Search

Chronic obstructive pulmonary disease (COPD) was previously known as chronic bronchitis and emphysema. It has various main symptoms, such as dyspnea, chronic cough, and sputum, and is often accompanied by dysphagia. Although many published clinical reports have described COPD-related dysphagia, the physiological mechanisms underlying swallowing changes due to COPD remain unclear. Therefore, we analyzed how COPD affects the swallowing reflex using COPD model rats. We performed an electrophysiological study of respiration and swallowing using COPD model induced by intratracheal administration of porcine pancreatic elastase and lipopolysaccharide in Sprague-Dawley male rats. To identify the respiration and swallowing responses, electromyographic activity was recorded from the diaphragm, digastric (Dig), and thyrohyoid (TH) muscles. We confirmed COPD using micro-computed tomography analysis and hematoxylin and eosin staining of the lungs. The duty cycle was defined as the ratio of the inspiration duration to the total respiratory duration. In COPD model rats, the duty cycle was significantly higher than that in control rats. The frequency of the swallowing reflex evoked by electrical stimulation of the superior laryngeal nerve during the inspiration phase was higher in COPD model rats than in control rats. Furthermore, long-term COPD altered Dig and TH muscle activity without pathological muscle change. Our results suggest that COPD increases the frequency of swallowing initiation during the inspiration phase. Furthermore, long-term COPD affects swallowing-related muscle activity without pathological muscle changes. These physiological changes may increase the risk of developing dysphagia. Further studies are necessary to clarify the mechanisms contributing to the functional changes in respiration and swallowing in COPD.

Abstract Genome Editing is widely used in biomedical research and medicine. Zinc finger nucleases (ZFNs) are smaller in size than transcription activator‐like effector (TALE) nucleases (TALENs) and CRISPR‐Cas9. Therefore, ZFN‐encoding DNAs can be easily packaged into a viral vector with limited cargo space, such as adeno‐associated virus (AAV) vectors, for in vivo and clinical applications. ZFNs have great potential for translational research and clinical use. However, constructing functional ZFNs and improving their genome editing efficiency is extremely difficult. Here, the efficient construction of functional ZFNs and the improvement of their genome editing efficiency using AlphaFold, Coot, and Rosetta are described. Plasmids encoding ZFNs consisting of six fingers using publicly available zinc‐finger resources are assembled. Two functional ZFNs from the ten ZFNs tested are successfully obtained. Furthermore, the engineering of ZFNs using AlphaFold, Coot, or Rosetta increases the efficiency of genome editing by 5%, demonstrating the effectiveness of engineering ZFNs based on structural modeling.

Abstract Background Isopropanol (IPA) is a commodity chemical used as a solvent or raw material for polymeric products, such as plastics. Currently, IPA production depends largely on high-CO2-emission petrochemical methods that are not sustainable. Therefore, alternative low-CO2 emission methods are required. IPA bioproduction using biomass or waste gas is a promising method. Results Moorella thermoacetica, a thermophilic acetogenic microorganism, was genetically engineered to produce IPA. A metabolic pathway related to acetone reduction was selected, and acetone conversion to IPA was achieved via the heterologous expression of secondary alcohol dehydrogenase (sadh) in the thermophilic bacterium. sadh-expressing strains were combined with acetone-producing strains, to obtain an IPA-producing strain. The strain produced IPA as a major product using hexose and pentose sugars as substrates (81% mol-IPA/mol-sugar). Furthermore, IPA was produced from CO, whereas acetate was an abundant byproduct. Fermentation using syngas containing both CO and H2 resulted in higher IPA production at the specific rate of 0.03 h−1. The supply of reducing power for acetone conversion from the gaseous substrates was examined by supplementing acetone to the culture, and the continuous and rapid conversion of acetone to IPA showed a sufficient supply of NADPH for Sadh. Conclusions The successful engineering of M. thermoacetica resulted in high IPA production from sugars. M. thermoacetica metabolism showed a high capacity for acetone conversion to IPA in the gaseous substrates, indicating acetone production as the bottleneck in IPA production for further improving the strain. This study provides a platform for IPA production via the metabolic engineering of thermophilic acetogens.

Abstract Fatty acid-binding protein 7 (FABP7) is vital for uptake and trafficking of fatty acids in the nervous system. To investigate the involvement of FABP7 in noise-induced hearing loss (NIHL) pathogenesis, we used Fabp7 knockout (KO) mice generated via CRISPR/Cas9 in the C57BL/6 background. Initial auditory brainstem response (ABR) measurements were conducted at 9 weeks, followed by noise exposure at 10 weeks. Subsequent ABRs were performed 24 h later, with final measurements at 12 weeks. Inner ears were harvested 24 h after noise exposure for RNA sequencing and metabolic analyses. We found no significant differences in initial ABR measurements, but Fabp7 KO mice showed significantly lower thresholds in the final ABR measurements. Hair cell survival was also enhanced in Fabp7 KO mice. RNA sequencing revealed that genes associated with the electron transport chain were upregulated or less impaired in Fabp7 KO mice. Metabolomic analysis revealed various alterations, including decreased glutamate and aspartate in Fabp7 KO mice. In conclusion, FABP7 deficiency mitigates cochlear damage following noise exposure. This protective effect was supported by the changes in gene expression of the electron transport chain, and in several metabolites, including excitotoxic neurotransmitters. Our study highlights the potential therapeutic significance of targeting FABP7 in NIHL.

Acetogens are among the key microorganisms involved in the bioproduction of commodity chemicals from diverse carbon resources, such as biomass and waste gas. Thermophilic acetogens are particularly attractive because fermentation at higher temperatures offers multiple advantages. However, the main target product is acetic acid. Therefore, it is necessary to reshape metabolism using genetic engineering to produce the desired chemicals with varied carbon lengths. Although such metabolic engineering has been hampered by the difficulty involved in genetic modification, a model thermophilic acetogen, M. thermoacetica ATCC 39073, is the case with a few successful cases of C2 and C3 compound production, other than acetate. This brief report attempts to expand the product spectrum to include C4 compounds by using strain Y72 of Moorella thermoacetica. Strain Y72 is a strain related to the type strain ATCC 39073 and has been reported to have a less stringent restriction-modification system, which could alleviate the cumbersome transformation process. A simplified procedure successfully introduced a key enzyme for acetoin (a C4 chemical) production, and the resulting strains produced acetoin from sugars and gaseous substrates. The culture profile revealed varied acetoin yields depending on the type of substrate and culture conditions, implying the need for further engineering in the future. Thus, the use of a user-friendly chassis could benefit the genetic engineering of M. thermoacetica.

Abstract Recently, prediction of gestational diabetes mellitus (GDM) using artificial intelligence (AI) from medical records has been reported. We aimed to evaluate GDM-predictive AI-based models using birth cohort data with a wide range of information and to explore factors contributing to GDM development. This investigation was conducted as a part of the Japan Environment and Children's Study. In total, 82,698 pregnant mothers who provided data on lifestyle, anthropometry, and socioeconomic status before pregnancy and the first trimester were included in the study. We employed machine learning methods as AI algorithms, such as random forest (RF), gradient boosting decision tree (GBDT), and support vector machine (SVM), along with logistic regression (LR) as a reference. GBDT displayed the highest accuracy, followed by LR, RF, and SVM. Exploratory analysis of the JECS data revealed that health-related quality of life in early pregnancy and maternal birthweight, which were rarely reported to be associated with GDM, were found along with variables that were reported to be associated with GDM. The results of decision tree-based algorithms, such as GBDT, have shown high accuracy, interpretability, and superiority for predicting GDM using birth cohort data.

Melanin is produced by melanocytes to protect human skin from harmful ultraviolet radiation. During skin cell renewal, melanin and dead skin cells are disposed of. However, prolonged exposure to ultraviolet rays or aging can disturb this cycle, leading to skin hyperpigmentation due to melanin accumulation. Tyrosinase is a crucial enzyme involved in melanin biosynthesis. Although various compounds, including tyrosine inhibitors, that counteract melanin accumulation have been reported, some, such as hydroquinone, are toxic and can cause vitiligo. Meanwhile, the skin is the largest organ and the outermost layer of the immune system, containing a diverse range of bacteria that produce low-toxicity compounds. In the current study, we aim to identify metabolites produced by skin microbiota that inhibit tyrosinase. Specifically, mushroom tyrosinase served as the study model. Following commensal skin bacteria screening, Corynebacterium tuberculostearicum was found to inhibit tyrosinase activity. The active compound was cyclo(l-Pro-l-Tyr); commercially available cyclo(l-Pro-l-Tyr) also exhibited inhibitory activity. Docking simulations suggested that cyclo(l-Pro-l-Tyr) binds to the substrate-binding site of mushroom tyrosinase, obstructing the substrate pocket and preventing its activity. Hence, cyclo(l-Pro-l-Tyr) might have potential applications as a cosmetic agent and food additive.

Abstract Future climate projections suggest a poleward shift of the maximum intensity of tropical cyclones (TCs) over the western North Pacific. However, the global nature of the latitudinal change in TC genesis under global warming remains poorly understood. We show, using large‐ensemble high‐resolution atmospheric model simulations (d4PDF) with four warming scenarios, that the poleward shift is a robust change over the globe, attributable to the weakening of the Hadley circulation. The weakened ascent driven by the upper‐tropospheric warming suppresses the TC genesis within 5°–20° latitudes, whereas the weakened descent enhances the TC genesis in the poleward latitudes. We further estimate the poleward shift of TC genesis to emerge at the 2 K global warming over the Arabian Sea, South Atlantic and Pacific Oceans and at the 4 K warming over the North Pacific. The present results underscore the potential for increasing social and economic risks associated with TCs at higher latitudes.

Antimicrobial-product package inserts and insufficient staffing impede routine carbapenem monitoring in the inpatient setting in Japan. The collaboration between antimicrobial stewardship teams and clinical pharmacists was associated with a sustained improvement in carbapenem dosing optimization. Our findings could be of use to countries with inadequate monitoring of carbapenem antimicrobial use.

Abstract The Pacific Walker circulation (PWC) weakens under global warming in climate change projections, supported by a global hydrological constraint. However, the PWC has strengthened over the past decades despite ongoing global warming, and the cause has been a puzzle. Because PWC is coupled with the pattern of sea surface temperature (SST) in the tropical Pacific, quantifying the relative impact of SST pattern change and global warming on the past PWC trend is important. We show, using an atmosphere model driven by observed boundary conditions for 1979–2013 and a hypothetical uniform surface warming trend with varying magnitude, that the PWC scales with warming and weakens by 8% per °C, but this effect cannot overcome the SST pattern effect that intensifies the circulation. Further attribution experiments show that the past strengthening of PWC is explained directly by the SST warming pattern in the narrow equatorial band, about 30% of which is induced by the Indian Ocean.

Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R–PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways.

Abstract In the equatorial and subtropical east Pacific Ocean, strong ocean‐atmosphere coupling results in large‐amplitude interannual variability. Recent literature debates whether climate models reproduce observed short and long‐term surface temperature trends in this region. We reconcile the debate by reevaluating a large range of trends in initial condition ensembles of 15 climate models. We confirm that models fail to reproduce long‐term trends, but also find that many models do not reproduce the observed decadal‐scale swings in the East to West gradient of the equatorial Pacific. Models with high climate sensitivity are less likely to reproduce observed decadal‐scale swings than models with a modest climate sensitivity, possibly due to an incorrect balance of cloud feedbacks driven by changing inversion strength versus surface warming. Our findings suggest that two not well understood problems of the current generation of climate models are connected and we highlight the need to increase understanding of decadal‐scale variability.

Abstract La Niña persisted from 2020 to 2023, but its mechanisms are still unclear. In this study, atmosphere and ocean reanalysis and 100‐member initialized forecasts using a state‐of‐the‐art climate model were analyzed to identify factors contributing to the persistence of the first‐ to second‐year La Niña during 2020–2022. We found that North Pacific high pressure anomalies in the winter of 2020/2021 forced a negative phase of the Pacific meridional mode through the following spring, forming the broader structure of La Niña. The resultant broader La Niña pattern slowed down the recharge‐discharge process by Ekman transport, persisting La Niña. Ensemble forecast sensitivity analysis revealed that the meridional extent of La Niña explains its forecast spread, reaffirming the importance of La Niña spatial pattern. Advancing predictive understanding of 2020–2022 multi‐year La Niña can help to improve the extended seasonal forecast.

In the construction work, flat plates for building materials are transported by a suspension mechanism using wires in air flow. Then, a flutter could be caused to the suspended plates due to the interaction between plate motion and fluid flow. The violent vibration due to flutter loses the efficiency and safety of the operation. To improve the efficiency and safety of the operation, a detailed understanding of the flutter characteristics is crucial. In this paper, the flutter analysis and experiments of a flat plate suspended by wires in air flow are carried out. In the flutter analysis, the Doublet-point method based on the unsteady lifting surface theory is used to calculate the unsteady fluid force acting on the plate surface. The equation of motion of the plate suspended by wires considering restoring force due to gravity is derived based on the Lagrange equation. The flat plate is modeled as a rigid body. The flutter velocity and frequency are examined through the root locus of the characteristic equation of the system with changing the flow velocity. Moreover, wind - tunnel experiments are conducted to verify the analytical results. The influence of a suspending angle on the flutter velocity, frequency and mode are investigated in detail. Finally, the work done by the fluid force acting on the plate surface is examined.

Mannosylerythritol lipids (MELs) are extracellular glycolipids produced by the basidiomycetous yeast strains. MELs consist of the disaccharide mannosylerythritol, which is acylated with fatty acids and acetylated at the mannose moiety. In the MEL biosynthesis pathway, an acyltransferase from Pseudozyma tsukubaensis, PtMAC2p, a known excellent MEL producer, has been identified to catalyze the acyl-transfer of fatty acid to the C3′-hydroxyl group of mono-acylated MEL; however, its structure remains unclear. Here, we performed X-ray crystallography of recombinant PtMAC2p produced in Escherichia coli and homogeneously purified it with catalytic activity in vitro. The crystal structure of PtMAC2p was determined by single-wavelength anomalous dispersion using iodide ions. The crystal structure shows that PtMAC2p possesses a large putative catalytic tunnel at the center of the molecule. The structural comparison demonstrated that PtMAC2p is homologous to BAHD acyltransferases, although its amino acid-sequence identity was low (

Astrocytoma and oligodendroglioma are primary brain tumors classified as gliomas. Because there is difference in the prognostic significance of the extent of resection between IDH-mutant astrocytoma and oligodendroglioma, intraoperative differential diagnosis between them provides important information for optimal extent of resection. Although the characteristics of genetic mutations and chromosomal aberrations in both tumors have been reported, there is no molecular diagnostic methods that is able to be used quickly and simply for differentiate the two tumors. Therefore, we aimed to search for biomarker candidates for differentiating them with metabolome analysis using liquid chromatography/tandem mass spectrometry and develop a molecular diagnostic method based on quantitative analysis. We searched for peaks that differed in two types of gliomas using global metabolomics. Next, we identified five biomarker candidates as hypoxanthine, inosine, cystine, proline and uric acid, respectively. Next, we developed an LC/MS/MS analytical method for five biomarker candidates and quantified them in brain tumors. Cystine had significantly lower amounts in astrocytomas than in oligodendrogliomas. We developed two prediction models for differentiation of the two gliomas and validated them using the separated two dataset. The logistic regression model with only cystine provided the best prediction performance. It was suggested that mass spectrometric analysis of cystine in surgery might be useful for differentiating astrocytoma and oligodendroglioma with 91.7% positive prediction value and 80.0% specificity whereas negative predictive value and sensitivity was lesser than 70%, so that further exploration for unknown metabolite is mandatory.

Tropical cyclones (TCs), commonly called cyclones in the southern Indian Ocean (SIO), represent one of the most devastating disasters in the oceanfront regions of Africa. The present study explores the long-term tendency of annual mean TC genesis location in the SIO. A notable westward shift is detected in the SIO TC genesis longitude since 1979, which is linked to an increase in the TC genesis frequency in the southwestern SIO and a decrease in the TC genesis frequency in the northeastern SIO. The dipole trend pattern of the TC genesis frequency in the SIO is intimately linked to the weakening of the westerly vertical wind shear over the western SIO and the strengthening of the easterly vertical wind shear over the eastern SIO, resulting from a reduced meridional temperature gradient. The weakened meridional temperature gradient is attributed to the enhanced warming of the subtropical troposphere that is a response of atmospheric temperature to global warming. Our study implies a potential increase in the risks faced by coastal and island countries in eastern Africa.

A fetal growth restriction is related to adverse child outcomes. We investigated risk ratios and population-attributable fractions (PAF) of small-for-gestational-age (SGA) infants in the Japanese population. Among 28,838 infants from five ongoing prospective birth cohort studies under the Japan Birth Cohort Consortium, two-stage individual-participant data meta-analyses were conducted to calculate risk ratios and PAFs for SGA in advanced maternal age, pre-pregnancy underweight, and smoking and alcohol consumption during pregnancy. Risk ratio was calculated using modified Poisson analyses with robust variance and PAF was calculated in each cohort, following common analyses protocols. Then, results from each cohort study were combined by meta-analyses using random-effects models to obtain the overall estimate for the Japanese population. In this meta-analysis, an increased risk (risk ratio, [95% confidence interval of SGA]) was significantly associated with pre-pregnancy underweight (1.72 [1.42–2.09]), gestational weight gain (1.95 [1.61–2.38]), and continued smoking during pregnancy (1.59 [1.01–2.50]). PAF of underweight, inadequate gestational weight gain, and continued smoking during pregnancy was 10.0% [4.6–15.1%], 31.4% [22.1–39.6%], and 3.2% [−4.8–10.5%], respectively. In conclusion, maternal weight status was a major contributor to SGA births in Japan. Improving maternal weight status should be prioritized to prevent fetal growth restriction.

Abstract We investigated umbilical cord serum microRNA (miRNA) profiles to identify biomarkers of a risk for obesity later in life. Participating children were divided into high‐ and low‐risk groups of obesity based on the timing of adiposity rebound and the body mass index (BMI) at 5 years and randomly selected from each group for this study. 3D‐Gene® Human miRNA Oligo Chip was performed using cord serum in five children of both groups. The most relevant miRNAs were confirmed in 33 children of the groups using the TaqMan® microRNA assay. We detected five cord serum miRNAs differentially expressed in children at high risk of obesity compared with the levels in children at low risk, namely, miR‐516‐3p and miR‐130a‐3p with increased levels and miR‐1260b, miR‐4709‐3p, and miR194‐3p with decreased levels. This study provides the first identification of altered umbilical cord serum miRNAs in childhood obesity.

Climate model simulations show that for 1970-2017 externally-forced sea surface temperature increases in the Gulf Stream explain up to 56% of the sea-ice decline in the Barents-Kara Sea during winter via poleward oceanic heat transport.

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder with progressive neurodegeneration. Although the causative genes were previously identified, NPC has unclear pathophysiological aspects, and patients with NPC present various symptoms and onset ages. However, various novel biomarkers and metabolic alterations have been investigated; at present, few comprehensive proteomic alterations have been reported in relation to NPC. In this study, we aimed to elucidate proteomic alterations in NPC and perform a global proteomics analysis for NPC model cells. First, we developed two NPC cell models by knocking out NPC1 using CRISPR/Cas9 (KO1 and KO2). Second, we performed a label-free (LF) global proteomics analysis. Using the LF approach, more than 300 proteins, defined as differentially expressed proteins (DEPs), changed in the KO1 and/or KO2 cells, while the two models shared 35 DEPs. As a bioinformatics analysis, the construction of a protein–protein interaction (PPI) network and an enrichment analysis showed that common characteristic pathways such as ferroptosis and mitophagy were identified in the two model cells. There are few reports of the involvement of NPC in ferroptosis, and this study presents ferroptosis as an altered pathway in NPC. On the other hand, many other pathways and DEPs were previously suggested to be associated with NPC, supporting the link between the proteome analyzed here and NPC. Therapeutic research based on these results is expected in the future.

Arctic warming amplification is intensified in a low-emission scenario after the mid-2040s, compared to a high-emission scenario, because of a continuing ice-albedo feedback, according to 50-member ensemble simulations with a climate model.

IntroductionA subdecadal (i.e. , three-year running mean) variation over the tropical Pacific is very distinctively observed in the 2000s.Results and methodsHere, we have demonstrated that sea surface temperature (SST) anomalies in the tropical Atlantic contribute to forming high ocean-temperature anomalies in the tropical Pacific in the early 2000s by performing partial data assimilation of a global climate model. Low SSTs over the equatorial Atlantic change the Walker circulation, and the associated weakening of the Pacific trade winds raises the equatorial SST on subdecadal timescales. At the same time, a high SST anomaly is also generated in the off-equatorial North Pacific through deepening of the upper ocean thermocline due to an accompanying anticyclonic surface wind anomaly aloft. While the subtropical North Atlantic SSTs may help the subdecadal warming in the equatorial Pacific, the resultant SST anomalies show a one-year delay in the phase transition and are modestly accompanied by ocean thermocline deepening.DiscussionIt roughly follows the IMRaD format.

Changes in intracellular calcium concentrations regulate heart beats. However, the decline in the left ventricular pressure during early diastole is much sharper than that of the Ca2+ transient, resulting in a rapid supply of blood to the left ventricle during the diastole. At the tissue level, cardiac muscles have a distinct characteristic, known as stretch activation, similar to the function of insect flight muscles. Stretch activation, which is a delayed increase in force following a rapid muscle length increase, has been thought to be related to autonomous control in these muscles. In this numerical simulation study, we introduced a molecular mechanism of stretch activation and investigated the role of this mechanism in the pumping function of the heart, using the previously developed coupling multiple-step active stiffness integration scheme for a Monte Carlo (MC) cross-bridge model and a bi-ventricular finite element model. In the MC cross-bridge model, we introduced a mechanism for trapping the myosin molecule in its post-power stroke state. We then determined the rate constants of transitions for trapping and escaping in a thermodynamically consistent manner. Based on our numerical analysis, we draw the following conclusions regarding the stretch activation mechanism: (i) the delayed force becomes larger than the original isometric force because the population of trapped myosin molecules and their average force increase after stretching; (ii) the delayed force has a duration of more than a few seconds owing to a fairly small rate constant of escape from the trapped state. For the role of stretch activation in heart pumping, we draw the following conclusions: (iii) for the regions in which the contraction force decreases earlier than the neighboring region in the end-systole phase, the trapped myosin molecules prevent further lengthening of the myocytes, which then prevents further shortening of neighboring myocytes; (iv) as a result, the contraction forces are sustained longer, resulting in a larger blood ejection, and their degeneration is synchronized.

Abstract El Niño-Southern Oscillation (ENSO), characterized by anomalous sea surface temperature in the central-eastern equatorial Pacific, is a dominant interannual variability, impacting worldwide weather and socioeconomics. The ENSO cycle contains irregularity, in which La Niña often persists for more than two years, called “multi-year La Niña”. Observational records show that multi-year La Niña tends to accompany strong El Niño in the preceding year, but their physical linkage remains unclear. Here we show using reanalysis data that a strong El Niño excites atmospheric conditions that favor the generation of multi-year La Niña in subsequent years. Easterly wind anomalies along the northern off-equatorial Pacific during the decay phase of the strong El Niño are found crucial as they act to discharge ocean heat content (OHC) via an anomalous northward Ekman transport. The negative OHC anomaly is large enough to be restored by a single La Niña and, therefore, causes another La Niña to occur in the second year. Furthermore, analyses of the Coupled Model Intercomparison Project Phase 6 (CMIP6) climate models support the abovementioned mechanisms and indicate that the occurrence frequencies of multi-year La Niña and strong El Niño are highly correlated.

It still remains unclear how the suprahyoid muscles function in bolus formation during mastication. This study aimed to investigate the contributory role of the suprahyoid muscles during mastication. A total of 20 healthy young volunteers were asked to perform tongue pressure generation tasks and unilateral mastication tasks using peanuts and two different types of rice crackers. Surface electromyographic (EMG) activity of the masseter and suprahyoid muscles and mandibular kinematics were recorded. Suprahyoid activity increased with increasing tongue pressure. Masticatory duration until the first deglutition differed significantly among the different foods; the harder the food, the longer the duration. This was also the case in masseter activity per masticatory cycle. Masticatory rate and suprahyoid activity per masticatory cycle were significantly higher during soft rice cracker mastication. Masseter activity was higher on the masticatory side than on the non-masticatory side, however, there was no difference in suprahyoid activity between the sides. Suprahyoid activity and jaw gape showed significant positive correlation in the early stage on both the masticatory and non-masticatory sides. The suprahyoid muscles functioned dominantly for jaw-opening during peanut mastication, and for bolus formation, especially in the late stage during soft rice cracker mastication. Bolus formation was performed dominantly on the masticatory side during rice cracker mastication. These findings clearly demonstrate a functional role of the suprahyoid muscles during mastication of solid foods from assessments using both EMG activity and mandibular kinematic recordings.

The increase in non-vaccine serotypes of Streptococcus pneumoniae and their multidrug resistance have become an issue following the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). In this study, we investigated the serotypes and drug resistance of S. pneumoniae detected in adult and pediatric outpatients at a hospital in a rural area of Japan between April 2012 and December 2016. Serotypes of the bacterium were identified using the capsular swelling test and multiplex polymerase chain reaction testing of DNA extracted from the specimens. Antimicrobial susceptibility was determined using the broth microdilution method. The serotype 15A was classified using multilocus sequence typing. The results showed that the prevalence of non-vaccine serotypes increased significantly in children from 50.0% in 2012–2013 to 74.1% in 2016 (p ≤ 0.006) and in adults from 15.8% in 2012–2013 to 61.5% in 2016 (p ≤ 0.026), but no increase in drug-resistant isolates was evident. However, an increase in the drug-resistant serotypes 15A and 35B was observed in children. Although isolates of these two serotypes showed cefotaxime susceptibility, cefotaxime resistance was confirmed for the serotype 15A isolates. Future trends in the spread of these isolates should be monitored with caution.

Long-range predictions of the Asian summer monsoon remain challenging due to its complex atmosphere–land–ocean interactions. Here, the authors show that a large ensemble of model simulations can predict the Asian summer monsoon and associated summer tropical cyclone activity more than one year ahead.

Abstract Gastric stump cancer (GSC) has distinct clinicopathological characteristics from primary gastric cancer. However, the detailed molecular and pathological characteristics of GSC remain to be clarified because of its rarity. In this study, a set of tissue microarrays from 89 GSC patients was analysed by immunohistochemistry and in situ hybridisation. Programmed death ligand 1 (PD-L1) was expressed in 98.9% of tumour-infiltrating immune cells (TIICs) and 6.7% of tumour cells (TCs). Epstein–Barr virus (EBV) was detected in 18 patients (20.2%). Overexpression of human epidermal growth factor receptor 2 and deficiency of mismatch repair (MMR) protein expression were observed in 5.6% and 1.1% of cases, respectively. Moreover, we used next-generation sequencing to determine the gene mutation profiles of a subset of the 50 most recent patients. The most frequently mutated genes were TP53 (42.0%) followed by SMAD4 (18.0%) and PTEN (16.0%), all of which are tumour suppressor genes. A high frequency of PD-L1 expression in TIICs and a high EBV infection rate suggest immune checkpoint inhibitors for treatment of GSC despite a relatively low frequency of deficient MMR gene expression. Other molecular characteristics such as PTEN and SMAD4 mutations might be considered to develop new treatment strategies.

Abstract In extreme event attribution, which aims to answer whether and to what extent a particular extreme weather event can be attributed to global warming, the probability of an event is generally estimated through large ensemble simulations, using an atmospheric general circulation model (AGCM). In islands, such as Japan, it has been considered that surface air temperature (SAT) can be significantly affected by the surrounding sea surface temperature (SST), which mostly is affected by atmospheric circulation at mid- and high-latitudes. Therefore, the absence of SST responses to atmospheric variability in AGCMs impacts the estimation of the occurrence of extreme events, such as heat waves in Japan. In this study, we examined the impact of air–sea coupling on the probability of occurrence of severe heat waves that occurred in Japan in the summer of 2010 by analyzing the probability differences obtained from AGCM and coupled general circulation model (CGCM) large-ensemble experiments. The observed ocean temperature, salinity, and sea ice were assimilated in the 100-member CGCM experiments, as they were assigned as boundary conditions in the 100-member AGCM experiments. The SAT around Japan in the northern summer is largely related to the Bonin high, whose interannual variability is largely affected by the Silk Road and Pacific-Japan (PJ) pattern teleconnections in the real world. The SAT anomaly over Japan was related to the pressure variability due to the Silk Road and PJ patterns in the CGCM experiment. By contrast, the SAT over Japan simulated by AGCM was less sensitive to such pressure variability, and the SAT ensemble spread became narrower in AGCM. The results suggest that the probability of occurrence of the 2010 heat wave in Japan would tend to be underestimated by the AGCM ensemble compared to the CGCM ensemble, provided that the ensemble averages of the SAT anomalies were equal between CGCM and AGCM experiments. This study raised the issue of the absence of SST response to atmospheric variability in AGCMs, which can critically impact the estimation of extreme event probability, particularly in mid-latitude islands, such as Japan.

Octacalcium phosphate (OCP) has received considerable attention in the field of ceramic biomaterials as an advanced functional material. It exhibits a layered structure composed of apatitic and hydrated layers and can incorporate various dicarboxylate ions into the hydrated layer. Saturated dicarboxylic acids (HOOC(CH2)nCOOH) with an odd number of methylene groups (–CH2–) exhibit lower incorporation fractions than those with an even number of methylene groups, possibly owing to a compositional dependence on the synthetic method. In this study, calcium carbonate, phosphoric acid, and various amounts of glutaric acid were used to produce glutarate-ion-incorporated OCP by a wet chemical method, which is different from the conventional synthetic strategy. While utilising 1–20 mmol of glutaric acid during synthesis did not produce the desired product, using 25 mmol of glutaric acid resulted in the formation of single-phase glutarate-ion-incorporated OCP with a Ca/P molar ratio of 1.57 and a 90% incorporation fraction of glutarate ions. This glutarate-ion-incorporation fraction is significantly higher than that reported in the previous studies (35%). Thus, the synthetic procedure proposed herein was able to produce single-phase OCP containing glutarate ions with a high incorporation fraction. Our findings can contribute to development of novel functional ceramic biomaterials in the future.

Xylanase B, a member of subfamily 7 of the GH30 (glycoside hydrolase family 30) from Talaromyces cellulolyticus (TcXyn30B), is a bifunctional enzyme with glucuronoxylanase and xylobiohydrolase activities. In the present study, crystal structures of the native enzyme and the enzyme–product complex of TcXyn30B expressed in Pichia pastoris were determined at resolutions of 1.60 and 1.65 Å, respectively. The enzyme complexed with 22‐(4‐O‐methyl‐α‐d‐glucuronyl)‐xylobiose (U4m2X) revealed that TcXyn30B strictly recognizes both the C‐6 carboxyl group and the 4‐O‐methyl group of the 4‐O‐methyl‐α‐d‐glucuronyl side chain by the conserved residues in GH30‐7 endoxylanases. The crystal structure and site‐directed mutagenesis indicated that Asn‐93 on the β2‐α2‐loop interacts with the non‐reducing end of the xylose residue at subsite‐2 and is likely to be involved in xylobiohydrolase activity. These findings provide structural insight into the mechanisms of substrate recognition of GH30‐7 glucuronoxylanase and xylobiohydrolase.

Abstract Aims/Introduction Gut microbiota have various effects on human health. Some previous reports have shown that gut microbiota change during pregnancy and affect metabolism, but others have shown that microbiota do not change. Here, we examined the gut microbiota and glycoalbumin levels of 45 healthy Japanese women during pregnancy. Materials and Methods We carried out 16S rRNA gene sequencing analyses of maternal stool samples and compared the gut microbiota composition of samples from women in early and late pregnancy. We also examined the association between gut microbiota and maternal characteristics, including glycoalbumin. Results Microbiota composition in early and late pregnancy did not differ, according to principal coordinate analysis of weighted and unweighted UniFrac distances. Shannon indices were not different between early and late pregnancy. The proportion of one phylum, TM7, significantly decreased in late pregnancy compared with early pregnancy, but the proportions of other major phyla did not change. The Shannon index of late pregnancy was negatively associated with pregestational body mass index and positively correlated with glycoalbumin level, with adjustment of covariates. Conclusions We concluded that Japanese women did not show obvious differences in gut microbiota during pregnancy, except for TM7, and that the diversity of gut microbiota might affect maternal metabolism. As this study had limited statistical power, further large‐scale studies are required.

Long and heavy cables need to be laid during the construction of plant. The present-day cable installation system drives the cables through by power assistance in order to reduce physical stress on the workers. However, the system cannot pull a long and heavy cable sequentially at the desired timing of the tension triggered onto the cable head by the worker. To solve this problem, we propose a multihop wireless controlled system that works to push the cable at a time set by instruction packets delivered according to the applied tension. This paper explains the design and adoption of a multihop wireless controlled sensor and actuator network into the cable installation system. Keywords: Cable installation, Wireless network, Multihop communication, Sensor, Actuator

Pneumorrhachis refers to the clinical presentation of air within the spinal canal, and it is rarely associated with pneumomediastinum, particularly in young children. Pneumorrhachis associated with pneumomediastinum is generally asymptomatic. Here we report 2 unusual cases involving very young children with pneumorrhachis secondary to pneumomediastinum and present a review of the relevant literature. Case 1 involved a 4-year-old girl who presented with wheezing, violent coughing, and dyspnea associated with bronchiolitis. Case 2 involved a 3-year-old boy who presented with wheezing, violent coughing, and dyspnea associated with interstitial pneumonia possibly caused by graft-versus-host disease with human herpesvirus 6 infection after allogeneic hematopoietic stem cell transplantation. In both cases, pneumorrhachis improved with oxygen inhalation therapy and treatment of the underlying disease. Pneumorrhachis is rarely associated with neurological problems; however, decompressive laminectomy may be indicated to relieve the air block. Because pneumorrhachis is rare in children and neurological sequelae may be difficult to identify, close clinical, and radiographic observations are necessary. Plain radiography is not sufficient, and computed tomography should be performed to rule out intraspinal air. Keywords: Pneumorrhachis, Pneumomediastinum, Children

Human parainfluenza virus type 1 (hPIV1) and 3 (hPIV3) cause seasonal epidemics, but little is known about their interaction with human airway cells. In this study, we determined cytopathology, replication, and progeny virion release from human airway cells during long-term infection in vitro. Both viruses readily established persistent infection without causing significant cytopathic effects. However, assembly and release of hPIV1 rapidly declined in sharp contrast to hPIV3 due to impaired viral ribonucleocapsid (vRNP) trafficking and virus assembly. Transcriptomic analysis revealed that both viruses induced similar levels of type I and III IFNs. However, hPIV1 induced specific ISGs stronger than hPIV3, such as MX2, which bound to hPIV1 vRNPs in infected cells. In addition, hPIV1 but not hPIV3 suppressed genes involved in lipid biogenesis and hPIV1 infection resulted in ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. Consequently, formation of cholesterol-rich lipid rafts was impaired in hPIV1 infected cells. These results indicate that hPIV1 is capable of regulating cholesterol biogenesis, which likely together with ISGs contributes to establishment of a quiescent infection.

In a multiscale simulation of a beating heart, the very large difference in the time scales between rapid stochastic conformational changes of contractile proteins and deterministic macroscopic outcomes, such as the ventricular pressure and volume, have hampered the implementation of an efficient coupling algorithm for the two scales. Furthermore, the consideration of dynamic changes of muscle stiffness caused by the cross-bridge activity of motor proteins have not been well established in continuum mechanics. To overcome these issues, we propose a multiple time step scheme called the multiple step active stiffness integration scheme (MusAsi) for the coupling of Monte Carlo (MC) multiple steps and an implicit finite element (FE) time integration step. The method focuses on the active tension stiffness matrix, where the active tension derivatives concerning the current displacements in the FE model are correctly integrated into the total stiffness matrix to avoid instability. A sensitivity analysis of the number of samples used in the MC model and the combination of time step sizes confirmed the accuracy and robustness of MusAsi, and we concluded that the combination of a 1.25 ms FE time step and 0.005 ms MC multiple steps using a few hundred motor proteins in each finite element was appropriate in the tradeoff between accuracy and computational time. Furthermore, for a biventricular FE model consisting of 45,000 tetrahedral elements, one heartbeat could be computed within 1.5 h using 320 cores of a conventional parallel computer system. These results support the practicality of MusAsi for uses in both the basic research of the relationship between molecular mechanisms and cardiac outputs, and clinical applications of perioperative prediction.

This paper presents a novel technique of an active control to suppress sheet flutter. In this technique, sheet flutter is actively and non-contactly suppressed by injection and suction air flows through a nozzle. A nozzle is combined with a speaker as an actuator, and this device is drove in a sheet displacement feedback system. PET sheet is used as a controlled object, and the sheet is supported upper end in a wind tunnel. To show the effectiveness of this technique for sheet flutter suppression, the suppression characteristics are experimentally examined. Then, the suppression effectiveness is evaluated at the increased rate of the flutter velocity with control as compared to it without control. Moreover, air flow patterns around the nozzle and the sheet during control are visualized by the smoke wire method. Lastly, the control effects by injection and suction air flows to the sheet are examined in terms of air flow patterns, frequency response characteristics, and unsteady pressure. As a result, this paper shows the effectiveness of the proposed device and technique for sheet flutter suppression, and the flutter velocity is increased by 50 % with control as compared to without control. In this technique, the injection and suction air flows from the nozzle change the airflow around the sheet, not directly apply momentum on the sheet. Therefore, this technique is an air flow control.

This study presents a dynamic stability analysis of the self-excited vibration of a plate supported by air pressure. In the analysis, the unsteady fluid force acting on the plate surface is calculated based on the theory of two-dimensional leakage flow. The model built in the dynamic stability analysis applies iterative calculation using a numerical solution to determine the floating displacement of the plate, its steady state, and the pressure and rate of air that flow through the bottom of the plate. This model demonstrates the dynamic stability of the plate when it vibrates close to the steady state. In addition, the local work done by the unsteady fluid force acting on the plate (bottom surface) is calculated, and the region on which the excitation fluid force acts is examined. Furthermore, the fluid force acting on the plate is separated into factors such as compressibility and viscosity. This is necessary for analyzing the effect of the work done by the fluid force derived from these factors on the dynamic stability of the system. The results reveal a critical factor for the occurrence of self-excited vibration; additionally, the detailed instability mechanism of the self-excited vibration is discussed.

Abstract Aims/Introduction We aimed to explore novel predictive markers for gestational diabetes mellitus using metabolomic analysis in pregnant Japanese women. Materials and Methods We carried out a case–control study with a cohort of participants enrolled during the first or early second trimester in the Center of Chiba Unit of the Japan Environment and Children's Study. Participants were classified as either gestational diabetes mellitus cases or matched controls based on age, body mass index and parity. Metabolite levels of their serum and urine obtained randomly before the diagnosis of gestational diabetes mellitus were analyzed using hydrophilic interaction chromatography tandem mass spectrometry. Orthogonal projections to latent structures discriminant analysis was carried out to investigate metabolome profiles for the different groups. Metabolites with a variable importance in projection value of >1.5 were identified as potential markers. Results In total, 242 participants were enrolled in the study, of which 121 were cases. The R2X, R2Y and Q2 parameters for the discrimination ability of the resulting models were 0.388, 0.492 and 0.45 for serum, and 0.454, 0.674 and 0.483 for urine, respectively. We finally identified three metabolites in serum and 20 in urine as potential biomarkers. Glutamine in serum and ethanolamine and 1,3‐diphosphoglycerate in urine showed >0.8 area under the receiver operating characteristic curves. Conclusions The present study identified serum and urine metabolites that are possible predictive markers of subsequent gestational diabetes mellitus in Japanese women. Further studies are required to elucidate their efficacy.

Background: Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins—chemicals present at relatively high levels in green and oolong teas—on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. Methods: Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children’s Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self-administered food frequency questionnaire that was previously evaluated in Japanese populations. Results: The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. Conclusions: Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution.

Abstract The present paper presents results of seasonal‐to‐decadal climate predictions based on a coupled climate model called the Model for Interdisciplinary Research on Climate version 6 (MIROC6) contributing to the Coupled Model Intercomparison Project Phase 6 (CMIP6). MIROC6 is initialized every year for 1960–2018 by assimilating observed ocean temperature and salinity anomalies and full fields of sea ice concentration and by prescribing atmospheric initial states from reanalysis data. The impacts of updating the system on prediction skill are then evaluated by comparing hindcast experiments between the MIROC6 prediction system and a previous system based on MIROC version 5 (MIROC5). Skill of seasonal prediction is overall improved in association with representation and initialization of El Niño/Southern Oscillation (ENSO), the Quasi‐Biennial Oscillation (QBO), and the Northern Hemisphere sea ice concentration in MIROC6. In particular, the QBO is skillfully predicted up to 3 years ahead with a maximum anomaly correlation exceeding r = 0.8. The prediction skill for the North Atlantic Oscillation in winter is also enhanced, but the prediction still suffers from model's inherent errors. On decadal timescales, MIROC6 has a larger fraction of areas of the globe with better surface temperature skill at all lead times than MIROC5, and it has predictive skill in the annual‐mean sea surface temperature (SST) in the North Atlantic and the Pacific. In particular, MIROC6 hindcasts at 2–5 years lead time are able to capture the spatial structure of SST changes in the North Pacific and the eastern tropical Pacific associated with the 1970s regime shift better than MIROC5 hindcasts.

This paper describes vibration characteristics of a cantilevered flexible sheet under the periodic aerodynamic excitation. In the experiment, movable plates(exciter) are set at the upstream side from the sheet in a wind-tunnel. Moreover, a theoretical model for calculation of a frequency response (amplitude ratio between the movable plate and sheet) subjected to aerodynamic excitation by the movable plate is developed. Fluid force acting on the sheet surface is calculated by the Doublet-point Method based on the unsteady lifting surface theory. Finally, the local work done by the fluid force acting on the sheet surface under aerodynamic excitation is determined theoretically and the region in which the exciting fluid force acts is clarified.

Cryptococcus is a mycosis founded in immunocompromised patients. Cryptococcus in the oral cavity is rare and skeletal infection is uncommon.We report the case of a 31-year-old man in whom cellulitis developed due to infection after tooth extraction complicated by acute myeloid leukemia (AML). Cellulitis of the left mandible did not improve after conservative therapy, including antimicrobial therapy, because of AML and chemotherapy, and gas was generated in the left cervical and supraclavicular regions. We considered the infection symptoms to be life-threatening, and surgery was performed for the infection of the head and neck under poor general conditions. As histopathological examination of the removed tissue revealed cryptococcus, antifungal agents were administered for cryptococcal infection. The surgical site healed after the operation.Surgical treatment, including debridement and drainage, should be avoided for patients with a poor general condition caused by AML and chemotherapy. However, the detection of Cryptococcus in the surgical site in such a condition is important. Keywords: Cryptococcus, Acute myeloid leukemia, Skeletal infection

Background: The prenatal maternal microbiome, including the gut microbiota, has been suggested to influence the incidence of allergies in offspring. Moreover, epidermal barrier dysfunction in early infancy has been attributed to the development of subsequent allergies. We hypothesized that the prenatal microbiome may affect the gut microbiota, acting as an initial trigger to alter immune development in the foetus. The maternal microbial composition may be linked to the prevalence of dermatitis in early infancy (DEI) of the offspring, leading to subsequent allergic symptoms. Methods: This study was conducted as part of the Chiba Study of Mother and Child Health (C-MACH) birth cohort that was initiated in 2013; 434 healthy pregnant women at

Brown adipose tissue (BAT) plays an important role in regulation of energy expenditure while adapting to a cold environment. BAT thermogenesis depends on uncoupling protein 1 (UCP1), which is expressed in the inner mitochondrial membranes of BAT. Gene expression profiles induced by cold exposure in BAT have been studied, but the metabolomic biological pathway that contributes to the activation of thermogenesis in BAT remains unclear. In this study, we comprehensively compared the relative levels of metabolites between the BAT of rats kept at room temperature (22 °C) and of those exposed to a cold temperature (4 °C) for 48 h using capillary electrophoresis (CE) time-of-flight mass spectrometry (TOFMS) and liquid chromatography (LC)-TOFMS. We identified 218 metabolites (137 cations and 81 anions) by CE-TOFMS and detected 81 metabolites (47 positive and 34 negative) by LC-TOFMS in BAT. We found that cold exposure highly influenced the BAT metabolome. We showed that the cold environment lead to lower levels of glycolysis and gluconeogenesis intermediates and higher levels of the tricarboxylic acid (TCA) cycle metabolites, fatty acids, and acyl-carnitine metabolites than control conditions in the BAT of rats. These results indicate that glycolysis and β-oxidation of fatty acids in BAT are positive biological pathways that contribute to the activation of thermogenesis by cold exposure, thereby facilitating the generation of heat by UCP1. These data provide useful information for understanding the basal metabolic functions of BAT thermogenesis in rats in response to cold exposure. Keywords: Brown adipose tissue, Metabolomics, Cold exposure

Chemokine (C-C motif) ligand 17 (CCL17) is a pro-allergic factor: high CCL17 levels in cord blood (CB) precede later allergic predisposition. Short-chain fatty acid (SCFA) treatment during pregnancy has been shown to protect mouse pups against allergic diseases. The maternal microbial metabolome during pregnancy may affect fetal allergic immune responses. We therefore examined the associations between CB CCL17 and gut SCFA levels in healthy pregnant Japanese women. CB CCL17 serum levels at birth, and maternal non-specific IgE levels in maternal sera at 32 weeks of gestation were measured. Maternal stool samples were collected at 12 (n = 59) and 32 (n = 58) weeks of gestation for gut microbiota analysis, based on barcoded 16S rRNA sequencing and metabolite levels. The CB CCL17 levels correlated negatively with butyrate concentrations and positively with isobutyrate at 12 weeks; CB CCL17 correlated positively with valerate and lactate at 32 weeks. Similarly, butyrate levels correlated negatively with maternal non-specific IgE levels, whereas the lactate concentration correlated positively with IgE levels. At 32 weeks, the Shannon diversity index (SDI) of Firmicutes and Proteobacteria correlated negatively with CB CCL17 levels, while those of the total microbiota correlated positively with the CB CCL17 levels. These metabolites may alter fetal immune responses. This study provides the first link between maternal metabolites during pregnancy and the risk of allergic diseases in human offspring.