start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=5 article-no= start-page=eaav9053 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20190501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Layer-specific activation of sensory input and predictive feedback in the human primary somatosensory cortex en-subtitle= kn-subtitle= en-abstract= kn-abstract=When humans perceive a sensation, their brains integrate inputs from sensory receptors and process them based on their expectations. The mechanisms of this predictive coding in the human somatosensory system are not fully understood. We fill a basic gap in our understanding of the predictive processing of somatosensation by examining the layer-specific activity in sensory input and predictive feedback in the human primary somatosensory cortex (S1). We acquired submillimeter functional magnetic resonance imaging data at 7T (n = 10) during a task of perceived, predictable, and unpredictable touching sequences. We demonstrate that the sensory input from thalamic projects preferentially activates the middle layer, while the superficial and deep layers in S1 are more engaged for cortico-cortical predictive feedback input. These findings are pivotal to understanding the mechanisms of tactile prediction processing in the human somatosensory cortex. en-copyright= kn-copyright= en-aut-name=YuYinghua en-aut-sei=Yu en-aut-mei=Yinghua kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HuberLaurentius en-aut-sei=Huber en-aut-mei=Laurentius kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=JangrawDavid C. en-aut-sei=Jangraw en-aut-mei=David C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HandwerkerDaniel A. en-aut-sei=Handwerker en-aut-mei=Daniel A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MolfesePeter J. en-aut-sei=Molfese en-aut-mei=Peter J. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChenGang en-aut-sei=Chen en-aut-mei=Gang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=EjimaYoshimichi en-aut-sei=Ejima en-aut-mei=Yoshimichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=WuJinglong en-aut-sei=Wu en-aut-mei=Jinglong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=BandettiniPeter A. en-aut-sei=Bandettini en-aut-mei=Peter A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=Section on Functional Imaging Methods, National Institute of Mental Health 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=Section on Functional Imaging Methods, National Institute of Mental Health kn-affil= affil-num=5 en-affil=Section on Functional Imaging Methods, National Institute of Mental Health kn-affil= affil-num=6 en-affil=Section on Functional Imaging Methods, National Institute of Mental Health kn-affil= affil-num=7 en-affil=Scientific and Statistical Computing Core, National Institute of Mental Health kn-affil= affil-num=8 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems,Okayama University kn-affil= affil-num=9 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems,Okayama University kn-affil= affil-num=10 en-affil=Section on Functional Imaging Methods, National Institute of Mental Health kn-affil= END start-ver=1.4 cd-journal=joma no-vol=366 cd-vols= no-issue=6463 article-no= start-page=334 end-page=338 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191018 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=An oxyl/oxo mechanism for dioxygen bond formation in PSII revealed by X-ray free electron lasers en-subtitle= kn-subtitle= en-abstract= kn-abstract= Photosynthetic water oxidation is catalyzed by the Mn4CaO5 cluster of photosystem II (PSII) with linear progression through five S-state intermediates (S0 to S4). To reveal the mechanism of water oxidation, we analyzed structures of PSII in the S1, S2, and S3 states by x-ray free-electron laser serial crystallography. No insertion of water was found in S2, but flipping of D1 Glu189 upon transition to S3 leads to the opening of a water channel and provides a space for incorporation of an additional oxygen ligand, resulting in an open cubane Mn4CaO6 cluster with an oxyl/oxo bridge. Structural changes of PSII between the different S states reveal cooperative action of substrate water access, proton release, and dioxygen formation in photosynthetic water oxidation. en-copyright= kn-copyright= en-aut-name=SugaMichihiro en-aut-sei=Suga en-aut-mei=Michihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AkitaFusamichi en-aut-sei=Akita en-aut-mei=Fusamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamashitaKeitaro en-aut-sei=Yamashita en-aut-mei=Keitaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakajimaYoshiki en-aut-sei=Nakajima en-aut-mei=Yoshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=UenoGo en-aut-sei=Ueno en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=LiHongjie en-aut-sei=Li en-aut-mei=Hongjie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamaneTakahiro en-aut-sei=Yamane en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HirataKunio en-aut-sei=Hirata en-aut-mei=Kunio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=UmenaYasufumi en-aut-sei=Umena en-aut-mei=Yasufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YonekuraShinichiro en-aut-sei=Yonekura en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YuLong-Jiang en-aut-sei=Yu en-aut-mei=Long-Jiang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MurakamiHironori en-aut-sei=Murakami en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NomuraTakashi en-aut-sei=Nomura en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KimuraTetsunari en-aut-sei=Kimura en-aut-mei=Tetsunari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KuboMinoru en-aut-sei=Kubo en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=BabaSeiki en-aut-sei=Baba en-aut-mei=Seiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KumasakaTakashi en-aut-sei=Kumasaka en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=TonoKensuke en-aut-sei=Tono en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YabashiMakina en-aut-sei=Yabashi en-aut-mei=Makina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=IsobeHiroshi en-aut-sei=Isobe en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=YamaguchiKizashi en-aut-sei=Yamaguchi en-aut-mei=Kizashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=YamamotoMasaki en-aut-sei=Yamamoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=AgoHideo en-aut-sei=Ago en-aut-mei=Hideo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=ShenJian-Ren en-aut-sei=Shen en-aut-mei=Jian-Ren kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= affil-num=1 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=4 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=6 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=9 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=12 en-affil=Japan Synchrotron Radiation Research Institute kn-affil= affil-num=13 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=14 en-affil=Department of Chemistry, Graduate School of Science, Kobe University kn-affil= affil-num=15 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=16 en-affil=Japan Synchrotron Radiation Research Institute kn-affil= affil-num=17 en-affil=Japan Synchrotron Radiation Research Institute kn-affil= affil-num=18 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=19 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=20 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=21 en-affil=The Institute for Scientific and Industrial Research, Osaka University kn-affil= affil-num=22 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=23 en-affil=RIKEN SPring-8 Center kn-affil= affil-num=24 en-affil=Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=573 article-no= start-page=eabb3336 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201209 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)?mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy. en-copyright= kn-copyright= en-aut-name=HiraiKenta en-aut-sei=Hirai en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OusakaDaiki en-aut-sei=Ousaka en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaYosuke en-aut-sei=Fukushima en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KondoMaiko en-aut-sei=Kondo en-aut-mei=Maiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=EitokuTakahiro en-aut-sei=Eitoku en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShigemitsuYusuke en-aut-sei=Shigemitsu en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HaraMayuko en-aut-sei=Hara en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=BabaKenji en-aut-sei=Baba en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IwasakiTatsuo en-aut-sei=Iwasaki en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KasaharaShingo en-aut-sei=Kasahara en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OhtsukiShinichi en-aut-sei=Ohtsuki en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhHidemasa en-aut-sei=Oh en-aut-mei=Hidemasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Pediatric Cardiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Regenerative Medicine, Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=5 article-no= start-page=eabd5271 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year= dt-pub= dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The structure of the actin filament uncapping complex mediated by twinfilin en-subtitle= kn-subtitle= en-abstract= kn-abstract= Uncapping of actin filaments is essential for driving polymerization and depolymerization dynamics from capping protein?associated filaments; however, the mechanisms of uncapping leading to rapid disassembly are unknown. Here, we elucidated the x-ray crystal structure of the actin/twinfilin/capping protein complex to address the mechanisms of twinfilin uncapping of actin filaments. The twinfilin/capping protein complex binds to two G-actin subunits in an orientation that resembles the actin filament barbed end. This suggests an unanticipated mechanism by which twinfilin disrupts the stable capping of actin filaments by inducing a G-actin conformation in the two terminal actin subunits. Furthermore, twinfilin disorders critical actin-capping protein interactions, which will assist in the dissociation of capping protein, and may promote filament uncapping through a second mechanism involving V-1 competition for an actin-binding surface on capping protein. The extensive interactions with capping protein indicate that the evolutionary conserved role of twinfilin is to uncap actin filaments. en-copyright= kn-copyright= en-aut-name=MwangangiDennis M. en-aut-sei=Mwangangi en-aut-mei=Dennis M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ManserEdward en-aut-sei=Manser en-aut-mei=Edward kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=RobinsonRobert C. en-aut-sei=Robinson en-aut-mei=Robert C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research) kn-affil= affil-num=2 en-affil=Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research) kn-affil= affil-num=3 en-affil=Research Institute for Interdisciplinary Science (RIIS), Okayama University kn-affil= END