The extracellular environment regulates the dynamic behaviors of cells. However, the effects of hydrostatic pressure (HP) on cell fate determination of mesenchymal stem cells (MSCs) are not clearly ...understood. Here, we established a cell culture chamber to control HP. Using this system, we found that the promotion of osteogenic differentiation by HP is depend on bone morphogenetic protein 2 (BMP2) expression regulated by Piezo type mechanosensitive ion channel component 1 (PIEZO1) in MSCs. The PIEZO1 was expressed and induced after HP loading in primary MSCs and MSC lines, UE7T-13 and SDP11. HP and Yoda1, an activator of PIEZO1, promoted BMP2 expression and osteoblast differentiation, whereas inhibits adipocyte differentiation. Conversely, PIEZO1 inhibition reduced osteoblast differentiation and BMP2 expression. Furthermore, Blocking of BMP2 function by noggin inhibits HP induced osteogenic maker genes expression. In addition, in an in vivo model of medaka with HP loading, HP promoted caudal fin ray development whereas inhibition of piezo1 using GsMTx4 suppressed its development. Thus, our results suggested that PIEZO1 is responsible for HP and could functions as a factor for cell fate determination of MSCs by regulating BMP2 expression.
•The suspected mechanism is rebound stretch following early septal shortening.•A right-sided accessory pathway (AP), particularly on the septal aspect, poses a risk of preexcitation-induced ...cardiomyopathy (PIC)•PIC often occurs in children.•Its diagnosis would be definitive when left ventricular function recovered after elimination of an AP.
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Preexcitation-induced cardiomyopathy (PIC) is defined as a disease presenting ventricular dyssynchrony because of preexcitation through an accessory pathway (AP), being a cousin of pacing-induced cardiomyopathy. The present review aims at providing perspective of this uncharted subgroup.
In order to determine mechanisms and clinical characteristics of PIC, 63 patients in 29 literature reports were reviewed.
A median age at onset was 4 (0.1–59) years; 55 patients (87%) under 18 years old including 16 infants. Twenty patients (32%) experienced supraventricular tachycardia prior and subsequent to the PIC onset. Heart failure and left ventricular (LV) dysfunction did not correlate with other clinical features. All the 65 APs identified (duplicated in 2 patients) were located on the right side of the atrioventricular junction; at the septal area (in 55%) or the anterolateral aspect (in 22%). AP conduction was successfully eliminated by medical or interventional treatments where attempted. LV function returned to normal within 6 months in 67% of patients, while recovery took longer than 3 years in 8%. Frequently seen at the basal segments of the interventricular septum were early contraction within the QRS complex, dyskinesis at mid-systole, and aneurysm/bulging or local thinning.
Several characteristic factors became clear as described above. Rebound stretch following early shortening of the interventricular septum is seemingly the major mechanism of PIC, and thus a right septal or right anterior/anterolateral AP needs attention as a higher risk for PIC.
Against the background of these remarkable developments, the guidelines needed to undergo many changes and revisions. ...the format has been revised again to include cardiac implantable electronic ...devices and catheter ablation therapies. ...prevention of systemic embolism using a left atrial appendage closure (LAAC) device is being established as a breakthrough treatment for AF patients who have difficulty in continuing anticoagulation therapy. Because early implantable cardioverter-defibrillators (ICDs) were highly invasive owing to the requirement for a thoracotomy, the indications for this treatment were highly limited. In 2004, cardiac resynchronization therapy (CRT) became available for patients with impaired cardiac function, and the usefulness of this treatment has been verified. especially in heart failure patients with complete left bundle branch block in Japan. Because patients with heart failure have a high risk of sudden death, an ICD with a biventricular pacing function (CRT defibrillator CRT-D) was also developed and approved in 2006.
The general strategy for forming an opposite enantiomeric product from an asymmetric reaction involves using the opposite enantiomeric catalyst. For the Michael addition of ...4‐substituted‐5‐pyrazolones (1) to 1,4‐dicarbonyl but‐2‐enes (2) catalyzed by rare earth with the chiral N,N′‐dioxide derivative ligand (L), the product enantioselectivity was switched only by changing the rare earth from Sc to Y. To understand the mechanism, we investigated the reaction energy profile using the density functional theory combined with the automated reaction path search method. The enantioselectivity on 1 was determined by the coordination structure of the pre‐reaction complex. The pre‐reaction complex of the Sc system was ScL(OTf)1, where only the Si‐face attack of 2 was blocked. Conversely, the pre‐reaction complex of the Y system had one more triflate anion, (YL(OTf)21), which stabilized the different coordination structure, where only the Re‐face attack of 2 was blocked. The origin of the diastereoselectivity was also investigated based on the transition states (TSs) of the C−C bond formation. The orientation of 2 at the TSs was fixed because of the proton transfer, which destabilized the TS affording the minor diastereomer.
Watch who you have around: The enantioselectivity of the rare‐earth‐catalyzed Michael addition was switched by changing the rare‐earth from Sc to Y. Here, we report the mechanism of the reaction and clarify the reason for the different enantioselectivity, which was mainly attributed to the different coordination numbers of the metal centers.
Background Elevated central venous pressure (CVP), low cardiac output and mild hypoxia are common early and late after Fontan operation. However, the association of these characteristics with late ...mortality is unclear. We aimed to elucidate the hemodynamic determinants of mortality after Fontan operation. Method We evaluated early (group Early; 0.5 to 5 years postoperatively, n = 387) and late (group Late; ≥15 years postoperatively, n = 161) Fontan hemodynamics that included CVP (mmHg), cardiac index (CI; L/min/m2 ), systemic ventricular end-diastolic volume index (EDVI; ml/m2 ), ejection fraction (EF; %), and arterial blood oxygen saturation (SaO2 ; %). We examined the effect of these variables on 5-year all-cause mortality. Results Mortality was higher in group Late than in group Early (17 vs. 11, P < .0001). In both Groups, higher CVP (hazard ratio HR:1.46 and 1.38, respectively, P < .001–0.0001) and lower SaO2 (HR: 1.12, P < .001 for both) were associated with increased mortality. Greater EDVI (HR per 20: 1.73) and lower EF (HR per 10%: 3.38) were associated with increased mortality only in group Early ( P < .0001 for both). In contrast, only in group Late was higher CI associated with increased mortality (HR: 2.50, 95% confidence interval: 1.30–4.55, P < .01). Seven patients in group Late with both high CVP (≥14) and CI (≥3.0) had the highest mortality (HR: 18.1, 5.55–52.4, P < .0001). Conclusions Elevated CVP and low SaO2 correlate with mortality in both early and late Fontan survivors. EDVI and EF are associated with mortality only in the earlier cohort, whereas interestingly, elevated cardiac output is associated with increased mortality in the later cohort.
Protein N-myristoylation of Src-family kinases (SFKs) is a critical co-translational modification to anchor the enzymes in the plasma membrane. Phosphorylation of SFKs is also an essential ...modification for regulating their enzymatic activities. In this study, we used Phos-tag SDS-PAGE to investigate N-myristoylation-dependent phosphorylation of SFKs and their non-N-myristoylated G2A mutants. The serine-13 residue of Lyn (Lyn-S13) was shown to be N-myristoylation-dependently phosphorylated. Although there have been more than 40 reports of mass spectrometric studies on phosphorylation at Lyn-S13, the kinase responsible remained unclear. We succeeded in identifying casein kinase 1γ (CK1γ) as the kinase responsible for phosphorylation of Lyn-S13. In HEK293 cells co-expressing Lyn and CK1γ, the phosphorylation level of Lyn-S13 increased significantly. CK1γ is unique among the CK1 family (α, γ, δ, and ε) in carrying an S-palmitoylation site for membrane binding. Co-expression with the non-S-palmitoylated CK1γ mutant, which localized in the cytosol, gave no increase in the phosphorylation level at Lyn-S13. In HEK293 cells expressing the non-S-palmitoylated Lyn-C3A mutant, on the other hand, the Lyn-C3A mutant was phosphorylated at Lyn-S13, and the mutant remained at the Golgi. These results showed that S-palmitoylated CK1γ can phosphorylate S13 of N-myristoylated Lyn at the Golgi during intracellular protein traffic.
The usefulness of a treadmill exercise test for determining optimal pacemaker settings remains unknown. An 8-year-old boy with Fontan circulation and a dual-chamber pacemaker for a rate-dependent ...advanced atrioventricular block suffered from dullness and poor school attendance. Although the pacemaker log showed an atrial tachycardia/fibrillation episode, treadmill exercise testing revealed sinus tachycardia, which converted to a 2:1 atrioventricular block. The pacemaker setting was optimized, with improvement in the patient's condition.Treadmill exercise testing helps optimize dual-chamber pacemaker settings in children with complex congenital heart disease involved in energy-consuming physical activities and having a wide working range in sinus rate.
Signal transmission from the mechanical forces to the various intracellular activities is a fundamental process during tissue development. Despite their critical role, the mechanism of mechanical ...forces in the biological process is poorly understood. In this study, we demonstrated that in the response to hydrostatic pressure (HP), the piezo type mechanosensitive ion channel component 1 (PIEZO1) is a primary mechanosensing receptor for odontoblast differentiation through coordination of the WNT expression and ciliogenesis. In stem cells from human exfoliated deciduous teeth (SHED), HP significantly promoted calcium deposition as well as the expression of odontogenic marker genes, PANX3 and DSPP, and WNT related-genes including WNT5b and WNT16, whereas HP inhibited cell proliferation and enhanced primary cilia expression. WNT signaling inhibitor XAV939 and primary cilia inhibitor chloral hydrate blocked the HP-induced calcium deposition. The PIEZO1 activator Yoda1 inhibited cell proliferation but induced ciliogenesis and WNT16 expression. Interestingly, HP and Yoda1 promoted nuclear translocation of RUNX2, whereas siRNA-mediated silencing of PIEZO1 decreased HP-induced nuclear translocation of RUNX2. Taken together, these results suggest that PIEZO1 functions as a mechanotransducer that connects HP signal to the intracellular signalings during odontoblast differentiation.
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