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The glenoid labrum acts as a bumper, deepening glenoid concavity and amplifying the concavity-compression mechanism, and serves as the scapular attachment for glenohumeral ligaments. The role of the posterosuperior labrum in anteroinferior glenohumeral stability, and the role of the anterior labrum in posterior stability has been debated. The purpose of this study was to quantify the contribution of anteroinferior and posterosuperior labral tears to loss of glenohumeral stability in multiple directions.Fourteen fresh-frozen cadaveric shoulders were tested on a custom stability ratio measurement apparatus. The peak force that was required to translate the humeral head in anterior, anteroinferior, posterior, and posteroinferior directions was measured under 5 conditions: intact labrum (N = 14), anteroinferior labral tear (N = 7), posterosuperior labral tear (N = 7), combined labral tear (N = 14), and no labrum (N = 14). The stability ratio was defined as the peak translational force divided by the compressive force. Within force-translation curves, we defined the suction cup effect as the force required to release the negative pressure created by an intact labrum.The suction cup effect was usually present with the intact labrum and always disappeared after removal of the labrum for anterior (100% vs 0%) and posterior (86% vs 0%) translations (P0.001). After creation of an anteroinferior labral tear, the stability ratio for posterior direction decreased (P0.001) and the suction cup effect disappeared (P0.001). After creation of a posterosuperior labral tear, stability ratios in the anterior and anteroinferior directions decreased (P ≤ 0.006) and the suction cup effect disappeared (P ≤ 0.015). The stability ratio for anterior and anteroinferior testing was more diminished by posterosuperior labral tears than anteroinferior labral tears, and the stability ratio for posterior testing was more diminished by anteroinferior labral tears than posterosuperior labral tears.Anteroinferior labral tears decreased posterior stability and posterosuperior labral tears decreased anterior and anteroinferior stability, largely because of loss of the suction cup effect.

DNA methylation in the CpG sites of intron 1 ofDNA methylation ofDNA methylation ofPeripheral blood DNA methylation at the CpG site (cg27146050) of

Eukaryotic cilia and flagella are microtubule-based organelles whose relatively simple shape makes them ideal for investigating the fundamental question of organelle size regulation. Most of the flagellar materials are transported from the cell body via an active transport process called intraflagellar transport (IFT). The rate of IFT entry into flagella, known as IFT injection, has been shown to negatively correlate with flagellar length. However, it remains unknown how the cell measures the length of its flagella and controls IFT injection. One of the most-discussed theoretical models for length sensing to control IFT is the ion-current model, which posits that there is a uniform distribution of Ca2+channels along the flagellum and that the Ca2+current from the flagellum into the cell body increases linearly with flagellar length. In this model, the cell uses the Ca2+current to negatively regulate IFT injection. The recent discovery that IFT entry into flagella is regulated by the phosphorylation of kinesin through a calcium-dependent protein kinase has provided further impetus for the ion-current model. To test this model, we measured and manipulated the levels of Ca2+inside ofChlamydomonasflagella and quantified IFT injection. Although the concentration of Ca2+inside of flagella was weakly correlated with the length of flagella, we found that IFT injection was reduced in calcium-deficient flagella, rather than increased as the model predicted, and that variation in IFT injection was uncorrelated with the occurrence of flagellar Ca2+spikes. Thus, Ca2+does not appear to function as a negative regulator of IFT injection, hence it cannot form the basis of a stable length control system.

We experimentally and theoretically investigate systems with a pair of source and inert particles that interacts through the concentration field. The experimental system comprises a camphor disk as the source particle and a metal washer as the inert particle. Both are floated on a red aqueous solution at various concentrations, where the glycerol modifies the viscosity of the aqueous phase. The particles form a pair owing to the attractive lateral capillary force. As the camphor disk spreads surface-active molecules at the aqueous surface, the camphor disk and metal washer move together, driven by the surface tension gradient. The washer is situated in the front of the camphor disk, keeping the distance constant during their motion, which we call a pairing-induced motion. The pairing-induced motion exhibited a transition between circular and straight motions as the glycerol concentration in the aqueous phase changed. Numerical calculations using a model that considers forces caused by the surface tension gradient and lateral capillary interaction reproduced the observed transition in the pairing-induced motion. Moreover, this transition agrees with the result of the linear stability analysis on the reduced dynamical system obtained by the expansion with respect to the particle velocity. Our results reveal that the effect of the particle velocity cannot be overlooked to describe the interaction through the concentration field., Comment: 12 pages, 8 figures

We previously reported that maternal fructose consumption increases blood corticosterone levels in rat offspring. However, the underlying mechanism of action remains unclear. In the present study, we aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring (GC; corticosterone in rodents and cortisol in humans). Female Sprague Dawley rats received HFCS solution during gestation and lactation. The male offspring were fed distilled water from weaning to 60 days of age. We investigated the activities of GC-metabolizing enzymes (11β-Hsd1 and 11β-Hsd2) in various tissues (i.e., liver, kidney, adrenal glands, muscle, and white adipose tissue) and epigenetic modification. 11β-Hsd2 activity decreased in the kidney of the HFCS-fed dams. Moreover, the epigenetic analysis suggested that miR-27a reduced Hsd11b2 mRNA expression in the kidney of offspring. Maternal HFCS-induced elevation of circulating GC levels in offspring may be explained by a decrease in 11β-Hsd2 activity via renal miR-27a expression. The present study may allow us to determine one of the mechanisms of GC elevation in rat offspring that is often observed in the developmental origins of the health and disease (DOHaD) phenomenon.

BackgroundDNA methylation plays an important role in the pathogenesis and progression of cardiovascular disease (CVD) but the prospective association of DNA methylation with CVD has not been evaluated. Here, we conducted a prospective study to examine whether long interspersed nuclear element-1 (LINE-1) DNA methylation is associated with CVD mortality in a Japanese population.MethodsWe targeted 822 Japanese who participated in a health check-up in 1990 and had no clinical history of cancer, stroke or ischaemic heart disease. DNA was extracted from peripheral blood mononuclear cells and LINE-1 DNA methylation at three CpG sites was measured using a pyrosequencing method. We used propensity score (PS) matching to reduce the effect of potential confounding.ResultsDuring 18 118.7 persons-years of follow-up, there were 329 deaths from all-causes and 85 deaths from CVD. In PS-matched analysis, a significantly higher HR for CVD mortality was observed in the hypermethylation group than in the hypomethylation group for elderly participants (HR 2.77; 95% CI 1.55 to 4.93). No significant association between LINE-1 DNA methylation and CVD was observed for middle-aged participants.ConclusionsBased on this prospective study, we suggest that LINE-1 DNA hypermethylation is associated with increased CVD mortality risk in an elderly population.

Background: Altered scapular motion is thought to be one of the factors associated with the development of symptomatic rotator cuff tears. However, the differences in kinematics and muscle activities of scapular upward/downward rotation between patients with symptomatic and asymptomatic tears are unclear. The purpose of this study was to compare the differences in kinematics and muscle activities of scapular rotation among patients with symptomatic and asymptomatic tears, and healthy individuals. Methods: Twenty-three patients with rotator cuff tears and 9 healthy individuals (healthy group) participated in this study. Based on a visual analog scale (VAS, 0-100 mm), the patients were divided into symptomatic (13 patients; VAS ≥20 mm) and asymptomatic (10 patients; VAS

DNA methylation can be affected by numerous lifestyle factors, including diet. Tobacco smoking induces aryl hydrocarbon receptor repressor (AHRR) DNA hypomethylation, which increases the risk of lung and other cancers. However, no lifestyle habits that might increase or restore percentage of AHRR DNA methylation have been identified. We hypothesized that dietary intakes of vegetables/fruits and serum carotenoid concentrations are related to AHRR DNA methylation. A total of 813 individuals participated in this cross-sectional study. A food frequency questionnaire was used to assess dietary intake of vegetables and fruits. AHRR DNA methylation in peripheral blood mononuclear cells were measured using pyrosequencing method. In men, dietary fruit intake was significantly and positively associated with AHRR DNA methylation among current smokers (P for trend = .034). A significant positive association of serum provitamin A with AHRR DNA methylation was observed among current smokers (men: standardized β = 0.141 [0.045 to 0.237], women: standardized β = 0.570 [0.153 to 0.990]). However, compared with never smokers with low provitamin A concentrations, percentages of AHRR DNA methylation were much lower among current smokers, even those with high provitamin A concentrations (men: β = -19.1% [-33.8 to -19.8], women: β = -6.0% [-10.2 to -1.7]). Dietary intake of vegetables and fruits rich in provitamin A may increase percentage of AHRR DNA methylation in current smokers. However, although we found a beneficial effect of provitamin A on AHRR DNA methylation, this beneficial effect could not completely remove the effect of smoking on AHRR DNA demethylation.

Adjuvant cisplatin‑vinorelbine is a standard therapy for stage II/III lung cancer. However, a poor survival rate of patients with lung cancer is attributed to vinorelbine resistance arising from ATP‑binding cassette (ABC) sub‑family B member 1 (ABCB1) and phosphorylated Fyn (p‑Fyn) overexpression. However, the underlying mechanisms remain unclear. NF‑E2‑related factor 2 (Nrf2) regulates the ABC family and activates the nuclear transport of Fyn. The present study evaluated the roles of the Nrf2/p‑Fyn/ABCB1 axis in vinorelbine‑resistant (VR) cells and clinical samples. To establish VR cells, H1299 cells were exposed to vinorelbine, and the intracellular reactive oxygen species (ROS) level in the H1299 cells was determined using a DCFH‑DA assay. The total and subcellular expression of Nrf2, ABCB1 and p‑Fyn in VR cells was evaluated. Immunofluorescence was used to detect the subcellular localization of p‑Fyn in VR cells. A cell viability assay was used to examine whether the sensitivity of VR cells to vinorelbine is dependent on Nrf2 activity. Immunohistochemistry was performed on 104 tissue samples from patients with lung cancer who underwent surgery followed by cisplatin‑vinorelbine treatment. The results revealed that persistent exposure to vinorelbine induced intracellular ROS formation in H1299 cells. p‑Fyn was localized in the nucleus, and ABCB1 and Nrf2 were overexpressed in VR cells. ABCB1 expression was dependent on Nrf2 downstream activation. The decreased expression of Nrf2 restored the sensitivity of VR cells to vinorelbine. In the surgical samples, Nrf2 and ABCB1 were associated with disease‑free survival, and p‑Fyn was associated with overall survival (P0.05). On the whole, the present study demonstrates that Nrf2 upregulates ABCB1 and, accompanied by the nuclear accumulation of p‑Fyn, induces vinorelbine resistance. These findings may facilitate the development of drug resistance prevention strategies or new drug targets against non‑small cell lung cancer.

形態: カラー図版あり, Physical characteristics: Original contains color illustrations, Accepted:2020-09-17, 資料番号: PA2120038000

We examined whether orally administered octacosanol, a long-chain aliphatic saturated alcohol, improves the features of high fructose-induced metabolic syndrome in rats. Five-week-old rats were fed a high fructose diet containing 60% fructose for 3 weeks. Then, the high fructose fed rats received a daily single oral administration of octacosanol (10 or 100 mg/kg body weight) with high fructose feeding for one week. Three- or four-week high fructose feeding increased insulin resistance, serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, and lipid peroxide concentrations, and hepatic triglyceride and cholesterol contents significantly and decreased serum high-density lipoprotein cholesterol and adiponectin concentrations significantly but did not affect blood pressure and hepatic lipid peroxide and reduced glutathione contents. Four-week high fructose feeding decreased hepatic ascorbic acid content significantly. Oral administration of octacosanol (10 or 50 mg/kg body weight) to high fructose-fed rats for the last 1-week fructose diet feeding attenuated these changes except serum insulin level and insulin resistance significantly and increased hepatic reduced glutathione content significantly. The higher dose of Oct decreased hepatic lipid peroxide content significantly. These results indicate that orally administered octacosanol improves dyslipidemia, hyperuricemia, hypoadiponectinemia, and oxidative stress associated with the features of high fructose-induced metabolic syndrome rats.

Background: MicroRNAs (miRNAs) play crucial roles in the development of various diseases, including chronic kidney disease (CKD). Although previous studies in clinically severe patients have investigated associations between CKD and miRNAs, with particular attention on renal fibrosis, relationships in a general population have yet to be established. The aim of this study was to examine the relationship between expression level of circulating miRNAs and CKD in a middle-aged Japanese population. Methods: A final total of 513 individuals (216 men and 297 women) who participated in the health check-up program in 2012 were included in our analysis. Quantitative real-time polymerase chain reaction was used to determine expression levels of 22 miRNAs. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine level, sex, and age. Participants with eGFR

Length control of flagella represents a simple and tractable system to investigate the dynamics of organelle size. Models for flagellar length control in the model organism, Chlamydomonas reinhardtii have focused on the length-dependence of the intraflagellar transport (IFT) system which manages the delivery and removal of axonemal subunits at the tip of the flagella. One of these cargoes, tubulin, is the major axonemal subunit, and its frequency of arrival at the tip plays a central role in size control models. However, the mechanisms determining tubulin dynamics at the tip are still poorly understood. We discovered a loss-of-function mutation that leads to shortened flagella, and found that this was an allele of a previously described gene, SHF1, whose molecular identity had not previously been determined. We found that SHF1 encodes a Chlamydomonas ortholog of Crescerin, previously identified as a cilia-specific TOG-domain array protein that can bind tubulin via its TOG domains and increase tubulin polymerization rates. In this mutant, flagellar regeneration occurs with the same initial kinetics as wild-type cells, but plateaus at a shorter length. Using a computational model in which the flagellar microtubules are represented by a differential equation for flagellar length combined with a stochastic model for cytoplasmic microtubule dynamics, we found that our experimental results are best described by a model in which Crescerin/SHF1 binds tubulin dimers in the cytoplasm and transports them into the flagellum. We suggest that this TOG-domain protein is necessary to efficiently and preemptively increase intra-flagella tubulin levels to offset decreasing IFT cargo at the tip as flagellar assembly progresses.

DNA methylation in the CpG sites of intron 1 of HIF3A is associated with body mass index (BMI). This cross-sectional study investigated correlations between DNA methylation of HIF3A and BMI or adiposity parameters in the Japanese population. DNA methylation of HIF3A was quantified via pyrosequencing. DNA methylation of HIF3A differed only in women; DNA methylation level at cg27146050 was associated with visceral adipose tissue thickness and correlated with BMI and percent (%) body fat after excluding smokers. Peripheral blood DNA methylation at the CpG site (cg27146050) of HIF3A correlated with VAT thickness in Japanese women.

Although tension on the supraspinatus tendon may be increased by wearing an abduction brace in an improper position or activities of daily living with the operated arm in the brace, the amount of tension has not been objectively evaluated.Eighteen patients who underwent arthroscopic rotator cuff repair were enrolled. The stiffness of the repaired supraspinatus tendon was measured with ultrasound elastography to estimate the tension on the repaired tendon. Measurements were performed in 5 immobilization positions (0°, 30°, and 45° of arm elevation in the scapular plane; 30° of arm elevation in the scapular plane+60° (horizontal adduction) and -60° (horizontal abduction)) and 3 static positions simulating drinking, brushing teeth, and dressing.Stiffness at 30° of scapular plane elevation was lower than 0° of scapular plane elevation (P = 0.034), 30° of elevation in the scapular plane+60° (P 0.001), and -60° (P 0.001). There was no significant difference in the stiffness between 30° and 45° of scapular plane elevation (P = 1.000). The stiffness was the greatest at 30° of elevation in the scapular plane-60° among the 5 immobilization positions. The stiffnesses at drinking and brushing teeth were greater than 30° of scapular plane elevation (P 0.001).Immobilization with the arm ≥30° of elevation in the scapular plane may be an optimal position for minimizing stiffness or tension on the repaired tendon. Drinking and brushing teeth may need to be performed using the non-operated arm to protect the repaired tendon.

Smoking is well known to be a major risk factor for cancer, and to decrease the levels of aryl hydrocarbon receptor repressor (AHRR) DNA methylation. AHRR is a key regulator for AHR signaling, which is involved in chemical metabolism and cancer development. Therefore, smoking-induced AHRR DNA hypomethylation may be associated with cancer development. However, it has not been reported that association between AHHR DNA methylation and cancer mortality in Asian population. Hence, we examined whether AHRR DNA methylation levels were associated with cancer mortality in a Japanese population.This study was conducted with 812 participants (aged 38-80 years) who received a health check-up in 1990, and did not have a clinical histories. We followed up the participants until the end of 2019 (median: 27.8 years), and 100 participants died from cancer. The AHRR DNA methylation levels in peripheral blood mononuclear cells (PBMCs) were measured by the pyrosequencing method. We calculated the hazard ratio (HR) and 95% confidence interval (CI) for cancer mortality according to the baseline levels of AHRR DNA methylation.We found that AHRR DNA hypomethylation was associated with a higher risk of all cancer mortality, especially smoking related cancers and lung cancer. (all cancer: HR, 1.28, 95% CI, 1.09-1.51; smoking-related cancers: HR, 1.35, 95% CI, 1.12-1.62; lung cancer: HR, 1.68, 95% CI, 1.24-2.26).Smoking-induced AHRR DNA hypomethylation in PBMCs was associated with the risk of cancer mortality in Japanese population; therefore, hypomethylation of AHRR may be a useful biomarker of cancer mortality risk.

Length control of flagella represents a simple and tractable system to investigate the dynamics of organelle size. Models for flagellar length control in the model organism

Changes in soft-tissue structures such as anterior laxity and posterior tightness are thought to contribute to the development of pathologic internal impingement in baseball players. Although side-to-side differences in shoulder rotational range of motion (ROM) is commonly used in clinical practice to quantify the soft-tissue changes, the ROM does not accurately reflect the soft-tissue changes because the ROM is affected not only by the soft tissues, but also by the bone. Increased retroversion of the humeral head is often observed in the dominant shoulder of throwing athletes. The purpose of this study was to determine the relationship between the soft-tissue-related (STR) ROM and pathologic internal impingement in baseball players.Bilateral humeral retroversion and ranges of glenohumeral external rotation (ER) and internal rotation (IR) were investigated in 81 high-school baseball players. The players were divided into two groups: the internal impingement group (19 players) and the control group (62 players). Humeral retroversion was measured using the ultrasound-assisted technique to assess the bone-related ER and IR. The STR ER and IR were defined as subtracting the amount of humeral retroversion from the measured ER and IR.The side-to-side difference (throwing shoulder - nonthrowing shoulder) in humeral retroversion showed no significant difference between the internal impingement group (6° ± 10°) and control group (11° ± 11°) (P = .064). The side-to-side difference in STR ER was significantly greater in the internal impingement group (12° ± 12°) than that in the control group (1° ± 14°) (P = .002). No significant difference was observed in the side-to-side difference in STR IR between the internal impingement group (-7° ± 16°) and control group (-5° ± 15°) (P = .696). Pathologic internal impingement was significantly associated with the side-to-side difference of STR ER (odds ratio, 1.06 for increase of 1°; 95% confidence interval, 1.02-1.11; P = .008).In high-school baseball players, the increased STR ER in the throwing shoulder may be associated with pathologic internal impingement. An increase of 10° in side-to-side difference in STR ER would increase the risk of pathologic internal impingement by 1.8 times.

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders.

Background Thioredoxin-interacting protein (TXNIP) inhibits the activity of thioredoxin (TXN), leading to increased oxidative stress. Expression of the TXNIP gene is regulated by DNA methylation. However, no study has reported the influence of lifestyle factors on TXNIP DNA methylation. Our goal was to determine the association between drinking habits and TXNIP DNA methylation levels in the general Japanese population. Methods We conducted a cross-sectional study of 404 subjects (176 males and 228 females) participating in a health examination. Subjects were divided into non-, moderate (male: 1-39g; female: 1-19g ethanol/day) and heavy (male: ≥40g; female: ≥20g ethanol/day) drinkers based on self-reported drinking habits. We used a pyrosequencing assay to determine TXNIP DNA methylation levels in leukocytes. Results Among men, the mean TXNIP DNA methylation level in heavy drinkers (73.2%) was significantly lower than that in non- and moderate drinkers (non: 76.7%, p Conclusions We found that heavy drinkers had TXNIP DNA hypomethylation compared to non- and moderate drinkers in men. Moreover, alcohol consumptions were also negatively associated with TXNIP DNA methylation levels in male current drinkers. Key messages Heavy drinkers had decreased levels of TXNIP DNA methylation compared to non- and moderate drinkers in men.

Background DNA methylation plays an important role in progression of cardiovascular disease (CVD). The methylation status of long interspersed nuclear element-1 (LINE-1) reflects the global DNA methylation level and is associated with lipid profiles and glycemia. We conducted a longitudinal study to examine the association between LINE-1 DNA methylation and CVD mortality in a Japanese elderly population. Methods We targeted for 357 subjects (143 men and 214 women) who were more than 60 years, participated in the health checkup in 1990, and had no clinical history of cancer, stroke, or ischemic heart disease. During 29 years of follow-up period, total 69 subjects were died from CVD, and died of cerebrovascular disease (CBD) and ischemic heart disease (IHD) were 25 and 13, respectively. LINE-1 DNA methylation was measured using PBMCs. We defined the hypermethylation group as greater than median of the LINE-1 DNA methylation levels and hypomethylation group as others. Multivariable Hazard ratios (HRs) for each disease mortality were calculated by the Cox proportional hazard model. We adjusted for age, sex, smoking habits, and alcohol consumption. Results Significantly higher HRs for CVD and CBD mortality were observed in the hypermethylation group compared to the hypomethylation group (CVD: HR 1.67 [95%CI 1.02-2.73], CBD: HR 3.29 [95%CI 1.29-8.40]). However, IHD mortality did not associated with LINE-1 DNA methylation. Conclusions We found that LINE-1 DNA hypermethylation in PBMCs was associated with high CVD mortality, especially CBD mortality. Key messages Higher levels of LINE-1 methylation in PBMCs can be a predictive marker for CBD risk

Background Although previous studies have demonstrated that n-3 polyunsaturated fatty acids (PUFA) are inversely associated with a risk of CVD through gene expression, recent evidence suggests that it may arise from changes in DNA methylation. Therefore, we investigated whether dietary FA intake and serum FA levels are associated with ATP-binding cassette transporter A1 (ABCA1), a gene associated with HDL-cholesterol metabolism. Methods A total of 298 subjects (137 men, mean age of 63.2) without clinical history and medication participated in this cross-sectional study. We used the pyrosequencing method to measure DNA methylation levels at 8 CpG sites within ABCA1 gene and calculated mean DNA methylation level. Dietary FA intake were assessed with the food frequency questionnaire. Results We found that ABCA1 DNA methylation levels were significantly lower with higher dietary intake of n-3PUFA (β = –5.75, p = 0.001), which is observed both in men (β = –4.85, p = 0.001) and women (β = –7.24, p = 0.007). In addition, ABCA1 DNA methylation levels were significantly lower with higher serum levels of n-3PUFA in men (β = –2.78, p = 0.05), but not in women (β = 1.61, p = 0.31). Conclusions The results suggest that higher dietary n-3 PUFA intake and serum levels of n-3 PUFA are associated with lower ABCA1 DNA methylation in a Japanese population. Key messages Higher dietary n-3 PUFA intake can be a prevention from dyslipidemia and CVD via low level of ABCA1 DNA methylation

Background Although dementia is a huge problem in public health, no fundamental biomarker has been established to detect cognitive decline at the early stage. MicroRNAs (miRNAs) regulate gene expression, and are associated with the development of various diseases. Methods The subjects of this prospective study were 162 (75 men, 87 women) residents who attended a health examination in Yakumo town in Hokkaido, in 2012 and re-attended at least once while 2013 to 2015. Serum samples were collected in 2012 and serum miRNA were measured by qRT-PCR. We used a short version of the Mini-Mental State Examination (SMMSE) to screen cognitive function, and calculated the change in SMMSE score per year. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) of serum miRNA levels for cognitive decline (decrease of greater than 0.5 points per year) using the lowest tertile group of miRNAs as the reference by logistic regression analysis. Results The mean age and change in SMMSE score of the subjects was 63.9±9.6 years and -0.03±1.19 points. Odds ratios (ORs) for cognitive decline were significantly higher in the highest tertile of serum miR-221 (OR = 3.24, 95%CI=1.20-8.72) and miR-222 (OR = 4.01, 95%CI=1.36-11.80) even if confounding factors were adjusted. Conclusions High serum levels of miR-221 and -222 were significantly associated with cognitive decline. Key messages High serum levels of miR-221 and -222 may be potential candidate biomarkers for prediction of cognitive decline.

Accepted: 2021-07-06, 資料番号: PA2220028000

BackgroundThe adverse health effects of sugar-sweetened beverage consumption have been studied worldwide. There are several reports on actual sugar contents in sugar-sweetened beverages. However, there is no recent report on actual sugar contents in Japanese sugar-sweetened beverages. Therefore, we attempted to analyze glucose, fructose, and sucrose contents in Japanese common beverages.MethodsGlucose, fructose, and sucrose contents in 49 beverages including 8 energy drinks, 11 sodas, 4 fruit juices, 7 probiotic drinks, 4 sports drinks, 5 coffee drinks, 6 green tea drinks, and 4 tea drinks were determined using the enzymatic methods.ResultsTow zero calorie drinks, 2 sugarless coffee drinks, and 6 green tea drinks contained no sugar. Three coffee drinks contained only sucrose. The orders of median glucose, fructose, and sucrose contents in categorized beverages containing sugars were as follows: for glucose, fruit juice > energy drink ≥ soda >> probiotic drink > black tea drink > sports drink; for fructose, probiotic drink ≥ energy drink > fruit juice > soda >> sports drink > black tea drink; and for sucrose, black tea drink > energy drink ≥ probiotic drink > fruit juice > soda > coffee drink >> sports drink. The rate of total fructose content in total sugar content in 38 sugar-containing beverages was approximately 40-60%. The total sugar content analyzed was not always equivalent to carbohydrate content indicated on the nutrition label.ConclusionsThese results indicate that actual sugar content in Japanese common beverages is necessary for the exact assessment of beverage-derived sugar intake.

There are concerns about the negative effects of fructose intake during pregnancy on the next generation. We have previously reported that offspring from dams fed with fructose during gestation and lactation demonstrate abnormal lipid metabolism in the liver. In this study, we aimed to elucidate the molecular mechanism of the effects of maternal high-fructose corn syrup (HFCS) consumption on offspring. Pregnant Sprague-Dawley rats were fed with 20% HFCS water solution during gestation and lactation. Offspring were put on a normal diet after weaning, and the serum parameters and gene expression patterns were studied at predetermined intervals. Offsprings from pregnant rats fed with 20% HFCS (HFCS group) developed insulin resistance and hyperlipidemia at 60 d of age. RNA-seq analysis demonstrated that peroxisome proliferator-activated receptor α (PPARα) expression is downregulated by maternal HFCS intake. Hepatic Pparα expression in the HFCS group appeared to be suppressed by the enhanced DNA methylation of its promoter region. It is suggested that the development of insulin resistance and hyperlipidemia in the HFCS group may be attributable to aberrant Pparα methylation in the offspring liver. Pparα hypermethylation may be one of molecular mechanism underlying the toxicity of maternal fructose intake.

Visual hallucinations (VHs) are common in patients with Parkinson disease (PD), especially those with dementia, whereas auditory hallucinations are quite rare. Recent studies have revealed the involvement of several regions along the visual information-processing system that contribute to the pathophysiological mechanism of VHs: the eyes and retina, retinofugal projection, lateral geniculate nucleus, striate cortex, ventral pathways in the temporal cortices, and frontal and parietal cortices. In addition, the concurrent involvement of other systems in the brainstem and basal forebrain further modify VHs in PD. In this review, we discuss the pathophysiological association between the regional involvement of these areas and VHs.

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity, metabolic syndrome, and type II diabetes mellitus. Recently, circulating microRNAs (miRNAs) have been proposed as useful disease biomarkers. We examined whether circulating miRNAs, such as miR-20a, miR-27a, and miR-126, were useful biomarkers for NAFLD. We conducted a cross-sectional analysis of 527 subjects aged 39 years or older who had undergone a health examination in the Yakumo Study. Of the residents, 92 were diagnosed with NAFLD using a registered medical sonographer. Serum miR-20a, miR-27a and miR-126 levels were measured by quantitative real-time PCR. We then calculated the odds ratios for serum miRNA level changes according to the severity of NAFLD using normal liver status as the reference group. Serum levels of miR-20a and 27a, but not miR-126, were significantly lower in NAFLD subjects than normal subjects. Serum miR-20a and miR-27a levels were significantly lower in both male and female severe NAFLD subjects. Logistic regression analysis showed a significant relationship between low circulating miR-20a and 27a levels and severe NAFLD. Down-regulated circulating miR-20a and 27a levels were significantly associated with severe NAFLD in the general population. Circulating miR-20a and miR-27a may be useful biomarkers for severe NAFLD.

Fructose consumption is rising globally, but maternal high fructose intake might adversely affect offspring. Our previous report demonstrated that excess maternal fructose intake impairs hippocampa...

MicroRNAs (miRNAs) dysregulate gene expression by binding to target messenger RNAs, and play an important role in the pathogenesis of various diseases, including cancers, cardiovascular diseases and diabetes. Circulating miRNAs have increasingly been recognized as biomarkers for detecting and diagnosing those diseases. Few studies have investigated the association of circulating miRNA with the early stages of cognitive impairment, such as mild cognitive impairment, in the general population. The purpose of this study was to examine the association between cognitive function and several serum miRNAs levels related to amyloid precursor protein (APP) proteolysis in a Japanese general population who had never been diagnosed with dementia.We conducted a cross-sectional study of 337 Japanese subjects (144 men, 193 women) who attended a health examination. The short form of the Mini-Mental State Examination (SMMSE) was used to assess cognitive function. Serum levels of 6 miRNAs (let-7d, miR-17, miR-20a, miR-27a, miR-34a, miR-103a) were measured by quantitative real-time polymerase chain reaction.Multivariable-adjusted odds ratios (ORs) for lower SMMSE score (SMMSE score28) were significantly increased in the lowest tertile of serum miR-20a (OR, 2.08; 95% confidence interval (CI), 1.09-4.04) and miR-103a (OR, 1.91; 95%CI, 1.00-3.69) compared to the highest tertile. Moreover, serum levels of miR-20a, -27a, and -103a were linearly and positively associated with SMMSE scores after adjustment for confounding factors.Low serum levels of miR-20a, -27a, and -103a are independently associated with cognitive impairment.

Pasteurella multocida, which colonizes upper respiratory and digestive tracts, is a leading cause of respiratory diseases in many host species. Here, we describe a case of P. multocida pneumonia with hemoptysis. A 72-year-old female diagnosed with bronchiectasis with a 36-year history presented with a worsened infiltrative and granular shadow in the lower right lobe and lingular segment. Bronchial lavage fluid culturing suggested Pasteurella pneumonia. P. multocida was confirmed by 16S rRNA sequencing. The patient was readmitted to our hospital because of hemoptysis, and she was treated successfully with antibiotic therapy. The possibility of P. multocida infection must be considered in patients who own pets. Keywords: Pasteurella multocida, Pasteurella canis, Hemoptysis, Pasteurellosis

Physical characteristics: Original contains color illustrations, Accepted: 2018-06-05, 資料番号: PA1920039000

Hintergrund: Die exzessive Inhalation von Aluminiumstaub führt gelegentlich zu einer überwiegend die Oberlappen betreffenden Lungenfibrose, die einer idiopathischen pleuroparenchymalen Fibroelastose (IPPFE) ähnelt und bei der es sich den Annahmen zufolge um eine sekundäre PPFE handelt. Fallbericht: Ein 67-jähriger Mann, der 50 Jahre lang in einem aluminiumverarbeitenden Unternehmen gearbeitet hatte, stellte sich mit Belastungsdyspnoe in unserer Klinik vor. Die Computertomographie (CT) des Thorax zeigte eine bilaterale dichte subpleurale Konsolidierung in den oberen und mittleren Lungenfeldern entsprechend einer IPPFE; eine etwaige sekundäre PPFE im Zusammenhang mit einer Aluminose wurde jedoch nicht ausgeschlossen. Aufgrund des kritischen Zustands des Patienten erfolgten eine transbronchiale Lungenbiopsie (TBLB) anstatt einer chirurgischen Lungenbiopsie sowie eine Elementaranalyse der entnommenen Gewebeprobe. Da die mittels TBLB gewonnene Probe bedauerlicherweise kein Alveolargewebe enthielt, konnte die Diagnose PPFE nicht pathologisch gesichert werden. Die radiologischen Befunde sprachen jedoch stark für eine PPFE. In der Elementaranalyse wurden hohe Mengen an Aluminium in den Bronchiolarwänden nachgewiesen, so dass die Diagnose einer Aluminose der Atemwege mit wahrscheinlich sekundärer PPFE infolge Aluminiumexposition gestellt wurde. Schlussfolgerungen: Eine TBLB mit Elementaranalyse kann zur Abgrenzung der idiopathischen PPFE von sekundären Ursachen bei staubbedingten Erkrankungen wie Aluminose hilfreich sein. Der vorliegende Fall zeigt, dass die Inhalation von Aluminium eine sekundäre PPFE verursachen kann; ein besonderes Augenmerk sollte auf die Vermeidung einer weiteren Exposition gelegt werden.

Throwing injuries to the shoulder joint often occur during shoulder external rotation. An appropriate combination of thoracic, scapular, and humeral motion during throwing is important to prevent such injuries, but it is unclear how thoracic posture contributes to shoulder motion during throwing.The purpose of this study, therefore, was to clarify the influence of thoracic posture on scapulothoracic and glenohumeral motion during shoulder external rotation.Eccentric external rotation at 90° of shoulder abduction in thoracic flexion and extension postures was performed by 15 asymptomatic participants. Three-dimensional scapulothoracic and glenohumeral movements were measured with an electromagnetic tracking device at 75°, 80°, 85°, and maximum shoulder external rotation. The thoracic angle and maximum shoulder external rotation in absolute coordination were measured with a three-dimensional motion capture system.The results showed that scapular posterior tilting and external rotation in the thoracic extension posture were significantly greater than those in the flexion posture (p 0.05). Glenohumeral horizontal extension was significantly less in the thoracic extension posture than in the flexion posture (p 0.05), whereas maximum shoulder external rotation was significantly greater (p 0.01). Thus, thoracic extension increased scapulothoracic posterior tilting and external rotation and reduced glenohumeral horizontal extension during shoulder external rotation, as well as increasing maximum shoulder external rotation.These findings suggest that thoracic extension may contribute to reduction of mechanical demand in the glenohumeral joint during throwing, potentially reducing shoulder injuries.

Summary Any proposed mechanism for organelle size control should be able to account not only for average size but also for the variation in size. We analyzed cell-to-cell variation and within-cell variation of length for the two flagella in Chlamydomonas, finding that cell-to-cell variation is dominated by cell size, whereas within-cell variation results from dynamic fluctuations. Fluctuation analysis suggests tubulin assembly is not directly coupled with intraflagellar transport (IFT) and that the observed length fluctuations reflect tubulin assembly and disassembly events involving large numbers of tubulin dimers. Length variation is increased in long-flagella mutants, an effect consistent with theoretical models for flagellar length regulation. Cells with unequal flagellar lengths show impaired swimming but improved gliding, raising the possibility that cells have evolved mechanisms to tune biological noise in flagellar length. Analysis of noise at the level of organelle size provides a way to probe the mechanisms determining cell geometry., Graphical abstract, Highlights • Chlamydomonas flagella show dynamic length fluctuations • Length variation involves processes inside the cell body and in the flagella • Long-flagella mutants have increased length variability • Flagellar length variation leads to variation in cell motility, Biological Sciences; Molecular Biology; Cell Biology; Biophysics; Mathematical Biosciences

Obesity is a major public health problem worldwide owing to the substantial increase in risk of metabolic diseases. Hypoxia-inducible factors (HIFs) regulate transcriptional responses to hypoxic stress. DNA methylation in the CpG sites of intron 1 of HIF3A is associated with body mass index in the whole blood and adipose tissue. This study investigates the correlation between DNA methylation of HIF3A and parameters of obesity, including thickness of visceral (VAT) and subcutaneous adipose tissues, in the general Japanese population. Participants (220 men and 253 women) who underwent medical examination were enrolled in this cross-sectional study. We used pyrosequencing to quantify DNA methylation (CpG sites of cg16672562, cg22891070, and cg27146050) in HIF3A. DNA methylation of HIF3A was only different in women. Multiple regression analysis showed that DNA methylation level at cg27146050 was associated with thickness of VAT in women. DNA methylation level at cg27146050 also correlated with body mass index and percentage of body fat in women after excluding smokers and non-smokers who quit smoking with the last 5 years. DNA methylation in the CpG site (cg27146050) of HIF3A correlated with parameters of obesity in Japanese women.

Background Although rotator cuff repair is performed to restore the function of the rotator cuff muscles and glenohumeral (GH) joint motion, little has been known regarding the recovery process. The purpose of this study was (1) to investigate changes over time in activities of the supraspinatus and deltoid muscles assessed by ultrasound real-time tissue elastography (RTE) after rotator cuff repair and (2) to determine contributions of the activities of these muscles to the GH joint motion. Methods Twenty patients after rotator cuff repair and 13 control participants were enrolled in this study. Elasticity of the supraspinatus and middle deltoid muscles were measured at rest and 30° of humerothoracic elevation in the scapular plane (scaption) by using RTE. The elasticity at 30° of scaption was normalized to that at rest in each muscle to quantify their muscle activities. In addition, the supraspinatus-to-middle deltoid (SSP/MD) ratio for the normalized elasticity was calculated. The GH elevation angle was measured with a digital inclinometer, which was calculated by subtracting the scapular upward rotation angle from 30° of scaption. For patients after rotator cuff repair, all measurements were performed at 6 weeks, 8 weeks, 3 months, and 6 months after surgery. Rotator cuff integrity was examined with magnetic resonance imaging at 6 months after surgery. Results Fifteen of 20 patients who remained intact at 6 months after surgery completed this study. The supraspinatus activity at 6 weeks was significantly smaller than that at 3 months (P = .006) and 6 months (P = .010). There was no significant difference in the supraspinatus activity between the patients at 3 months and the control participants (P = .586). The middle deltoid activity at 6 weeks was significantly greater than that at 6 months (P = .003). There was positive correlation between GH elevation angle and the activity of the supraspinatus relative to the deltoid at 6 weeks (r = 0.75, P = .001) and 8 weeks (r = 0.53, P = .041). Conclusion The supraspinatus activity increased from 6 weeks to 3 months after surgery. The supraspinatus activity at 3 months after surgery was the same level as that in healthy individuals. On the other hand, the deltoid activity decreased from 6 weeks to 6 months after surgery. The increase in activity of the supraspinatus relative to the deltoid was likely to be related to the increase in GH elevation during postoperative at 8 weeks.

For human risk assessment of toxic chemicals, especially volatile organic compounds (VOCs), the Ministry of the Environment, Government of Japan, has called for the interconversion of inhalation-dose and oral-dose data, two common exposure routes. To address this issue, the present study investigated the time-course changes of ethylbenzene (EB) concentrations in the blood of rats during and after 6-hr inhalation exposure to EB (25, 50, 100, and 200 ppm) and after oral administration of EB by a single oral gavage (25, 50, 100, and 200 mg/kg) of EB. The Area Under the blood concentration-time Curve (AUC) at each blood collection time point (0, 30, 60, 120, 180, 360, 420, 540, and 1440 min, after starting exposure) was determined. The inhalation dose of 25 ppm corresponded closely to the oral administration of 25 mg/kg・bw (r value of 0.859), and the inhalation dose of 200 ppm correlated with the oral administration of 100 mg/kg・bw (r value of 0.948). These results suggest that this comparison using the AUC data at each blood collection time point is valuable for understanding the route- and dose-effects of EB. This study will improve risk assessment of human exposure to EB and other VOCs.

Analysis of fluctuation in organelle size provides a new way to probe the mechanisms of organelle size control systems. By analyzing cell-to-cell variation and within-cell fluctuations of flagellar length inChlamydomonas, we show that the flagellar length control system exhibits both types of variation. Cell to cell variation is dominated by cell size, while within-cell variation results from dynamic fluctuations that are subject to a constraint, providing evidence for a homeostatic size control system. We analyzed a series of candidate genes affecting flagella and found that flagellar length variation is increased in mutations which increase the average flagellar length, an effect that we show is consistent with a theoretical model for flagellar length regulation based on length-dependent intraflagellar transport balanced by length-independent disassembly. Comparing the magnitude and time-scale of length fluctuations with simple models suggests that tubulin assembly is not directly coupled with IFT-mediated arrival and that observed fluctuations involve tubulin assembly and disassembly events involving large numbers of tubulin dimers. Cells with greater differences in their flagellar lengths show impaired swimming but improved gliding motility, raising the possibility that cells have evolved mechanisms to tune intrinsic noise in length. Taken together our results show that biological noise exists at the level of subcellular structures, with a corresponding effect on cell function, and can provide new insights into the mechanisms of organelle size control.

Objective MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression and play essential roles in the pathogenesis of cardiovascular disease. Previous cross-sectional studies showed that the levels of several circulating miRNA are associated with hypertension, but there are no prospective longitudinal studies using a general population. The aim of this study is to evaluate the impact of circulating vascular-related miRNA (miR-126, miR-221, and miR-222) on changes in blood pressure and new-onset hypertension in a Japanese population. Methods We conducted a 5-year longitudinal study using 192 health examination participants (87 men and 105 women). Serum miRNAs were measured using quantitative reverse transcription-PCR. Information regarding lifestyle and health condition was obtained using a self-administered questionnaire. Logistic regression analyses were performed to calculate odds ratios and 95% confidence intervals for new-onset hypertension in the 5-year period between the low and high group of serum miRNAs. Results Serum levels of miR-126, miR-221, and miR-222 were significantly and negatively associated with changes in SBP and the rate of change of SBP. Serum miR-126, miR-221, and miR-222 levels were significantly lower in new-onset hypertensive patients compared with normotensive individuals. The confounding factors adjusted odds ratios of each 1 increment in serum miR-126, miR-221, and miR-222 levels were 0.82 (95% confidence interval: 0.69-0.98), 0.79 (0.68-0.91), and 0.61 (0.46-0.81) for new-onset hypertension, respectively. Conclusion Low serum levels of miR-126, miR-221, and miR-222 were associated with increased blood pressure and new-onset of hypertension. These circulating miRNAs are potential candidate biomarkers for the prediction of hypertension.

In this work, the design methodologies and technical rationales for the design of JAXA’s low-boom S4 (System integration of Silent SuperSonic airplane technologies) airliner are detailed with a focus on aerodynamic engine-airframe integration with respect to efficiency and sonic-boom abatement, respectively. The approach to high-fidelity CFD grid generation, flow simulation, and signature propagation for sonic boom assessment is explained, resulting in sonic-boom data maps with respect to flight physics parameters. Thereafter, DLR inserts the aircraft in operational scenarios for supersonic overland prohibition and permission, respectively, based on forecasted origin-destination passenger demand. Overwater flight routes are designed for the restrictive scenario, and the S4’s flight performance data are used to simulate flight missions on all routes, yielding flight durations. Eventually, the respective market sizes for S4-type airliners are estimated and discussed.

Background: Pitch velocity is associated with elbow injuries among skillful baseball players. However, the relationship between pitch velocity and throwing elbow injuries among youth players has not yet been clarified. Purpose: To investigate the influence of pitch velocity on medial elbow pain and medial epicondyle abnormality among youth baseball players. Study Design: Cohort study; Level of evidence, 3. Methods: The participants consisted of 256 elementary school players (mean age, 11 ± 1 years; range, 9-12 years). The medial aspect of the elbow was evaluated using ultrasound imaging. A questionnaire was used to investigate past or present pain in the elbow, background of the players (age, height, body mass index, and years of baseball experience), and playing environment (number of days of practice in a week, experience as a pitcher, and cryotherapy of the shoulder and elbow after practice). Positioning of the scapula, range of motion in shoulder internal/external rotations and hip internal rotation, angle of the straight-leg raise, and heel-to-buttock distance were measured. The pitch velocity was recorded using a pitch velocity radar gun. The relationship between these variables and the presence of medial epicondyle abnormality, as well as past or present elbow pain, were statistically analyzed. Results: A medial epicondyle abnormality was observed in 130 players (51%), elbow pain in the past in 65 players (25%), and elbow pain during the examination in 14 players (5%). Sixty-nine players (27%) experienced elbow pain either in the past or during examination. Abnormality of the medial epicondyle had a relationship with the pitch velocity (odds ratio [OR], 1.1 for increase of 1 km/h; 95% CI, 1.1-1.2; P < .0001) and the number of practice days in a week (OR, 1.8 for increase of the practice days; 95% CI, 1.4-2.5; P < .0001). Pitch velocity was also significantly related with past pain, present pain, and past and/or present pain of the elbow (OR [km/h], 1.1, 1.1, 1.1; 95% CI, 1.0-1.1, 1.0-1.2, 1.1-1.2; P < .0001, P = .002, P < .0001, respectively). Conclusion: Pitch velocity was significantly associated with abnormality of the medial epicondyle and elbow pain. A 10-km/h increase in pitch velocity would increase the risk of medial epicondyle abnormality and medial elbow pain by 3 times.

Objectives A diet rich in fish and ω-3 polyunsaturated fatty acids (PUFAs) has been thought to reduce the risk for cardiovascular disease (CVD). The beneficial effects of fish oil and ω-3 PUFA on CVD can be mediated by epigenetic status of the genes associated with lipid metabolism and inflammation. The aim of this study was to investigate whether dietary fish and fatty acid (FA) intakes are associated with leukocyte ATP-binding cassette transporter A1 (ABCA1) DNA methylation levels in a Japanese population. Methods This cross-sectional study included 298 adults (137 men and 161 women) without clinical history of CVD or cancer. The pyrosequencing method was used to measure leukocyte ABCA1 DNA methylation levels. Dietary fish and FA intakes were assessed based on the validated food frequency questionnaire. Results Mean ABCA1 DNA methylation levels were significantly lower in the highest fish intake groups (≥5–6/wk) compared with the lowest intake group (≤1–2/wk; P = 0.004). In multivariable linear regression analyses, higher dietary intake of ω-3 PUFAs and ω-3 highly unsaturated fatty acids was significantly associated with decreased levels of ABCA1 DNA methylation (P = 0.001 and 0.005); whereas no significant associations were seen between intake of dietary saturated fatty acid, monounsaturated fatty acid, and ω-6 PUFAs and ABCA1 DNA methylation. Conclusion Higher dietary fish and ω-3 PUFA intake were associated with lower ABCA1 DNA levels in a Japanese population. The present results may bring potential insights on biological mechanisms underlying the protective effects of dietary fish and ω-3 PUFA intakes on CVD.