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Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

The Panamanian golden frog (Atelopus zeteki) is a critically endangered species and currently is believed to survive and reproduce only in human care. Panamanian golden frog males are considerably vocal which may be an important component in their successful reproduction, though little is currently known about their calls. To better understand the behavior and vocal patterns of this species and to improve breeding efforts in the assurance colony, we employed individual sound recording of male advertisement calls and acoustic monitoring of a breeding colony to investigate variation in the vocal behavior of Panamanian golden frogs. The goal was to capture variability within and among frogs as well as patterns of periodicity over time. First, the advertisement calls from individual male Panamanian golden frogs were recorded, and acoustic parameters were analyzed for individual differences. Results suggest that male advertisement calls demonstrate individual- and population specificity. Second, data collected through a year-long acoustic monitoring of the breeding colony were investigated for circadian and circannual periodicity. Male vocal activity revealed a circadian periodicity entrained by the daily light schedule. Seasonal periodicity was also found with highest vocal activities between December and March. The finding of a seasonal periodicity is worth noting given that the population had been bred for 20 years under constant environmental conditions. Finally, results suggest that vocal activity was responsive to daily animal care activity. Vocal activity decreased substantially when personnel entered the room and engaged in animal husbandry activities. The findings illustrate the usefulness of acoustic monitoring to provide insight into animal behavior in a zoo setting in a key breeding colony of endangered animals, and calling pattern observations may be utilized to modify husbandry practices to improve Panamanian golden frog breeding success and general care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zigler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The influx of intestinal bacteria-derived lipopolysaccharide (LPS) into the blood has attracted attention as a cause of diseases. The aim of this study is investigating the associations between the influx of LPS, dietary factors, gut microbiota, and health status in the general adult population. Food/nutrient intake, gut microbiota, health status and plasma LPS-binding protein (LBP; LPS exposure indicator) were measured in 896 residents (58.1% female, mean age 54.7 years) of the rural Iwaki district of Japan, and each correlation was analyzed. As the results, plasma LBP concentration correlated with physical (right/left arms' muscle mass [ β = -0.02, -0.03]), renal (plasma renin activity [ β = 0.27], urine albumin creatinine ratio [ β = 0.50]), adrenal cortical (cortisol [ β = 0.14]), and thyroid function (free thyroxine [ β = 0.05]), iron metabolism (serum iron [ β = -0.14]), and markers of lifestyle-related diseases (all Q s < 0.20). Plasma LBP concentration were mainly negatively correlated with vegetables/their nutrients intake (all βs ≤ -0.004, Q s < 0.20). Plasma LBP concentration was positively correlated with the proportion of Prevotella ( β = 0.32), Megamonas ( β = 0.56), and Streptococcus ( β = 0.65); and negatively correlated with Roseburia ( β = -0.57) (all Q s < 0.20). Dietary factors correlated with plasma LBP concentration correlated with positively (all β s ≥ 0.07) or negatively (all β s ≤ -0.07) the proportion of these bacteria (all Q s < 0.20). Our results suggested that plasma LBP concentration in the Japanese general adult population was associated with various health issues, and that dietary habit was associated with plasma LBP concentration in relation to the intestinal bacteria.

Upon food digestion, the gut microbiota plays a pivotal role in energy metabolism, thus affecting the development of type 2 diabetes (DM). We aimed to examine the influence of the composition of selected nutrients consumed on the association between the gut microbiota and DM. This cross-sectional study of a general population was conducted on 1019 Japanese volunteers. Compared with non-diabetic subjects, diabetic subjects had larger proportions of the genera Bifidobacterium and Streptococcus but smaller proportions of the genera Roseburia and Blautia in their gut microbiotas. The genera Streptococcus and Roseburia were positively correlated with the amounts of energy ( p = 0.027) and carbohydrate and fiber ( p = 0.007 and p = 0.010, respectively) consumed, respectively. In contrast, the genera Bifidobacterium and Blautia were not correlated with any of the selected nutrients consumed. Cluster analyses of these four genera revealed that the Blautia -dominant cluster was most negatively associated with DM, whereas the Bifidobacterium -dominant cluster was positively associated with DM (vs. the Blautia -dominant cluster; odds ratio 3.97, 95% confidence interval 1.68-9.35). These results indicate the possible involvement of nutrient factors in the association between the gut microbiota and DM. Furthermore, independent of nutrient factors, having a Bifidobacterium -dominant gut microbiota may be a risk factor for DM compared to having a Blautia -dominant gut microbiota in a general Japanese population.

Introduction: We are trying to create a platform for social innovation to extend life span., Methods: Since 2005, health data (approximately 3000 items per person as of 2020) of approximately 1000 adults have been collected each year during the Iwaki Health Promotion Project. The industry, government, academia, and citizens have involvements in data collection, aiming to build a platform that encourages societal innovation and subsequently extends life expectancy in Aomori. The Iwaki Health Promotion Project has been supported financially by the Japanese government since it was selected as the Center of Innovation program in 2013., Results: Since the numbers of academia, industries, governments, and citizens involved in the Iwaki Health Promotion Project increased over the years, the big data produced during the project has become increasingly pluripotent and adaptable. It has been used to promote public health, which has also created a stronger partnership among companies and research organizations. Consequently, the amount of data collected from the project has gained attention and became more open to companies and researchers participating in the Iwaki Health Promotion Project, resulted in establishing a larger platform. It also led to the acquisition of external funding, publications of numerous research papers, creation of new health examinations, and the establishment of the Health Promotion Center (an institution for cultivating health volunteers)., Conclusion: The Iwaki Health Promotion Project aims not only to produce a pluripotent big data but also to improve the average life expectancy of Aomori by creating a large platform in the society. Its positive impact in the future is infinite and will keep growing as long as it is maintained by the society., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Objectives: Retinol and β-carotene have been reported to be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, clinical studies are limited. The aim of this study was to investigate the relationship between serum the ratio of β-carotene to retinol (SC/SR) and hepatic steatosis in NAFLD diagnosed by ultrasonography., Methods: The participants were 606 Japanese adults who were enrolled in a health survey. Clinical profile, dietary nutrition intake, blood biochemistry, serum retinol, and carotenoids were analyzed. NAFLD was defined as fatty liver on ultrasonography in the absence of other causes of steatosis., Results: Women had higher daily intake of α- and β-carotene, although there were no differences in daily retinol and carotenoid intake between participants with or without NAFLD in both men and women. Women had a higher SC/SR ratio than men regardless of the presence or absence of NAFLD, and the SC/SR ratio in women decreased with exacerbation of hepatic steatosis, whereas the SC/SR ratio in men did not change despite exacerbation of hepatic steatosis. After adjusting for confounding factors, the likelihood of NAFLD among participants in the highest quartile of SC/SR ratio decreased by two-thirds compared with participants in the lowest quartile (adjusted odds ratio, 0.64; 95% confidence interval, 0.21-1.92; P = 0.041). The SC/SR ratio was positively correlated with serum high-density lipoprotein cholesterol level, and negatively correlated with serum triacylglycerol level., Conclusions: The SC/SR ratio was lower in NAFLD with sex differences, and was associated with the severity of hepatic steatosis and lipid profile. Future studies are needed to expand on these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since type 2 diabetes (DM) is a life-style related disease, life-style should be considered when association between genetic factors and DM are examined. However, most studies did not examine genetic associations in consideration with lifestyle. Glucagon-like peptide-1 (GLP-1) receptor (GLP1R) mediates the insulinotropic action of GLP-1 in β-cells. We here examined the association while taking into consideration of interactions between the gene polymorphism and various nutrient factors. Participants from the population-based Iwaki study of Japanese subjects held in 2014-2017 with information on nutritional intake evaluated by self-administered dietary history questionnaire, and GLP1R genotype (rs3765467: A/G), were included (n = 1,560). Although not significant, insulin secretion indices assessed by homeostasis model assessment of β-cell function (HOMA-β) in subjects with the GG genotype tended to be lower than in those with the AA+AG genotypes in most groups stratified into tertiles based on daily nutrient consumptions (high, middle, and low). Stratification also showed that the GG genotype was a significant risk for decreased insulin secretion (HOMA-β ≤ 30) even after adjustment for multiple factors (age, body mass index, alcohol consumption), but only in the highest tertiles of energy, protein and carbohydrate consumption in men [odds ratios (95% confidence interval) 3.95 (1.03-15.1), 15.83 (1.58-158.9), and 4.23 (1.10-11.2), respectively]. A polymorphism of the GLP1R gene was associated with decreased insulin secretion in a nutrient consumption-dependent manner in Japanese men, indicating an interaction between GLP1R and nutritional factors in the pathophysiology of DM.

Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk of type 2 diabetes (DM), therefore, early diagnosis of NAFLD is important to prevent incident DM. FIB-4 index, a biomarker, often used to evaluate severity of NAFLD, may be useful to evaluate risk for incident DM in ordinary clinical setting. Here, we determined the association of FIB-4 index with changes in indices representing glucose metabolism with aging in a non-diabetic population. From among the participants of the population-based Iwaki study of Japanese people conducted during 2014-2017, 1,268 non-diabetic individuals with complete data sets (age: 51.4 ± 15.9 years; men/women: 485/773) were enrolled in a cross-sectional study. In addition, of the participants, 439 who attended consecutive appointments between 2014 and 2017 were enrolled in a longitudinal study that aimed to evaluate the changes in insulin secretion and resistance with aging (age: 53.1 ± 13.7 years; men/women: 178/261). The cross-sectional study showed significant correlations of FIB-4 index with homeostasis model of assessment (HOMA) indices, even after adjustment for multiple factors (HOMA-β: β =  - 0.254, p < 0.001; HOMA-R: β =  - 0.247, p < 0.001). The longitudinal study showed a significant association between FIB-4 index and the change in HOMA-β (p < 0.001) but not HOMA-R (p = 0.639) during the 3-year study period. Use of the optimal cut-off value of the FIB-4 index for the prediction of decreased insulin secretion (HOMA-β < 30), determined using receiver operating characteristic analysis (1.592), showed that individuals at risk had a hazard ratio of 2.22 (confidence interval 1.17-4.06) for decreased insulin secretion, after adjustment for confounders. FIB-4 index may represent a useful predictor of a subsequent decrease in insulin secretion, at least in a non-diabetic Japanese population.

Single nucleotide polymorphisms in mitochondrial DNA, such as mitochondrial 1555 A>G (m.1555 A>G) and mitochondrial 1494 C>T (m.1494 C>T), are known to be causative mutations of nonsyndromic hearing loss following exposure to aminoglycoside antibiotics. The prevalence of the m.1555 A>G and m.1494 C>T mutations has not been reported for the general population in Japan. The purpose of this study was to investigate the prevalence of m.1555 A>G and m.1494 C>T mutations in a community-dwelling population in Japan in order to prevent aminoglycoside-induced hearing loss. We recruited participants older than 20 years of age to the Iwaki Health Promotion Project in 2014, 2015, and 2016, resulting in the recruitment of 1,683 participants. For each participant, we performed a hearing test and a genetic test for the m.1555 A>G and m.1494 C>T mutations using the TaqMan genotyping method. The m.1555 A>G mutation was detected in only 1 of the 1,683 participants (0.06%). This carrier of the m.1555 A>G mutation was a 69-year-old male with bilateral, symmetric, and high-frequency hearing loss. We provided genetic counseling and distributed a drug card advising him to avoid the administration of aminoglycoside antibiotics. In contrast, the m.1494 C>T mutation was not detected in this study population., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Several studies have demonstrated that carotenoid-rich vegetables are useful against cardiovascular diseases (CVDs). However, it is still unclear when a healthy population should start eating these vegetables to prevent CVDs. In this study, we evaluated the role of carotenoids in CVD markers in healthy subjects using age-stratified analysis. We selected 1350 subjects with no history of apparent illness who were undergoing health examinations. We then evaluated the relationship between the serum concentrations of six major carotenoids as well as their total, and nine CVD markers (i.e., body mass index (BMI), pulse wave velocity (PWV), systolic blood pressure (SBP), diastolic blood pressure (DBP), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), blood insulin, fasting blood glucose (FBG), triglycerides (TGs), and high-density lipoprotein (HDL) cholesterol) using multiple regression analysis. It was found that the total carotenoid level was significantly associated with seven markers other than BMI and FBG in males and with eight markers other than DBP in females. Many of these relationships were independent of lifestyle habits. Many significant relationships were found in young males (aged 20-39) and middle-aged females (aged 40-59). These findings can be used as lifestyle guidance for disease prevention although the causal relationships should be confirmed.

To confirm the usefulness of noninvasive measurements of skin carotenoids to indicate vegetable intake and to elucidate relationships between skin carotenoid levels and biomarkers of circulatory diseases and metabolic syndrome, we conducted a cross-sectional study on a resident-based health checkup ( n = 811; 58% women; 49.5 ± 15.1 years). Skin and serum carotenoid levels were measured via reflectance spectroscopy and high-performance liquid chromatography, respectively. Vegetable intake was estimated using a dietary questionnaire. Levels of 9 biomarkers (body mass index [BMI], brachial-ankle pulse wave velocity [baPWV], systolic and diastolic blood pressure [SBP and DBP], homeostasis model assessment as an index of insulin resistance [HOMA-IR], blood insulin, fasting blood glucose [FBG], triglycerides [TGs], and high-density lipoprotein cholesterol [HDL-C]) were determined. Skin carotenoid levels were significantly positively correlated with serum total carotenoids and vegetable intake ( r = 0.678 and 0.210, respectively). In women, higher skin carotenoid levels were significantly associated with lower BMI, SBP, DBP, HOMA-IR, blood insulin, and TGs levels and higher HDL-C levels. In men, it was also significantly correlated with BMI and blood insulin levels. In conclusion, dermal carotenoid level may indicate vegetable intake, and the higher level of dermal carotenoids are associated with a lower risk of circulatory diseases and metabolic syndrome.

Aims/Introduction: Chronic kidney disease (CKD)-mineral and bone disorders (CKD-MBD) are an adverse outcome derived from decreases in kidney function, where abnormality of serum concentrations of calcium (Ca), phosphorus, parathyroid hormone (PTH), and vitamin D can be seen simultaneously. To identify individuals at risk for CKD-MBD or secondary hyperparathyroidism, the relationships between estimated glomerular filtration rate (eGFR) and serum PTH concentration were evaluated, allowing for confounding factors, in particular vitamin D status, in a general Japanese population. Materials and Methods: Nine-hundred-and-thirty participants in the population-based Iwaki study conducted in 2016 who were not on drugs affecting mineral metabolism nor hemodialysis, were included in the study (326 men and 604 women; age: 55.4 ± 15.9 years). Results: Regression analysis showed a significant correlation between eGFR and serum intact PTH concentration, after adjustment for possible confounding factors (β = -0.122, p < 0.001). The smoothed spline curve applied for the correlation analysis revealed a biphasic correlation, with a division at an eGFR of ~60 mL/min/1.73 m 2 , below which the correlation coefficient was higher (β = -0.405, p < 0.001). Stratification on the basis of vitamin D status showed that the correlation was present only in participants with vitamin D deficiency (25-dihydroxyvitamin D3: <15 pg/mL) (β = -0.154, p < 0.001). Conclusions: These results indicate that a reduction in eGFR is a significant risk factor for an increase in serum PTH concentration when it is <60 mL/min/1.73 m 2 and vitamin D is deficient, in the general Japanese population., (Copyright © 2020 Daimon, Fujita, Murabayashi, Mizushiri, Murakami, Nishiya, Tanabe, Matsuhashi, Yanagimachi, Tokuda, Sawada and Ihara.)

This study aimed (1) to assess serum trace elements concentrations and hematological parameters, (2) to evaluate the sex differences in the associations between serum trace elements levels and hematological parameters, and (3) to identify the associations between serum trace elements concentrations and risk of anemia among Japanese community dwellers. This is a community-based cross-sectional study that utilized the data of the 2014 Iwaki Health Promotion Project. Participants were 1176 community dwellers (>18 years) residing in the Iwaki District, Aomori Prefecture, Japan. We assessed the data of serum trace elements concentrations of cadmium (Cd), cobalt (Co), copper (Cu), selenium (Se), zinc (Zn), and iron (Fe) as well as the hematological parameters of red blood cells (RBC) counts, hemoglobin, packed cells volume (PCV), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH). Serum concentrations of Zn (871.5 μg/L vs. 900.1 μg/L) and Fe (946.8 μg/L vs. 1096.1 μg/L) were significantly lower in females than in males, while serum concentrations of Co (0.4 μg/L vs. 0.3 μg/L) and Cu (1062.4 μg/L vs. 965.3 μg/L) were significantly higher in females. By multivariate linear regression, serum Se concentration was significantly, positively associated with PCV (β = 1.04; 95% confidence interval (CI): 0.17, 1.92; p = 0.016) among the study participants. Serum Zn also had positive associations with hemoglobin (β = 0.42; 95% CI: 0.07, 0.77; p = 0.020), PCV (β = 1.79; 95% CI: 0.78, 2.81; p < 0.001), and RBCs count (β = 15.56; 95% CI: 7.31, 31.69; p = 0.002). On the other hand, serum Co concentration was negatively associated with the hematological parameters, particularly in females. Moreover, serum Zn concentration had a decreased risk of anemia (lowest vs. highest quartiles: odds ratio (OR) = 0.42; 95% CI: 0.23, 0.76; p = 0.005) while higher Co concentrations had an increased risk of anemia (lowest vs. highest quartiles: OR = 1.95; 95% CI: 1.04, 3.67; p = 0.037). However, no significant association was found between serum Cu level and hematological parameters. There were substantial sex differences in serum trace elements, implying that trace elements metabolism differed between males and females. Zn can play a protective role in the development of anemia. Surprisingly, increased Co concentration increased the risk of anemia among our study population, which called for further studies to confirm and to consider for speciation analysis.

Background : The oral microbiome, which consists of various habitats, has been shown to be influenced by smoking. However, differences in the tongue microbiomes of current and former smokers, as well as their resultant functional consequences, have rarely been investigated in East Asian populations. Methods : We used 16S rRNA amplicon sequencing of tongue-coating samples obtained from East Asian subjects who were current, former, or never smokers to identify differences in their tongue microbiomes and related metagenomic functions. Two sets of participants from 2016 to 2017 (n = 657 and n = 187, respectively) were analyzed separately. Results : We found significant differences between the overall microbiome compositions of current versus never smokers (p = 0.0015), but not between former versus never smokers (p = 0.43) based on the weighted UniFrac distance. Twenty-nine of 43 investigated genera showed significantly different expression levels in current versus never smokers. Neisseria and Capnocytophaga were less abundant, and Streptococcus and Megasphaera were more abundant in current smokers. Moreover, the abundances of metagenomic pathways, including those related to nitrate reduction and the tricarboxylic acid cycle, were significantly different between current and never smokers. Conclusions : The tongue microbiomes and related metagenomic pathways of current smokers differ from those of never smokers among East Asians., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Cigarette smoking affects the oral microbiome, which is related to various systemic diseases. While studies that investigated the relationship between smoking and the oral microbiome by 16S rRNA amplicon sequencing have been performed, investigations involving metagenomic sequences are rare. We investigated the bacterial species composition in the tongue microbiome, as well as single-nucleotide variant (SNV) profiles and gene content of these species, in never and current smokers by utilizing metagenomic sequences. Among 234 never smokers and 52 current smokers, beta diversity, as assessed by weighted UniFrac measure, differed between never and current smokers (pseudo-F = 8.44, R 2  = 0.028, p = 0.001). Among the 26 species that had sufficient coverage, the SNV profiles of Actinomyces graevenitzii, Megasphaera micronuciformis, Rothia mucilaginosa, Veillonella dispar, and one Veillonella sp. were significantly different between never and current smokers. Analysis of gene and pathway content revealed that genes related to the lipopolysaccharide biosynthesis pathway in Veillonella dispar were present more frequently in current smokers. We found that species-level tongue microbiome differed between never and current smokers, and 5 species from never and current smokers likely harbor different strains, as suggested by the difference in SNV frequency.

High visceral fat area (VFA) is a stronger predictor of cardiovascular disease and overall mortality, compared with body mass index (BMI) and waist circumference (WC). Recent reports demonstrate that obesity is related to breath gas, which is produced by the intestinal microflora. However, these studies define obesity using BMI, not VFA. In this population-based cross-sectional study, we investigated the relationship between breath gases (methane and hydrogen) and both VFA and BMI. A total of 1033 participants (62% women; age [mean ± standard deviation] 54.4 ± 14.9 years) in the 2015 Iwaki Health Promotion Project in Japan were enrolled in the study. Breath samples were collected using a breath bag and analyzed by gas chromatography. VFA was measured using a visceral fat meter. The proportion of methanogenic bacteria to total intestinal microbiota was measured by polymerase chain reaction and 16S rRNA gene sequencing analysis. Our analysis revealed a significant association between high VFA and low breath methane, even after adjusting for confounding factors (B = -0.024 and P = 0.004). To identify the association between breath methane and VFA in participants with methane-producing bacteria in their intestinal microflora, participants were divided into two groups based on the presence or absence of methanogenic bacteria in their stool. The Methanogen + group was further divided into two subgroups with breath methane higher (Methane-UP) or lower (Methane-LO) than the median breath methane concentration. VFA was significantly lower in the Methane-UP group than in the Methane-LO group. In participants with methanogenic bacteria, breath methane concentration might be an independent biomarker of visceral fat accumulation.

Since activation of the sympathetic nervous system is associated with both impaired insulin secretion and insulin resistance, or namely with diabetes, evaluation of such activation in ordinary clinical settings may be important. Therefore, we evaluated the relationships between urinary concentrations of the catecholamine metabolites, urinary normetanephrine (U-NM) and urinary metanephrine (U-M), and glucose metabolism in a general population. From 1,148 participants in the 2016 population-based Iwaki study of Japanese, enrolled were 733 individuals (gender (M/F): 320/413; age: 52.1±15.1), who were not on medication affecting serum catecholamines, not diabetic, and had complete data-set and blood glucose levels appropriate for the evaluation of insulin secretion and resistance, using homeostasis model assessment (HOMA-β and HOMA-R, respectively). Univariate linear regression analyses revealed significant correlations between both U-NM and U-M, and HOMA-β, but adjustment for multiple factors correlated with HOMA indices abolished these (β = -0.031, p = 0.499, and β = -0.055, p = 0.135, respectively). However, the correlation between U-NM and HOMA-R observed using univariate linear regression analysis (β = 0.132, p<0.001) remained significant even after these adjustments (β = 0.107, p = 0.007), whereas U-M did not correlate with HOMA-R. Furthermore, use of the optimal cut-off value of U-NM for the prediction of insulin resistance (HOMA-R >1.6) determined by ROC analysis (0.2577 mg/gCr) showed that individuals at risk had an odds ratio of 2.65 (confidence interval: 1.42-4.97) after adjustment for the same factors used above. Higher U-NM concentrations within the physiologic range are a significant risk factor for increased insulin resistance in a general Japanese population., Competing Interests: The authors have declared that no competing interests exist.

Dysphonia is often caused by level difference between left and right vocal folds, which are positioned on different angles with respect to the transverse plane, resulting in angular asymmetry. Unilateral vocal fold paralysis may cause such angular asymmetry. In this case, the normal vocal fold is located on the transverse plane, whereas the paralyzed vocal fold is rotated in the sagittal plane as its posterior edge is moved up to the superior direction. The effect of such angular asymmetry (up to 25°) between the left and right vocal fold on the auto-oscillation is experimentally studied using mechanical replicas. For all replicas, it is observed that, as full contact between vocal folds is lost, increase of angular asymmetry results in a decrease of the signal-to-noise ratio, an increase of the total harmonic distortion rate, and an increase of the oscillation threshold pressure. These general tendencies are in agreement with clinical findings reported for vertical level difference during phonation. In analogy to the preceding experimental study in which vocal folds are spaced in parallel with a vertical trade-off, a formula is proposed to describe the oscillation threshold as a function of angular asymmetry.

: High visceral fat area (VFA) is a stronger predictor of cardiovascular disease and overall mortality than body mass index or waist circumference. VFA may be decreased by proper dietary habits. Although previous epidemiologic studies demonstrated an association between nutritional components or foodstuffs and VFA, only the associations of a few nutrients, such as dietary fiber and calcium, are reported. We performed a comprehensive 2-year longitudinal study in more than 624 healthy people and analyzed 33 micronutrients to investigate nutrients that contribute to changes in visceral fat. Our analyses revealed that "macronutrients" and "micronutrients" were "mutual confounders". Therefore, when evaluating the association between VFA and micronutrients, associations were adjusted by macronutrients. The ingestion of 7 nutrients: soluble dietary fiber, manganese, potassium, magnesium, vitamin K, folic acid, and pantothenic acid, which are abundant components in vegetable diets, was significantly inversely correlated with a change in VFA. Additionally, a change in the ingestion of one nutrient, monounsaturated fat, was significantly positively correlated with a change in VFA. These associations were independent of body mass index and waist circumference. Thus, a predominantly vegetable diet may decrease VFA. In addition, adjusting the intake of macronutrients might help to clarify the association of micronutrients with VFA., Competing Interests: The authors declare no conflict of interest. N.O., S.S., T.Y., M.K., and Y.K. are employees of the Kao Corporation.

The gut microbiota is reported to be related to obesity, and visceral fat is reported to be strongly associated with cardiovascular disease and overall mortality. However, the association between the gut microbiota and obesity has mainly been studied using body mass index (BMI) as a proxy for obesity. We investigated the relationship of both visceral fat and BMI with the gut microbiota stratified by sex in a population-based cross-sectional study of Japanese men and women 20-76 years of age ( n  = 1001). Women with a higher visceral fat area (VFA) harboured a higher relative abundance of the Firmicutes phylum ( P for trend <0.001) and a lower relative abundance of the Bacteroidetes phylum ( P for trend 0.030), whereas men with higher VFA harboured a lower relative abundance of the Firmicutes phylum ( P for trend 0.076) and a higher relative abundance of the Bacteroidetes phylum ( P for trend 0.013). Similar results were obtained using BMI as an index, but the differences were not significant in men. At the genus level, Blautia was the only gut microbe significantly and inversely associated with VFA regardless of sex. In conclusion, at the genus level we found that Blautia was the only gut microbe significantly and inversely associated with VFA, regardless of sex., Competing Interests: Competing interestsAuthors N.O., S.S., T.Y., M.K., and Y.K. were employed by Kao Corporation (Tokyo, Japan). All other authors declare no competing interests. There are no patents, products in development or marketed products to declare., (© The Author(s) 2019.)

Although there are several diagnostic criteria for left ventricular hypertrophy (LVH), their sensitivity remains low. A recent study reported that the sum of the amplitude of the deepest S wave in any lead (SD) and the S wave in lead V4 (SV4) (SD + SV4) improved sensitivity compared with commonly used criteria. To test whether this new formula improves sensitivity in the Japanese general population, we analyzed 12-lead electrocardiograms for Japanese residents participating in the Iwaki Health Promotion Project (n = 866). Left ventricular mass was calculated by echocardiography, indicating that 156 (18%) of the study population had LVH. In receiver operating characteristic analyses, the sum of the R wave in limb lead Ι (RLΙ) and the S wave in V4 (SV4) (RLΙ + SV4) showed a higher area under the curve (AUC = 0.76) than the Sokolow-Lyon voltage criteria (0.61) and the SD + SV4 criteria (0.63), and almost the same AUC as the Cornell voltage criteria (0.74) and the Cornell product criteria (0.76). The validation study also showed similar results. The cutoff values of RLΙ + SV4 criteria were ≥1.6 mV in men and ≥1.4 mV in women with a sensitivity of 39% and a specificity of 89%, whereas the sensitivity and specificity calculated based on SD + SV4 criteria were 21% and 94%, respectively. Thus, the diagnostic criterion of RLΙ + SV4 seems to be more useful than the previous criteria for diagnosing LVH in the Japanese general population.

Almost all organisms maintain a circadian clock from birth to death to synchronize their own physiology and behavior with the earth's rotation. However, extensive studies based on animal experiments have showed that aging results in circadian dysfunction. Human studies have also indicated age-associated abnormal phase, reduced amplitude and enhanced fragmentation in circadian physiology and behavior, thereby strongly implying age-related dysfunction of the clock machinery. Here, we carried out functional assessment of the circadian clock machinery in elderly patients aged 83-94 with severe dementia who showed abnormal circadian behavior. To investigate whether or not the systemic pathway from the circadian input to peripheral clocks functioned normally, the circadian phase in peripheral clock gene expression rhythms was evaluated using plucked hair tissues. Unexpectedly, the phase in all volunteer patients was within a range similar to that of healthy subjects. The circadian pathway from external inputs to peripheral clocks may therefore function normally, even in the old-old with severe dementia., (© 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Association between serum calcium (Ca) levels and kidney dysfunction progression in a non-chronic kidney disease (CKD) population has not been well elucidated, especially in consideration for classical metabolic risk conditions such as hypertension, dyslipidemia, and diabetes, and those related to Ca metabolism. Among participants of the population-based Iwaki study of Japanese people, those with an estimated glomerular filtration rate (eGFR) ≧60 ml/min/1.73 m 2 and age ≧40 years, and who attended the study consecutively in 2014 and 2015 were enrolled (gender (M/F): 218/380; age: 58.9 ± 10.2). Regression analysis showed a significant correlation between serum Ca levels and a change in eGFR in the 1-year period (∆eGFR) after adjustment with multiple factors including those related to Ca metabolism (β = 0.184, p < 0.001). When subjects were stratified into tertiles based on their serum Ca levels (higher >9.6 mg/dL, middle 9.4-9.6 mg/dL, lower <9.4 mg/dL), lower serum Ca levels were a significant risk for a rapid decliner of eGFR designated as the lower one third of ∆eGFR (<-4.40 ml/min/1.73 m 2 ) (odds ratio 2.41, 95% confidence interval 1.47-3.94). Lower serum Ca levels are a significant risk for rapid decrease in eGFR, independent of previously reported metabolic risk factors in this general population with non-CKD, or eGFR ≧60 ml/min/1.73 m 2 .

Approximately 20% of workers in developed countries are involved in night work. Nevertheless, many studies have strongly suggested that night-work-induced chronic circadian misalignment increases the risk of a diverse range of health problems. Although a relation between night work and irregular menstrual cycles has been indicated epidemiologically, a direct causal link remains elusive. Here, we report that repetitive reversal of light-dark (LD) cycles triggers irregular estrous cycles in mice. The findings showed that the estrous cycle remained irregular for more than four weeks after the mice were returned to regular LD cycles. Importantly, the magnitude of the negative impact of reversed LD cycles on the estrous cycle, or more specifically the decreased number of normal estrous cycles during the observation period, was dependent on the difference in the frequency of LD reversal. Presently, no clear solution to prevent night-work-mediated menstrual abnormalities is available, and reducing night work in modern society is difficult. Our findings indicate that optimizing work schedules could significantly prevent menstrual problems without reducing total night-work time., (© 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

How the association between the hypothalamus-pituitary-adrenal (HPA) axis and the renin-angiotensin-aldosterone system (RAAS) affects glucose metabolism were not well examined in a general population. Participants of the population-based 2015 Iwaki study were enrolled (n: 1,016; age: 54.4 ± 15.1 years). Principal component (PC) analysis identified two PCs: PC1 represented levels of the HPA axis (serum cortisol) and the RAAS (plasma aldosterone) as a whole, and PC2 represented the HPA axis relative to the RAAS (HPA axis dominance). We examined the association between these PCs and glucose metabolism using homeostasis model assessment indices of reduced insulin sensitivity (HOMA-R) and secretion (HOMA-β). Univariate linear regression analyses showed a correlation between PC2 and HOMA-β (β = -0.248, p < 0.0001), but not between PC1 and HOMA-β (β = -0.004, p = 0.9048). The correration between PC2 and HOMA-β persisted after adjustment for multiple factors (β = -0.101, p = 0.0003). No correlations were found between the PCs and HOMA-R. When subjects were tertiled based on PC2, the highest tertile was at greater risk of decreased insulin secretion (defined as the lower one third of HOMA-β (≤68.9)) than the lowest tertile after adjustment for multiple factors (odds ratio, 2.00; 95% confidence interval, 1.35-2.97). The HPA axis dominance is associated with decreased insulin secretion in a Japanese population.

Prolactin (PRL) has roles in various physiological functions. Although experimental studies showed that PRL has both beneficial and adverse effects on type 2 diabetes mellitus, clinical findings in subjects with hyperprolactinemia indicate adverse effects on glucose metabolism. However, effects of PRL within the physiological range in human are controversial. A population-based study of 370 Japanese men enrolled in the 2014 Iwaki study (aged 52.0 ± 14.8 years). In this cross-sectional study, associations between serum PRL levels and homeostatic model assessment (HOMA) indices representing glucose metabolism in a physiological setting were examined using multivariable regression analysis. Although univariate linear regression analyses showed significant associations between serum PRL levels and HOMA indices, adjustment with multiple factors made the association with HOMA-ß (insulin secretion) insignificant, while those with HOMA-R (insulin resistance) remained significant (ß = 0.084, p = 0.035). Non-linear regression analyses showed a regression curve with a peak at serum PRL level, 12.4 ng/mL and a positive association of serum PRL level with HOMA-R below the peak (ß = 0.119, p = 0.004). Higher serum PRL levels within the physiological range seem to be associated with insulin resistance in men.

Glucocorticoids (GCs) are well known to induce insulin resistance. However, the effect of GCs on insulin secretion has not been well characterized under physiological conditions in human. We here evaluated the effect of GCs on insulin secretion/ß-cell function precisely in a physiological condition. A population-based study of 1,071 Japanese individuals enrolled in the 2014 Iwaki study (390 men, 681 women; aged 54.1 ± 15.1 years), those excluded individuals taking medication for diabetes or steroid treatment, were enrolled in the present study. Association between serum cortisol levels and insulin resistance/secretion assessed by homeostasis model assessment using fasting blood glucose and insulin levels (HOMA-R and HOMA-ß, respectively) were examined. Univariate linear regression analyses showed correlation of serum cortisol levels with HOMA-ß (ß = -0.134, p <0.001) but not with HOMA-R (ß = 0.042, p = 0.172). Adjustments for age, gender, and the multiple clinical characteristics correlated with HOMA indices showed similar results (HOMA-ß: ß = -0.062, p = 0.025; HOMA-R: ß = -0.023, p = 0.394). The correlation between serum cortisol levels and HOMA-ß remained significant after adjustment for HOMA- R (ß = -0.057, p = 0.034). When subjects were tertiled based on serum cortisol levels, the highest tertile was at greater risk of decreased insulin secretion (defined as lower one third of HOMA-ß (≤70)) than the lowest tertile, after adjustment for multiple factors including HOMA- R (odds ratio 1.26, 95% confidence interval 1.03-1.54). In conclusion, higher serum cortisol levels are significantly associated with decreased insulin secretion in the physiological cortisol range in a Japanese population., Competing Interests: The authors have declared that no competing interests exist.

The circadian transcription factor CLOCK exhibits a circadian oscillation in its phosphorylation levels. Although it remains unclear whether this phosphorylation contributes to circadian rhythm generation, it has been suggested to be involved in transcriptional activity, intracellular localization, and degradative turnover of CLOCK. Here, we obtained direct evidence that CLOCK phosphorylation may be essential for autonomous circadian oscillation in clock gene expression. Importantly, we found that the circadian transcriptional repressors Cryptochrome (CRY) and Period (PER) showed an opposite effect on CLOCK phosphorylation; CRY impaired BMAL1-dependent CLOCK phosphorylation, whereas PER protected the phosphorylation against CRY. Interestingly, unlike PER1 and PER2, PER3 did not exert a protective action, which correlates with the phenotypic differences among mice lacking the Per genes. Further studies on the regulatory mechanism of CLOCK phosphorylation would thus lead to elucidation of the mechanism of CRY-mediated transcriptional repression and an understanding of the true role of PER in the negative feedback system., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: The suprachiasmatic nucleus (SCN), the master circadian clock, is a heterogeneous oscillator network, yet displays a robust synchronization dynamics. Recent single-cell bioluminescent imaging revealed temporal gradients in circadian clock gene expression in the SCN ex vivo. However, due to technical difficulty in biological approaches to elucidate the entire network structure of the SCN, characteristics of the gradient, which we refer to as phase wave, remain unknown., Methodology/principal Findings: We implemented new approaches, i.e., quantitative analysis and model simulation to characterize the phase waves in Per2::Luciferase clock reporter gene expression of the rat SCN slice. Our quantitative study demonstrated not only a high degree of synchronization between the neurons and regular occurrence of the phase wave propagation, but also a significant amount of phase fluctuations contained in the wave. In addition, our simulations based on local coupling model suggest that the intercellular coupling strength estimated by the model simulations is significantly higher than the critical value for generating the phase waves. Model simulations also suggest that heterogeneity of the SCN neurons is one of the main factors causing the phase wave fluctuations. Furthermore, robustness of the SCN network against dynamical noise and variation of the natural frequencies inherent in these neurons was quantitatively assessed., Conclusions/significance: To our knowledge, this is the first quantitative evaluation of the phase wave and further characterization of the SCN neuronal network features generating the wave i.e., intercellular synchrony, phase fluctuation, strong local coupling, heterogeneous periodicity and robustness. Our present study provides an approach, which will lead to a comprehensive understanding of mechanistic and/or biological significance of the phase wave in the central circadian oscillatory system.

Measuring noise as a component of mammalian vocalizations is of interest because of its potential relevance to the communicative function. However, methods for characterizing and quantifying noise are less well established than methods applicable to harmonically structured aspects of signals. Using barks of coyotes and domestic dogs, we compared six acoustic measures and studied how they are related to human perception of noisiness. Measures of harmonic-to-noise-ratio (HNR), percent voicing, and shimmer were found to be the best predictors of perceptual rating by human listeners. Both acoustics and perception indicated that noisiness was similar across coyote and dog barks, but within each species there was significant variation among the individual vocalizers. The advantages and disadvantages of the various measures are discussed.

A nonlinear modeling approach is presented for the reconstruction of the synchronization structure in an asymmetric two-mass model from time series data. The asymmetric two-mass model describes a variety of normal and pathological human voices associated with synchronous and desynchronous oscillations of the two asymmetric vocal folds. Our technique recovers the synchronization diagram, which yields the regimes of synchronization as well as desynchronization, which are dependent upon the asymmetry parameter and the subglottal pressure. This allows the prediction of the regime of pathological phonation associated with desynchronization of the vocal folds from a few sets of recorded time series. It is shown that the modeling is quite effective when the time series data are chaotic and if they are taken from a regime of desynchronization. We discuss the applicability of the present approach as a diagnostic tool for voice pathologies.

An approach is presented for the reconstruction of phase synchronization phenomena in a chaotic CO2 laser from experimental data. We analyze this laser system in a regime able to phase synchronize with a weak sinusoidal forcing. Our technique recovers the synchronization diagram of the experimental system from only few measurement data sets, thus allowing the prediction of the regime of phase synchronization as well as nonsynchronization in a broad parameter space of forcing frequency and amplitude without further experiments.

This paper presents numerical studies of applying back-propagation learning to a delayed recurrent neural network (DRNN). The DRNN is a continuous-time recurrent neural network having time delayed feedbacks and the back-propagation learning is to teach spatio-temporal dynamics to the DRNN. Since the time-delays make the dynamics of the DRNN infinite-dimensional, the learning algorithm and the learning capability of the DRNN are different from those of the ordinary recurrent neural network (ORNN) having no time-delays. First, two types of learning algorithms are developed for a class of DRNNs. Then, using chaotic signals generated from the Mackey-Glass equation and the Rössler equations, learning capability of the DRNN is examined. Comparing the learning algorithms, learning capability, and robustness against noise of the DRNN with those of the ORNN and time delay neural network, advantages as well as disadvantages of the DRNN are investigated.

Neural networks composed of excitable neurons with noise generate rich nonlinear dynamics with spatiotemporal structures of neuronal spikes. Among various spatiotemporal patterns of spikes, synchronous firing has been studied most extensively both with physiological experimentation and with theoretical analysis. In this paper, we consider nonlinear neurodynamics in terms of synchronous firing and possibility of neural coding with such synchronous firing, which may be used in the "noisy brain." In particular, reconstruction of a chaotic attractor modeling a dynamical environment is explored with interevent intervals of synchronous firing from the perspective of nonlinear time series analysis and stochastic resonance.

Animal vocalizations range from almost periodic vocal-fold vibration to completely atonal turbulent noise. Between these two extremes, a variety of nonlinear dynamics such as limit cycles, subharmonics, biphonation, and chaotic episodes have been recently observed. These observations imply possible functional roles of nonlinear dynamics in animal acoustic communication. Nonlinear dynamics may also provide insight into the degree to which detailed features of vocalizations are under close neural control, as opposed to more directly reflecting biomechanical properties of the vibrating vocal folds themselves. So far, nonlinear dynamical structures of animal voices have been mainly studied with spectrograms. In this study, the deterministic versus stochastic (DVS) prediction technique was used to quantify the amount of nonlinearity in three animal vocalizations: macaque screams, piglet screams, and dog barks. Results showed that in vocalizations with pronounced harmonic components (adult macaque screams, certain piglet screams, and dog barks), deterministic nonlinear prediction was clearly more powerful than stochastic linear prediction. The difference, termed low-dimensional nonlinearity measure (LNM), indicates the presence of a low-dimensional attractor. In highly irregular signals such as juvenile macaque screams, piglet screams, and some dog barks, the detectable amount of nonlinearity was comparatively small. Analyzing 120 samples of dog barks, it was further shown that the harmonic-to-noise ratio (HNR) was positively correlated with LNM. It is concluded that nonlinear analysis is primarily useful in animal vocalizations with strong harmonic components (including subharmonics and biphonation) or low-dimensional chaos.

We present a novel modeling approach for reconstruction of the global behavior of coupled chaotic systems from bivariate time series. We analyze two coupled chaotic oscillators, which are able to phase synchronize due to coupling. It is shown that our technique enables the recovery of the synchronization diagram from only three data sets. In particular, this allows the estimate of the relative strength of the coupling and the parameter mismatch of both subsystems. The method is most efficient if only data from the nonsynchronized regime are used for the model learning. We also apply this approach to experimental data of a paced plasma tube.

Normal vowels are known to have irregularities in the pitch-to-pitch variation which is quite important for speech signals to be perceived as natural human sound. Such pitch-to-pitch variation of vowels is studied in the light of nonlinear dynamics. For the analysis, five normal vowels recorded from three male and two female subjects are exploited, where the vowel signals are shown to have normal levels of the pitch-to-pitch variation. First, by the false nearest-neighbor analysis, nonlinear dynamics of the vowels are shown to be well analyzed by using a relatively low-dimensional reconstructing dimension of 4 < or = d < or = 7. Then, we further studied nonlinear dynamics of the vowels by spike-and-wave surrogate analysis. The results imply that there exists nonlinear dynamical correlation between one pitch-waveform pattern to another in the vowel signals. On the basis of the analysis results, applicability of the nonlinear prediction technique to vowel synthesis is discussed.