Am80, a retinoic acid receptor agonist, activates the cardiomyocyte cell cycle and enhances engraftment in the heart

ヒトiPS細胞由来心筋細胞の生着能改善に向けた新しい方法. 京都大学プレスリリース. 2023-07-14.Am80, a retinoic acid receptor agonist, activates cell cycle in induced cardiomyocytes and enhances heart tissue engraftment. 京都大学プレスリリース. 2023-07-14.Human induced pluripotent stem cell-derived (hiPSC) cardiomyocytes are a promising source for regenerative therapy. To realize this therapy, however, their engraftment potential after their injection into the host heart should be improved. Here, we established an efficient method to analyze the cell cycle activity of hiPSC cardiomyocytes using a fluorescence ubiquitination-based cell cycle indicator (FUCCI) system. In vitro high-throughput screening using FUCCI identified a retinoic acid receptor (RAR) agonist, Am80, as an effective cell cycle activator in hiPSC cardiomyocytes. The transplantation of hiPSC cardiomyocytes treated with Am80 before the injection significantly enhanced the engraftment in damaged mouse heart for 6 months. Finally, we revealed that the activation of endogenous Wnt pathways through both RARA and RARB underlies the Am80-mediated cell cycle activation. Collectively, this study highlights an efficient method to activate cell cycle in hiPSC cardiomyocytes by Am80 as a means to increase the graft size after cell transplantation into a damaged heart

Association of blood pressure and renal outcome in patients with chronic kidney disease; a post hoc analysis of FROM-J study

It is well-known that hypertension exacerbates chronic kidney disease (CKD) progression, however, the optimal target blood pressure (BP) level in patients with CKD remains unclear. This study aimed to assess the optimal BP level for preventing CKD progression. The risk of renal outcome among different BP categories at baseline as well as 1 year after, were evaluated using individual CKD patient data aged between 40 and 74 years from FROM-J [Frontier of Renal Outcome Modifications in Japan] study. The renal outcome was defined as >= 40% reduction in estimated glomerular filtration rate to130 mmHg group. A significant increase in the renal outcome was found only in the group of diastolic BP >= 90 mmHg. The group of BP= 130 mmHg at baseline. Targeting SBP level<130 mmHg would be associated with the preferable renal outcome.Clinical Trial Registration-URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000001159 (16/05/2008)

The Lipid-Binding Defective Dynamin 2 Mutant in Charcot-Marie-Tooth Disease Impairs Proper Actin Bundling and Actin Organization in Glomerular Podocytes

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

Physical properties of the Dome Fuji deep ice core (review)

Recent results of physical analyses of the Dome Fuji ice core are summarized with special attention to new methods introduced in the present studies. Microphysical processes which affect the ice core records are reviewed to better understand the paleoclimatic and paleoenvironmental signals stored

How many times can patients tolerate reoperation?

The frequency of resection for the recurrence of colorectal cancer has not been investigated in previous studies. Likewise, the related postoperative complications and the limit for indicating surgical resection has not been reported. Herein, we reported the complications of a highly frequent surgical approach for rectal cancer recurrence, i.e., exceeding three reoperations, based on our clinical experience. We included 15 cases exceeding two operations for the local recurrence of colorectal cancer from 2014 to 2019. We examined the postoperative complications classified as Clavien–Dindo IIIb. The positive rates of the complications were 0 (0.0%), 0 (0.0%), 2 (13.3%), 3 (37.5%), and 0 (0.0%) for the primary, 1st recurrent, 2nd recurrent, 3rd recurrent, and 4th recurrent operation group (p = 0.027), respectively. It is important to exercise caution in handling cases exceeding two reoperations (exceeding three reoperations including the primary operation)