. Virus-host immune interaction during latent infection has not been fully determined. In the present study, virus-specific antibody and T-cell responses in asymptomatic HTLV-1 carriers were investigated. Neutralizing antibody responses were positively correlated with proviral loads. Tax-specific CD8 + T-cell frequencies were not associated with proviral loads but inversely correlated with the ratios of p19-expressing CD4 + T-cell frequencies to proviral loads, supporting the notion that Tax-specific CD8 + T-cell responses play an important role in the control of HTLV-1 replication. These results provide insights into the mechanism of virus-host immune interaction in latent HTLV-1 infection.

Yamashita Y., Morimoto T., Muraoka N., Shioyama W., Chatani R., Shibata T., Nishimoto Y., Ogihara Y., Doi K., Oi M., Shiga T., Sueta D., Kim K., Tanabe Y., Koitabashi N., et. al.

BACKGROUND: The optimal duration of anticoagulation therapy for patients with cancer and acute low-risk pulmonary embolism (PE) is clinically relevant, but evidence is lacking. Prolonged anticoagulation therapy could have a potential benefit for prevention of thrombotic events; however, it could also increase the risk of bleeding. METHODS: In a multicenter, open-label, adjudicator-blinded, randomized clinical trial at 32 institutions in Japan, we randomly assigned patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, in a 1:1 ratio, to receive either an 18-month or a 6-month rivaroxaban treatment. The primary end point was recurrent venous thromboembolism (VTE) at 18 months. The major secondary end point was major bleeding at 18 months according to the criteria of the International Society on Thrombosis and Hemostasis. The primary hypothesis was that an 18-month treatment was superior to a 6-month treatment in terms of the primary end point. RESULTS: From February 2021 to March 2023, 179 patients were randomized, and after the exclusion of one patient who withdrew consent, 178 were included in the intention-to-treat population: 89 patients in the 18-month rivaroxaban group and 89 in the 6-month rivaroxaban group. The mean age was 65.7 years; 47% of the patients were men, and 12% had symptoms of PE at baseline. The primary end point of recurrent VTE occurred in 5 of the 89 patients (5.6%) in the 18-month rivaroxaban group and in 17 of the 89 (19.1%) in the 6-month rivaroxaban group (odds ratio, 0.25 [95% CI, 0.09–0.72]; P =0.01). Among 22 recurrent VTE, 5 patients presented with a symptomatic recurrent VTE; recurrent PE occurred in 11 patients, including 2 with main and 4 with lobar PEs; and recurrent deep vein thrombosis was seen in 11 patients, including 3 with proximal deep vein thromboses. The major secondary end point of major bleeding occurred in 7 of the 89 patients (7.8%) in the 18-month rivaroxaban group and in 5 of the 89 patients (5.6%) in the 6-month rivaroxaban group (odds ratio, 1.43 [95% CI, 0.44–4.70]; P =0.55). CONCLUSIONS: In patients with cancer and acute low-risk PE of the simplified version of the Pulmonary Embolism Severity Index score of 1, the 18-month rivaroxaban treatment was superior to the 6-month rivaroxaban treatment with respect to recurrent VTE events. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04724460.

Yamamoto H., Matano T.

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIVmac239-infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8+ T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.

Yamamoto H., Matano T.

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIVmac239-infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8+ T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.

Kaneda Y., Lu Y., Sun J., Shimada K., Emori C., Noda T., Koyano T., Matsuyama M., Miyata H., Ikawa M.

Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) male mice are infertile. Tex38 KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of Tex38 KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.

Ichinose K., Kurita Y., Higuchi R., Mizumoto I.

NANAO M., NOZAKI T., FUJIE Y., MUKUNOKI T.

Nagayama T., Anselmucci F., Lenoir N., Sibille L., Mukunoki T., Otani J., Viggiani G.

While many aspects of the growth mechanisms of plant roots and their ability to adapt to the surrounding environment are now clearer from a biological perspective, relatively limited research has focused on the mechanical interaction of a root and the soil in which it grows, including the root trajectory and the strain developing in the soil. The use of X-ray tomography allows for the 4D (space plus time) analysis of such an interaction. This paper investigates how plant roots grow when approaching a harder-to-penetrate soil – here, a finer and denser sand. The root trajectories in nine bilayered sand samples are imaged and characterised in terms of their tortuosity. The angle between the root axis and the gravity direction is also measured to characterise the change of trajectory of the root when approaching the stiffer sand layer. In addition, we report, for one test, the strain path experienced by the soil around the root when the latter is elongating and bending, through imaging conducted at regular intervals during the root growth.

Funama Y., Nagayama Y., Sakabe D., Ito Y., Chiba Y., Nakaura T., Oda S., Kidoh M., Hirai T.

This study evaluated the performance of super-resolution deep learning-based reconstruction (SR-DLR) and compared with it that of hybrid iterative reconstruction (HIR) and normal-resolution DLR (NR-DLR) for enhancing image quality in computed tomography (CT) images across various field of view (FOV) sizes, radiation doses, and noise reduction strengths.

Sueta D., Araki S., Usuku H., Fujisaki T., Kiyama T., Ishii M., Tabata N., Fujisue K., Kusaka H., Hanatani S., Yamamoto E., Haruguchi H., Takamori H., Tsujita K.

Despite strong recommendations in the latest guidelines for implementing guideline-directed medical therapy (GDMT) before discharge, there is a lack of data on the clinical characteristics and outcomes of older patients with heart failure (HF). Therefore, this study aimed to investigate the clinical characteristics and outcomes of patients with HF in a super-aging society during the GDMT era.

Miyauchi S., Morooka K., Kurazume R.