start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=1035690 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221117 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Subliminal meaning-contingent attentional orienting: The role of attentional control setting based on displaywide features en-subtitle= kn-subtitle= en-abstract= kn-abstract=People's subjective factors can affect the spatial allocation of attention, and objects that are more in line with people's expectations are easier to attract attention. In the current study, we wanted to know whether the meaning-contingent spatial attentional orienting could occur at the subliminal level, that is, whether conscious awareness was needed, and which attentional control settings worked. The current study employed a modified spatial cueing paradigm and the cues were made imperceptible by backward masking. The results showed that the capture effects of the left and the right positions stemmed from the meaning-contingent attentional control setting based on displaywide features, while the inhibition effect of the lower position and the capture effect of the upper position stemmed from the abrupt onset of subliminal cues and their masks. It is concluded that the attentional orienting of meaning contingency could occur at the subliminal level, which was not restricted by conscious perception. In particular, the attentional control setting based on displaywide features played an important role in spatial attentional orienting, which was manifested in the consistent capture effects on the horizontal sides. This study refined and separated the spatial attentional orienting effects, supported the contingent involuntary attentional orienting hypothesis, and expanded its scope of application. en-copyright= kn-copyright= en-aut-name=WangHuiyuan en-aut-sei=Wang en-aut-mei=Huiyuan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YangJiajia en-aut-sei=Yang en-aut-mei=Jiajia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GaoYulin en-aut-sei=Gao en-aut-mei=Yulin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhangMing en-aut-sei=Zhang en-aut-mei=Ming kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Psychology, Jilin University kn-affil= affil-num=2 en-affil=Faculty of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Department of Psychology, Jilin University kn-affil= affil-num=4 en-affil=Faculty of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=subliminal kn-keyword=subliminal en-keyword=meaning contingency kn-keyword=meaning contingency en-keyword=attentional orienting kn-keyword=attentional orienting en-keyword=displaywide features kn-keyword=displaywide features en-keyword=attentional control setting kn-keyword=attentional control setting END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=1048863 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221108 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction
While it is well known that thyroid function may affect kidney function, the transition of the chronic kidney disease (CKD) status before and after treatment for thyroid disorders, as well as the factors affecting this change, remains to be explored. In the present study, we focused on the change in kidney function and their affecting factors during the treatment for both hyperthyroidism and hypothyroidism.

Methods
Eighty-eight patients with hyperthyroidism and fifty-two patients with hypothyroidism were enrolled in a retrospective and longitudinal case series to analyze the changes in kidney function and their affecting factors after treatment for thyroid disorders.

Results
Along with the improvement of thyroid function after treatment, there was a significant decrease in estimated glomerular filtration rate (eGFR) in hyperthyroidism (an average Delta eGFR of -41.1 mL/min/1.73 m(2)) and an increase in eGFR in hypothyroidism (an average Delta eGFR of 7.1 mL/min/1.73 m(2)). The multiple linear regression analysis revealed that sex, eGFR, free thyroxine (FT4) and free triiodothyronine (FT3) could be considered independent explanatory variables for Delta eGFR in hyperthyroidism, while age, eGFR, and FT3 were detected as independent explanatory variables in hypothyroidism. In addition, the stratification by kidney function at two points, pre- and post-treatment for thyroid disorders, revealed that 4.5% of the participants with hyperthyroidism were pre-defined as non-CKD and post-defined as CKD, indicating the presence of "masked" CKD in hyperthyroidism. On the other hand, 13.5% of the participants with hypothyroidism presented pre-defined CKD and post-defined non-CKD, indicating the presence of "reversible" CKD status in hypothyroidism.

Conclusions
We uncovered the population of masked CKD in hyperthyroidism and reversible CKD status in hypothyroidism, thereby re-emphasizing the importance of a follow-up to examine kidney function after treatment for hyperthyroidism and the routine evaluation of thyroid function in CKD patients as well as the appropriate hormone therapy if the patient has hypothyroidism. en-copyright= kn-copyright= en-aut-name=Uchiyama-MatsuokaNatsumi en-aut-sei=Uchiyama-Matsuoka en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsujiKenji en-aut-sei=Tsuji en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KitamuraShinji en-aut-sei=Kitamura en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ItohYoshihiko en-aut-sei=Itoh en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NishiyamaYuki en-aut-sei=Nishiyama en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MorimotoEisaku en-aut-sei=Morimoto en-aut-mei=Eisaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujisawaSatoshi en-aut-sei=Fujisawa en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TerasakaTomohiro en-aut-sei=Terasaka en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HaraTakayuki en-aut-sei=Hara en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Ogura-OchiKanako en-aut-sei=Ogura-Ochi en-aut-mei=Kanako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=InagakiKenichi en-aut-sei=Inagaki en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Academic field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Academic Field of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=chronic kidney disease kn-keyword=chronic kidney disease en-keyword=masked CKD kn-keyword=masked CKD en-keyword=reversible CKD kn-keyword=reversible CKD en-keyword=hyperthyroidism kn-keyword=hyperthyroidism en-keyword=hypothyroidism kn-keyword=hypothyroidism en-keyword=eGFR kn-keyword=eGFR END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=957890 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221006 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Features of the oral microbiome in Japanese elderly people with 20 or more teeth and a non-severe periodontal condition during periodontal maintenance treatment: A cross-sectional study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction
The aim of the present study was to characterize the profile and diversity of the oral microbiome of a periodontally non-severe group with >= 20 teeth in comparison with a severe periodontitis group of elderly Japanese people.
Methods
A total of 50 patients who had >= 20 teeth and aged >= 60 years were recruited, and 34 participants (13 non-severe participants) were analyzed. After oral rinse (saliva after rinsing) sample collection, the V3-V4 regions of the 16S rRNA gene were sequenced to investigate microbiome composition, alpha diversity (Shannon index, Simpson index, richness, and evenness), and beta diversity using principal coordinate analysis (PCoA) based on weighted and unweighted UniFrac distances. A linear discriminant analysis effect size was calculated to identify bacterial species in the periodontally non-severe group.
Results
The periodontally non-severe group showed lower alpha diversity than that of the severe periodontitis group (p <0.05); however, the beta diversities were not significantly different. A higher relative abundance of four bacterial species (Prevotella nanceiensis, Gemella sanguinis, Fusobacterium periodonticum, and Haemophilus parainfluenzae) was observed in the non-severe group than that in the severe periodontitis group.
Conclusion
The oral microbiome in elderly Japanese people with >= 20 teeth and a non-severe periodontal condition was characterized by low alpha diversity and the presence of four bacterial species. en-copyright= kn-copyright= en-aut-name=ToyamaNaoki en-aut-sei=Toyama en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=EkuniDaisuke en-aut-sei=Ekuni en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YokoiAya en-aut-sei=Yokoi en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FukuharaDaiki en-aut-sei=Fukuhara en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IslamMd Monirul en-aut-sei=Islam en-aut-mei=Md Monirul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SawadaNanami en-aut-sei=Sawada en-aut-mei=Nanami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakashimaYukiho en-aut-sei=Nakashima en-aut-mei=Yukiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakaharaMomoko en-aut-sei=Nakahara en-aut-mei=Momoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SumitaIchiro en-aut-sei=Sumita en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MoritaManabu en-aut-sei=Morita en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Preventive Dentistry, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Preventive Dentistry, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Preventive Dentistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=oral microbiome kn-keyword=oral microbiome en-keyword=elderly people kn-keyword=elderly people en-keyword=diversity kn-keyword=diversity en-keyword=bacteria kn-keyword=bacteria en-keyword=non-severe periodontal condition kn-keyword=non-severe periodontal condition END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=930683 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221005 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Histamine induced high mobility group box-1 release from vascular endothelial cells through H-1 receptor en-subtitle= kn-subtitle= en-abstract= kn-abstract=BackgroundSystemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied. Methods and resultsEA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H-1 receptor antagonist, but not by H-2 or H-3/4 receptor antagonists. Moreover, an H-1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H-2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension. ConclusionHistamine induces HMGB1 release from vascular endothelial cells solely through H-1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis. en-copyright= kn-copyright= en-aut-name=GaoShangze en-aut-sei=Gao en-aut-mei=Shangze kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=LiuKeyue en-aut-sei=Liu en-aut-mei=Keyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuWenhan en-aut-sei=Ku en-aut-mei=Wenhan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangDengli en-aut-sei=Wang en-aut-mei=Dengli kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WakeHidenori en-aut-sei=Wake en-aut-mei=Hidenori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=QiaoHandong en-aut-sei=Qiao en-aut-mei=Handong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TeshigawaraKiyoshi en-aut-sei=Teshigawara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishiboriMasahiro en-aut-sei=Nishibori en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Translational Research and Drug Development, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Histamine kn-keyword=Histamine en-keyword=HMGB1 kn-keyword=HMGB1 en-keyword=vascular endothelial cell kn-keyword=vascular endothelial cell en-keyword=H-1 receptor kn-keyword=H-1 receptor en-keyword=hypotension kn-keyword=hypotension END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=1004184 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220915 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Time-series transcriptome of Brachypodium distachyon during bacterial flagellin-induced pattern-triggered immunity en-subtitle= kn-subtitle= en-abstract= kn-abstract=Plants protect themselves from microorganisms by inducing pattern-triggered immunity (PTI) via recognizing microbe-associated molecular patterns (MAMPs), conserved across many microbes. Although the MAMP perception mechanism and initial events during PTI have been well-characterized, knowledge of the transcriptomic changes in plants, especially monocots, is limited during the intermediate and terminal stages of PTI. Here, we report a time-series high-resolution RNA-sequencing (RNA-seq) analysis during PTI in the leaf disks of Brachypodium distachyon. We identified 6,039 differentially expressed genes (DEGs) in leaves sampled at 0, 0.5, 1, 3, 6, and 12 hours after treatment (hat) with the bacterial flagellin peptide flg22. The k-means clustering method classified these DEGs into 10 clusters (6 upregulated and 4 downregulated). Based on the results, we selected 10 PTI marker genes in B. distachyon. Gene ontology (GO) analysis suggested a tradeoff between defense responses and photosynthesis during PTI. The data indicated the recovery of photosynthesis started at least at 12 hat. Over-representation analysis of transcription factor genes and cis-regulatory elements in DEG promoters implied the contribution of 12 WRKY transcription factors in plant defense at the early stage of PTI induction. en-copyright= kn-copyright= en-aut-name=OgasaharaTsubasa en-aut-sei=Ogasahara en-aut-mei=Tsubasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KouzaiYusuke en-aut-sei=Kouzai en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeMegumi en-aut-sei=Watanabe en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakahashiAkihiro en-aut-sei=Takahashi en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahagiKotaro en-aut-sei=Takahagi en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimJune-Sik en-aut-sei=Kim en-aut-mei=June-Sik kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsuiHidenori en-aut-sei=Matsui en-aut-mei=Hidenori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoMikihiro en-aut-sei=Yamamoto en-aut-mei=Mikihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ToyodaKazuhiro en-aut-sei=Toyoda en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IchinoseYuki en-aut-sei=Ichinose en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MochidaKeiichi en-aut-sei=Mochida en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NoutoshiYoshiteru en-aut-sei=Noutoshi en-aut-mei=Yoshiteru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Kihara Institute for Biological Research, Yokohama City University kn-affil= affil-num=6 en-affil=Bioproductivity Informatics Research Team, RIKEN Center for Sustainable Resource Science kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=9 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=10 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=11 en-affil=Bioproductivity Informatics Research Team, RIKEN Center for Sustainable Resource Science kn-affil= affil-num=12 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=Brachypodium distachyon kn-keyword=Brachypodium distachyon en-keyword=monocotyledonous plant kn-keyword=monocotyledonous plant en-keyword=microbe-associated molecular pattern kn-keyword=microbe-associated molecular pattern en-keyword=time-series transcriptome analysis kn-keyword=time-series transcriptome analysis en-keyword=reactive oxygen species kn-keyword=reactive oxygen species en-keyword=pattern-triggered immunity kn-keyword=pattern-triggered immunity END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=982068 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220912 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Structure and function of a silicic acid channel Lsi1 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Silicon is a beneficial element for plant growth and production, especially in rice. Plant roots take up silicon in the form of silicic acid. Silicic acid channels, which belong to the NIP subfamily of aquaporins, are responsible for silicic acid uptake. Accumulated experimental results have deepened our understanding of the silicic acid channel for its uptake mechanism, physiological function, localization, and other aspects. However, how the silicic acid channel efficiently and selectively permeates silicic acid remains to be elucidated. Recently reported crystal structures of the silicic acid channel enabled us to discuss the mechanism of silicic acid uptake by plant roots at an atomic level. In this mini-review, we focus on the crystal structures of the silicic acid channel and provide a detailed description of the structural determinants of silicic acid permeation and its transport mechanism, which are crucial for the rational creation of secure and sustainable crops. en-copyright= kn-copyright= en-aut-name=SaitohYasunori en-aut-sei=Saitoh en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SugaMichihiro en-aut-sei=Suga en-aut-mei=Michihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= affil-num=2 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= en-keyword=silicon kn-keyword=silicon en-keyword=aquaporin kn-keyword=aquaporin en-keyword=NIP kn-keyword=NIP en-keyword=rice kn-keyword=rice en-keyword=crystal structure kn-keyword=crystal structure en-keyword=substrate selectivity kn-keyword=substrate selectivity en-keyword=channel kn-keyword=channel en-keyword=transporter kn-keyword=transporter END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=994014 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220913 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cnm of Streptococcus mutans is important for cell surface structure and membrane permeability en-subtitle= kn-subtitle= en-abstract= kn-abstract=Streptococcus mutans, a Gram-positive facultative anaerobic bacterium, is a major pathogen of dental caries. The protein Cnm of S. mutans is involved in collagen binding, but its other biological functions are unknown. In this study, a Cnm-deficient isogenic mutant and a complementation strain were generated from a Cnm-positive S. mutans strain to help determine the properties of Cnm. Initially, comparison of the cell surface structure was performed by electron microscopy, which demonstrated that Cnm appears to be localized on the cell surface and associated with a protruding cell surface structure. Deep RNA sequencing of the strains revealed that the defect in Cnm caused upregulated expression of many genes related to ABC transporters and cell-surface proteins, while a few genes were downregulated. The amount of biofilm formed by the Cnm-defective strain increased compared with the parental and complemented strains, but the biofilm structure was thinner because of elevated expression of genes encoding glucan synthesis enzymes, leading to increased production of extracellular polysaccharides. Particular antibiotics, including bacitracin and chloramphenicol, had a lower minimum inhibitory concentration for the Cnm-defective strain than particular antibiotics, including bacitracin and chloramphenicol, compared with the parental and complemented strains. Our results suggest that S. mutans Cnm is located on the cell surface, gives rise to the observed protruding cell surface, and is associated with several biological properties related to membrane permeability. en-copyright= kn-copyright= en-aut-name=NakaShuhei en-aut-sei=Naka en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsuokaDaiki en-aut-sei=Matsuoka en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GotoKana en-aut-sei=Goto en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MisakiTaro en-aut-sei=Misaki en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagasawaYasuyuki en-aut-sei=Nagasawa en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItoSeigo en-aut-sei=Ito en-aut-mei=Seigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NomuraRyota en-aut-sei=Nomura en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakanoKazuhiko en-aut-sei=Nakano en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Matsumoto-NakanoMichiyo en-aut-sei=Matsumoto-Nakano en-aut-mei=Michiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Nephrology, Seirei Hamamatsu General Hospital kn-affil= affil-num=5 en-affil=Department of General Internal Medicine, Hyogo College of Medicine kn-affil= affil-num=6 en-affil=Department of Internal Medicine, Japan Self-Defense Iruma Hospital kn-affil= affil-num=7 en-affil=Department of Pediatric Dentistry, Division of Oral infection and Disease Control, Osaka University Graduate School of Dentistry kn-affil= affil-num=8 en-affil=Department of Pediatric Dentistry, Division of Oral infection and Disease Control, Osaka University Graduate School of Dentistry kn-affil= affil-num=9 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Streptococcus mutans kn-keyword=Streptococcus mutans en-keyword=collagen-binding protein kn-keyword=collagen-binding protein en-keyword=membrane permeability kn-keyword=membrane permeability en-keyword=cell structure kn-keyword=cell structure en-keyword=RNA-seq kn-keyword=RNA-seq END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=890048 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220812 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition en-subtitle= kn-subtitle= en-abstract= kn-abstract=Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 mu g/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior. en-copyright= kn-copyright= en-aut-name=UshioSoichiro en-aut-sei=Ushio en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WadaYudai en-aut-sei=Wada en-aut-mei=Yudai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraMizuki en-aut-sei=Nakamura en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsumotoDaiki en-aut-sei=Matsumoto en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HoshikaKota en-aut-sei=Hoshika en-aut-mei=Kota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiromizuShoya en-aut-sei=Shiromizu en-aut-mei=Shoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IwataNaohiro en-aut-sei=Iwata en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=EsumiSatoru en-aut-sei=Esumi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KajizonoMakoto en-aut-sei=Kajizono en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SendoToshiaki en-aut-sei=Sendo en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Clinical Pharmacy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= en-keyword=anxiolytic kn-keyword=anxiolytic en-keyword=inflammation kn-keyword=inflammation en-keyword=immunomodulation kn-keyword=immunomodulation en-keyword=macrophages kn-keyword=macrophages en-keyword=Kampo medicine kn-keyword=Kampo medicine END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=983599 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220825 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=NFYA promotes the anti-tumor effects of gluconeogenesis in hepatocellular carcinoma through the regulation of PCK1 expression en-subtitle= kn-subtitle= en-abstract= kn-abstract=Reprogramming of glucose metabolism occurs in many human tumor types, and one of these, gluconeogenesis, is known to exhibit anti-tumor effects in hepatocellular carcinoma (HCC). The transcription factor NFYA regulates gluconeogenesis in the normal liver tissue, but the function of the NFYA-gluconeogenesis axis in cancer and the functional differences of NFYA splicing variants in the regulation of gluconeogenesis is still unclear. Here, we demonstrate that NFYAv2, the short-form variant, upregulates the transcription of a gluconeogenic enzyme PCK1. We further reveal that its regulation induces high ROS levels and energy crisis in HCC and promotes cell death. These indicate that the NFYAv2-gluconeogenesis axis has enhanced anti-tumor effects in HCC, suggesting that the axis may be a potential therapeutic target for HCC. Furthermore, Nfyav1-deficient mice, spontaneously overexpressing Nfyav2, had no increasing gluconeogenesis in the liver. Taken together, our results reveal NFYAv2-gluconeogenesis axis has anti-tumor effects and the potential for NFYAv2 to be a safer therapeutic target for HCC. en-copyright= kn-copyright= en-aut-name=TsujimotoGoki en-aut-sei=Tsujimoto en-aut-mei=Goki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ItoRin en-aut-sei=Ito en-aut-mei=Rin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshikawaKei en-aut-sei=Yoshikawa en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UekiChihiro en-aut-sei=Ueki en-aut-mei=Chihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkadaNobuhiro en-aut-sei=Okada en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=hepatocellular carcinoma (HCC) kn-keyword=hepatocellular carcinoma (HCC) en-keyword=cancer metabolism kn-keyword=cancer metabolism en-keyword=gluconeogenesis kn-keyword=gluconeogenesis en-keyword=cell death kn-keyword=cell death en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=NFYA kn-keyword=NFYA en-keyword=PCK1 kn-keyword=PCK1 END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=918226 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220713 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Examining the Role of Low Temperature in Satsuma Mandarin Fruit Peel Degreening via Comparative Physiological and Transcriptomic Analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Peel degreening is the most conspicuous aspect of fruit ripening in many citrus fruits because of its importance for marketability. In this study, peel degreening in response to propylene (an ethylene analog) and at varying storage temperatures was characterized in Satsuma mandarin (Citrus unshiu Marc.) fruit. Propylene treatment triggered rapid peel degreening (within 4-6 days), indicated by an increase in the citrus color index (CCI) and chlorophyll loss. Peel degreening was also observed in fruit at 10 degrees C and 15 degrees C after 28-42 days, with gradual CCI increase and chlorophyll reduction. However, fruit at 5 degrees C, 20 degrees C, and 25 degrees C remained green, and no substantial changes in peel CCI and chlorophyll content were recorded during the 42-day storage duration. The transcriptomes of peels of fruit treated with propylene for 4 days and those stored at varying temperatures for 28 days were then analyzed by RNA-Seq. We identified three categories of differentially expressed genes that were regulated by (i) propylene (and by analogy, ethylene) alone, (ii) low temperature (5 degrees C, 10 degrees C, or 15 degrees C vs. 25 degrees C) alone, and (iii) either propylene or low temperature. Gene-encoding proteins associated with chlorophyll degradation (such as CuSGR1, CuNOL, CuACD2, CuCAB2, and CuLHCB2) and a transcription factor (CuERF114) were differentially expressed by propylene or low temperature. To further examine temperature-induced pathways, we also monitored gene expression during on-tree fruit maturation vs. postharvest. The onset of on-tree peel degreening coincided with autumnal drops in field temperatures, and it was accompanied by differential expression of low temperature-regulated genes. On the contrary, genes that were exclusively regulated by propylene (such as CuCOPT1 and CuPOX-A2) displayed insignificant expression changes during on-tree peel degreening. These findings indicate that low temperatures could be involved in the fruit ripening-related peel degreening independently of ethylene. en-copyright= kn-copyright= en-aut-name=MitaloOscar W. en-aut-sei=Mitalo en-aut-mei=Oscar W. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsicheWilliam O. en-aut-sei=Asiche en-aut-mei=William O. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KangSeung W. en-aut-sei=Kang en-aut-mei=Seung W. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=EzuraHiroshi en-aut-sei=Ezura en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AkagiTakashi en-aut-sei=Akagi en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KuboYasutaka en-aut-sei=Kubo en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UshijimaKoichiro en-aut-sei=Ushijima en-aut-mei=Koichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Research and Development, Del Monte Kenya Ltd kn-affil= affil-num=3 en-affil=Graduate School of Life and Environmental Sciences, University of Tsukuba kn-affil= affil-num=4 en-affil=Graduate School of Life and Environmental Sciences, University of Tsukuba kn-affil= affil-num=5 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=chlorophyll kn-keyword=chlorophyll en-keyword=citrus kn-keyword=citrus en-keyword=degreening kn-keyword=degreening en-keyword=ethylene kn-keyword=ethylene en-keyword=RNA-Seq kn-keyword=RNA-Seq en-keyword=on-tree kn-keyword=on-tree en-keyword=storage kn-keyword=storage END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=921635 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220707 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Siderophore for Lanthanide and Iron Uptake for Methylotrophy and Plant Growth Promotion in Methylobacterium aquaticum Strain 22A en-subtitle= kn-subtitle= en-abstract= kn-abstract=Methylobacterium and Methylorubrum species are facultative methylotrophic bacteria that are abundant in the plant phyllosphere. They have two methanol dehydrogenases, MxaF and XoxF, which are dependent on either calcium or lanthanides (Lns), respectively. Lns exist as insoluble minerals in nature, and their solubilization and uptake require a siderophore-like substance (lanthanophore). Methylobacterium species have also been identified as plant growth-promoting bacteria although the actual mechanism has not been well-investigated. This study aimed to reveal the roles of siderophore in Methylobacterium aquaticum strain 22A in Ln uptake, bacterial physiology, and plant growth promotion. The strain 22A genome contains an eight-gene cluster encoding the staphyloferrin B-like (sbn) siderophore. We demonstrate that the sbn siderophore gene cluster is necessary for growth under low iron conditions and was complemented by supplementation with citrate or spent medium of the wild type or other strains of the genera. The siderophore exhibited adaptive features, including tolerance to oxidative and nitrosative stress, biofilm formation, and heavy metal sequestration. The contribution of the siderophore to plant growth was shown by the repressive growth of duckweed treated with siderophore mutant under iron-limited conditions; however, the siderophore was dispensable for strain 22A to colonize the phyllosphere. Importantly, the siderophore mutant could not grow on methanol, but the siderophore could solubilize insoluble Ln oxide, suggesting its critical role in methylotrophy. We also identified TonB-dependent receptors (TBDRs) for the siderophore-iron complex, iron citrate, and Ln, among 12 TBDRs in strain 22A. Analysis of the siderophore synthesis gene clusters and TBDR genes in Methylobacterium genomes revealed the existence of diverse types of siderophores and TBDRs. Methylorubrum species have an exclusive TBDR for Ln uptake that has been identified as LutH. Collectively, the results of this study provide insight into the importance of the sbn siderophore in Ln chelation, bacterial physiology, and the diversity of siderophore and TBDRs in Methylobacterium species. en-copyright= kn-copyright= en-aut-name=JumaPatrick Otieno en-aut-sei=Juma en-aut-mei=Patrick Otieno kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujitaniYoshiko en-aut-sei=Fujitani en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AlessaOla en-aut-sei=Alessa en-aut-mei=Ola kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OyamaTokitaka en-aut-sei=Oyama en-aut-mei=Tokitaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YurimotoHiroya en-aut-sei=Yurimoto en-aut-mei=Hiroya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakaiYasuyoshi en-aut-sei=Sakai en-aut-mei=Yasuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TaniAkio en-aut-sei=Tani en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil= Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil= Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=3 en-affil= Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Science, Kyoto University kn-affil= affil-num=5 en-affil=Graduate School of Agriculture, Kyoto University kn-affil= affil-num=6 en-affil=Graduate School of Agriculture, Kyoto University kn-affil= affil-num=7 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=Methylobacterium species kn-keyword=Methylobacterium species en-keyword=lanthanide kn-keyword=lanthanide en-keyword=lanthanophore kn-keyword=lanthanophore en-keyword=siderophore kn-keyword=siderophore en-keyword=plant growth promoter kn-keyword=plant growth promoter en-keyword=heavy metal sequestration kn-keyword=heavy metal sequestration END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=921636 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220623 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Periplasmic Lanthanide Mediator, Lanmodulin, in Methylobacterium aquaticum Strain 22A en-subtitle= kn-subtitle= en-abstract= kn-abstract=Methylobacterium and Methylorubrum species oxidize methanol via pyrroloquinoline quinone-methanol dehydrogenases (MDHs). MDHs can be classified into two major groups, Ca2+-dependent MDH (MxaF) and lanthanide (Ln(3+))-dependent MDH (XoxF), whose expression is regulated by the availability of Ln(3+). A set of a siderophore, TonB-dependent receptor, and an ABC transporter that resembles the machinery for iron uptake is involved in the solubilization and transport of Ln(3+). The transport of Ln(3+) into the cytosol enhances XoxF expression. A unique protein named lanmodulin from Methylorubrum extorquens strain AM1 was identified as a specific Ln(3+)-binding protein, and its biological function was implicated to be an Ln(3+) shuttle in the periplasm. In contrast, it remains unclear how Ln(3+) levels in the cells are maintained, because Ln(3+) is potentially deleterious to cellular systems due to its strong affinity to phosphate ions. In this study, we investigated the function of a lanmodulin homolog in Methylobacterium aquaticum strain 22A. The expression of a gene encoding lanmodulin (lanM) was induced in response to the presence of La3+. A recombinant LanM underwent conformational change upon La3+ binding. Phenotypic analyses on lanM deletion mutant and overexpressing strains showed that LanM is not necessary for the wild-type and XoxF-dependent mutant's methylotrophic growth. We found that lanM expression was regulated by MxcQE (a two-component regulator for MxaF) and TonB_Ln (a TonB-dependent receptor for Ln(3+)). The expression level of mxcQE was altered to be negatively dependent on Ln(3+) concentration in increment lanM, whereas it was constant in the wild type. Furthermore, when exposed to La3+, increment lanM showed an aggregating phenotype, cell membrane impairment, La deposition in the periplasm evidenced by electron microscopy, differential expression of proteins involved in membrane integrity and phosphate starvation, and possibly lower La content in the membrane vesicle (MV) fractions. Taken together, we concluded that lanmodulin is involved in the complex regulation mechanism of MDHs and homeostasis of cellular Ln levels by facilitating transport and MV-mediated excretion. en-copyright= kn-copyright= en-aut-name=FujitaniYoshiko en-aut-sei=Fujitani en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShibataTakeshi en-aut-sei=Shibata en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TaniAkio en-aut-sei=Tani en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=K.K. AB SCIEX kn-affil= affil-num=3 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=lanmodulin kn-keyword=lanmodulin en-keyword=lanthanide kn-keyword=lanthanide en-keyword=methanol dehydrogenase kn-keyword=methanol dehydrogenase en-keyword=Methylobacterium species kn-keyword=Methylobacterium species en-keyword=membrane vesicles kn-keyword=membrane vesicles END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=864225 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220629 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8(+) T Cells for Enhanced IFN gamma Production by Metformin en-subtitle= kn-subtitle= en-abstract= kn-abstract=Metformin (Met), a first-line drug for type 2 diabetes, lowers blood glucose levels by suppressing gluconeogenesis in the liver, presumably through the liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK) after inhibiting respiratory chain complex I. Met is also implicated as a drug to be repurposed for cancers; its mechanism is believed identical to that of gluconeogenesis inhibition. However, AMPK activation requires high Met concentrations at more than 1 mM, which are unachievable in vivo. The immune-mediated antitumor response might be the case in a low dose Met. Thus, we proposed activating or expanding tumor-infiltrating CD8(+) T cells (CD8TILs) in a mouse model by orally administering Met in free drinking water. Here we showed that Met, at around 10 mu M and a physiologically relevant concentration, enhanced production of IFN gamma,TNF alpha and expression of CD25 of CD8(+) T cells upon TCR stimulation. Under a glucose-rich condition, glycolysis was exclusively involved in enhancing IFN gamma production. Under a low-glucose condition, fatty acid oxidation or autophagy-dependent glutaminolysis, or both, was also involved. Moreover, phosphoenolpyruvate carboxykinase 1 (PCK1), converting oxaloacetate to phosphoenolpyruvate, became essential. Importantly, the enhanced IFN gamma production was blocked by a mitochondrial ROS scavenger and not by an inhibitor of AMPK. In addition, IFN gamma production by CD8TILs relied on pyruvate translocation to the mitochondria and PCK1. Our results revealed a direct effect of Met on IFN gamma production of CD8(+) T cells that was dependent on differential metabolic pathways and determined by nutrient conditions in the microenvironment. en-copyright= kn-copyright= en-aut-name=ChaoRuoyu en-aut-sei=Chao en-aut-mei=Ruoyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishidaMikako en-aut-sei=Nishida en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamashitaNahoko en-aut-sei=Yamashita en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TokumasuMiho en-aut-sei=Tokumasu en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhaoWeiyang en-aut-sei=Zhao en-aut-mei=Weiyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KudoIkuru en-aut-sei=Kudo en-aut-mei=Ikuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UdonoHeiichiro en-aut-sei=Udono en-aut-mei=Heiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=CD8+T lymphocytes kn-keyword=CD8+T lymphocytes en-keyword=glycolysis kn-keyword=glycolysis en-keyword=FAO kn-keyword=FAO en-keyword=glutaminolysis kn-keyword=glutaminolysis en-keyword=IFNg kn-keyword=IFNg en-keyword=autophagy plus T kn-keyword=autophagy plus T en-keyword=metformin kn-keyword=metformin END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue= article-no= start-page=904215 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220630 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist, on AAA formation and rupture.
Methods: Experimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE(-)(/)(-) mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).
Results: The size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-alpha in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPAR alpha significantly attenuated the anti-oxidative effect of pemafibrate.
Conclusion: Pemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells. en-copyright= kn-copyright= en-aut-name=AmiokaNaofumi en-aut-sei=Amioka en-aut-mei=Naofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyoshiToru en-aut-sei=Miyoshi en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YonezawaTomoko en-aut-sei=Yonezawa en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KondoMegumi en-aut-sei=Kondo en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AkagiSatoshi en-aut-sei=Akagi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YoshidaMasashi en-aut-sei=Yoshida en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SaitoYukihiro en-aut-sei=Saito en-aut-mei=Yukihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakamuraKazufumi en-aut-sei=Nakamura en-aut-mei=Kazufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ItoHiroshi en-aut-sei=Ito en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=pemafibrate kn-keyword=pemafibrate en-keyword=angiotensin II kn-keyword=angiotensin II en-keyword=abdominal aortic aneurysm kn-keyword=abdominal aortic aneurysm en-keyword=oxidative stress kn-keyword=oxidative stress en-keyword=catalase kn-keyword=catalase END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=884509 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220510 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Lipid-Binding Defective Dynamin 2 Mutant in Charcot-Marie-Tooth Disease Impairs Proper Actin Bundling and Actin Organization in Glomerular Podocytes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Dynamin is an endocytic protein that functions in vesicle formation by scission of invaginated membranes. Dynamin maintains the structure of foot processes in glomerular podocytes by directly and indirectly interacting with actin filaments. However, molecular mechanisms underlying dynamin-mediated actin regulation are largely unknown. Here, biochemical and cell biological experiments were conducted to uncover how dynamin modulates interactions between membranes and actin in human podocytes. Actin-bundling, membrane tubulating, and GTPase activities of dynamin were examined in vitro using recombinant dynamin 2-wild-type (WT) or dynamin 2-K562E, which is a mutant found in Charcot-Marie-Tooth patients. Dynamin 2-WT and dynamin 2-K562E led to the formation of prominent actin bundles with constant diameters. Whereas liposomes incubated with dynamin 2-WT resulted in tubule formation, dynamin 2-K562E reduced tubulation. Actin filaments and liposomes stimulated dynamin 2-WT GTPase activity by 6- and 20-fold, respectively. Actin-filaments, but not liposomes, stimulated dynamin 2-K562E GTPase activity by 4-fold. Self-assembly-dependent GTPase activity of dynamin 2-K562E was reduced to one-third compared to that of dynamin 2-WT. Incubation of liposomes and actin with dynamin 2-WT led to the formation of thick actin bundles, which often bound to liposomes. The interaction between lipid membranes and actin bundles by dynamin 2-K562E was lower than that by dynamin 2-WT. Dynamin 2-WT partially colocalized with stress fibers and actin bundles based on double immunofluorescence of human podocytes. Dynamin 2-K562E expression resulted in decreased stress fiber density and the formation of aberrant actin clusters. Dynamin 2-K562E colocalized with alpha-actinin-4 in aberrant actin clusters. Reformation of stress fibers after cytochalasin D-induced actin depolymerization and washout was less effective in dynamin 2-K562E-expressing cells than that in dynamin 2-WT. Bis-T-23, a dynamin self-assembly enhancer, was unable to rescue the decreased focal adhesion numbers and reduced stress fiber density induced by dynamin 2-K562E expression. These results suggest that the low affinity of the K562E mutant for lipid membranes, and atypical self-assembling properties, lead to actin disorganization in HPCs. Moreover, lipid-binding and self-assembly of dynamin 2 along actin filaments are required for podocyte morphology and functions. Finally, dynamin 2-mediated interactions between actin and membranes are critical for actin bundle formation in HPCs. en-copyright= kn-copyright= en-aut-name=HamasakiEriko en-aut-sei=Hamasaki en-aut-mei=Eriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WakitaNatsuki en-aut-sei=Wakita en-aut-mei=Natsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YasuokaHiroki en-aut-sei=Yasuoka en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NagaokaHikaru en-aut-sei=Nagaoka en-aut-mei=Hikaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoritaMasayuki en-aut-sei=Morita en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakashimaEizo en-aut-sei=Takashima en-aut-mei=Eizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchihashiTakayuki en-aut-sei=Uchihashi en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakedaTetsuya en-aut-sei=Takeda en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AbeTadashi en-aut-sei=Abe en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=LeeJi-Won en-aut-sei=Lee en-aut-mei=Ji-Won kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=IimuraTadahiro en-aut-sei=Iimura en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SaleemMoin A. en-aut-sei=Saleem en-aut-mei=Moin A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OgoNaohisa en-aut-sei=Ogo en-aut-mei=Naohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=AsaiAkira en-aut-sei=Asai en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NaritaAkihiro en-aut-sei=Narita en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TakeiKohji en-aut-sei=Takei en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=YamadaHiroshi en-aut-sei=Yamada en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= affil-num=1 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Division of Malaria Research, Proteo-Science Center, Ehime University kn-affil= affil-num=5 en-affil=Division of Malaria Research, Proteo-Science Center, Ehime University kn-affil= affil-num=6 en-affil=Division of Malaria Research, Proteo-Science Center, Ehime University kn-affil= affil-num=7 en-affil=Department of Physics, Nagoya University kn-affil= affil-num=8 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University kn-affil= affil-num=11 en-affil=Department of Pharmacology, Faculty and Graduate School of Dental Medicine, Hokkaido University kn-affil= affil-num=12 en-affil=Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol kn-affil= affil-num=13 en-affil=Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=14 en-affil=Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=15 en-affil=Graduate School of Science, Nagoya University kn-affil= affil-num=16 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=17 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=dynamin kn-keyword=dynamin en-keyword=podocyte kn-keyword=podocyte en-keyword=actin kn-keyword=actin en-keyword=bundle kn-keyword=bundle en-keyword=GTPase kn-keyword=GTPase en-keyword=CMT kn-keyword=CMT END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=893879 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220516 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=El Ninõ and Commodity Prices: New Findings From Partial Wavelet Coherence Analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study investigates whether the El Nino Southern Oscillation (ENSO) affects primary commodity prices over time. We employ a wavelet approach that allows us to disentangle the time and frequency domains and to uncover time-varying nonlinear relationships at different frequency levels. Moreover, we adopt partial wavelet coherence (PWC) and eliminate macroeconomic effects on commodity prices. We observe that ENSO is associated with agricultural, food, and raw material commodity prices at lower frequencies of 32-64 and 64-128 months. These results are stronger from 2000 onward, which are not observed using a conventional wavelet method. Our results suggest a recent strong relationship between ENSO and commodity prices, which has important implications for policymakers regarding climate change risk. en-copyright= kn-copyright= en-aut-name=CaiXiaojing en-aut-sei=Cai en-aut-mei=Xiaojing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakemotoRyuta en-aut-sei=Sakemoto en-aut-mei=Ryuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Faculty of Humanities and Social Sciences, Okayama University kn-affil= affil-num=2 en-affil=Faculty of Humanities and Social Sciences, Okayama University kn-affil= en-keyword=climate risk kn-keyword=climate risk en-keyword=commodity prices kn-keyword=commodity prices en-keyword=partial wavelet coherence kn-keyword=partial wavelet coherence en-keyword=El Nino kn-keyword=El Nino en-keyword=ENSO kn-keyword=ENSO END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=892356 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220502 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Potential Strategies for Kidney Regeneration With Stem Cells: An Overview en-subtitle= kn-subtitle= en-abstract= kn-abstract=Kidney diseases are a major health problem worldwide. Despite advances in drug therapies, they are only capable of slowing the progression of kidney diseases. Accordingly, potential kidney regeneration strategies with stem cells have begun to be explored. There are two different directions for regenerative strategies, de novo whole kidney fabrication with stem cells, and stem cell therapy. De novo whole kidney strategies include: 1) decellularized scaffold technology, 2) 3D bioprinting based on engineering technology, 3) kidney organoid fabrication, 4) blastocyst complementation with chimeric technology, and 5) the organogenic niche method. Meanwhile, stem cell therapy strategies include 1) injection of stem cells, including mesenchymal stem cells, nephron progenitor cells, adult kidney stem cells and multi-lineage differentiating stress enduring cells, and 2) injection of protective factors secreted from these stem cells, including growth factors, chemokines, and extracellular vesicles containing microRNAs, mRNAs and proteins. Over the past few decades, there have been remarkable step-by-step developments in these strategies. Here, we review the current advances in the potential strategies for kidney regeneration using stem cells, along with their challenges for possible clinical use in the future. en-copyright= kn-copyright= en-aut-name=TsujiKenji en-aut-sei=Tsuji en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamuraShinji en-aut-sei=Kitamura en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=kidney regeneration kn-keyword=kidney regeneration en-keyword=stem cell kn-keyword=stem cell en-keyword=de novo kidney kn-keyword=de novo kidney en-keyword=cell therapy kn-keyword=cell therapy en-keyword=CKD kn-keyword=CKD END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=858747 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220318 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mapping of Nematode Resistance in Hexaploid Sweetpotato Using an Next-Generation Sequencing-Based Association Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=The southern root-knot nematode (SRKN; Meloidogyne incognita) is a typical parasitic nematode that affects sweetpotato [Ipomoea batatas (L.) Lam.], causing a significant decrease in crop yield and commercial value. In Japan, the SRKN is classified into 10 races: SP1-SP5, SP6-1, SP6-2, and SP7-SP9, with the dominant race differing according to the cultivation area. Soil insecticides have previously been used to reduce the soil density of SRKNs; however, this practice is both costly and labor intensive. Therefore, the development of SRKN-resistant sweetpotato lines and cultivars is necessary. However, due to the complexity of polyploid inheritance and the highly heterogeneous genomic composition of sweetpotato, genetic information and research for this species are significantly lacking compared to those for other major diploid crop species. In this study, we utilized the recently developed genome-wide association approach, which uses multiple-dose markers to assess autopolyploid species. We performed an association analysis to investigate resistance toward SRKN-SP2, which is the major race in areas with high sweetpotato production in Japan. The segregation ratio of resistant and susceptible lines in the F-1 mapping population derived from the resistant "J-Red" and susceptible "Choshu" cultivars was fitted to 1: 3, suggesting that resistance to SP2 may be regulated by two loci present in the simplex. By aligning the double digest restriction-site associated DNA sequencing reads to the published Ipomoea trifida reference sequence, 46,982 single nucleotide polymorphisms (SNPs) were identified (sequencing depth > 200). The association study yielded its highest peak on chromosome 7 (Chr07) and second highest peak on chromosome 3 (Chr03), presenting as a single-dose in both loci. Selective DNA markers were developed to screen for resistant plants using the SNPs identified on Chr03 and Chr07. Our results showed that SRKN-SP2-resistant plants were selected with a probability of approximately 70% when combining the two selective DNA markers. This study serves as a model for the identification of genomic regions that control agricultural traits and the elucidation of their effects, and is expected to greatly advance marker-assisted breeding and association studies in polyploid crop species. en-copyright= kn-copyright= en-aut-name=ObataNozomi en-aut-sei=Obata en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TabuchiHiroaki en-aut-sei=Tabuchi en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuriharaMiyu en-aut-sei=Kurihara en-aut-mei=Miyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoEiji en-aut-sei=Yamamoto en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShirasawaKenta en-aut-sei=Shirasawa en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MondenYuki en-aut-sei=Monden en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil= Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Kyusyu Okinawa Agricultural Research Center, National Agriculture and Food Research Organization kn-affil= affil-num=3 en-affil=Faculty of Agriculture, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Agriculture, Meiji University kn-affil= affil-num=5 en-affil=Department of Frontier Research and Development, Kazusa DNA Research Institute kn-affil= affil-num=6 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=polyploidy kn-keyword=polyploidy en-keyword=nematode kn-keyword=nematode en-keyword=sweetpotato kn-keyword=sweetpotato en-keyword=resistant cultivar kn-keyword=resistant cultivar en-keyword=breeding kn-keyword=breeding en-keyword=association study kn-keyword=association study END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue= article-no= start-page=694018 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220118 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Meclozine Attenuates the MARK Pathway in Mammalian Chondrocytes and Ameliorates FGF2-Induced Bone Hyperossification in Larval Zebrafish en-subtitle= kn-subtitle= en-abstract= kn-abstract=Meclozine has been developed as an inhibitor of fibroblast growth factor receptor 3 (FGFR3) to treat achondroplasia (ACH). Extracellular signal regulated kinase (ERK) phosphorylation was attenuated by meclozine in FGF2-treated chondrocyte cell line, but the site of its action has not been elucidated. Although orally administered meclozine promoted longitudinal bone growth in a mouse model of ACH, its effect on craniofacial bone development during the early stage remains unknown. Herein, RNA-sequencing analysis was performed using murine chondrocytes from FGF2-treated cultured tibiae, which was significantly elongated by meclozine treatment. Gene set enrichment analysis demonstrated that FGF2 significantly increased the enrichment score of mitogen-activated protein kinase (MAPK) family signaling cascades in chondrocytes; however, meclozine reduced this enrichment. Next, we administered meclozine to FGF2-treated larval zebrafish from 8 h post-fertilization (hpf). We observed that FGF2 significantly increased the number of ossified vertebrae in larval zebrafish at 7 days post-fertilization (dpf), while meclozine delayed vertebral ossification in FGF2-induced zebrafish. Meclozine also reversed the FGF2-induced upregulation of ossified craniofacial bone area, including ceratohyal, hyomandibular, and quadrate. The current study provided additional evidence regarding the inhibitory effect of meclozine on the FGF2-induced upregulation of MAPK signaling in chondrocytes and FGF2-induced development of craniofacial and vertebral bones. en-copyright= kn-copyright= en-aut-name=TakemotoGenta en-aut-sei=Takemoto en-aut-mei=Genta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsushitaMasaki en-aut-sei=Matsushita en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OkamotoTakaaki en-aut-sei=Okamoto en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ItoToshinari en-aut-sei=Ito en-aut-mei=Toshinari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsuuraYuki en-aut-sei=Matsuura en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakashimaChieko en-aut-sei=Takashima en-aut-mei=Chieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Chen-YoshikawaToyofumi Fengshi en-aut-sei=Chen-Yoshikawa en-aut-mei=Toyofumi Fengshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=EbiHiromichi en-aut-sei=Ebi en-aut-mei=Hiromichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ImagamaShiro en-aut-sei=Imagama en-aut-mei=Shiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KitohHiroshi en-aut-sei=Kitoh en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OhnoKinji en-aut-sei=Ohno en-aut-mei=Kinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HosonoYasuyuki en-aut-sei=Hosono en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine kn-affil= affil-num=4 en-affil=Division of Molecular Therapeutics, Aichi Cancer Center Research Institute kn-affil= affil-num=5 en-affil=Division of Molecular Therapeutics, Aichi Cancer Center Research Institute kn-affil= affil-num=6 en-affil=Division of Molecular Therapeutics, Aichi Cancer Center Research Institute kn-affil= affil-num=7 en-affil=Department of Thoracic Surgery, Nagoya University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Division of Molecular Therapeutics, Aichi Cancer Center Research Institute kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Aichi Children’s Health and Medical Center kn-affil= affil-num=11 en-affil=Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=FGFR3 kn-keyword=FGFR3 en-keyword=achondroplasia kn-keyword=achondroplasia en-keyword=meclozine kn-keyword=meclozine en-keyword=zebrafish kn-keyword=zebrafish en-keyword=bone kn-keyword=bone END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=750261 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220103 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4 en-subtitle= kn-subtitle= en-abstract= kn-abstract=MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir221 and Mir222 are paralogous genes and share the common seed sequence and Mir221/222AdipoKO mice fed with HFHS chow demonstrated resistance to the development of obesity compared with Mir221/222(flox/y). Ddit4 is a direct target of Mir221 and Mir222, and the upregulation of Ddit4 in Mir221/222AdipoKO was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy. en-copyright= kn-copyright= en-aut-name=YamaguchiSatoshi en-aut-sei=Yamaguchi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ZhangDongxiao en-aut-sei=Zhang en-aut-mei=Dongxiao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KatayamaAkihiro en-aut-sei=Katayama en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KurookaNaoko en-aut-sei=Kurooka en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SugawaraRyosuke en-aut-sei=Sugawara en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AlbuayjanHaya Hamed Hassan en-aut-sei=Albuayjan en-aut-mei=Haya Hamed Hassan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakatsukaAtsuko en-aut-sei=Nakatsuka en-aut-mei=Atsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=EguchiJun en-aut-sei=Eguchi en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=non-coding RNAs kn-keyword=non-coding RNAs en-keyword=microRNA kn-keyword=microRNA en-keyword=adipose tissues kn-keyword=adipose tissues en-keyword=Adipogenesis kn-keyword=Adipogenesis en-keyword=mTORC1 kn-keyword=mTORC1 END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue= article-no= start-page=794948 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20211220 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Exploring the Retinal Binding Cavity of Archaerhodopsin-3 by Replacing the Retinal Chromophore With a Dimethyl Phenylated Derivative en-subtitle= kn-subtitle= en-abstract= kn-abstract=Rhodopsins act as photoreceptors with their chromophore retinal (vitamin-A aldehyde) and they regulate light-dependent biological functions. Archaerhodopsin-3 (AR3) is an outward proton pump that has been widely utilized as a tool for optogenetics, a method for controlling cellular activity by light. To characterize the retinal binding cavity of AR3, we synthesized a dimethyl phenylated retinal derivative, (2E,4E,6E,8E)-9-(2,6-Dimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenal (DMP-retinal). QM/MM calculations suggested that DMP-retinal can be incorporated into the opsin of AR3 (archaeopsin-3, AO3). Thus, we introduced DMP-retinal into AO3 to obtain the non-natural holoprotein (AO3-DMP) and compared some molecular properties with those of AO3 with the natural A1-retinal (AO3-A1) or AR3. Light-induced pH change measurements revealed that AO3-DMP maintained slow outward proton pumping. Noteworthy, AO3-DMP had several significant changes in its molecular properties compared with AO3-A1 as follows; 1) spectroscopic measurements revealed that the absorption maximum was shifted from 556 to 508 nm and QM/MM calculations showed that the blue-shift was due to the significant increase in the HOMO-LUMO energy gap of the chromophore with the contribution of some residues around the chromophore, 2) time-resolved spectroscopic measurements revealed the photocycling rate was significantly decreased, and 3) kinetical spectroscopic measurements revealed the sensitivity of the chromophore binding Schiff base to attack by hydroxylamine was significantly increased. The QM/MM calculations show that a cavity space is present at the aromatic ring moiety in the AO3-DMP structure whereas it is absent at the corresponding beta-ionone ring moiety in the AO3-A1 structure. We discuss these alterations of the difference in interaction between the natural A1-retinal and the DMP-retinal with binding cavity residues. en-copyright= kn-copyright= en-aut-name=TsuneishiTaichi en-aut-sei=Tsuneishi en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakahashiMasataka en-aut-sei=Takahashi en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsujimuraMasaki en-aut-sei=Tsujimura en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KojimaKeiichi en-aut-sei=Kojima en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IshikitaHiroshi en-aut-sei=Ishikita en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakeuchiYasuo en-aut-sei=Takeuchi en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SudoYuki en-aut-sei=Sudo en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Laboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Applied Chemistry, The University of Tokyo kn-affil= affil-num=4 en-affil=Laboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Applied Chemistry, The University of Tokyo kn-affil= affil-num=6 en-affil=Laboratory of Synthetic and Medicinal Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Laboratory of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=retinal kn-keyword=retinal en-keyword=rhodopsin kn-keyword=rhodopsin en-keyword=proton pump kn-keyword=proton pump en-keyword=derivative kn-keyword=derivative en-keyword=photoreceptor kn-keyword=photoreceptor END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=703298 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210827 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Crosstalk Between Intestinal Microbiota Derived Metabolites and Tissues in Allogeneic Hematopoietic Cell Transplantation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an evidence based- cellular immunotherapy for hematological malignancies. Immune reactions not only promote graft-versus-tumor effects that kill hematological malignant cells but also graft-versus-host disease (GVHD) that is the primary complication characterized by systemic organ damages consisting of T-cells and antigen presenting cells (APCs) activation. GVHD has long been recognized as an immunological reaction that requires an immunosuppressive treatment targeting immune cells. However immune suppression cannot always prevent GVHD or effectively treat it once it has developed. Recent studies using high-throughput sequencing technology investigated the impact of microbial flora on GVHD and provided profound insights of the mechanism of GVHD other than immune cells. Allo-HSCT affects the intestinal microbiota and microbiome-metabolome axis that can alter intestinal homeostasis and the severity of experimental GVHD. This axis can potentially be manipulated via dietary intervention or metabolites produced by intestinal bacteria affected post-allo-HSCT. In this review, we discuss the mechanism of experimental GVHD regulation by the complex microbial community-metabolites-host tissue axis. Furthermore, we summarize the major findings of microbiome-based immunotherapeutic approaches that protect tissues from experimental GVHD. Understanding the complex relationships between gut microbiota-metabolites-host tissues axis provides crucial insight into the pathogenesis of GVHD and advances the development of new therapeutic approaches. en-copyright= kn-copyright= en-aut-name=FujiwaraHideaki en-aut-sei=Fujiwara en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=graft-versus-host disease kn-keyword=graft-versus-host disease en-keyword=microbial metabolite kn-keyword=microbial metabolite en-keyword=dysbiosis kn-keyword=dysbiosis en-keyword=microbiota kn-keyword=microbiota en-keyword=allogeneic stem cell transplantation kn-keyword=allogeneic stem cell transplantation END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue= article-no= start-page=730550 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210917 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Assessment of Possible Contributions of Hyaluronan and Proteoglycan Binding Link Protein 4 to Differential Perineuronal Net Formation at the Calyx of Held en-subtitle= kn-subtitle= en-abstract= kn-abstract=The calyx of Held is a giant nerve terminal mediating high-frequency excitatory input to principal cells of the medial nucleus of the trapezoid body (MNTB). MNTB principal neurons are enwrapped by densely organized extracellular matrix structures, known as perineuronal nets (PNNs). Emerging evidence indicates the importance of PNNs in synaptic transmission at the calyx of Held. Previously, a unique differential expression of aggrecan and brevican has been reported at this calyceal synapse. However, the role of hyaluronan and proteoglycan binding link proteins (HAPLNs) in PNN formation and synaptic transmission at this synapse remains elusive. This study aimed to assess immunohistochemical evidence for the effect of HAPLN4 on differential PNN formation at the calyx of Held. Genetic deletion of Hapln4 exhibited a clear ectopic shift of brevican localization from the perisynaptic space between the calyx of Held terminals and principal neurons to the neuropil surrounding the whole calyx of Held terminals. In contrast, aggrecan expression showed a consistent localization at the surrounding neuropil, together with HAPLN1 and tenascin-R, in both gene knockout (KO) and wild-type (WT) mice. An in situ proximity ligation assay demonstrated the molecular association of brevican with HAPLN4 in WT and HAPLN1 in gene KO mice. Further elucidation of the roles of HAPLN4 may highlight the developmental and physiological importance of PNN formation in the calyx of Held.

en-copyright= kn-copyright= en-aut-name=NojimaKojiro en-aut-sei=Nojima en-aut-mei=Kojiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiHaruko en-aut-sei=Miyazaki en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HoriTetsuya en-aut-sei=Hori en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=VargovaLydia en-aut-sei=Vargova en-aut-mei=Lydia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OohashiToshitaka en-aut-sei=Oohashi en-aut-mei=Toshitaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= affil-num=4 en-affil=Department of Neuroscience, Charles University, Second Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=perineuronal net kn-keyword=perineuronal net en-keyword=chondroitin sulfate proteoglycan kn-keyword=chondroitin sulfate proteoglycan en-keyword=calyx of Held kn-keyword=calyx of Held en-keyword=hyaluronan and proteoglycan binding link protein 4 kn-keyword=hyaluronan and proteoglycan binding link protein 4 en-keyword=synapse kn-keyword=synapse en-keyword=in situ proximity ligation assay kn-keyword=in situ proximity ligation assay END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=713358 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210830 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives en-subtitle= kn-subtitle= en-abstract= kn-abstract=CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) are functionally distinct subsets of mature T cells with broad suppressive activity and have been shown to play an important role in the establishment of immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). Tregs exhibit an activated phenotype from the stage of emigration from the thymus and maintain continuous proliferation in the periphery. The distinctive feature in homeostasis enables Tregs to respond sensitively to small environmental changes and exert necessary and sufficient immune suppression; however, on the other hand, it also predisposes Tregs to be susceptible to apoptosis in the inflammatory condition post-transplant. Our studies have attempted to define the intrinsic and extrinsic factors affecting Treg homeostasis from the acute to chronic phases after allogeneic HSCT. We have found that altered cytokine environment in the prolonged post-HSCT lymphopenia or peri-transplant use of immune checkpoint inhibitors could hamper Treg reconstitution, leading to refractory graft-versus-host disease. Using murine models and clinical trials, we have also demonstrated that proper intervention with low-dose interleukin-2 or post-transplant cyclophosphamide could restore Treg homeostasis and further amplify the suppressive function after HSCT. The purpose of this review is to reconsider the distinctive characteristics of post-transplant Treg homeostasis and discuss how to harness Treg homeostasis to optimize posttransplant immunity for developing a safe and efficient therapeutic strategy.

en-copyright= kn-copyright= en-aut-name=IkegawaShuntaro en-aut-sei=Ikegawa en-aut-mei=Shuntaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsuokaKen-ichi en-aut-sei=Matsuoka en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= en-keyword=regulatory T cell kn-keyword=regulatory T cell en-keyword=graft-versus-host disease kn-keyword=graft-versus-host disease en-keyword=interleukin 2 kn-keyword=interleukin 2 en-keyword=immune checkpoint inhibitor kn-keyword=immune checkpoint inhibitor en-keyword=post-transplant cyclophosphamide kn-keyword=post-transplant cyclophosphamide END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=726273 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210820 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Virulence of Cholera Toxin Gene-Positive Vibrio cholerae Non-O1/non-O139 Strains Isolated From Environmental Water in Kolkata, India en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cholera toxin (CT)-producing Vibrio cholerae O1 and O139 cause acute diarrheal disease and are proven etiological agents of cholera epidemics and pandemics. On the other hand, V. cholerae non-O1/non-O139 are designated as non-agglutinable (NAG) vibrios and are not associated with epidemic cholera. The majority of NAG vibrios do not possess the gene for CT (ctx). In this study, we isolated three NAG strains (strains No. 1, 2, and 3) with ctx from pond water in Kolkata, India, and examined their pathogenic properties. The enterotoxicity of the three NAG strains in vivo was examined using the rabbit ileal intestinal loop test. Strain No. 1 induced the accumulation of fluid in the loop, and the volume of fluid was reduced by simultaneous administration of anti-CT antiserum into the loop. The volume of fluid in the loop caused by strains No. 2 and 3 was small and undetectable, respectively. Then, we cultured these three strains in liquid medium in vitro at two temperatures, 25 degrees C and 37 degrees C, and examined the amount of CT accumulated in the culture supernatant. CT was accumulated in the culture supernatant of strain No.1 when the strain was cultured at 25 degrees C, but that was low when cultured at 37 degrees C. The CT amount accumulated in the culture supernatants of the No. 2 and No. 3 strains was extremely low at both temperature under culture conditions examined. In order to clarify the virulence properties of these strains, genome sequences of the three strains were analyzed. The analysis showed that there was no noticeable difference among three isolates both in the genes for virulence factors and regulatory genes of ctx. However, vibrio seventh pandemic island-II (VSP-II) was retained in strain No. 1, but not in strains No. 2 or 3. Furthermore, it was revealed that the genotype of the B subunit of CT in strain No. 1 was type 1 and those of strains No. 2 and 3 were type 8. Histopathological examination showed the disappearance of villi in intestinal tissue exposed to strain No. 1. In addition, fluid accumulated in the loop due to the action of strain No. 1 had hemolytic activity. This indicated that strain No. 1 may possesses virulence factors to induce severe syndrome when the strain infects humans, and that some strains of NAG vibrio inhabiting pond water in Kolkata have already acquired virulence, which can cause illness in humans. There is a possibility that these virulent NAG vibrios, which have acquired genes encoding factors involved in virulence of V. cholerae O1, may emerge in various parts of the world and cause epidemics in the future. en-copyright= kn-copyright= en-aut-name=TakahashiEizo en-aut-sei=Takahashi en-aut-mei=Eizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OchiSadayuki en-aut-sei=Ochi en-aut-mei=Sadayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MizunoTamaki en-aut-sei=Mizuno en-aut-mei=Tamaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MoritaDaichi en-aut-sei=Morita en-aut-mei=Daichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoritaMasatomo en-aut-sei=Morita en-aut-mei=Masatomo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OhnishiMakoto en-aut-sei=Ohnishi en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KoleyHemanta en-aut-sei=Koley en-aut-mei=Hemanta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=DuttaMoumita en-aut-sei=Dutta en-aut-mei=Moumita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ChowdhuryGoutam en-aut-sei=Chowdhury en-aut-mei=Goutam kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MukhopadhyayAsish K. en-aut-sei=Mukhopadhyay en-aut-mei=Asish K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=DuttaShanta en-aut-sei=Dutta en-aut-mei=Shanta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MiyoshiShin-Ichi en-aut-sei=Miyoshi en-aut-mei=Shin-Ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OkamotoKeinosuke en-aut-sei=Okamoto en-aut-mei=Keinosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Collaborative Research Center of Okayama University for Infectious Diseases in India kn-affil= affil-num=2 en-affil=Department of Health Pharmacy, Yokohama University of Pharmacy kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences of Okayama University kn-affil= affil-num=4 en-affil=Collaborative Research Center of Okayama University for Infectious Diseases in India kn-affil= affil-num=5 en-affil=Department of Bacteriology I, National Institute of Infectious Diseases kn-affil= affil-num=6 en-affil=Department of Bacteriology I, National Institute of Infectious Diseases kn-affil= affil-num=7 en-affil=National Institute of Cholera and Enteric Diseases kn-affil= affil-num=8 en-affil=National Institute of Cholera and Enteric Diseases kn-affil= affil-num=9 en-affil=National Institute of Cholera and Enteric Diseases kn-affil= affil-num=10 en-affil=National Institute of Cholera and Enteric Diseases kn-affil= affil-num=11 en-affil=National Institute of Cholera and Enteric Diseases kn-affil= affil-num=12 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences of Okayama University kn-affil= affil-num=13 en-affil=Collaborative Research Center of Okayama University for Infectious Diseases in India kn-affil= en-keyword=Vibrio cholerae kn-keyword=Vibrio cholerae en-keyword=NAG Vibrio kn-keyword=NAG Vibrio en-keyword=cholera toxin kn-keyword=cholera toxin en-keyword=virulence kn-keyword=virulence en-keyword=environmental water kn-keyword=environmental water en-keyword=gene analysis kn-keyword=gene analysis END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=715752 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210812 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RB(high)CD4(+) T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-gamma-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs. en-copyright= kn-copyright= en-aut-name=MatsumotoRyohtaroh en-aut-sei=Matsumoto en-aut-mei=Ryohtaroh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakahashiDaisuke en-aut-sei=Takahashi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeMasaki en-aut-sei=Watanabe en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakataniShunsuke en-aut-sei=Nakatani en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakamuraYuta en-aut-sei=Takamura en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KurosakiYuji en-aut-sei=Kurosaki en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaseKoji en-aut-sei=Hase en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= affil-num=2 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University kn-affil= en-keyword=RXR kn-keyword=RXR en-keyword=NEt-3IB kn-keyword=NEt-3IB en-keyword=inflammatory bowel disease kn-keyword=inflammatory bowel disease en-keyword=colitis kn-keyword=colitis en-keyword=Th1 cells kn-keyword=Th1 cells END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=715545 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210819 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Identification of a Novel Quinvirus in the Family Betaflexiviridae That Infects Winter Wheat en-subtitle= kn-subtitle= en-abstract= kn-abstract=Yellow mosaic disease in winter wheat is usually attributed to the infection by bymoviruses or furoviruses; however, there is still limited information on whether other viral agents are also associated with this disease. To investigate the wheat viromes associated with yellow mosaic disease, we carried out de novo RNA sequencing (RNA-seq) analyses of symptomatic and asymptomatic wheat-leaf samples obtained from a field in Hokkaido, Japan, in 2018 and 2019. The analyses revealed the infection by a novel betaflexivirus, which tentatively named wheat virus Q (WVQ), together with wheat yellow mosaic virus (WYMV, a bymovirus) and northern cereal mosaic virus (a cytorhabdovirus). Basic local alignment search tool (BLAST) analyses showed that the WVQ strains (of which there are at least three) were related to the members of the genus Foveavirus in the subfamily Quinvirinae (family Betaflexiviridae). In the phylogenetic tree, they form a clade distant from that of the foveaviruses, suggesting that WVQ is a member of a novel genus in the Quinvirinae. Laboratory tests confirmed that WVQ, like WYMV, is potentially transmitted through the soil to wheat plants. WVQ was also found to infect rye plants grown in the same field. Moreover, WVQ-derived small interfering RNAs accumulated in the infected wheat plants, indicating that WVQ infection induces antiviral RNA silencing responses. Given its common coexistence with WYMV, the impact of WVQ infection on yellow mosaic disease in the field warrants detailed investigation. en-copyright= kn-copyright= en-aut-name=KondoHideki en-aut-sei=Kondo en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshidaNaoto en-aut-sei=Yoshida en-aut-mei=Naoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujitaMiki en-aut-sei=Fujita en-aut-mei=Miki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MaruyamaKazuyuki en-aut-sei=Maruyama en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HyodoKiwamu en-aut-sei=Hyodo en-aut-mei=Kiwamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HisanoHiroshi en-aut-sei=Hisano en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TamadaTetsuo en-aut-sei=Tamada en-aut-mei=Tetsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AndikaIda Bagus en-aut-sei=Andika en-aut-mei=Ida Bagus kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SuzukiNobuhiro en-aut-sei=Suzuki en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=2 en-affil=Agricultural Research Institute, HOKUREN Federation of Agricultural Cooperatives kn-affil= affil-num=3 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=4 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=5 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=6 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=7 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= affil-num=8 en-affil=College of Plant Health and Medicine, Qingdao Agricultural University kn-affil= affil-num=9 en-affil=Institute of Plant Science and Resources (IPSR), Okayama University kn-affil= en-keyword=Betaflexiviridae kn-keyword=Betaflexiviridae en-keyword=quinvirus kn-keyword=quinvirus en-keyword=bymovirus kn-keyword=bymovirus en-keyword=yellow mosaic disease kn-keyword=yellow mosaic disease en-keyword=wheat kn-keyword=wheat en-keyword=virome kn-keyword=virome en-keyword=soil borne kn-keyword=soil borne en-keyword=variants kn-keyword=variants END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue= article-no= start-page=689662 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210804 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Meta-Analysis-Assisted Detection of Gravity-Sensitive Genes in Human Vascular Endothelial Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Gravity affects the function and maintenance of organs, such as bones, muscles, and the heart. Several studies have used DNA microarrays to identify genes with altered expressions in response to gravity. However, it is technically challenging to combine the results from various microarray datasets because of their different data structures. We hypothesized that it is possible to identify common changes in gene expression from the DNA microarray datasets obtained under various conditions and methods. In this study, we grouped homologous genes to perform a meta-analysis of multiple vascular endothelial cell and skeletal muscle datasets. According to the t-distributed stochastic neighbor embedding (t-SNE) analysis, the changes in the gene expression pattern in vascular endothelial cells formed specific clusters. We also identified candidate genes in endothelial cells that responded to gravity. Further, we exposed human umbilical vein endothelial cells (HUVEC) to simulated microgravity (SMG) using a clinostat and measured the expression levels of the candidate genes. Gene expression analysis using qRT-PCR revealed that the expression level of the prostaglandin (PG) transporter gene SLCO2A1 decreased in response to microgravity, consistent with the meta-analysis of microarray datasets. Furthermore, the direction of gravity affected the expression level of SLCO2A1, buttressing the finding that its expression was affected by gravity. These results suggest that a meta-analysis of DNA microarray datasets may help identify new target genes previously overlooked in individual microarray analyses. en-copyright= kn-copyright= en-aut-name=LiangYin en-aut-sei=Liang en-aut-mei=Yin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WangMengxue en-aut-sei=Wang en-aut-mei=Mengxue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LiuYun en-aut-sei=Liu en-aut-mei=Yun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangChen en-aut-sei=Wang en-aut-mei=Chen kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahashiKen en-aut-sei=Takahashi en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NaruseKeiji en-aut-sei=Naruse en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=DNA microarrays kn-keyword=DNA microarrays en-keyword=meta-analysis kn-keyword=meta-analysis en-keyword=microgravity kn-keyword=microgravity en-keyword=human umbilical vein endothelial cells kn-keyword=human umbilical vein endothelial cells en-keyword=prostaglandin transporter kn-keyword=prostaglandin transporter en-keyword=clinostat kn-keyword=clinostat en-keyword=spaceflight-associated neuro-ocular syndrome kn-keyword=spaceflight-associated neuro-ocular syndrome END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=647684 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210810 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Purification, Characterization, and Gene Expression of Rice Endo-beta-N-Acetylglucosaminidase, Endo-Os en-subtitle= kn-subtitle= en-abstract= kn-abstract=In the endoplasmic reticulum-associated degradation system of plant and animal cells, high-mannose type free N-glycans (HMT-FNGs) are produced from misfolded glycoproteins prior to proteasomal degradation, and two enzymes, cytosolic peptide:N-glycanase (cPNGase) and endo-beta-N-acetylglucosaminidase (endo-beta-GlcNAc-ase), are involved in the deglycosylation. Although the physiological functions of these FNGs in plant growth and development remain to be elucidated, detailed characterization of cPNGase and endo-beta-GlcNAc-ase is required. In our previous work, we described the purification, characterization, and subcellular distribution of some plant endo-beta-GlcNAc-ases and preliminarily reported the gene information of rice endo-beta-GlcNAc-ase (Endo-Os). Furthermore, we analyzed the changes in gene expression of endo-beta-GlcNAc-ase during tomato fruit maturation and constructed a mutant line of Arabidopsis thaliana, in which the two endo-beta-GlcNAc-ase genes were knocked-out based on the Endo-Os gene. In this report, we describe the purification, characterization, amino acid sequence, and gene cloning of Endo-Os in detail. Purified Endo-Os, with an optimal pH of 6.5, showed high activity for high-mannose type N-glycans bearing the Man alpha 1-2Man alpha 1-3Man beta 1 unit; this substrate specificity was almost the same as that of other plant endo-beta-GlcNAc-ases, suggesting that Endo-Os plays a critical role in the production of HTM-FNGs in the cytosol. Electrospray ionization-mass spectrometry analysis of the tryptic peptides revealed 17 internal amino acid sequences, including the C terminus; the N-terminal sequence could not be identified due to chemical modification. These internal amino acid sequences were consistent with the amino acid sequence (UniProt ID: Q5W6R1) deduced from the Oryza sativa cDNA clone AK112067 (gene ID: Os05g0346500). Recombinant Endo-Os expressed in Escherichia coli using cDNA showed the same enzymatic properties as those of native Endo-Os. en-copyright= kn-copyright= en-aut-name=MaedaMegumi en-aut-sei=Maeda en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OkamotoNaoko en-aut-sei=Okamoto en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ArakiNode en-aut-sei=Araki en-aut-mei=Node kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraYoshinobu en-aut-sei=Kimura en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Biofunctional Chemistry, Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Biofunctional Chemistry, Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University kn-affil= affil-num=4 en-affil=Department of Biofunctional Chemistry, Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=endo-beta-N-acetylglucosaminidase kn-keyword=endo-beta-N-acetylglucosaminidase en-keyword=free N-glycans kn-keyword=free N-glycans en-keyword=Oryza sativa kn-keyword=Oryza sativa en-keyword=ER associated degradation kn-keyword=ER associated degradation en-keyword=peptide:N-glycanase kn-keyword=peptide:N-glycanase END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue= article-no= start-page=729192 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210720 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion (vol 11, 665273, 2021) en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=HeFang en-aut-sei=He en-aut-mei=Fang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoYoshinori en-aut-sei=Matsumoto en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AsanoYosuke en-aut-sei=Asano en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamuraYuriko en-aut-sei=Yamamura en-aut-mei=Yuriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KatsuyamaTakayuki en-aut-sei=Katsuyama en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=RoseJose La en-aut-sei=Rose en-aut-mei=Jose La kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TomonobuNahoko en-aut-sei=Tomonobu en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KomalasariNi Luh Gede Yoni en-aut-sei=Komalasari en-aut-mei=Ni Luh Gede Yoni kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SakaguchiMasakiyo en-aut-sei=Sakaguchi en-aut-mei=Masakiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=RottapelRobert en-aut-sei=Rottapel en-aut-mei=Robert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Princess Margaret Cancer Center, University Health Network, University of Toronto kn-affil= affil-num=7 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Princess Margaret Cancer Center, University Health Network, University of Toronto kn-affil= affil-num=11 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=ABL-Abelson murine leukemia viral oncogene homolog kn-keyword=ABL-Abelson murine leukemia viral oncogene homolog en-keyword=Runx2 (runt-related transcription factor 2) kn-keyword=Runx2 (runt-related transcription factor 2) en-keyword=tyrosine kn-keyword=tyrosine en-keyword=phosphorylation kn-keyword=phosphorylation en-keyword=invasion kn-keyword=invasion END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue= article-no= start-page=696882 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210615 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Exclusion of the Possibility of "False Ripples" From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aim Ripple-band epileptic high-frequency oscillations (HFOs) can be recorded by scalp electroencephalography (EEG), and tend to be associated with epileptic spikes. However, there is a concern that the filtration of steep waveforms such as spikes may cause spurious oscillations or "false ripples." We excluded such possibility from at least some ripples by EEG differentiation, which, in theory, enhances high-frequency signals and does not generate spurious oscillations or ringing. Methods The subjects were 50 pediatric patients, and ten consecutive spikes during sleep were selected for each patient. Five hundred spike data segments were initially reviewed by two experienced electroencephalographers using consensus to identify the presence or absence of ripples in the ordinary filtered EEG and an associated spectral blob in time-frequency analysis (Session A). These EEG data were subjected to numerical differentiation (the second derivative was denoted as EEG ''). The EEG '' trace of each spike data segment was shown to two other electroencephalographers who judged independently whether there were clear ripple oscillations or uncertain ripple oscillations or an absence of oscillations (Session B). Results In Session A, ripples were identified in 57 spike data segments (Group A-R), but not in the other 443 data segments (Group A-N). In Session B, both reviewers identified clear ripples (strict criterion) in 11 spike data segments, all of which were in Group A-R (p < 0.0001 by Fisher's exact test). When the extended criterion that included clear and/or uncertain ripples was used in Session B, both reviewers identified 25 spike data segments that fulfilled the criterion: 24 of these were in Group A-R (p < 0.0001). Discussion We have demonstrated that real ripples over scalp spikes exist in a certain proportion of patients. Ripples that were visualized consistently using both ordinary filters and the EEG '' method should be true, but failure to clarify ripples using the EEG '' method does not mean that true ripples are absent. Conclusion The numerical differentiation of EEG data provides convincing evidence that HFOs were detected in terms of the presence of such unusually fast oscillations over the scalp and the importance of this electrophysiological phenomenon. en-copyright= kn-copyright= en-aut-name=KobayashiKatsuhiro en-aut-sei=Kobayashi en-aut-mei=Katsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShibataTakashi en-aut-sei=Shibata en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsuchiyaHiroki en-aut-sei=Tsuchiya en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AkiyamaTomoyuki en-aut-sei=Akiyama en-aut-mei=Tomoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital kn-affil= en-keyword=epilepsy kn-keyword=epilepsy en-keyword=child kn-keyword=child en-keyword=scalp EEG kn-keyword=scalp EEG en-keyword=false ripple kn-keyword=false ripple en-keyword=high-frequency oscillation (HFO) kn-keyword=high-frequency oscillation (HFO) en-keyword=fast oscillation (FO) kn-keyword=fast oscillation (FO) END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue= article-no= start-page=674366 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210608 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-kappa B Ligand-Induced Osteoclastogenesis by Suppressing Protein Kinase-C alpha/beta II Phosphorylation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKC alpha/beta II, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis. en-copyright= kn-copyright= en-aut-name=SakaidaKyosuke en-aut-sei=Sakaida en-aut-mei=Kyosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OmoriKazuhiro en-aut-sei=Omori en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakayamaMasaaki en-aut-sei=Nakayama en-aut-mei=Masaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MandaiHiroki en-aut-sei=Mandai en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakagawaSaki en-aut-sei=Nakagawa en-aut-mei=Saki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakoHidefumi en-aut-sei=Sako en-aut-mei=Hidefumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KameiChiaki en-aut-sei=Kamei en-aut-mei=Chiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoSatoshi en-aut-sei=Yamamoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KobayashiHiroya en-aut-sei=Kobayashi en-aut-mei=Hiroya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IshiiSatoki en-aut-sei=Ishii en-aut-mei=Satoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IbaragiSoichiro en-aut-sei=Ibaragi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamashiroKeisuke en-aut-sei=Yamashiro en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YamamotoTadashi en-aut-sei=Yamamoto en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SugaSeiji en-aut-sei=Suga en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TakashibaShogo en-aut-sei=Takashiba en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Periodontics and Endodontics, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science kn-affil= affil-num=5 en-affil=Department of Periodontics and Endodontics, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Periodontics and Endodontics, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Periodontics and Endodontics, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University kn-affil= affil-num=11 en-affil=Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Department of Oral Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=13 en-affil=Department of Periodontics and Endodontics, Okayama University Hospital, Okayama, Japan, 3Department of Oral Microbiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=14 en-affil=Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=15 en-affil=Division of Applied Chemistry, Graduate School of Natural Sciences and Technology, Okayama University kn-affil= affil-num=16 en-affil=Department of Pathophysiology-Periodontal Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=(+)-terrein kn-keyword=(+)-terrein en-keyword=ovariectomy kn-keyword=ovariectomy en-keyword=osteoporosis kn-keyword=osteoporosis en-keyword=RANKL kn-keyword=RANKL en-keyword=PKC kn-keyword=PKC END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue= article-no= start-page=665273 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210531 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion en-subtitle= kn-subtitle= en-abstract= kn-abstract=Activity of transcription factors is normally regulated through interaction with other transcription factors, chromatin remodeling proteins and transcriptional co-activators. In distinction to these well-established transcriptional controls of gene expression, we have uncovered a unique activation model of transcription factors between tyrosine kinase ABL and RUNX2, an osteoblastic master transcription factor, for cancer invasion. We show that ABL directly binds to, phosphorylates, and activates RUNX2 through its SH2 domain in a kinase activity-dependent manner and that the complex formation of these proteins is required for expression of its target gene MMP13. Additionally, we show that the RUNX2 transcriptional activity is dependent on the number of its tyrosine residues that are phosphorylated by ABL. In addition to regulation of RUNX2 activity, we show that ABL transcriptionally enhances RUNX2 expression through activation of the bone morphogenetic protein (BMP)-SMAD pathway. Lastly, we show that ABL expression in highly metastatic breast cancer MDA-MB231 cells is associated with their invasive capacity and that ABL-mediated invasion is abolished by depletion of endogenous RUNX2 or MMP13. Our genetic and biochemical evidence obtained in this study contributes to a mechanistic insight linking ABL-mediated phosphorylation and activation of RUNX2 to induction of MMP13, which underlies a fundamental invasive capacity in cancer and is different from the previously described model of transcriptional activation. en-copyright= kn-copyright= en-aut-name=HeFang en-aut-sei=He en-aut-mei=Fang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoYoshinori en-aut-sei=Matsumoto en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AsanoYosuke en-aut-sei=Asano en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamuraYuriko en-aut-sei=Yamamura en-aut-mei=Yuriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KatsuyamaTakayuki en-aut-sei=Katsuyama en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=La RoseJose en-aut-sei=La Rose en-aut-mei=Jose kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TomonobuNahoko en-aut-sei=Tomonobu en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KomalasariNi Luh Gede Yoni en-aut-sei=Komalasari en-aut-mei=Ni Luh Gede Yoni kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SakaguchiMasakiyo en-aut-sei=Sakaguchi en-aut-mei=Masakiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=RottapelRobert en-aut-sei=Rottapel en-aut-mei=Robert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Princess Margaret Cancer Center, University Health Network, University of Toronto kn-affil= affil-num=7 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Princess Margaret Cancer Center, University Health Network, University of Toronto kn-affil= affil-num=11 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=ABL kn-keyword=ABL en-keyword=Abelson murine leukemia viral oncogene homolog kn-keyword=Abelson murine leukemia viral oncogene homolog en-keyword=Runx2 (runt-related transcription factor 2) kn-keyword=Runx2 (runt-related transcription factor 2) en-keyword=tyrosine kn-keyword=tyrosine en-keyword=phosphorylation kn-keyword=phosphorylation en-keyword=invasion kn-keyword=invasion END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue= article-no= start-page=668059 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210524 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear. Methods: Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease. Results: During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24-2.55, P = 0.002) and Calsepa [High-Man (Man2-6)]: 1.56 (1.19-2.04, P = 0.001). Common glycan binding to these lectins was high-mannose type of N-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001-0.055, P = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045-0.692, P = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively]. Conclusion: The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal N-glycosylation occurring in patients with diabetes at higher risk of CVE. en-copyright= kn-copyright= en-aut-name=MiseKoki en-aut-sei=Mise en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ImamuraMariko en-aut-sei=Imamura en-aut-mei=Mariko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamaguchiSatoshi en-aut-sei=Yamaguchi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMayu en-aut-sei=Watanabe en-aut-mei=Mayu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HiguchiChigusa en-aut-sei=Higuchi en-aut-mei=Chigusa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KatayamaAkihiro en-aut-sei=Katayama en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyamotoSatoshi en-aut-sei=Miyamoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NakatsukaAtsuko en-aut-sei=Nakatsuka en-aut-mei=Atsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=EguchiJun en-aut-sei=Eguchi en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HidaKazuyuki en-aut-sei=Hida en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NakatoTatsuaki en-aut-sei=Nakato en-aut-mei=Tatsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ToneAtsuhito en-aut-sei=Tone en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TeshigawaraSanae en-aut-sei=Teshigawara en-aut-mei=Sanae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MatsuokaTakashi en-aut-sei=Matsuoka en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KameiShinji en-aut-sei=Kamei en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MurakamiKazutoshi en-aut-sei=Murakami en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=ShimizuIkki en-aut-sei=Shimizu en-aut-mei=Ikki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=MiyashitaKatsuhiro en-aut-sei=Miyashita en-aut-mei=Katsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=AndoShinichiro en-aut-sei=Ando en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=NunoueTomokazu en-aut-sei=Nunoue en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=YoshidaMichihiro en-aut-sei=Yoshida en-aut-mei=Michihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=YamadaMasao en-aut-sei=Yamada en-aut-mei=Masao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Diabetes Center, Okayama University Hospital kn-affil= affil-num=7 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Diabetology and Metabolism, National Hospital Organization Okayama Medical Center kn-affil= affil-num=12 en-affil=Okayama Saiseikai General Hospital kn-affil= affil-num=13 en-affil=Okayama Saiseikai General Hospital kn-affil= affil-num=14 en-affil=Okayama Saiseikai General Hospital kn-affil= affil-num=15 en-affil=Kurashiki Central Hospital kn-affil= affil-num=16 en-affil=Kurashiki Central Hospital kn-affil= affil-num=17 en-affil=Kurashiki Central Hospital kn-affil= affil-num=18 en-affil=The Sakakibara Heart Institute of Okayama kn-affil= affil-num=19 en-affil=Japanese Red Cross Okayama Hospital kn-affil= affil-num=20 en-affil=Okayama City General Medical Center kn-affil= affil-num=21 en-affil=Nunoue Clinic kn-affil= affil-num=22 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=23 en-affil=GlycoTechnica Ltd. kn-affil= affil-num=24 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=25 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=cardiovascular event kn-keyword=cardiovascular event en-keyword=diabetes kn-keyword=diabetes en-keyword=lectins kn-keyword=lectins en-keyword=N-glycans kn-keyword=N-glycans en-keyword=urinary biomarkers kn-keyword=urinary biomarkers END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=17 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190122 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract= Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome. en-copyright= kn-copyright= en-aut-name=OhkuraTakahiro en-aut-sei=Ohkura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MarutaniRie en-aut-sei=Marutani en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UsamiKaya en-aut-sei=Usami en-aut-mei=Kaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil= Department of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Ras/Raf/ERK/MAPK kn-keyword=Ras/Raf/ERK/MAPK en-keyword=Spred2 kn-keyword=Spred2 en-keyword=adipocyte kn-keyword=adipocyte en-keyword=inflammation kn-keyword=inflammation en-keyword=macrophage kn-keyword=macrophage en-keyword=obesity kn-keyword=obesity END