Publications by authors named "Minoru Tanaka"

266 Publications

Nucleoprotein-enriched diet enhances the protein synthesis pathway and satellite cell activation via ERK1/2 phosphorylation in the unloaded rat muscle.

Exp Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Suma-ku, Kobe, Hyogo, 654-0142, Japan.

New Findings: What is the central question of this study? The purpose of this study was to determine if the nucleotides in a nucleoprotein diet could ameliorate the unloading-associated decrease in soleus muscle mass and fiber size. What is the main finding and its importance? The results indicate that the nucleotides in the nucleoprotein-enriched diet could ameliorate the unloading-associated decrease in type I fiber size and muscle mass most likely due to the activation of protein synthesis pathways and satellite cell proliferation and differentiation via ERK1/2 phosphorylation. Thus nucleotide supplementation appears to be an effective countermeasure for muscle atrophy.

Abstract: Hindlimb unloading decreases both protein synthesis pathway and satellite cell activation results in muscle atrophy. Nucleotides are included in nucleoprotein and provide the benefits of increasing ERK1/2 phosphorylation. ERK 1/2 phosphorylation is also important in the activation of satellite cells, especially for myoblast proliferation and stimulating protein synthesis pathways. Therefore, we hypothesized that nucleotide in the nucleoproteins would ameliorate muscle atrophy via increasing the protein synthesis pathways and satellite cell activation during hindlimb unloading in rat soleus. Twenty-four female Wistar rats were divided into four groups: control rats fed a basal diet without nucleoprotein (CON), control rats fed a nucleoprotein-enriched diet (CON+NP), hindlimb unloaded rats fed a basal diet (HU), or hindlimb unloaded rats fed a NP diet (HU+NP). HU for two-weeks resulted in decreases in p70S6K- and rpS6-phosphorylation, the numbers of MyoD and myogenin, type I muscle fiber size, and muscle mass. Both CON and HU rats fed the NP diet showed an increase in ERK1/2, p70S6K- and rpS6-phosphorylation, and in the number of MyoD and myogenin compared to their basal diet groups. The NP diet also ameliorated the unloading-associated decrease in type I muscle fiber size and muscle mass. The results indicate that the nucleotides in the nucleoprotein-enriched diet could ameliorate the unloading-associated decrease in type I fiber size and muscle mass most likely due to the activation of protein synthesis pathways and satellite cell proliferation and differentiation via ERK1/2 phosphorylation. Thus nucleotide supplementation appears to be an effective countermeasure for muscle atrophy. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/EP089337DOI Listing
April 2021

Reduced metabolic capacity in fast and slow skeletal muscle via oxidative stress and the energy-sensing of AMPK/SIRT1 in malnutrition.

Physiol Rep 2021 Mar;9(5):e14763

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

The effects of malnutrition on skeletal muscle result in not only the loss of muscle mass but also fatigue intolerance. It remains unknown whether the metabolic capacity is related to the fiber type composition of skeletal muscle under malnourished condition although malnutrition resulted in preferential atrophy in fast muscle. The purpose of the present study was to investigate the effects of metabolic capacity in fast and slow muscles via the energy-sensing of AMPK and SIRT1 in malnutrition. Wistar rats were randomly divided into control and malnutrition groups. The rats in the malnutrition group were provided with a low-protein diet, and daily food intake was limited to 50% for 12 weeks. Malnutrition with hypoalbuminemia decreased the body weight and induced the loss of plantaris muscle mass, but there was little change in the soleus muscle. An increase in the superoxide level in the plasma and a decrease in SOD-2 protein expression in both muscles were observed in the malnutrition group. In addition, the expression level of AMPK in the malnutrition group increased in both muscles. Conversely, the expression level of SIRT1 decreased in both muscles of the malnutrition group. In addition, malnutrition resulted in a decrease in the expression levels of PGC-1α and PINK protein, and induced a decrease in the levels of two key mitochondrial enzymes (succinate dehydrogenase and citrate synthase) and COX IV protein expression in both muscles. These results indicate that malnutrition impaired the metabolic capacity in both fast and slow muscles via AMPK-independent SIRT1 inhibition induced by increased oxidative stress.
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http://dx.doi.org/10.14814/phy2.14763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923585PMC
March 2021

Observation of Medaka Larval Gonads by Immunohistochemistry and Confocal Laser Microscopy.

Methods Mol Biol 2021 ;2218:209-218

Division of Biological Sciences, Graduate School of Science, Nagoya University, Nagoya, Japan.

The combination of immunohistochemistry and confocal laser microscopy enables the observation of cellular structures and protein localization within cells using whole-mount tissues. However, such high-resolution imaging requires several steps, such as proper dissection before fixation and antibody staining, and the appropriate positioning of tissues on a glass slide for observation. Here, we describe the method developed by our laboratory for the immunohistochemistry of medaka embryonic and larval gonads, focusing on the dissection and mounting of tissues for confocal laser microscopy. Positioning the gonad just beneath the coverslips is essential to obtain high-resolution images at a level where cellular components of germ cells, such as germ plasm and nuclear structures, can be clearly observed using an oil immersion objective lens.
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http://dx.doi.org/10.1007/978-1-0716-0970-5_17DOI Listing
March 2021

Photoperiod-Specific Expression of Eyes Absent 3 Splice Variant in the Pars Tuberalis of the Japanese Quail.

J Poult Sci 2021 Jan;58(1):64-69

Department of Animal Science, Faculty of Applied Life Science, Nippon Veterinary and Life Science University, Musashino, Tokyo 180-8602, Japan.

The molecular mechanism underlying photoperiodic response in seasonal breeding animals such as the Japanese quail, red jungle fowl, sheep, mouse, and hamster involves thyroid-stimulating hormone beta subunit () mRNA expression in the pars tuberalis stimulated by the extension in day length. Furthermore, this mechanism is regulated by eyes absent 3 () in mammals. Even in birds, the expression of both and is induced in the pars tuberalis by the extension in day length; however, the relationship between the two genes is unknown. To clarify the function of EYA3 in quail photoperiodism, in the present study, we performed mRNA structure analysis of the Japanese quail mRNA using reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis. The results revealed that there are four types of splice variants within regions of exons 7, 8, and 9 of quail mRNA. Among the four splice variants of quail , the splice variant containing exon 7 was expressed in the pars tuberalis on the first long day, when quails were transferred from the short-day condition to the long-day condition. The results indicate that splice variant containing exon 7 is involved in the photoperiodic response of the pars tuberalis in the Japanese quail.
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http://dx.doi.org/10.2141/jpsa.0190135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837804PMC
January 2021

Preventive effects of low-intensity endurance exercise for severe hyperglycemia-induced capillary regression in non-obese type 2 diabetes rat skeletal muscle.

Physiol Rep 2021 Jan;9(2):e14712

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.

Although endurance exercise is effective for reducing diabetes-related capillary regression, it is difficult to prescribe high-intensity endurance exercise due to the potential worsening of complications in patients with severe hyperglycemia. Therefore, this study aimed to examine whether chronic low-intensity exercise training may prevent severe hyperglycemia-induced capillary regression of skeletal muscle in non-obese type 2 diabetes. Non-diabetic Sprague Dawley rats were assigned to a control (Con) group and an exercise (Ex) group. Likewise, spontaneously diabetic Torii rats were assigned to a diabetic sedentary (DM) group or a diabetic exercise (DMEx) group. Rats in the Ex and DMEx groups were placed on a motor-driven treadmill running at low speed (15 m/min) for 60 min/day, 5 days/week, for 14 weeks. Serum glucose levels were significantly increased in the DM group, but not in the DMEx group. Although the capillary-to-fiber ratio in the plantaris muscle was significantly lower in the DM group compared to the control group, the ratio in the DMEx group was significantly higher compared to the DM group. Moreover, the succinate dehydrogenase activity and expression levels of vascular endothelial growth factor and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) were reduced in the plantaris muscle of the DM group. However, those in the DMEx group were significantly higher than those in the DM group. These results indicate that low-intensity chronic endurance exercise training has the potential to prevent the progression of capillary regression in the skeletal muscles of non-obese type 2 diabetes patients with severe hyperglycemia.
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http://dx.doi.org/10.14814/phy2.14712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814498PMC
January 2021

Dietary casein, egg albumin, and branched-chain amino acids attenuate phosphate-induced renal tubulointerstitial injury in rats.

Sci Rep 2020 11 4;10(1):19038. Epub 2020 Nov 4.

Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Dietary phosphate intake is closely correlated with protein intake. However, the effects of the latter on phosphate-induced organ injuries remain uncertain. Herein, we investigated the effects of low (10.8%), moderate (23.0%), and high (35.2%) dietary casein and egg albumin administration on phosphate-induced organ injuries in rats. The moderate and high casein levels suppressed renal tubulointerstitial fibrosis and maintained mitochondrial integrity in the kidney. The serum creatinine levels were suppressed only in the high casein group. Phosphate-induced muscle weakness was also ameliorated by high dietary casein. The urinary and fecal phosphate levels in the early experiment stage showed that dietary casein did not affect phosphate absorption from the intestine. High dietary egg albumin showed similar kidney protective effects, while the egg albumin effects on muscle weakness were only marginally significant. As the plasma branched-chain amino acid levels were elevated in casein- and egg albumin-fed rats, we analyzed their effects. Dietary supplementation of 10% branched-chain amino acids suppressed phosphate-induced kidney injury and muscle weakness. Although dietary protein restriction is recommended in cases of chronic kidney disease, our findings indicate that the dietary casein, egg albumin, and branched-chain amino acid effects might be reconsidered in the era of a phosphate-enriched diet.
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http://dx.doi.org/10.1038/s41598-020-76228-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643071PMC
November 2020

Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles.

FASEB J 2020 11 5;34(11):14389-14406. Epub 2020 Sep 5.

Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

We hypothesized that pre-exercise may effectively prevent cancer cachexia-induced muscle atrophy in both fast- and slow-twitch muscle types. Additionally, the fast-twitch muscle may be more affected by cancer cachexia than slow-twitch muscle. This study aimed to evaluate the effects of pre-exercise on cancer cachexia-induced atrophy and on atrophy in fast- and slow-twitch muscles. Twelve male Wistar rats were randomly divided into sedentary and exercise groups, and another 24 rats were randomly divided into control, pre-exercise, cancer cachexia induced by intraperitoneal injections of ascites hepatoma AH130 cells, and pre-exercise plus cancer cachexia groups. We analyzed changes in muscle mass and in gene and protein expression levels of major regulators and indicators of muscle protein degradation and synthesis pathways, angiogenic factors, and mitochondrial function in both the plantaris and soleus muscles. Pre-exercise inhibited muscle mass loss, rescued protein synthesis, prevented capillary regression, and suppressed hypoxia in the plantaris and soleus muscles. Pre-exercise inhibited mitochondrial dysfunction differently in fast- and slow-twitch muscles. These results suggested that pre-exercise has the potential to inhibit cancer-cachexia-induced muscle atrophy in both fast- and slow-twitch muscles. Furthermore, the different progressions of cancer-cachexia-induced muscle atrophy in fast- and slow-twitch muscles are related to differences in mitochondrial function.
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http://dx.doi.org/10.1096/fj.202001330RDOI Listing
November 2020

Critical roles of the ddx5 gene in zebrafish sex differentiation and oocyte maturation.

Sci Rep 2020 09 1;10(1):14157. Epub 2020 Sep 1.

Laboratory for Developmental Biology, Center for Medical Education and Sciences, Graduate School of Medical Science, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan.

DEAD-box helicase 5 (Ddx5) functions as an ATP-dependent RNA helicase and as a transcriptional coactivator for several transcription factors; however, the developmental function of the ddx5 gene in vertebrates is not fully understood. We found that the zebrafish ddx5 gene was expressed in developing gonads. Using the genome editing technology transcription activator-like effector nuclease, we established a ddx5-disrupted zebrafish and examined the morphological phenotypes of the mutant. We found that the majority of ddx5-deficient mutants developed as fertile males with normal testes and a small number of ddx5-deficient mutants developed as infertile females with small ovaries. Apoptotic cell death at 31 days post fertilization was increased in thick immature gonads (presumptive developing ovaries) of the ddx5-deficient mutant compared to those of heterozygous wild-type fish, while the number of apoptotic cells in thin immature gonads (presumptive developing testes) was comparable between the mutant and wild-type animals. Histological analysis revealed that ovaries of adult ddx5-deficient females had fewer vitellogenic oocytes and a larger number of stage I and II oocytes. The amount of cyclic adenosine monophosphate in the ddx5-deficient ovaries was high compared to that of wild-type ovaries, presumably leading to the mitotic arrest of oocyte maturation. Therefore, the ddx5 gene is dispensable for testis development, but it is essential for female sex differentiation and oocyte maturation in zebrafish.
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http://dx.doi.org/10.1038/s41598-020-71143-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463030PMC
September 2020

Preventive effects of medium-chain triglycerides supplementation on the oxidative capacity in skeletal muscle under cachectic condition.

Biomed Res 2020 ;41(4):179-186

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences.

Cachexia is a multifactorial condition characterized by muscle mass loss and induces metabolic dysfunction of the skeletal muscles. The preventive effects of medium-chain triglycerides (MCT) supplementation on the oxidative capacity in skeletal muscle under cachectic condition were investigated in the present study. ICR mice were randomly divided into four groups; control, lipopolysaccharide (LPS), LPS plus long-chain triglycerides (LCT) and LPS plus MCT supplementation. LCT and MCT oil were administered to the LPS + LCT and LPS + MCT groups orally (5.0 g/kg body weight/day) by a catheter for one week. Cachexia was induced in the LPS, LPS + LCT, and LPS + MCT groups via LPS injection (7.5 mg/kg body weight, i.p.) after the supplementation. LPS induced a reduction of ketone bodies concentration in blood plasma. LPS also induced a decrease in succinate dehydrogenase activity and PGC-1α expression level in tibialis anterior muscles. Meanwhile, MCT supplementation suppressed a decrease in ketone bodies concentration and succinate dehydrogenase activity. In addition, MCT supplementation increased the level of citrate synthase activity in the muscles. These results suggested the preventive effect of MCT supplementation on oxidative capacity in skeletal muscle and the involvements of ketone bodies regulation under cachectic condition.
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http://dx.doi.org/10.2220/biomedres.41.179DOI Listing
January 2020

Giant Fusiform and Dolichoectatic Aneurysms of the Basilar Trunk and Vertebrobasilar Junction-Clinicopathological and Surgical Outcome.

Neurosurgery 2020 12;88(1):82-95

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.

Background: Giant fusiform and dolichoectatic aneurysms of the basilar trunk and vertebrobasilar junction (BTVBJ-GFDA) are extremely difficult to treat.

Objective: To evaluate factors influencing survival and outcome of BTVBJ-GFDA by performing a retrospective multicenter cohort study.

Methods: A total of 32 patients with BTVBJ-GFDA were included in this study. Clinicopathological characteristics, treatment measures, and outcomes were collected from medical records and imaging studies. Autopsy and histological findings of the aneurysm and adjacent brain tissue were also obtained in 9 cases.

Results: A total of 11 patients did not undergo surgery, of whom 10 died; 3 from progressive brainstem compression, 4 from subarachnoid hemorrhage, 2 from brainstem infarction, and 1 from associated atherosclerotic disease. The remaining 21 patients underwent a surgical treatment, consisting of immediately proximal parent artery occlusion, remotely proximal parent artery occlusion, clip reconstruction, and distal bypass and achieved significantly longer overall survival compared with those who received conservative therapy (adjusted hazard ratio 1.508, 95% CI 1.058-2.148, P = .02). Histological examination of the aneurysms demonstrated staged clots, open lumen, and intrathrombotic channels with endothelial lining. The patients younger than 45 yr of age showed statistically longer survival than those equal and older than 45 yr (P = .03).

Conclusion: Surgical intervention achieved greater survival than conservative management in BTVBJ-GFDA. Narrow ideal treatment window of the blood flow within the aneurysm to maintain sufficient but not excess supply should be targeted based on the hemodynamics of both the posterior communicating arteries and perforating vessel collaterals.
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http://dx.doi.org/10.1093/neuros/nyaa317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891276PMC
December 2020

Acute effects of lactic acid-fermented and enzyme-digested soybean on protein synthesis via mTOR signaling in the skeletal muscle.

Biosci Biotechnol Biochem 2020 Nov 22;84(11):2360-2366. Epub 2020 Jul 22.

Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences , Kobe, Japan.

Protein-containing nutrients result in the efficient hypertrophy of muscles by increasing muscle protein synthesis. Soybean is often ingested by athletes or individuals who exercise; however, it takes very long to be absorbed. Lactic acid-fermented and enzyme-digested (LFED) soybean is absorbed faster than untreated soybean. This study aims at determining muscle protein synthesis after ingesting a single bolus of soybean or LFED soybean produced by lactic acid bacteria and protease digestion. Eight-week-old overnight-fasted ICR mice were administered powdered or LFED soybean. Mice were euthanized at 7, 15, 30, 60, 90, and 120 min after soybean intake. We have demonstrated that LFED soybean administration was quicker in stimulating muscle protein synthesis by activating mammalian target of rapamycin (mTOR) signaling than orally ingesting untreated soybean in the gastrocnemius muscle. These results suggested that LFED soybean is a more efficient source of nutrition for muscle hypertrophy than untreated soybean.
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http://dx.doi.org/10.1080/09168451.2020.1795810DOI Listing
November 2020

Factors in Color Fundus Photographs That Can Be Used by Humans to Determine Sex of Individuals.

Transl Vis Sci Technol 2020 01 30;9(2). Epub 2020 Jan 30.

Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Purpose: Artificial intelligence (AI) can identify the sex of an individual from color fundus photographs (CFPs). However, the mechanism(s) involved in this identification has not been determined. This study was conducted to determine the information in CFPs that can be used to determine the sex of an individual.

Methods: Prospective observational cross-sectional study of 112 eyes of 112 healthy volunteers. The following characteristics of CFPs were analyzed: the color of peripapillary area expressed by the mean values of red, green, and blue intensities, and the tessellation expressed by the tessellation fundus index (TFI). The optic disc ovality ratio, papillomacular angle, retinal artery trajectory, and retinal vessel angles were also quantified. Their differences between the sexes were assessed by Mann-Whitney tests. Regularized binomial logistic regression was used to select the decisive factors. In addition, its discriminative performance was evaluated through the leave-one-out cross validation.

Results: The mean age of 76 men and 36 women was 25.8 years. The regularized binomial logistic regression delivered the optimal model for sex selected variables of peripapillary temporal green and blue intensities, temporal TFI, supratemporal TFI, optic disc ovality ratio, artery trajectory, and supratemporal retinal artery angle. With this approach, the discrimination accuracy rate was 77.9%.

Conclusions: Human-assessed characteristics of CFPs are useful in investigating the new theme proposed by AI, the sex of an individual.

Translational Relevance: This is the first report to approach the thinking process of AI by humans and can be a new approach to medical AI research.
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http://dx.doi.org/10.1167/tvst.9.2.4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255626PMC
January 2020

, a sexual switch in germ cells, initiates two independent molecular pathways for commitment to oogenesis in medaka.

Proc Natl Acad Sci U S A 2020 06 14;117(22):12174-12181. Epub 2020 May 14.

Division of Biological Science, Graduate School of Science, Nagoya University, 464-8602 Nagoya, Japan;

Germ cells have the ability to differentiate into eggs and sperm and must determine their sexual fate. In vertebrates, the mechanism of commitment to oogenesis following the sexual fate decision in germ cells remains unknown. () is a switch gene involved in the germline sexual fate decision in the teleost fish medaka (). Here, we show that organizes two independent pathways of oogenesis regulated by (), a cohesin component, and (FBP (), a subunit of E3 ubiquitin ligase. In mutants of either gene, germ cells failed to undergo oogenesis but developed normally into sperm in testes. Disruption of resulted in arrest at a meiotic pachytenelike stage specifically in females, revealing a sexual difference in meiotic progression. Analyses of mutants showed that this gene regulates transcription factors that facilitate folliculogenesis: (), α (), and (). Interestingly, we found that the pathway ensures that germ cells do not deviate from an oogenic pathway until they reach diplotene stage. The mutant phenotypes together with the timing of their expression imply that germline feminization is established during early meiotic prophase I.
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http://dx.doi.org/10.1073/pnas.1918556117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275758PMC
June 2020

The Influence of Pitch Velocity on Medial Elbow Pain and Medial Epicondyle Abnormality Among Youth Baseball Players.

Am J Sports Med 2020 06 4;48(7):1601-1607. Epub 2020 May 4.

Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan.

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; < .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; < .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; < .0001, = .002, < .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.
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http://dx.doi.org/10.1177/0363546520914911DOI Listing
June 2020

Efficacy of a Third-Generation Oncolytic Herpes Virus G47Δ in Advanced Stage Models of Human Gastric Cancer.

Mol Ther Oncolytics 2020 Jun 8;17:205-215. Epub 2020 Apr 8.

Division of Innovative Cancer Therapy, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.

Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies. G47Δ, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer. In this study, we investigated the therapeutic potential of G47Δ for human gastric cancer. , G47Δ showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. , intratumoral inoculations with G47Δ (2 × 10 or 1 × 10 plaque-forming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47Δ for advanced-stage models of gastric cancer, we generated an orthotopic tumor model and peritoneal dissemination models of human scirrhous gastric cancer (MKN45-luc and 44As3Luc), which have features mimicking intractable scirrhous cancer patients. G47Δ (1 × 10 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47Δ injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors. Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47Δ injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47Δ for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.
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http://dx.doi.org/10.1016/j.omto.2020.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178322PMC
June 2020

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior.

Proc Natl Acad Sci U S A 2020 04 10;117(17):9594-9603. Epub 2020 Apr 10.

Institute of Transformative Bio-Molecules (ITbM), Nagoya University, 464-8601 Nagoya, Japan;

Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.
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http://dx.doi.org/10.1073/pnas.2000278117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196813PMC
April 2020

Starvation causes female-to-male sex reversal through lipid metabolism in the teleost fish, medaka ().

Biol Open 2020 04 7;9(4). Epub 2020 Apr 7.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan

The teleost fish, medaka (), employs the XX/XY genetic sex determination system. We show here that the phenotypic sex of medaka is affected by changes in lipid metabolism. Medaka larvae subjected to 5 days of starvation underwent female-to-male sex reversal. Metabolomic and RT-qPCR analyses indicated that pantothenate metabolism was suppressed by starvation. Consistently, inhibiting the pantothenate metabolic pathway caused sex reversal. The final metabolite in this pathway is coenzyme A, an essential factor for lipogenesis. Inhibiting fatty acid synthesis, the first step of lipogenesis, also caused sex reversal. The expression of , a critical gene for male development, was suppressed by starvation, and a (Δ13) mutant did not show sex reversal under starvation. Collectively, these results indicate that fatty acid synthesis is involved in female-to-male sex reversal through ectopic expression of male gene under starvation.
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http://dx.doi.org/10.1242/bio.050054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132775PMC
April 2020

Relationship between peripapillary choroidal thickness and degree of tessellation in young healthy eyes.

Graefes Arch Clin Exp Ophthalmol 2020 Aug 4;258(8):1779-1785. Epub 2020 Apr 4.

Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Purpose: To determine the relationship between the peripapillary choroidal thickness (ppCT) and the degree and distribution of the tessellation in the fundus of normal eyes.

Methods: This was a prospective, observational cross-sectional study of 118 right eyes of young healthy volunteers. The ppCT was measured from the optical coherence tomography (OCT) circle scans manually at eight sectors: the nasal, supranasal superior, supratemporal, temporal, infratemporal, inferior, and infranasal sectors. The subjective degree of the tessellation in the color fundus photographs (CFPs) was classified into three categories: non-tessellated (NT), weakly tessellated (WT), and strongly tessellated (ST) in same sectors. The objective degree of tessellation designated by the tessellation fundus index (TFI) which was calculated as TFI = (R - G)/(R + G + B) using the mean value of the red-green-blue intensities of the CFPs. The differences in the ppCT and TFI for the three tessellation groups were analyzed. The correlations between the TFI and the ppCT were also determined.

Results: The mean age of the subjects was 25.8 years and the mean axial length of the eye was 25.5 mm. The inter-rater agreement of the subjective classifications was high with a Fleiss kappa of 0.71. The ppCT was significantly thinner in eyes with higher degrees of tessellation (P < 0.05) in all sectors. The TFIs were significantly and negatively correlated with the ppCTs in all sectors (r = - 0.44 to - 0.24, P < 0.05) except the nasal and the supranasal sectors.

Conclusion: The degree of peripapillary tessellation is significantly correlated with the ppCT in young healthy eyes, and it has large individual and geographic variations.
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http://dx.doi.org/10.1007/s00417-020-04644-5DOI Listing
August 2020

Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery.

J Biol Eng 2020 19;14:11. Epub 2020 Mar 19.

1Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.

Background: Liver metabolites are used to diagnose disease and examine drugs in clinical pharmacokinetics. Therefore, development of an in vitro assay system that reproduces liver metabolite recovery would provide important benefits to pharmaceutical research. However, liver models have proven challenging to develop because of the lack of an appropriate bile duct structure for the accumulation and transport of metabolites from the liver parenchyma. Currently available bile duct models, such as the bile duct cyst-embedded extracellular matrix (ECM), lack any morphological resemblance to the tubular morphology of the living bile duct. Moreover, these systems cannot overcome metabolite recovery issues because they are established in isolated culture systems. Here, we successfully established a non-continuous tubular bile duct structure model in an open-culture system, which closely resembled an in vivo structure. This system was utilized to effectively collect liver metabolites separately from liver parenchymal cells.

Results: Triple-cell co-culture of primary rat hepatoblasts, rat biliary epithelial cells, and mouse embryonic fibroblasts was grown to mimic the morphogenesis of the bile duct during liver development. Overlaying the cells with ECM containing a Matrigel and collagen type I gel mixture promoted the development of a tubular bile duct structure. In this culture system, the expression of specific markers and signaling molecules related to biliary epithelial cell differentiation was highly upregulated during the ductal formation process. This bile duct structure also enabled the separate accumulation of metabolite analogs from liver parenchymal cells.

Conclusions: A morphogenesis-based culture system effectively establishes an advanced bile duct structure and improves the plasticity of liver models feasible for autologous in vitro metabolite-bile collection, which may enhance the performance of high-throughput liver models in cell-based assays.
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http://dx.doi.org/10.1186/s13036-020-0230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081557PMC
March 2020

Relationship Between Funduscopic Conus and Optic Disc Factors Associated with Myopia in Young Healthy Eyes.

Invest Ophthalmol Vis Sci 2020 02;61(2):40

,.

Purpose: To determine the relationship between funduscopic findings in myopic eyes and the prevalence and structure of the conus in the optical coherence tomographic (OCT) images.

Methods: A prospective observational cross-sectional study of 121 right eyes of 121 young healthy volunteers. All participants underwent color fundus photography (CFP), scanning laser ophthalmoscopy, and OCT. Based on the OCT analyses, the area between the edge of the ellipsoid zone (EZ) and that of choroid was defined as the "choroidal conus (CC)", and the area between the edge of the choroid and the scleral edge as the "scleral conus (SC)". The eyes were classified into three groups such as the non-conus (NC) group, CC group, and SC group. The differences in the axial length, optic disc tilt, ovality ratio, papillomacular position angle, and peripapillary nerve fiber elevation (pNFE) between the three groups were determined.

Results: CFPs detected a conus in 79 eyes (65.3 %). The outer border of the conus in CFPs corresponded with the edge of the EZ in the OCT in all subjects. Thirty-seven eyes had CC alone (CC group) and 42 eyes had both CC and SC (SC group). The CC and SC groups had longer axial lengths and more frequent pNFEs than the NC group. There was a significant difference in the optic disc tilt and ovality ratio between the CC and SC groups.

Conclusions: The eyes with SC tend to have larger optic disc tilt and smaller ovality ratio than the eyes with CC only.
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http://dx.doi.org/10.1167/iovs.61.2.40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329628PMC
February 2020

Osteointegration of a Biocomposite Suture Anchor After Arthroscopic Shoulder Labral Repair.

Arthroscopy 2019 12 14;35(12):3173-3178. Epub 2019 Nov 14.

Matsudo Orthopaedic Hospital, Matsudo, Japan.

Purpose: To evaluate osteoconductivity of a poly-L-lactide co-glycolide (PLG)-calcium sulfate (CS)-β-tricalcium phosphate (β-TCP) biocomposite suture anchor after arthroscopic shoulder labral repair.

Methods: The subjects of this study were patients who participated in a clinical trial for acquisition of marketing approval of a PLG-CS-β-TCP biocomposite anchor in Japan. They underwent arthroscopic labral repair using the anchor, and computed tomographic (CT) images of the glenoid were obtained 2 years after surgery. Osteoconductivity at the anchor sites was evaluated with the CT images using the established ossification quality score. Shoulder function scores including the Rowe score and Japanese Shoulder Society shoulder instability score were also assessed 2 years after surgery.

Results: CT images and functional scores were obtained from 37 patients, comprising 29 men and 8 women with a mean age of 29 years (range, 25-33 years) at surgery. A total of 148 anchors were implanted in the 37 shoulders. Osteoconductivity was seen in 133 of 148 anchor sites (90.0%) 2 years after implantation. No significant differences in osteoconductivity were found by anchor diameter or position. The Rowe score significantly improved from 39.9 points (95% confidence interval [CI], 33.8-45.9 points) preoperatively to 96.6 points (95% CI, 95.1-98.1 points) at 2 years postoperatively (P < .001). The Japanese Shoulder Society shoulder instability score also significantly improved, from 63.1 points (95% CI, 58.4-67.7 points) preoperatively to 96.3 points (95% CI, 94.7-97.8 points) at 2 years postoperatively (P < .001).

Conclusions: Biocomposite suture anchors made of PLG, CS, and β-TCP exhibited some osteoconductivity 2 years after arthroscopic labral repair, as well as good clinical outcomes.

Level Of Evidence: Level IV, therapeutic case series.
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http://dx.doi.org/10.1016/j.arthro.2019.06.023DOI Listing
December 2019

Effects of combined treatment with blood flow restriction and low-current electrical stimulation on muscle hypertrophy in rats.

J Appl Physiol (1985) 2019 11 26;127(5):1288-1296. Epub 2019 Sep 26.

Department of Rehabilitation Science, Kobe University Graduate School of Health Science, Kobe, Japan.

This study aimed to clarify the effects of a combined treatment comprising blood flow restriction and low-current electrical stimulation on skeletal muscle hypertrophy in rats. Male Wistar rats were divided into control (Cont), blood flow restriction (Bfr), electrical stimulation (Es), or Bfr with Es (Bfr + Es) groups. Pressure cuffs (80 mmHg) were placed around the thighs of Bfr and Bfr + Es rats. Low-current Es was applied to calf muscles in the Es and Bfr + Es rats. In , a 1-day treatment regimen (5-min stimulation, followed by 5-min rest) was delivered four times to study the acute effects. In , the same treatment regimen was delivered three times/wk for 8 wk. Body weight, muscle mass, changes in maximal isometric contraction, fiber cross-sectional area of the soleus muscle, expression of phosphorylated and total-ERK1/2, phosphorylated-rpS6 Ser, phosphorylated and total Akt, and phosphorylated-rpS6 Ser were measured. Bfr and Es treatment alone failed to induce muscle hypertrophy and increase the expression of phosphorylated rpS6 Ser. Combined Bfr + Es upregulated muscle mass, increased the fiber cross-sectional area, and increased phosphorylated rpS6 Ser expression and phosphorylated rpS6 Ser expression compared with controls. Combined treatment with Bfr and low-current Es can induce muscle hypertrophy via activation of two protein synthesis signaling pathways. This treatment should be introduced for older patients with sarcopenia and others with muscle weakness. We investigated the acute and chronic effect of low-current electrical stimulation with blood flow restriction on skeletal muscle hypertrophy and the mechanisms controlling the hypertrophic response. Low-current electrical stimulation could not induce skeletal muscle hypertrophy, but a combination treatment did. Blood lactate and growth hormone levels were increased in the early response. Moreover, activation of ERK1/2 and mTOR pathways were observed in both the acute and chronic response, which contribute to muscle hypertrophy.
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http://dx.doi.org/10.1152/japplphysiol.00070.2019DOI Listing
November 2019

Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis.

Cell Death Dis 2019 06 18;10(6):449. Epub 2019 Jun 18.

Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.
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http://dx.doi.org/10.1038/s41419-019-1678-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579767PMC
June 2019

Increase of cortisol levels after temperature stress activates dmrt1a causing female-to-male sex reversal and reduced germ cell number in medaka.

Mol Reprod Dev 2019 10 29;86(10):1405-1417. Epub 2019 May 29.

Physiological Chemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.

In vertebrates, there is accumulating evidence that environmental factors as triggers for sex determination and genetic sex determination are not two opposing alternatives but that a continuum of mechanisms bridge those extremes. One prominent example is the model fish species Oryzias latipes which has a stable XX/XY genetic sex determination system, but still responds to environmental cues, where high temperatures lead to female-to-male sex reversal. However, the mechanisms behind are still unknown. We show that high temperatures increase primordial germ cells (PGC) numbers before they reach the genital ridge, which, in turn, regulates the germ cell proliferation. Complete ablation of PGCs led to XX males with germ cell less testis, whereas experimentally increased PGC numbers did not reverse XY genotypes to female. For the underlying molecular mechanism, we provide support for the explanation that activation of the dmrt1a gene by cortisol during early development of XX embryos enables this autosomal gene to take over the role of the male determining Y-chromosomal dmrt1bY.
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http://dx.doi.org/10.1002/mrd.23177DOI Listing
October 2019

Regulation of germ cell sex identity in medaka.

Authors:
Minoru Tanaka

Curr Top Dev Biol 2019 18;134:151-165. Epub 2019 Feb 18.

Division of Biological Science, Nagoya University, Nagoya, Japan. Electronic address:

Germline stem cells are sexually indifferent or flexible even in the mature ovary and testis. Acquiring sex identity consistent with the sex of the body is a critical issue in germline stem cells for producing eggs or sperm. However, the molecular mechanism of the sexual fate decision in germ cells is unclear. Medaka is the first vertebrate in which germline stem cells were found in the mature ovary (Nakamura, Kobayashi, Nishimura, Higashijima, & Tanaka, 2010), and a germ cell autonomous switch gene involved in the sexual fate decision, foxl3, was identified (Nishimura et al., 2015) in vertebrates. Here, the mechanism underlying the sex identity of germ cells is described based on the current understanding of germ cell behavior during the sexual fate decision. The control of foxl3 expression in germ cells and components acting downstream of foxl3 are also described.
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http://dx.doi.org/10.1016/bs.ctdb.2019.01.010DOI Listing
May 2020

Seasonal regulation of the lncRNA LDAIR modulates self-protective behaviours during the breeding season.

Nat Ecol Evol 2019 05 8;3(5):845-852. Epub 2019 Apr 8.

Division of Seasonal Biology, National Institute for Basic Biology, Okazaki, Japan.

To cope with seasonal environmental changes, animals adapt their physiology and behaviour in response to photoperiod. However, the molecular mechanisms underlying these adaptive changes are not completely understood. Here, using genome-wide expression analysis, we show that an uncharacterized long noncoding RNA (lncRNA), LDAIR, is strongly regulated by photoperiod in Japanese medaka fish (Oryzias latipes). Numerous transcripts and signalling pathways are activated during the transition from short- to long-day conditions; however, LDAIR is one of the first genes to be induced and its expression shows a robust daily rhythm under long-day conditions. Transcriptome analysis of LDAIR knockout fish reveals that the LDAIR locus regulates a gene neighbourhood, including corticotropin releasing hormone receptor 2, which is involved in the stress response. Behavioural analysis of LDAIR knockout fish demonstrates that LDAIR affects self-protective behaviours under long-day conditions. Therefore, we propose that photoperiodic regulation of corticotropin releasing hormone receptor 2 by LDAIR modulates adaptive behaviours to seasonal environmental changes.
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http://dx.doi.org/10.1038/s41559-019-0866-6DOI Listing
May 2019

Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.

FASEB J 2019 07 27;33(7):7852-7862. Epub 2019 Mar 27.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

We hypothesized that low-intensity endurance exercise might be more effective in preventing cancer cachexia-induced muscle atrophy through both an increase in protein synthesis and a decrease in protein degradation. The purpose of present study was to evaluate the effects and to clarify the mechanism of low-intensity endurance exercise on cancer cachexia-induced muscle atrophy. Twenty-four male Wistar rats were randomly divided into 4 groups: control (Cont), Cont plus exercise (Ex), AH130-induced cancer cachexia (AH130), and AH130 plus Ex. Cancer cachexia was induced by intraperitoneal injections with AH130 Yoshida ascites hepatoma cells; we analyzed the changes in muscle mass and the gene and protein expression levels of major regulators or indicators of skeletal muscle protein degradation and synthesis pathway in the soleus muscles. Low-intensity exercise inhibited the muscle mass loss through a suppression of the ubiquitin-proteasome pathway, increased hypoxia-inducible factor- 1α and phosphorylated AMPK, and inhibited the deactivation of mammalian target of rapamycin pathway in the soleus muscle, which contributed to the prevention of cancer cachexia-induced muscle atrophy. These results suggest that low-intensity exercise has the potential to become an effective therapeutic intervention for the prevention of cancer cachexia-induced muscle atrophy.-Tanaka, M., Sugimoto, K., Fujimoto, T., Xie, K., Takahashi, T., Akasaka, H., Kurinami, H., Yasunobe, Y., Matsumoto, T., Fujino, H., Rakugi, H. Preventive effects of low-intensity exercise on cancer cachexia-induced muscle atrophy.
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http://dx.doi.org/10.1096/fj.201802430RDOI Listing
July 2019

Overexpression of Interleukin-15 exhibits improved glucose tolerance and promotes GLUT4 translocation via AMP-Activated protein kinase pathway in skeletal muscle.

Biochem Biophys Res Commun 2019 02 14;509(4):994-1000. Epub 2019 Jan 14.

Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Skeletal muscle performs 80% of the glucose metabolism in the body. Improvement of insulin resistance and prevention of diabetes by habitual exercise is considered beneficial due to the improved glucose uptake in skeletal muscles. Investigation of the mechanism by which skeletal muscles regulate glucose uptake can contribute to the prevention and treatment of diabetes. Myokines are a kind of cytokine secreted from skeletal muscle, which are expected to regulate muscle metabolism. Interleukin-15 (IL-15) is one such myokine that has been reported to improve glucose metabolism in vitro, although the mechanism remains unclear. In this study, we examined the glucose metabolism of skeletal muscle-specific IL-15 transgenic mice (IL-15TG), and investigated how IL-15 affects glucose metabolism in skeletal muscles. Although High Fat Diet-fed IL-15TG did not exhibit obvious difference in intraperitoneal insulin tolerance test, they had less impaired glucose tolerance compared to wild-type C57BL/6. Phosphorylation of AMP-activated protein kinase (AMPK), Akt substrate of 160 kDa (AS160), tre-2/USP6, BUB2, and cdc16 domain family member 1 (TBC1D1), and translocation of Glucose transporter type 4 (GLUT4) were accelerated in the skeletal muscle of IL-15TG. Our study demonstrated that overexpression of IL-15 in skeletal muscle improves glucose metabolism in skeletal muscle via AMPK pathway. We report the first in-vivo study that describes the signaling pathway of IL-15 in muscle glucose metabolism, and thereby contributes to the elucidation of the regulatory mechanism of muscle glucose metabolism by myokines.
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http://dx.doi.org/10.1016/j.bbrc.2019.01.024DOI Listing
February 2019

[Basic Investigation of a Cerebral Blood Flow Quantification Method without Blood Sampling Method (Improved Brain Uptake Ratio (IBUR)) Using a Fan-beam Collimator].

Nihon Hoshasen Gijutsu Gakkai Zasshi 2018;74(11):1302-1312

Department of Radiology, Fukuoka University Hospital.

We performed a basic evaluation for measuring the input function using a fan-beam collimator. Furthermore, we examined the validity of the brain blood flow quantitative measurement from the input function. Using the fanbeam collimator, we imaged syringes of various diameters containing Tc as well as a virtual aorta inside a thoracic phantom. We changed the collimator distance and angle in relation to the sources, and the syringe was placed in vertical and horizontal positions as well. For evaluation, we used region of interest (ROI) of various sizes and positions. Furthermore, we conducted clinical evaluation for 19 subjects and calculated whole-brain mean cerebral blood flow using improved brain uptake ratio method by examination of Tc-ECD cerebral blood flow. For ROIs smaller in size than diameter of the syringes and virtual ascending aorta, amount of change in the ROI counts by fan-beam collimator became smaller as distance to the source became closer, with less than 5% at 175 mm. Also, change with respect to angle of the collimator was less than 5% at 20°. In a clinical study, aortas could be imaged without truncation and input-functions could be measured in all 19 patients. By using ROIs smaller than the aorta diameter and placing the collimator close to the source, it was suggested that fan-beam collimator can be used to determine the input function.
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http://dx.doi.org/10.6009/jjrt.2018_JSRT_74.11.1302DOI Listing
March 2019

Novel components of germline sex determination acting downstream of foxl3 in medaka.

Dev Biol 2019 01 27;445(1):80-89. Epub 2018 Oct 27.

Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan. Electronic address:

Germline sex determination is an essential process for the production of sexually dimorphic gametes. In medaka, Forkhead box L3 (foxl3) was previously identified as a germ cell-intrinsic regulator of sex determination that suppresses the initiation of spermatogenesis in female germ cells. To reveal the molecular mechanism of germline sex determination by foxl3, we conducted the following four analyses: Comparison of transcriptomes between wild-type and foxl3-mutant germ cells; epistatic analysis; identification of the FOXL3-binding motif; and ChIP-qPCR assay using a FOXL3-monoclonal antibody. We identified two candidate genes acting downstream of foxl3: Rec8a and fbxo47. It has been known that Rec8 regulates sister chromatid cohesion and Fbxo47 acts as a ubiquitin E3 ligase. These functions have not been, however, associated with sexual differentiation in germ cells. Our results uncover novel components acting downstream of foxl3, providing insights into the mechanism of germline sex determination.
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http://dx.doi.org/10.1016/j.ydbio.2018.10.019DOI Listing
January 2019