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Abstract Microscopic evaluation is one of the most effective methods in materials research. High-quality images are essential to analyze microscopic images using artificial intelligence. To overcome this challenge, we propose the machine learning of “fake micrographs” in this study. To verify the effectiveness of this method, we chose to analyze the optical microscopic images of the crystal growth process of a Ge thin film, which is a material in which it is difficult to obtain a contrast between the crystal and amorphous states. By learning the automatically generated fake micrographs that mimic the crystal growth process, the machine learning model can now identify the low-resolution real micrographs as crystalline or amorphous. Comparing the three types of machine learning models, it was found that ResUNet ++ exhibited high accuracy, exceeding 90%. The technology developed in this study for the automatic and rapid analysis of low-resolution images is widely helpful in material research.

Abstract Non-alcoholic steatohepatitis (NASH), caused by fat buildup, can lead to liver inflammation and damage. Elucidation of the spatial distribution of fibrotic tissue in the fatty liver in NASH can be immensely useful to understand its pathogenesis. Thus, we developed a novel serial section-3D (SS3D) technique that combines high-resolution image acquisition with 3D construction software, which enabled highly detailed analysis of the mouse liver and extraction and quantification of stained tissues. Moreover, we studied the underexplored mechanism of fibrosis progression in the fatty liver in NASH by subjecting the mice to a high-fat diet (HFD), followed by lipopolysaccharide (LPS) administration. The HFD/LPS (+) group showed extensive fibrosis compared with control; additionally, the area of these fibrotic regions in the HFD/LPS (+) group was almost double that of control using our SS3D technique. LPS administration led to an increase in Tnfα and Il1β mRNA expression and the number of macrophages in the liver. On the other hand, transforming growth factor-β1 (Tgfβ1) mRNA increased in HFD group compared to that of control group without LPS-administration. In addition, COL1A1 levels increased in hepatic stellate cell (HSC)-like XL-2 cells when treated with recombinant TGF-β1, which attenuated with recombinant latency-associated protein (rLAP). This attenuation was rescued with LPS-activated macrophages. Therefore, we demonstrated that fatty liver produced “latent-form” of TGF-β1, which activated by macrophages via inflammatory cytokines such as TNFα and IL1β, resulting in activation of HSCs leading to the production of COL1A1. Moreover, we established the effectiveness of our SS3D technique in creating 3D images of fibrotic tissue, which can be used to study other diseases as well.

Abstract Polycrystalline Ge thin films have attracted considerable attention as potential materials for use in various electronic and optical devices. We recently developed a low-temperature solid-phase crystallization technology for a doped Ge layer and achieved the highest electron mobility in a polycrystalline Ge thin film. In this study, we investigated the effects of strain on the crystalline and electrical properties of n-type polycrystalline Ge layers. By inserting a GeO x interlayer directly under Ge and selecting substrates with different coefficients of thermal expansion, we modulated the strain in the polycrystalline Ge layer, ranging from approximately 0.6% (tensile) to − 0.8% (compressive). Compressive strain enlarged the grain size to 12 µm, but decreased the electron mobility. The temperature dependence of the electron mobility clarified that changes in the potential barrier height of the grain boundary caused this behavior. Furthermore, we revealed that the behavior of the grain boundary barrier height with respect to strain is opposite for the n- and p-types. This result strongly suggests that this phenomenon is due to the piezoelectric effect. These discoveries will provide guidelines for improving the performance of Ge devices and useful physical knowledge of various polycrystalline semiconductor thin films.

Abstract Hypertensive disorders of pregnancy (HDP) increase the risk of preterm births and cesarean delivery. This study aimed to investigate whether maternal blood leukocyte, monocyte, or neutrophil counts in the first trimester are related to the development of HDP. Data were collected from the Japan Environment and Children’s Study, a large birth cohort study (n = 38,194) that recruited pregnant women in 15 Regional Centers across Japan (from January 2011 to March 2014). The odds ratios (ORs) for mild/severe HDP according to the cut-off value of leukocyte/neutrophil/monocyte counts by the receiver operating characteristic curve showed high ORs. Furthermore, pregnant women with the highest quartiles of leukocyte and monocyte counts had higher adjusted ORs (aORs) for mild (leukocyte: aOR = 1.27, 95% confidence interval [CI]: 1.02–1.58; monocyte: aOR = 1.30, 95% CI 1.04–1.63) and severe HDP (leukocyte: aOR = 1.51, 95% CI 1.08–2.13; monocyte: aOR = 1.44, 95% CI 1.03–2.01) compared with those with the lowest quartiles of those counts. In addition, pregnant women with the highest neutrophil counts had higher aOR for mild HDP (aOR = 1.26, 95% CI 1.02–1.56) compared with those with the lowest count. In conclusion, high leukocyte and monocyte counts in the first trimester are associated with the development of HDP. Thus, they may be used to predict subsequent HDP.

Abstract Quantum machine learning for predicting the physical properties of polymer materials based on the molecular descriptors of monomers was investigated. Under the stochastic variation of the expected predicted values obtained from quantum circuits due to finite sampling, the methods proposed in previous works did not make sufficient progress in optimizing the parameters. To enable parameter optimization despite the presence of stochastic variations in the expected values, quantum circuits that improve prediction accuracy without increasing the number of parameters and parameter optimization methods that are robust to stochastic variations in the expected predicted values, were investigated. The multi-scale entanglement renormalization ansatz circuit improved the prediction accuracy without increasing the number of parameters. The stochastic gradient descent method using the parameter-shift rule for gradient calculation was shown to be robust to sampling variability in the expected value. Finally, the quantum machine learning model was trained on an actual ion-trap quantum computer. At each optimization step, the coefficient of determination $$R^{2}$$ R 2 improved equally on the actual machine and simulator, indicating that our findings enable the training of quantum circuits on the actual quantum computer to the same extent as on the simulator.

Abstract Polycrystalline Ge thin films have recently attracted renewed attention as a material for various electronic and optical devices. However, the difficulty in the Fermi level control of polycrystalline Ge films owing to their high density of defect-induced acceptors has limited their application in the aforementioned devices. Here, we experimentally estimated the origin of acceptor defects by significantly modulating the crystallinity and electrical properties of polycrystalline Ge layers and investigating their correlation. Our proposed linear regression analysis method, which is based on deriving the acceptor levels and their densities from the temperature dependence of the hole concentration, revealed the presence of two different acceptor levels. A systematic analysis of the effects of grain size and post annealing on the hole concentration suggests that deep acceptor levels (53–103 meV) could be attributed to dangling bonds located at grain boundaries, whereas shallow acceptor levels (

Abstract Adequate management and conservation of instream thermal habitats requires an understanding of the control that different landscape features exert on water temperatures. Previous studies have extensively explored the influence of spatial scale on these relationships. However, the effect of temporal scale remains poorly understood. Here, we use paired air–water mean daily and monthly summer temperatures collected over four years from 130 monitoring stations in Japanese mid- to low-order streams to investigate whether perceived effects of different environmental controls on water temperature are dependent on the timescale of the temperature data, and whether those dependencies are related to the spatial scale at which these controls operate. We found a clear pattern for the significant cooling effect, high relative importance and strong dominance exerted by the riparian forest cover on daily temperatures at the reach scale becoming dampened by concomitant increases associated to the proportion of volcanic geology on monthly temperatures at the catchment scale. These results highlight the importance of contextualizing the effects of environmental controls on water temperatures to the timescale of the analysis. Such dependencies are particularly important for the management and conservation of instream thermal habitats in a rapidly warming world.

Abstract We compared clinical outcomes associated with seed brachytherapy (SEED-BT) alone and SEED-BT plus external-beam radiotherapy (EBRT) for intermediate-risk prostate cancer using propensity score-matched analysis. From 2006 to 2011, 993 patients diagnosed with intermediate-risk were treated with either SEED-BT alone (n = 775) or SEED-BT plus EBRT (n = 158) at 3 tertiary hospitals. In the propensity score-matched analysis (102 pairs), median follow-up was 95 months (range 18–153 months). The 8-year biochemical recurrence-free rate (bRFR) was significantly better with SEED-BT alone than with combined radiotherapy (93.3% vs. 88.4%; HR 0.396; 95% CI 0.158–0.991). Grade 2 or greater late genitourinary toxicities were significantly fewer with SEED-BT alone than with combined radiotherapy (21.0% vs. 33.2%; HR 0.521; 95% CI 0.308–0.881). Similarly, grade 2 or greater late gastrointestinal toxicities were significantly fewer with SEED-BT alone (0% vs. 12.2%; HR 0.125; 95% CI 0.040–0.390). For the unfavorable intermediate-risk subgroups, SEED-BT alone yielded a significantly better bRFR than the combined radiotherapy (HR 0.325; 95% CI 0.115–0.915). SEED-BT alone might be a better disease-management plan than SEED-BT plus EBRT for intermediate-risk prostate cancer regardless of favorable and unfavorable characteristics.

Abstract Protein functional effector sncRNAs (pfeRNAs) are approximately 30–60 nucleotides (nt), of which the extraction method from plasma has not yet been reported. Silver staining in a high-resolution polyacrylamide gel suggested that the majority of plasma sncRNAs extracted by some broadly used commercial kits were sncRNAs from 100 nt upwards. Additionally, TRIzol’s protocol is for long RNA but not sncRNA recovery. Here, we report a TRIzol-based frozen precipitation method (TFP method), which shows rigor and reproducibility in high yield and quality for plasma sncRNAs approximately 30–60 nt. In contrast to the yields by the commercial kit, plasma sncRNAs extracted by the TFP method enriched more sncRNAs. We used four different pfeRNAs of 34 nt, 45 nt, 53 nt, and 58 nt to represent typical sizes of sncRNAs from 30 to 60 nt and compared their levels in the recovered sncRNAs by the TFP method and by the commercial kit. The TFP method showed lower cycle threshold (CT) values by 2.01–9.17 cycles in 38 plasma samples from 38 patients, including Caucasian, Asian, African American, Latin, Mexican, and those who were a mix of more than one race. In addition, pfeRNAs extracted by two organic-based extraction methods and four commercial kits were undetermined in 22 of 38 samples. Thus, the quick and unbiased TFP method enriches plasma sncRNA ranging from 30 to 60 nt.

Abstract The purpose of this study was to evaluate the prognostic value of quality of life (QOL) scores acquired not only pre-treatment, but also 1 month after treatment for locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with pharyngeal cancer treated using radiotherapy. Data for 102 patients with naso-, oro-, or hypo-pharyngeal cancer treated between December 2008 and September 2017 were retrospectively analyzed. About 90% of the patients were male. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) was used for QOL assessments. Associations between QLQ-C30 scores before and 1 month after treatment and outcomes including LRC, DMFS, and OS were analyzed using Cox proportional hazard models. Median follow-up was 37 months (range, 5–117 months). Three-year LRC, DMFS, and OS rates were 77.8%, 60.0%, and 66.5%, respectively. Pre-treatment emotional functioning and diarrhea at 1 month after treatment were identified as significant predictors of LRC. Pre-treatment global QOL and diarrhea at 1 month after treatment were detected as significant predictors of DMFS. Pre-treatment emotional functioning, pre-treatment appetite loss, and diarrhea at 1 month after treatment were detected as significant predictors of OS. Diarrhea at 1 month after treatment was the most powerful QOL variable for predicting LRC, DMFS and OS. Our study revealed that several QOL scores not only before treatment but also 1 month after treatment correlated with LRC, DMFS and OS. In particular, the diarrhea domain of QOL at 1 month after treatment offered the most powerful prognosticator for pharyngeal cancer patients treated with radiotherapy.

The ultrastructural organization of the blood labyrinthine barrier (BLB) was investigated in the human vestibular endorgan, the utricular macula, using postmortem specimens from individuals with documented normal auditory and vestibular function and surgical specimens from patients with intractable Meniere's disease. Transmission electron microscopic analysis of capillaries located in the normal human utricular stroma showed vascular endothelial cells with few pinocytotic vesicles, covered by a smooth and uniform basement membrane surrounded by pericyte processes. Meniere's disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. With moderate degeneration of the BLB, there were numerous vesicles within the vascular endothelial cells (VECs), with increased numbers at the abluminal face, pericyte process detachment and disruption of the perivascular basement membrane surrounding the VECs. With severe degeneration of the BLB, there was severe vacuolization or frank apparent necrosis of VECs and loss of subcellular organelles. A higher severity of BLB degenerative changes was associated with a higher degree of basement membrane thickening and edematous changes within the vestibular stroma. This study presents the first ultrastructural analysis of the capillaries constituting the BLB in the human vestibular macula utricle from normal and Meniere's disease.

Abstract Despite the essentiality of Mn in terrestrial plants, its excessive accumulation in plant tissues can cause growth defects, known as Mn toxicity. Mn toxicity can be classified into apoplastic and symplastic types depending on its onset. Symplastic Mn toxicity is hypothesised to be more critical for growth defects. However, details of the relationship between growth defects and symplastic Mn toxicity remain elusive. In this study, we aimed to elucidate the molecular mechanisms underlying symplastic Mn toxicity in rice plants. We found that under excess Mn conditions, CO2 assimilation was inhibited by stomatal closure, and both carbon anabolic and catabolic activities were decreased. In addition to stomatal dysfunction, stomatal and leaf anatomical development were also altered by excess Mn accumulation. Furthermore, indole acetic acid (IAA) concentration was decreased, and auxin-responsive gene expression analyses showed IAA-deficient symptoms in leaves due to excess Mn accumulation. These results suggest that excessive Mn accumulation causes IAA deficiency, and low IAA concentrations suppress plant growth by suppressing stomatal opening and leaf anatomical development for efficient CO2 assimilation in leaves.

Abstract To report outcomes and risk factors of ultrahypofractionated (UHF) radiotherapy for Japanese prostate cancer patients. This multi-institutional retrospective analysis comprised 259 patients with localized prostate cancer from 6 hospitals. A total dose of 35–36 Gy in 4–5 fractions was prescribed for sequential or alternate-day administration. Biochemical failure was defined according to the Phoenix ASTRO consensus. Toxicities were assessed using National Cancer Institute Common Toxicity Criteria version 4. Tumor control and toxicity rates were analyzed by competing risk frames. Median follow-up duration was 32 months (range 22–97 months). 2- and 3-year biochemical control rates were 97.7% and 96.4%, respectively. Initial prostate-specific antigen (p

Abstract Diagnosis using artificial intelligence (AI) with deep learning could be useful in endoscopic examinations. We investigated the ability of AI to detect superficial esophageal squamous cell carcinoma (ESCC) from esophagogastroduodenoscopy (EGD) videos. We retrospectively collected 8428 EGD images of esophageal cancer to develop a convolutional neural network through deep learning. We evaluated the detection accuracy of the AI diagnosing system compared with that of 18 endoscopists. We used 144 EGD videos for the two validation sets. First, we used 64 EGD observation videos of ESCCs using both white light imaging (WLI) and narrow-band imaging (NBI). We then evaluated the system using 80 EGD videos from 40 patients (20 with superficial ESCC and 20 with non-ESCC). In the first set, the AI system correctly diagnosed 100% ESCCs. In the second set, it correctly detected 85% (17/20) ESCCs. Of these, 75% (15/20) and 55% (11/22) were detected by WLI and NBI, respectively, and the positive predictive value was 36.7%. The endoscopists correctly detected 45% (25–70%) ESCCs. With AI real-time assistance, the sensitivities of the endoscopists were significantly improved without AI assistance (p

Abstract In Japan, preoperatively diagnosed T1a-muscularis mucosae or T1b-submucosa 1 (MM/SM1) esophageal squamous cell carcinoma (ESCC) is a relative indication for endoscopic resection (ER). We evaluated long-term outcomes in patients after ER for non-circumferential ESCC with a preoperative diagnosis of MM/SM1 invasion. We retrospectively reviewed 66 patients with a preoperative diagnosis of non-circumferential MM/SM1 ESCC endoscopically resected between 2010 and 2015. Patients were divided into low- (adequate follow-up) and high-risk (requiring additional treatment) groups for lymph node metastasis according to risk factors (submucosal invasion, lymphovascular invasion, or droplet infiltration) and long-term outcomes were analyzed. Pathological invasion to T1a-lamina propria mucosa, MM/SM1, and T1b-SM2 was seen in 22, 38, and 6 lesions, respectively. Overall, 71.2% patients were classified into the “adequate follow-up” group. Of these, only one patient had a lymph node recurrence, which was successfully treated by additional therapy. The remaining 28.8% patients were classified into the “requiring additional treatment” group, where no recurrences were observed after additional treatments. After a median follow-up of 58.6 months, no deaths happened due to ESCC. The 3- and 5-year overall survival rates were 93.6% and 88.7%, respectively. ER is a valid initial treatment for non-circumferential ESCC with preoperatively diagnosed MM/SM1 invasion.

Abstract The ultrastructural organization of the blood labyrinthine barrier (BLB) was investigated in the human vestibular endorgan, the utricular macula, using postmortem specimens from individuals with documented normal auditory and vestibular function and surgical specimens from patients with intractable Meniere’s disease. Transmission electron microscopic analysis of capillaries located in the normal human utricular stroma showed vascular endothelial cells with few pinocytotic vesicles, covered by a smooth and uniform basement membrane surrounded by pericyte processes. Meniere’s disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. With moderate degeneration of the BLB, there were numerous vesicles within the vascular endothelial cells (VECs), with increased numbers at the abluminal face, pericyte process detachment and disruption of the perivascular basement membrane surrounding the VECs. With severe degeneration of the BLB, there was severe vacuolization or frank apparent necrosis of VECs and loss of subcellular organelles. A higher severity of BLB degenerative changes was associated with a higher degree of basement membrane thickening and edematous changes within the vestibular stroma. This study presents the first ultrastructural analysis of the capillaries constituting the BLB in the human vestibular macula utricle from normal and Meniere’s disease.

Abstract Secretory lysosomes are required for the specialised functions of various types of differentiated cells. In osteoclasts, the lysosomal proton pump V-ATPase (vacuolar-type ATPase) is targeted to the plasma membrane via secretory lysosomes and subsequently acidifies the extracellular compartment, providing optimal conditions for bone resorption. However, little is known about the mechanism underlying this trafficking of secretory lysosomes. Here, we demonstrate that the lysosome-specific a3 isoform of the V-ATPase a subunit plays an indispensable role in secretory lysosome trafficking, together with Rab7, a small GTPase involved in organelle trafficking. In osteoclasts lacking a3, lysosomes were not transported to the cell periphery, and Rab7 was not localised to lysosomes but diffused throughout the cytoplasm. Expression of dominant-negative (GDP-bound form) Rab7 inhibited lysosome trafficking in wild-type cells. Furthermore, a3 directly interacted with the GDP-bound forms of Rab7 and Rab27A. These findings reveal a novel role for the proton pump V-ATPase in secretory lysosome trafficking and an unexpected mechanistic link with Rab GTPases.

Abstract Divergent synthesis of antimalarial troponoids, including naturally occurring compounds, some of which were identified and isolated by our group, has been achieved utilizing the total synthetic route of puberulic acid. Structure-activity relationships of natural products and simple troponoids inspired us to explore more detailed properties of this class of compounds. Access to new derivatives was facilitated through intermediate compounds generated during the total synthesis of puberulic acid by a stepwise oxidation-aromatization sequence to provide 7-hydroxytropolones and bromination for conversion of the carboxylic acid moiety. The first total synthesis of viticolin A, as well as the synthesis of different methyl-substituted derivatives, has also been achieved. In vitro antimalarial activity and cytotoxicity of novel derivatives were evaluated and fundamental information to facilitate the discovery of more promising antimalarials was obtained.