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Abstract The westernmost Nankai Trough, southwest Japan, exhibits a rapid along-strike reduction in plate coupling in the proximity to the subducting Kyushu-Palau ridge. Yet how and to what extent the ridge subduction impacts physical properties at the megathrust have not been investigated. Here we present high-resolution seismic P-wave velocity models along the forearc wedge in the western Nankai Trough derived from full-waveform inversion analyses of seismic refraction data. The velocity models show that where the plate coupling is weak and the plate boundary presumably hosts slow earthquakes, the upper plate exhibits lower seismic velocities indicating higher degree of fracturing over a ~ 100 km length along trough. Intriguingly, the extent of the upper-plate low-velocity features is significantly larger than the surficial width of the Kyushu-Palau ridge, and this low-velocity zone is underthrust by the slab with increased crustal thickness by 2–4 km. Seismic reflection images consistently reveal that the thicker slab crust has appreciable basement roughness extending ~ 60 km from the eastern margin of the Kyushu-Palau ridge beneath the western Shikoku basin. We suggest that such a thicker and rugged slab crust, together with the main body of the Kyushu-Palau ridge, can cause significant fracture zones in the overriding plate, decrease the interplate coupling and produce preferable conditions for shallow slow earthquakes to occur when subducted. The results may also provide structural constraints on the western limit of future megathrust earthquakes in the Nankai Trough. Graphical Abstract

Background: The present genome-wide association study (GWAS) aimed to reveal the genetic loci associated with folate metabolites, as well as to detect related gene–environment interactions in Japanese. Methods: We conducted the GWAS of plasma homocysteine (Hcy), folic acid (FA), and vitamin B12 (VB12) levels in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study participants who joined from 2005 to 2012, and also estimated gene–environment interactions. In the replication phase, we used data from the Yakumo Study conducted in 2009. In the discovery phase, data of 2,263 participants from four independent study sites of the J-MICC Study were analyzed. In the replication phase, data of 573 participants from the Yakumo Study were analyzed. Results: For Hcy, MTHFR locus on chr 1, NOX4 on chr 11, CHMP1A on chr 16, and DPEP1 on chr 16 reached genome-wide significance (P < 5 × 10−8). MTHFR also associated with FA, and FUT2 on chr 19 associated with VB12. We investigated gene-environment interactions in both studies and found significant interactions between MTHFR C677T and ever drinking, current drinking, and physical activity >33% on Hcy (β = 0.039, 0.038 and −0.054, P = 0.018, 0.021 and

Abstract Background Single-cell droplet microfluidics is an important platform for high-throughput analyses and screening because it provides an independent and compartmentalized microenvironment for reaction or cultivation by coencapsulating individual cells with various molecules in monodisperse microdroplets. In combination with microbial biosensors, this technology becomes a potent tool for the screening of mutant strains. In this study, we demonstrated that a genetically engineered yeast strain that can fluorescently sense agonist ligands via the heterologous expression of a human G-protein-coupled receptor (GPCR) and concurrently secrete candidate peptides is highly compatible with single-cell droplet microfluidic technology for the high-throughput screening of new agonistically active peptides. Results The water-in-oil microdroplets were generated using a flow-focusing microfluidic chip to encapsulate engineered yeast cells coexpressing a human GPCR [i.e., angiotensin II receptor type 1 (AGTR1)] and a secretory agonistic peptide [i.e., angiotensin II (Ang II)]. The single yeast cells cultured in the droplets were then observed under a microscope and analyzed using image processing incorporating machine learning techniques. The AGTR1-mediated signal transduction elicited by the self-secreted Ang II peptide was successfully detected via the expression of a fluorescent reporter in single-cell yeast droplet cultures. The system could also distinguish Ang II analog peptides with different agonistic activities. Notably, we further demonstrated that the microenvironment of the single-cell droplet culture enabled the detection of rarely existing positive (Ang II-secreting) yeast cells in the model mixed cell library, whereas the conventional batch-culture environment using a shake flask failed to do so. Thus, our approach provided compartmentalized microculture environments, which can prevent the diffusion, dilution, and cross-contamination of peptides secreted from individual single yeast cells for the easy identification of GPCR agonists. Conclusions We established a droplet-based microfluidic platform that integrated an engineered yeast biosensor strain that concurrently expressed GPCR and self-secreted the agonistic peptides. This offers individually isolated microenvironments that allow the culture of single yeast cells secreting these peptides and gaging their signaling activities, for the high-throughput screening of agonistic peptides. Our platform base on yeast GPCR biosensors and droplet microfluidics will be widely applicable to metabolic engineering, environmental engineering, and drug discovery.

Background: Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. Methods: We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index (BMI)-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses using the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. Results: In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with increased risks of higher blood pressure, triglycerides, and uric acid, as well as lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent using different methods, including the directions. Conclusion: The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.

Abstract We examined the possible factors affecting the spatial distribution of very low frequency earthquakes and tremors in the shallow megathrust of Nankai Trough (

Abstract Estimates of heat flow can contribute to our understanding of geological structures in plate convergent zones that produce great earthquakes. We applied automated velocity analysis to obtain the accurate seismic profiles needed for precise heat flow estimates using six new seismic profiles acquired during R/V Kaimei KM18-10 voyage in 2018. We calculated heat flow values in the accretionary wedge of the Nankai Trough off the Kii Peninsula, Japan, from the positions of widespread bottom-simulating reflectors (BSRs) in seismic reflection profiles. Calculated conductive heat flow values from the depth of the BSR agree with previous studies where a regional trend is observed from ~ 50 mW/m2 to

Abstract In shallow subduction zones, fluid behavior impacts various geodynamic processes capable of regulating slip behaviors and forming mud volcanoes. However, evidence of structures that control the fluid transfer within an overriding plate is limited and the physical properties at the source faults of slow earthquakes are poorly understood. Here we present high-resolution seismic velocity models and reflection images of the Hyuga-nada area, Japan, where the Kyushu-Palau ridge subducts. We image distinct kilometer-wide columns in the upper plate with reduced velocities that extend vertically from the seafloor down to 10–13 km depth. We interpret the low-velocity columns as damaged zones caused by seamount subduction and suggest that they serve as conduits, facilitating vertical fluid migration from the plate boundary. The lateral variation in upper-plate velocity and seismic reflectivity along the plate boundary correlates with the distribution of slow earthquakes, indicating that the upper-plate drainage system controls the complex pattern of seismic slip at subduction faults.

Abstract Devastating megathrust earthquakes and slow earthquakes both occur along subducting plate interfaces. These interplate seismic activities are strongly dependent on the nature of the plate interface, such as the shape of the plate interface and the materials and physical conditions along the plate interface. The oceanic plate, which is the input to the subduction zone, is the first order control on the nature of the plate interface. To reveal the nature of the subduction inputs to the northeastern Japan arc, we have conducted large-scale controlled-source seismic surveys of the northwestern part of the oceanic Pacific plate. The obtained seismic data have revealed (1) oceanic plate structural evolution caused by plate bending prior to subduction, suggesting the promotion of the oceanic plate hydration; (2) spatial variation of the oceanic plate structure, such as variations in the thickness of sediment and crust; (3) that the spatial variations are caused by both ancient plate formation processes and more recent volcanic activities; and (4) that spatial variations of the nature of the subduction inputs show good correlation with the along-strike variations in the seismic structure and seismic activities after subduction, including the coseismic slip distribution of the 2011 Tohoku earthquakes and the structural differences between the northern and the southern Japan Trench. These observations indicate that the incoming oceanic plate structure is much more spatially variable than previously thought and also imply that the spatial variation of the subduction inputs is a key controlling factor of the spatial variation of various processes in subduction zones, including interplate seismic activities and evolution of the forearc structure.

Abstract The structure of the incoming plate is an important element that is often considered to be related to the occurrence of great earthquakes in subduction zones. In the Japan Trench, where the 2011 Tohoku earthquake occurred, we collected seismic profiles along survey lines separated by 2–8 km to examine the structural characteristics of the incoming Pacific plate in detail. The average thickness of the incoming sediments was

Background: Little is known about whether insufficient moderate-to-vigorous physical activity (MVPA) and longer sedentary behavior (SB) are independently associated with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), whether they interact with known risk factors for CKD, and the effect of replacing sedentary time with an equivalent duration of physical activity on kidney function. Methods: We examined the cross-sectional association of MVPA and SB with eGFR and CKD in 66,603 Japanese cohort study in 14 areas from 2004 to 2013. MVPA and SB were estimated using a self-reported questionnaire, and CKD was defined as eGFR

Summary: Biomolecular condensates (BCs) are formed by proteins with intrinsically disordered regions (IDRs) via liquid-liquid phase separation. Mieap/Spata18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of BCs involved in cardiolipin metabolism. Mieap BCs specifically phase separate the mitochondrial phospholipid, cardiolipin. Mieap directly binds to cardiolipin in vitro. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions in cardiolipin biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1 and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap BCs. Mieap-deficient cells exhibit altered crista structure, leading to decreased respiration activity and ATP production in mitochondria. These results suggest that Mieap may form membrane-less organelles to compartmentalize and facilitate cardiolipin metabolism, thus potentially contributing to mitochondrial quality control.

Abstract Recent research has shown that shallow tremors tend to occur in spatial association with heterogeneous conditions, which are formed by seamounts or ridges on the subducted oceanic crust. In the southern Kuril Trench, shallow tremors have been observed on the western side, although no apparent heterogeneity in the subducted oceanic crust has been identified. To investigate structures spatially associated with these shallow tremors, we processed reflection seismic data acquired along seven profiles. We examined structures ranging from the seafloor to the top of the oceanic crust, within a depth of up to 20 km. Our results reveal that undulations observed at the top of the subducted oceanic crust are related to the distribution and number of shallow tremors. The undulations would play a crucial role in the distribution of shallow tremors.

We investigate the impact of outer-rise normal fault subduction on the structural evolution of the décollement and frontal prism in a portion of the Japan trench that hosted the 2011 Tohoku earthquake. We use seismic reflection data to map the relative occurrence of sediment accretion, sediment subduction, and frontal tectonic erosion in the shallow portion of the subduction zone and correlate these deformation styles to the magnitude of outer-rise fault throw and incoming plate sediment thickness. These data reveal spatial heterogeneity in the modes of deformation over distances of 5-10 km that necessitate correlative heterogeneity in the geometry and composition of the shallow décollement over similar length-scales. We find that sediment accretion predominantly occurs in regions where incoming plate sediment thickness is greater than fault throw. In these areas, the décollement appears to be non-planar and compositionally homogenous. Conversely, frontal tectonic erosion and slope failures are predominantly observed in regions where fault throw is greater than sediment thickness. In these areas, the décollement may be planar but compositionally heterogeneous. Additionally, spatial variations in near trench slip appear to correlate with the dominant deformation modes, suggesting that both sediment thickness and outer-rise fault throw may be important controls on shallow megathrust behavior.

Abstract Objectives This study aims to investigate whether a cribriform pattern on prostate biopsy may be a factor in suspicion of intraductal carcinoma of the prostate after radical prostatectomy. Methods This retrospective study assessed 100 men who underwent prostatectomy from 2015 to 2019. Participants were grouped as 76 patients with Gleason pattern 4 and 24 patients without this pattern. All 100 participants underwent retrograde radical prostatectomy and limited lymph node dissection. The same pathologist evaluated all specimens. The cribriform pattern was evaluated with haematoxylin and eosin counterstaining, and intraductal carcinoma of the prostate was evaluated with immunohistochemical analysis of cytokeratin 34βE12. Results Patients with intraductal carcinoma of the prostate on immunohistochemical analysis showed a significant tendency to relapse in the postoperative period, and those with the cribriform pattern on biopsy had a significant recurrence rate. In univariate and multivariate analyses, intraductal carcinoma of the prostate confirmed in biopsy tissue was an independent predictor of biochemical recurrence after prostatectomy. The rate of intraductal carcinoma of the prostate confirmation was 28% of cases with a cribriform pattern in biopsy tissue, which was increased to 62% in prostatectomy tissues. Conclusion The cribriform pattern in the biopsy tissue may be a predictor for intraductal carcinoma of the prostate.

Abstract Since the 2011 Mw 9.0 Tohoku-oki earthquake, intra-plate normal-faulting earthquakes, including several M7-class earthquakes, have occurred in the outer trench slope area from the trench to the outer rise along the Japan Trench. Concerns regarding large earthquakes and associated tsunamis have also arisen. Based on aftershock distributions, several outer trench slope normal-faulting earthquakes (hereinafter referred to as outer-rise earthquakes) are likely related to the rupture of multiple faults. However, few observations have clearly shown how multiple faults act during outer-rise earthquakes. During the ocean bottom seismograph (OBS) observations in the outer trench slope area of the central Japan Trench from September 2017 to July 2018, three M6-class normal-faulting earthquakes (Mw 6.2 on September 20, Mw 6.2 on October 06, and Mw 6.0 on November 12) occurred around the OBS network. The near-field OBS observations provided detailed information on hypocenter locations and focal mechanisms of the mainshocks and aftershocks, including immediately after the mainshocks. We investigated the fault configurations of normal-faulting earthquakes based on OBS observations. During the September 2017 earthquake, the mainshock ruptured high-angle normal faults with a dip angle of 65°. Off-fault aftershock activities that were not directly related to the mainshock rupture and could be explained by the stress changes caused by the mainshock were confirmed. However, hypocenter distributions and focal mechanisms of the main and aftershocks of the October and November 2017 earthquakes suggest that the mainshock ruptured multiple faults with various dipping directions, angles, and strike orientations. The complicated fault geometry should be considered a possible fault model for large outer-rise earthquakes and related tsunamis.

To know phase diagrams is a time saving approach for developing novel materials. To efficiently construct phase diagrams, a machine learning technique was developed using uncertainty sampling, which is called as PDC (Phase Diagram Construction) package [K. Terayama et al. Phys. Rev. Mater. 3, 033802 (2019).]. In this method, the most uncertain point in the phase diagram was suggested as the next experimental condition. However, owing to recent progress in lab automation techniques and robotics, high-throughput batch experiments can be performed. To benefit from such a high-throughput nature, multiple conditions must be selected simultaneously to effectively construct a phase diagram using a machine learning technique. In this study, we consider some strategies to do so, and their performances were compared when exploring ternary isothermal sections (two-dimensional) and temperature-dependent ternary phase diagrams (three-dimensional). We show that even if the suggestions are explored several instead of one at a time, the performance did not change drastically. Thus, we conclude that PDC with multiple suggestions is suitable for high-throughput batch experiments and can be expected to play an active role in next-generation automated material development.

Recently, artificial intelligence (AI)-enabled de novo molecular generators (DNMGs) have automated molecular design based on data-driven or simulation-based property estimates. In some domains like the game of Go where AI surpassed human intelligence, humans are trying to learn from AI about the best strategy of the game. To understand DNMG’s strategy of molecule optimization, we propose an algorithm called characteristic functional group monitoring (CFGM). Given a time series of generated molecules, CFGM monitors statistically enriched functional groups in comparison to the training data. In the task of absorption wavelength maximization of pure organic molecules (consisting of H, C, N, and O), we successfully identified a strategic change from diketone and aniline derivatives to quinone derivatives. In addition, CFGM led us to a hypothesis that 1,2-quinone is an unconventional chromophore, which was verified with chemical synthesis. This study shows the possibility that human experts can learn from DNMGs to expand their ability to discover functional molecules.

Background: Inflammation is thought to be a risk factor for kidney disease. However, whether inflammatory status is either a cause or an outcome of chronic kidney disease remains controversial. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using Mendelian randomization (MR) approaches. Methods: A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IVCRP and IVAsian, based on SNPs previously identified in European and Asian populations. IVCRP and IVAsian explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Results: Using the IVCRP, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 0.000; 95% confidence interval [CI], −0.019 to 0.020 and −0.003; 95% CI, −0.019 to 0.014, respectively). For IVAsian, we found similar results using the IVW and the WM methods (estimate, 0.005; 95% CI, −0.020 to 0.010 and −0.004; 95% CI, −0.020 to 0.012, respectively). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IVCRP: −0.008; 95% CI, −0.058 to 0.042; IVAsian: 0.001; 95% CI, −0.036 to 0.036). Conclusion: Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.

Abstract Background Soft coagulation using the VIO soft coagulation system is used to treat minor lung air leaks during pulmonary resection in Japan. We previously reported that it has a similar effect as the air leak treatment with fibrin glue. We evaluated the efficacy of soft coagulation using the VIO soft coagulation system for lung air leakage during pulmonary resection. Methods Intraoperative air leaks from the interlobar lung parenchyma were observed in 42 of the 283 patients who underwent video-assisted thoracoscopic surgery lobectomy between 2016 and 2018. We retrospectively reviewed these 42 patients who were treated using the VIO soft coagulation system for air leaks. We classified the air leaks in to grades using the Macchiarini scale score and evaluated the surgical outcomes of air leak treatment. Results Air leaks from the interlobar lung parenchyma having Macchiarini scale scores 1, 2, and 3 occurred in 8, 17, and 17 patients, respectively. In all the 8 patients with score 1 air leaks (100%), the air leaks could be controlled using the VIO soft coagulation system alone, and none had delayed pneumothorax requiring intervention. Of the score 2 and 3 air leaks, 52.9% and 35.3% were controlled using the VIO soft coagulation system alone, respectively. Conclusions Macchiarini scale score 1 air leaks from the interlobar lung parenchyma could be well controlled using the VIO soft coagulation system. Therefore, soft coagulation with this system may be an alternative method for treating minor air leaks during pulmonary resection surgery.

Summary In our previous study, we serendipitously discovered that protein secretion in the methylotrophic yeast Pichia pastoris is enhanced by a mutation (V50A) in the mating factor alpha (MFα) prepro‐leader signal derived from Saccharomyces cerevisiae. In the present study, we investigated 20 single‐amino‐acid substitutions, including V50A, located within the MFα signal peptide, indicating that V50A and several single mutations alone provided significant increase in production of the secreted proteins. In addition to hydrophobicity index analysis, both an unfolded protein response (UPR) biosensor analysis and a microscopic observation showed a clear difference on the levels of UPR induction and mis‐sorting of secretory protein into vacuoles among the wild‐type and mutated MFα signal peptides. This work demonstrates the importance of avoiding entry of secretory proteins into the intracellular protein degradation pathways, an observation that is expected to contribute to the engineering of strains with increased production of recombinant secreted proteins.

Abstract Off Cape Muroto area, along the Nankai Trough in southwest Japan, is a typical area with adjacent occurrences of slow and megathrust earthquakes. High‐resolution monitoring of slow earthquakes is necessary to understand tectonic conditions. In the off Muroto area, distributed acoustic sensing (DAS) measurement, which provides high‐density strain data, has been conducted using offshore fiber‐optic cable. We observed shallow tremors, a type of slow earthquakes, using DAS measurement for the first time. The characteristics of the tremor signals recorded by DAS were longer durations than those recorded in seismographs and composed of several phases with apparent velocities of several hundreds of m/s to several km/s that are coherent only in tens of meters. By combining DAS and seismograph data, we located these tremors around a subducted seamount peak. Therefore, spatial relationship between slow earthquakes and structural characteristics is suggested. This is a pioneering study of slow earthquake observation using DAS.

A high-throughput workflow involving a streamlined genome-wide screen improves protein production in the non-conventional yeast, Komagataella phaffii, following adaptive laboratory evolution.

BackgroundThe relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk.MethodsThis study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model.ResultsThe mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (β = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (β = -0.12, 95% CI -0.22 to -0.03).ConclusionOur results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition.

Purpose Primary tumor location of colon cancer has been reported to affect the prognosis after curative resection. However, some reports suggested the impact was varied by tumor stage. This study analyzed the prognostic impact of the sidedness of colon cancer in stages II, III, and liver metastasis after curative resection using propensity-matched analysis. Methods Right-sided colon cancer was defined as a tumor located from cecum to splenic flexure, while any more distal colon cancer was defined as left-sided colon cancer. Patients who underwent curative resection at Nara Medical University hospital between 2000 and 2016 were analyzed. Results There were 110 patients with stage II, 100 patients with stage III, and 106 patients with liver metastasis. After propensity matching, 28 pairs with stage II and 32 pairs with stage III were identified. In the patients with stage II, overall survival (OS) and recurrence-free survival (RFS) were not significantly different for right- and left-sided colon cancers. In the patients with stage III, OS and RFS were significantly worse in right-sided colon cancer. In those with liver metastasis, OS of right-sided colon cancer was significantly worse than left-sided disease, while RFS was similar. Regarding metachronous liver metastasis, the difference was observed only in the patients whose primary colon cancer was stage III. In each stage, significantly higher rate of peritoneal recurrence was found in those with right-sided colon cancer. Conclusion Sidedness of colon cancer had a significant and varied prognostic impact in patients with stage II, III, and liver metastasis after curative resection.

Mitochondria-eating protein (MIEAP) is a molecule important for non-canonical mitophagy and thought to be a tumor suppressor. Our previous study found that MIEAP expression is defective in thyroid oncocytomas, irrespective of being benign or malignant, and also in non-oncocytic thyroid cancers. Thyroid oncocytomas are composed of large polygonal cells with eosinophilic cytoplasm that is rich in abnormal mitochondria. Thus, our data indicate that, together with increased mitochondrial biogenesis that compensates for the dysfunction of the mitochondria, MIEAP plays a critical role in the accumulation of mitochondria in thyroid oncocytic tumors, whereas a defective MIEAP expression alone is not sufficient for mitochondrial accumulation in non-oncocytic cancers with normal mitochondria. To clarify whether MIEAP is a tumor suppressor in the thyroids and whether MIEAP knockout (KO) alone is sufficient for the oncocytic phenotype and also to extend our effort toward canonical mitophagy (a selective autophagy), we here conducted mouse studies using genetically engineered mice. BrafCA/wt mice developed thyroid cancers 1 year after intrathyroidal injection of adenovirus expressing Cre, while cancer development was observed at 6 months in adenovirus-Cre-injected BrafCA/wt;MieapKO/KO and BrafCA/wt;Atg5flox/flox mice [where autophagy-related 5 (ATG5) is a component of autophagic machinery], although KO of either molecule alone was not sufficient for cancer development. These data demonstrate that MIEAP or ATG5 KO accelerated thyroid cancer development. However, cancers in adenovirus-Cre-injected BrafCA/wt;MieapKO/KO and BrafCA/wt;Atg5flox/flox mice were not oncocytic. In conclusion, we here show that MIEAP and ATG5 are both tumor suppressors in thyroid carcinogenesis, but as we have anticipated from our previous data, KO of either molecule does not confer the oncocytic phenotype to BRAFV600E-positive thyroid cancers. The combination of disruptive mitochondrial function and impaired mitochondrial quality control may be necessary to establish a mouse model of thyroid oncocytoma.

Abstract Background Ipsilateral recurrent laryngeal nerve paralysis is one of the rare complications during the superior mediastinal node dissection for lung cancer. However, very few reports of contralateral recurrent laryngeal nerve paralysis during the procedure are available. Case presentation Two women aged 74 and 80 years developed hoarseness after undergoing right upper lobectomy and right superior mediastinal node dissection for primary lung cancer. Postoperative laryngoscopy in the two patients confirmed left vocal cord paralysis. Conclusion Node dissection is performed in the standard procedure for right upper lobe lung cancer. At this time, care must be taken not to cause damage not only to the recurrent laryngeal nerve on the ipsilateral side but also to the recurrent laryngeal nerve on the contralateral side.

Nivolumab is a new immunological checkpoint inhibitor that blocks the interaction of programmed cell death-1 (PD-1) with its ligand, programmed death-ligand 1 (PD-L1). The efficacy of nivolumab against brain metastases from gastric cancer has remained unclear. Here, we report a case of metastatic brain tumor from gastric cancer during therapy with nivolumab. A 70-year-old man with advanced gastric cancer treated with nivolumab as 4th-line chemotherapy experienced nausea and dizziness. Magnetic resonance imaging demonstrated a 3-cm, enhancing lesion in the right cerebellar hemisphere on contrast-enhanced T1-weighted imaging. The patient underwent surgical resection of the tumor. The specimen was pathologically diagnosed as metastasis from the gastric cancer, and was immunohistochemically negative for PD-L1 and PD-1, suggesting a lack of sensitivity to nivolumab. Postoperatively, symptoms gradually improved and he could be discharged to home 3 days after surgery. If brain metastases from gastric cancer are identified as not sensitive to nivolumab therapy and are exerting mass effects, surgical resection should be selected in patients with good Karnofsky performance status.

Abstract Lateral spatial variations of weak portions at the plate boundary in subduction zones have been estimated primarily by the distribution of slow earthquakes mainly occurring around seismogenic zones. However, the detailed depth profile of weak faults remains elusive. Here, we deployed six ocean bottom seismometers in the Nankai subduction zone, Japan, to observe reflections originated from drilling vessel Chikyu ship noise (hydroacoustic P wave) that was persistently radiated from a fixed position at the sea surface, and retrieved P-to-s (Ps) reflections from multiple dipping faults near the plate boundary. The Ps amplitudes were stacked and compared according to the degrees of tidal stresses, and high amplitudes were observed at high tide (compression). A migration technique shows that the locations where velocity contrasts fluctuate were estimated at both the megasplay fault and another fault between the megasplay fault and the top of the oceanic crust. This indicates that the physical properties of these faults are altered by tidal stress. The physical-property changes are attributed to fluid connections and isolations within the faults due to tidal stress fluctuations, inducing the variation of seismic anisotropy. Such a variation was confirmed by a three-dimensional numerical simulation for wave propagation with anisotropic medium. Our observation suggests that multiple weak faults are present around the plate boundary, and the obtained changes of fault physical properties may have implications for in-depth understanding of tidal triggering of earthquakes.

Abstract A ship-based seismic survey was conducted close to a fiber-optic submarine cable, and 50 km-long distributed acoustic sensing (DAS) recordings with air-gun shots were obtained for the first time. We examine the acquired DAS dataset together with the co-located hydrophones to investigate the detection capability of underwater acoustic (hydroacoustic) signals. Here, we show the hydroacoustic signals identified by the DAS measurement characterizing in frequency-time space. The DAS measurement can be sensitive for hydroacoustic signals in a frequency range from $$10^{-1}\,\text {Hz}$$ 10 - 1 Hz to a few tens of Hz which is similar to the hydrophones. The observed phases of hydroacoustic signals are coherent within a few kilometers along the submarine cable, suggesting the DAS is suitable for applying correlation analysis using hydroacoustic signals. Although our study suggests that virtual sensor’s self-noise of the present DAS measurement is relatively high compared to the conventional in-situ hydroacoustic sensors above a few Hz, the DAS identifies the ocean microseismic background noise along the entire submarine cable except for some cable sections de-coupled from the seafloor.

Abstract Background Several severe intraoperative complications of lung cancer surgery have been reported, but the incorrect transection of the main bronchus is a very rare and serious complication. We report a surgical case of a patient with left lower lobe lung cancer invading the inferior segment of the lingula, with fused interlobar fissure and dense pleural adhesion, in which the left main bronchus was mistaken for the left lower lobe bronchus and was transected. Case presentation A 64-year-old woman with lung adenocarcinoma was referred to our hospital for surgical treatment. Chest computed tomography (CT) scan showed a 30-mm nodule with a clear border and irregular margins in the center of the anterior (S8) segment of the lower lobe of the left lung and another similar 30-mm nodule in the lateral (S9) segment of the same lobe. Metastasis within the same lobe was suspected. A thoracoscopic left lower lobectomy was scheduled for the patient. As the patient had a moderately, fused fissure, dense pleural adhesion, and suspicious tumor invasion from the left S8 segment to the left S5 segment, and the interlobar node tightly adhered to the main PA at the site of basilar artery origin of the LLL, we performed left lower lobectomy and a left S5 segmentectomy using the fissureless fissure-last technique. During surgery, the left main bronchus was mistaken for the left lower lobe bronchus and was transected. After transecting the left main bronchus, we performed a sleeve bronchoplasty to prevent pneumonectomy. Conclusions We experienced the rare and serious intraoperative complication of the incorrect transection of the main bronchus. There are few reports of this intraoperative complication, and it should not be overlooked by surgeons.

Abstract Although fluid behavior along faults has often been associated with earthquakes and hydrocarbon accumulation, few observations of active, ongoing fluid discharge along the faults exist. We conducted a dense-2D multi-channel seismic (MCS) reflection survey in Uchiura Bay off Numazu, Japan, in 2018 to obtain a high-resolution image of active faults. As a result, active faults cutting the seafloor and possibly active faults cutting reflections immediately below the seafloor have been clearly imaged on MCS profiles. The spatial variation in their displacement on the seafloor has also been quantified. The seafloor displacement of the most obvious active fault, Fault A, changes by more than 2 m within a short horizontal distance of 50 m. On one of the MCS profiles, an enigmatic wavefield (EWF) is observed within the water column above the seafloor near the faults. From careful observations of the raw field data and shot records, the EWF shows three patterns that suggest fluid flow. Based on a velocity analysis of the seawater, the velocity of the EWF zone was somewhat higher than that of its surroundings. Because the seawater velocity is a function of temperature and salinity at the same depth, the effect of temperature is generally greater than that of salinity, so that the higher velocity would suggest a higher temperature. If temperature of the fluid flow is higher than that of its surroundings, the fluid would rise with its buoyancy and spread out along the sea surface. This scenario could well explain the three EWF patterns. From the appearance and non-appearance of the most obvious EWF on adjacent seismic lines, some fluid discharge might have been occurring intermittently from the seafloor near the faults in Uchiura Bay.

PurposeThe association between metabolic syndrome (MetS) and the risk of death from cancer is still a controversial issue. The purpose of this study was to examine the associations of MetS and metabolically unhealthy obesity (MUHO) with cancer mortality in a Japanese population.MethodsWe used data from the Japan Multi-Institutional Collaborative Cohort Study. The study population consisted of 28,554 eligible subjects (14,103 men and 14,451 women) aged 35-69 years. MetS was diagnosed based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Japan Society for the Study of Obesity (JASSO), using the body mass index instead of waist circumference. The Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to MetS and its components. Additionally, the associations of obesity and the metabolic health status with cancer mortality were examined.ResultsDuring an average 6.9-year follow-up, there were 192 deaths from cancer. The presence of MetS was significantly correlated with increased total cancer mortality when the JASSO criteria were used (HR = 1.51, 95% CI 1.04-2.21), but not when the NCEP-ATP III criteria were used (HR = 1.09, 95% CI 0.78-1.53). Metabolic risk factors, elevated fasting blood glucose, and MUHO were positively associated with cancer mortality (P ConclusionMetS diagnosed using the JASSO criteria and MUHO were associated with an increased risk of total cancer mortality in the Japanese population.

Abstract Background The gender-specific characteristics of individuals at an increased risk of developing depression currently remain unclear despite a higher prevalence of depression in women than in men. This study clarified socioeconomic and lifestyle factors associated with an increased risk of subclinical depression in general Japanese men and women. Methods Study participants were residents not receiving psychiatric treatments in 300 sites throughout Japan in 2010 (1152 men, 1529 women). Multivariable-adjusted odds ratios (OR) and 95% confidence intervals (95%CIs) for socioeconomic factors and lifestyle factors were calculated using a logistic regression analysis. Results Risk of depressive tendencies was significantly higher in men who were single and living alone (OR, 3.27; 95% CI, 1.56–6.88) than those married. The risk was significantly lower in women who were not working and aged ≥ 60 years (OR, 0.39; 95% CI, 0.22–0.68) and higher in men who were not working and aged

Background: The trend of association between overweight and high serum total cholesterol (TC) among the elderly is unclear. In addition, there is little evidence of risk of underweight for high TC. Therefore, we examined the trend of association of overweight or underweight with high TC among Japanese elderly people using nationwide population-based data. Methods: Data of the National Survey on Circulatory Disorders and National Health and Nutrition Survey for 1980, 1990, 2000, and 2010 were used in the analysis. High TC was defined as 220 mg/dL and above. For participants aged ≥50 years, sex-specific odds ratios (ORs) of overweight or underweight compared with normal body mass index participants for high TC were calculated using a logistic regression model adjusted for age, smoking, drinking, exercise, food, and treatment of hyperlipidemia. Results: A total of 5,734, 4,673, 5,059, and 2,105 participants enrolled in these surveys in 1980, 1990, 2000, and 2010, respectively. Although overweight was positively and significantly associated with high TC in 1980, the association has gradually weakened since (ORs in 1980 and 2010 were 2.44; 95% confidence interval [CI], 1.83–3.24 and 0.92; 95% CI, 0.66–1.27 among men and 1.43; 95% CI, 1.18–1.72 and 1.08; 95% CI, 0.81–1.44 among women, respectively). While underweight was inversely and significantly associated with high TC in 1980, the association also gradually weakened among women (ORs in 1980 and 2010 were 0.28; 95% CI, 0.12–0.60 and 0.37; 95% CI, 0.10–1.28 among men and 0.39; 95% CI, 0.26–0.57 and 0.96; 95% CI, 0.58–1.57 among women, respectively). Conclusions: These findings provide evidence that high TC prevention efforts must expand the target to not only overweight but also to normal and underweight people.

Abstract Background Solitary adrenal metastasis from colorectal cancer is rare. Adrenal metastasis is usually detected with synchronous multiple metastases in other organs and is, therefore, considered to be unsuitable for surgical resection. The long-term outcomes of patients with solitary adrenal metastasectomy from colorectal cancer have been reported; however, the survival advantage has not been established. We herein report two cases of curative adrenal resection in patients with solitary adrenal metastasis from colorectal cancer who achieved long-term survival of > 9 years without recurrence after surgical resection. Case presentation The first case involved a 71-year-old man who underwent abdominoperineal rectal resection for rectal cancer. Preoperative CT revealed a mass in the right adrenal, which was growing after surgery. After chemotherapy the adrenal mass decreased in size, and adrenalectomy was performed at 8 months after the first surgery. A pathological examination confirmed metastasis from rectal cancer. The patient received adjuvant chemotherapy and is currently alive without recurrence at 9 years after the adrenalectomy. The second case involved a 53-year-old man who underwent sigmoidectomy for sigmoid colon cancer. Four years later, lobectomy was performed for isolated lung metastasis. Twenty months later, PET-CT revealed solitary metastasis in the left adrenal gland and adrenalectomy was performed. A histopathological examination revealed metastatic adenocarcinoma of sigmoid cancer. Postoperative chemotherapy was administered after adrenalectomy and the patient is currently alive and apparently disease-free at more than 9 years after undergoing adrenal metastasectomy. Conclusion Curative resection for solitary adrenal metastasis from colorectal cancer may be beneficial for survival.

Recent genome-wide association studies (GWAS) on the dietary habits of the Japanese population have shown that an effect rs671 allele was inversely associated with fish consumption, whereas it was directly associated with coffee consumption. Although meat is a major source of protein and fat in the diet, whether genetic factors that influence meat-eating habits in healthy populations are unknown. This study aimed to conduct a GWAS to find genetic variations that affect meat consumption in a Japanese population. We analysed GWAS data using 14 076 participants from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. We used a semi-quantitative food frequency questionnaire to estimate food intake that was validated previously. Association of the imputed variants with total meat consumption per 1000 kcal energy was performed by linear regression analysis with adjustments for age, sex, and principal component analysis components 1–10. We found that no genetic variant, including rs671, was associated with meat consumption. The previously reported single nucleotide polymorphisms that were associated with meat consumption in samples of European ancestry could not be replicated in our J-MICC data. In conclusion, significant genetic factors that affect meat consumption were not observed in a Japanese population.

Objectives: With endoscopic submucosal dissection and laparoscopic surgery, treatment for colorectal neoplasms has become minimally invasive. However, few studies have compared endoscopic submucosal dissection with laparoscopic surgery for colorectal neoplasms, excluding deeply invasive cancer on preoperative diagnosis. Methods: We retrospectively reviewed the files of patients who had undergone endoscopic submucosal dissection or laparoscopic surgery for colorectal neoplasms between November 2005 and December 2015. We limited patients who were not suspected preoperatively to have aggressive submucosal invasion >1,000 μm. Results: Ninety-five patients underwent endoscopic submucosal dissection and 37 underwent laparoscopic surgery. Cases of endoscopic submucosal dissection tended to involve rectal neoplasms more often than colonic neoplasms, shorter operative times, and shorter lengths of hospital stay compared with laparoscopic surgery. The perforation rate during colonic endoscopic submucosal dissection in the early period (November 2005 to December 2010) and late period (January 2011 to December 2015) was 14.8% and 2.9%, respectively. In all cases of perforation during colonic endoscopic submucosal dissection, the ability to maneuver the endoscope was compromised. Though tumors were larger in patients who underwent rectal endoscopic submucosal dissection compared with colonic endoscopic submucosal dissection, the perforation and postoperative bleeding rates with rectal endoscopic submucosal dissection were both 3.2%. The most common indication for laparoscopic surgery was difficulty performing endoscopic submucosal dissection. Serious complications were rare. Conclusions: For colonic neoplasms, laparoscopic surgery should be considered when endoscopic submucosal dissection is technically difficult in the early period. For rectal neoplasms, endoscopic submucosal dissection is desirable even for those of large size.

Abstract Background Anal gland carcinoma with perianal Paget’s disease is rare, and anal gland carcinoma in situ is extremely rare. No cases of anal gland carcinoma in situ with pagetoid spread have been previously reported. Case presentation Physical examination in a 75-year-old woman revealed an erythematous, inflamed, perianal skin lesion. Neither colposcopy, cystoscopy, colonoscopy, computed tomography, nor magnetic resonance imaging showed evidence of malignant genitourinary or gastrointestinal lesions. Histopathological examination of a biopsy specimen showed many Paget’s cells in the perianal skin lesion and no malignant cells in the rectal or vaginal mucosa. Therefore, primary extramammary Paget’s disease of the anogenital region was suspected, and we performed anus-preserving wide local excision. However, immunohistochemistry revealed a diagnosis of secondary extramammary Paget’s disease due to adenocarcinoma arising from the anal gland. We therefore proceeded with a radical operation. Histopathological examination showed no residual cancer cells. The final diagnosis was anal gland adenocarcinoma in situ with pagetoid spread in the perianal skin. Conclusions This is the first case report of anal gland adenocarcinoma in situ with pagetoid spread. We recommend immunohistochemical analysis of biopsy and locally resected specimens to obtain an accurate diagnosis and determine the appropriate treatment when there is no visible tumor.

The double burden of malnutrition refers to the co-occurrence of overweight and obesity and undernutrition. Eating quickly has been linked to overweight and obesity. However, no study has examined the association between eating speed and undernutrition. This retrospective, cross-sectional study analyzed data from 3529 community-dwelling residents. Eating speed was divided into three categories: fast, medium, and slow. Undernutrition was defined as body mass index (BMI) of 2 in adults aged < 70 years (adults) and as 2 in adults aged ≥ 70 years (older adults), in accordance with the Global Leadership Initiative on Malnutrition criteria for Asians. Multivariable logistic regression analysis was used to examine the association between eating speed and undernutrition. Among adult men, compared with eating quickly, eating slowly was associated with elevated prevalence of undernutrition (odds ratio (OR) 9.68, 95% confidence interval (CI) 2.32–40.51, p = 0.001). Among older adult women, the prevalence of undernutrition in the slow-eating group was higher than that in the fast-eating group (OR 3.82, 95% Cl 1.51–9.69, p = 0.005). Eating slowly is independently associated with the prevalence of undernutrition among community-dwelling adult men and older adult women in Japan.

We report a case of 59-year-old woman who has multiple lung metastases with renal cell carcinoma (RCC). She received neoadjuvant therapy using nivolumab following sunitinib. Thereafter, we performed cytoreductive nephrectomy and subsequently administered nivolumab. We also found a high expression of PD-L1 in tumor cell and infiltration of lymphocytes with CD8 expression by immunohistochemistry. A complete response was achieved 4 months after surgery. A perioperative treatment using nivolumab might be useful treatment for metastatic RCC. Keywords: Neoadjuvant, Nivolumab, Renal cell carcinoma, List of Abbreviations: CR, Complete response, CRP, C-relative protein, CT, Computed tomography, H&E, Hematoxylin and eosin, IHC, Immunohistochemistry, IHCs, Immunocheckpoint therapies, KPS, Karnofsky performance status, PD-1, Programmed death-1, PD-L1, Programmed death ligand-1, RCC, Renal cell carcinoma

An amendment to this paper has been published and can be accessed via the original article.

This review presents the latest developments in (bio)degradable approaches and functional aliphatic polyesters and polycarbonates prepared by typical ring-opening polymerization (ROP) of lactones and trimethylene carbonates. It also considers several recent innovative synthetic methods including radical ring-opening polymerization (RROP), atom transfer radical polyaddition (ATRPA), and simultaneous chain- and step-growth radical polymerization (SCSRP) that produce aliphatic polyesters. With regard to (bio)degradable approaches, we have summarized several representative cleavable linkages that make it possible to obtain cleavable polymers. In the section on functional aliphatic polyesters, we explore the syntheses of specific functional lactones, which can be performed by ring-opening copolymerization of typical lactone/lactide monomers. Last but not the least, in the recent innovative methods section, three interesting synthetic methodologies, RROP, ATRPA, and SCSRP are discussed in detail with regard to their reaction mechanisms and polymer functionalities.

Weakly coupled subduction zones may generate earthquakes that lead to tsunamis, but their structure and seismicity are poorly constrained with the Ryukyu subduction zone as one such example. Here, Arai et al. present seismological evidence from Ryukyu showing megathrust faults and low frequency earthquakes.

Background: Socioeconomic status (SES) imbalances in developed and developing countries may result in individuals being overweight and obese. However, few studies have investigated this issue in Japan. We herein examined the relationship between SES and being underweight, overweight or obese according to sex and age groups (20–64 or ≥65 years) in Japan. Methods: In 2010, we established a cohort of participants in the National Health and Nutrition Survey of Japan. We divided 2,491 participants (1,081 men and 1,410 women) according to the WHO definitions of underweight, overweight or obesity and performed multinomial logistic analyses using BMI

Background: This study examined the relationships among household income, other SES indicators, and macronutrient intake in a cross-sectional study of a representative Japanese population. Methods: In 2010, we established a cohort of participants in the National Health and Nutrition Survey (NHNS) from 300 randomly selected areas throughout Japan. A total of 2,637 participants (1,145 men and 1,492 women) were included in the study. Data from NHNS2010 and the Comprehensive Survey of Living Conditions 2010 (CSCL2010) were merged, and relationships among macronutrient intake and SES were evaluated. Additionally, socioeconomic factors associated with a risk of a higher carbohydrate/lower fat intake beyond dietary recommendations were evaluated. Results: Household income was positively associated with fat intake (P = 0.001 for men and

A low-intensity (6 W) light-emitting diode (LED) effectively activated an organotellurium chain transfer agent and the dormant species, promoting well-controlled radical polymerization. The use of the LED provided many advantages over the previously reported high-intensity Hg lamp, including high energy efficiency during the polymerization, and easy availability of the low-cost light source. Structurally well-defined poly(methyl methacrylate), poly(methyl acrylate), and polystyrene, with narrow molecular weight distributions, were synthesized under LED irradiation with or without a neutral density filter.

The long-term prognostic effect of non-specific 12-lead electrocardiogram findings is unknown. We aimed to evaluate the cumulative prognostic impact of axial, structural, and repolarization categorical abnormalities on cardiovascular death, independent from traditional risk scoring systems such as the Framingham risk score and the NIPPON DATA80 risk chart.A total of 16,816 healthy men and women from two prospective, longitudinal cohort studies were evaluated. 3,794 (22.6%) individuals died during a median follow-up of 15 years (range, 2.0-24 years). Hazard ratios for cardiovascular death, all-cause death, coronary death and stroke death were calculated for the cumulative and independent axial, structural, and repolarization categorical abnormalities adjusted for the Framingham risk score and the NIPPON DATA80 risk chart. Individuals with two or more abnormal categories had a higher risk of cardiovascular death after adjustment for Framingham risk score (men: HR 4.27, 95%CI 3.35-5.45; women: HR 4.83, 95%CI 3.76-6.22) and NIPPON DATA80 risk chart (men: HR 2.39, 95%CI 1.87-3.07; women: HR 2.04, 95%CI 1.58-2.64).Cumulative findings of axial, structural, and repolarization abnormalities are significant predictors of long-term cardiovascular death in asymptomatic, healthy individuals independent of traditional risk stratification systems.

G-protein-coupled receptors (GPCRs) are the largest group of cell-surface proteins and are major molecular targets for drug development. The protocol described herein is for the detection of human GPCR signaling in the yeast Saccharomyces cerevisiae. Using Zoanthus sp. green fluorescent protein (ZsGreen) as the reporter, engineered yeast cells expressing human GPCRs emit strong fluorescence in response to stimuli leading to receptor signal activation. This assay method would allow screening for agonistic ligands and critical mutations required for human GPCR signaling.