Immunosuppressants Tacrolimus and Sirolimus revert the cardiac antifibrotic properties of p38-MAPK inhibition in 3D-multicellular human iPSC-heart organoids

Immunosuppressive regimens after a heart transplant can hamper good therapeutic progressions in fibrosis. 京都大学プレスリリース. 2022-11-15.より本物の心臓に近い心臓オルガノイドによる薬剤の効果を評価するシステム --細胞間コミュニケーションを研究できるツールの開発--. 京都大学プレスリリース. 2022-11-21.Cardiac reactive fibrosis is a fibroblast-derived maladaptive process to tissue injury that exacerbates an uncontrolled deposition of large amounts of extracellular matrix (ECM) around cardiomyocytes and vascular cells, being recognized as a pathological entity of morbidity and mortality. Cardiac fibrosis is partially controlled through the sustained activation of TGF-β1 through IL-11 in fibroblasts. Yet, preclinical studies on fibrosis treatment require human physiological approaches due to the multicellular crosstalk between cells and tissues in the heart. Here, we leveraged an iPSC-derived multi-lineage human heart organoid (hHO) platform composed of different cardiac cell types to set the basis of a preclinical model for evaluating drug cardiotoxicity and assessing cardiac fibrosis phenotypes. We found that the inhibition of the p38-MAPK pathway significantly reduces COL1A1 depositions. Yet, concomitant treatment with organ-rejection immunosuppressant drugs Tacrolimus or Sirolimus reverts this effect, opening new questions on the clinical considerations of combined therapies in reducing fibrosis after organ transplantation

SMAD3 mediates the specification of human induced pluripotent stem cell-derived epicardium into progenitors for the cardiac pericyte lineage

Understanding the molecular mechanisms of epicardial epithelial-to-mesenchymal transition (EMT), particularly in directing cell fate toward epicardial derivatives, is crucial for regenerative medicine using human induced pluripotent stem cell (iPSC)-derived epicardium. Although transforming growth factor β (TGF-β) plays a pivotal role in epicardial biology, orchestrating EMT during embryonic development via downstream signaling through SMAD proteins, the function of SMAD proteins in the epicardium in maintaining vascular homeostasis or mediating the differentiation of various epicardial-derived cells (EPDCs) is not yet well understood. Our study reveals that TGF-β-independent SMAD3 expression autonomously predicts epicardial cell specification and lineage maintenance, acting as a key mediator in promoting the angiogenic-oriented specification of the epicardium into cardiac pericyte progenitors. This finding uncovers a novel role for SMAD3 in the human epicardium, particularly in generating cardiac pericyte progenitors that enhance cardiac microvasculature angiogenesis. This insight opens new avenues for leveraging epicardial biology in developing more effective cardiac regeneration strategies

回復期リハビリテーション病棟を退棟した脳卒中患者の分析 : 失語症の有無が治療効果と転帰先へ及ぼす影響

研究論文Original Articles　本研究の目的は，失語症の有無が訓練効果と在宅復帰に与える影響を明らかにすることである．回復期リハ病棟を退棟した脳卒中患者を対象にした．対象患者を失語症群と非失語症群に分け，患者の個人的因子や社会的因子，FIM をはじめとした諸検査の検査結果，入院期間，および転帰先などを比較した．その結果，失語症群は非失語症群に比して，入院時と退院時両方のFIM 成績が有意に低いこと，しかしながら失語症が在宅復帰へ及ぼす影響は確認できなかった．言語聴覚士は，理学療法士，作業療法士と連携して患者の日常生活機能の改善をコミュニケーションの側面から促進させる介入を積極的に実施する必要があると考えられた．　The purpose of this study is to investigate the effect of the presence or absence of aphasia on the treatment effect, discharge home, and the period of admission to the convalescent rehabilitation ward. We targeted stroke patients who left the convalescent rehabilitation ward. The patients were divided into aphasic group and non-aphasic group, and patientʼs personal factors, social factors, examination results of various examination including FIM, hospitalization period, and discharge home were compared. As a result, it was shown that the aphasia group has significantly lower FIM score at hospitalization and discharging compared to non - aphasia group, but the presence of aphasia did not affect discharge home. Speech therapists seemed to need to actively intervene in order to promote improvements of daily living functions of patients from the aspect of communication in collaboration with physiotherapists and occupational therapists

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

A series of aniline and m-phenylenediamine derivatives with electron-withdrawing 3,3,3-trifluoropropenyl substituents were synthesized as small and chemically stable fluorescent organic compounds. Their fluorescence performances were evaluated by converting 2,4-disubstituted aniline 1 to the non-fluorescent dipeptide analogue H-Gly-Pro-1 for the use as a fluorogenic substrate for dipeptidyl peptidase-4 (DPP-4). The progress of the enzymatic hydrolysis of H-Gly-Pro-1 with DPP-4 was monitored by fluorometric determination of 1 released into the reaction medium. The results suggest that 1 could be used as fluorophore in OFF–ON-type fluorogenic probes

Debye Temperature Evaluation for Secondary Battery Cathode of α-Sn<i>_x</i>Fe_1−<i>x</i>OOH Nanoparticles Derived from the ⁵⁷Fe- and ¹¹⁹Sn-Mössbauer Spectra

Debye temperatures of α-SnxFe1−xOOH nanoparticles (x = 0, 0.05, 0.10, 0.15 and 0.20, abbreviated as Sn100x NPs) prepared by hydrothermal reaction were estimated with 57Fe- and 119Sn-Mössbauer spectra measured by varying the temperature from 20 to 300 K. Electrical properties were studied by solid-state impedance spectroscopy (SS-IS). Together, the charge–discharge capacity of Li- and Na-ion batteries containing Sn100x NPs as a cathode were evaluated. 57Fe-Mössbauer spectra of Sn10, Sn15, and Sn20 measured at 300 K showed only one doublet due to the superparamagnetic doublet, while the doublet decomposed into a sextet due to goethite at the temperature below 50 K for Sn 10, 200 K for Sn15, and 100 K for Sn20. These results suggest that Sn10, Sn15 and Sn20 had smaller particles than Sn0. On the other hand, 20 K 119Sn-Mössbauer spectra of Sn15 were composed of a paramagnetic doublet with an isomer shift (δ) of 0.24 mm s−1 and quadrupole splitting (∆) of 3.52 mm s−1. These values were larger than those of Sn10 (δ: 0.08 mm s−1, ∆: 0.00 mm s−1) and Sn20 (δ: 0.10 mm s−1, ∆: 0.00 mm s−1), suggesting that the SnIV-O chemical bond is shorter and the distortion of octahedral SnO6 is larger in Sn15 than in Sn10 and Sn20 due to the increase in the covalency and polarization of the SnIV-O chemical bond. Debye temperatures determined from 57Fe-Mössbauer spectra measured at the low temperature were 210 K, 228 K, and 250 K for Sn10, Sn15, and Sn20, while that of α-Fe2O3 was 324 K. Similarly, the Debye temperature of 199, 251, and 269 K for Sn10, Sn15, and Sn20 were estimated from the temperature-dependent 119Sn-Mössbauer spectra, which were significantly smaller than that of BaSnO3 (=658 K) and SnO2 (=382 K). These results suggest that Fe and Sn are a weakly bound lattice in goethite NPs with low crystallinity. Modification of NPs and addition of Sn has a positive effect, resulting in an increase in DC conductivity of almost 5 orders of magnitude, from a σDC value of 9.37 × 10−7 (Ω cm)−1 for pure goethite Sn (Sn0) up to DC plateau for samples containing 0.15 and 0.20 Sn (Sn15 and Sn20) with a DC value of ~4 × 10−7 (Ω cm)−1 @423 K. This non-linear conductivity pattern and levelling at a higher Sn content suggests that structural modifications have a notable impact on electron transport, which is primarily governed by the thermally activated via three-dimensional hopping of small polarons (SPH). Measurements of SIB performance, including the Sn100x cathode under a current density of 50 mA g−1, showed initial capacities of 81 and 85 mAh g−1 for Sn0 and Sn15, which were larger than the others. The large initial capacities were measured at a current density of 5 mA g−1 found at 170 and 182 mAh g−1 for Sn15 and Sn20, respectively. It is concluded that tin-goethite NPs are an excellent material for a secondary battery cathode and that Sn15 is the best cathode among the studied Sn100x NPs