The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the ...combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.
A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer’s disease (AD), although sensitive detection of frontotemporal lobar degeneration ...(FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick’s disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.
•A new probe, PM-PBB3, captures pathological tau deposits in vivo with high contrast•PM-PBB3 allows an individual-based identification of AD and non-AD tauopathies•Autopsy assays of PET-scanned patients supported the in vivo performance of PM-PBB3
Tagai et al. developed a positron emission tomography probe, 18F-PM-PBB3, for tau deposits in Alzheimer’s and non-Alzheimer’s disease tauopathies. This probe was demonstrated to enable individual- and pathology-based diagnosis, differentiation, and staging of these disorders in addition to translational research and development on tauopathies from mouse models to humans.
Cardiac computed tomography (CT) is useful for the screening of coronary artery stenosis, and extracellular volume fraction (ECV) analysis by CT using new dedicated software is now available. Here, ...we evaluated the utility of ECV analysis using cardiac CT to predict patient prognosis in cases with dilated cardiomyopathy (DCM). We analyzed 70 cases with DCM and cardiac computed tomography (CT) with available late-phase images. We evaluated the ECV of the left ventricular myocardium (LVM) using commercially available software (Ziostation 2, Ziosoft Inc, Japan). ECV on LVM was 33.96 ± 5.04%. Major adverse cardiac events (MACE) occurred in 21 cases (30%). ECV of the LVM on CT, endo-systolic volume, and rate of significant valvular disease were significantly higher in cases with MACE than in those without (37.16 ± 5.91% vs. 32.59 ± 3.95%, 194 ± 109 vs. 138 ± 78 ml and 57% vs. 20%, all
P
values < 0.05). LVEF was significantly lower in cases with MACE than in those without (23 ± 8 vs. 31 ± 11%,
P
= 0.0024). The best cut-off value of ECV on LVM for prediction of MACE was 32.26% based on receiver operating characteristics analysis. Cases with ECV ≥ 32.26% had significantly higher MACE based on Kaplan–Meier analysis (
P
= 0.0032). Only ECV on LVM was an independent predictor of MACE based on a multivariate Cox proportional hazards model (
P
= 0.0354). Evaluation of ECV on LVM by CT is useful for predicting MACE in patients with DCM.
Background: Extracellular volume fraction (ECV) on magnetic resonance imaging can predict prognosis after aortic valve replacement in patients with aortic stenosis (AS). However, the usefulness of ...ECV on computed tomography (CT) for patients who have undergone transcatheter aortic valve replacement (TAVR) is unclear, so we investigated whether ECV analysis on CT is associated with clinical outcomes in TAVR candidates.Methods and Results: We analyzed 127 patients with severe AS who underwent preoperative CT for TAVR. We evaluated the utility of ECV analysis on single-energy CT for predicting patient prognosis after TAVR. The primary outcome was a composite of all-cause death and hospitalization due to heart failure (HF) after TAVR. 15 patients (12%) had composite outcomes: 4 deaths and 11 hospitalizations due to HF. In multivariate survival analysis using the Cox proportional hazard model, atrial fibrillation (AF) (hazard ratio (HR), 7.86; 95% confidence interval (CI), 2.57–24.03; P<0.001), history of congestive HF (HR, 4.91; 95% CI, 1.49–16.2; P=0.009) and ECV ≥32.6% on CT (HR, 6.96; 95% CI, 1.92–25.12; P=0.003) were independent predictors of composite outcomes. On Kaplan-Meier analysis, the higher ECV group (≥32.6%) had a significantly greater number of composite outcomes than the lower ECV group (P<0.001).Conclusions: ECV on CT is an independent predictor of prognosis after TAVR.
Vascular endothelial cell growth factor-C (VEGF-C) is a member of the VEGF family and plays a role in various biological activities. VEGF-C enhances proliferation and migration of lymphatic ...endothelial cells and vascular endothelial cells through VEGF receptor 2 (VEGFR2) and/or receptor 3 (VEGFR3), and thereby induces lymphangiogenesis or angiogenesis. However, it remains unclear whether VEGF-C promotes the migration of mesenchymal stem cells (MSCs). Here, we investigated the effects of VEGF-C on the migration of MSCs and evaluated the underlying molecular mechanisms. VEGF-C treatment significantly induced the migration of MSCs, which is accompanied by the promotion of actin cytoskeletal reorganization and focal adhesion assembly. VEGF-C treatment enhanced the phosphorylation of VEGFR2 and VEGFR3 proteins in MSCs, and pretreatment with VEGFR2 and VEGFR3 kinase inhibitors effectively suppressed the VEGF-C-induced MSC migration. In addition, VEGF-C treatment promoted phosphorylation of ERK and FAK proteins in MSCs, and inhibition of VEGFR2 and VEGFR3 signaling pathways abolished the VEGF-C-induced activation of ERK and FAK proteins. Furthermore, treatment with ERK and FAK inhibitors suppressed VEGF-C-induced actin cytoskeletal reorganization and focal adhesion assembly, and then significantly inhibited MSCs migration. These results suggest that VEGF-C-induced MSC migration is mediated via VEGFR2 and VEGFR3, and follows the activation of the ERK and FAK signaling pathway. Thus, VEGF-C may be valuable in tissue regeneration and repair in MSC-based therapy.
LL-37, the only member of the cathelicidin family of cationic antimicrobial peptides in humans has been shown to exhibit a wide variety of biological actions in addition to its antimicrobial ...activity. However, the lymphangiogenic effect of LL-37 has not been elucidated yet. In this study, we examined the effects of LL-37 on lymphangiogenesis and evaluated the underlying molecular mechanisms. LL-37 treatment significantly increased the migration and tube-like formation of human dermal lymphatic microvascular endothelial cells (HDLECs) and promoted the expression of lymphangiogenic factor in HDLECs. Treatment with LL-37 increased phosphorylation of ERK and Akt proteins in HDLECs, and pretreatment with ERK and Akt inhibitors significantly blocked the LL-37-induced HDLEC migration and tube-like formation. Furthermore, to investigate the involvement of formyl peptide receptor-like 1 (FPRL1) signaling in LL-37-induced lymphangiogenesis, HDLECs were treated with an FPRL1 antagonist. Pretreatment with the FPRL1 antagonist inhibited LL-37-induced phosphorylation of ERK and Akt proteins and attenuated LL-37-induced HDLEC migration and tube-like formation. These data indicated that LL-37 induces lymphangiogenesis in lymphatic endothelial cells via FPRL1, and the activation of the ERK and Akt-dependent signaling pathways.
Objective High-quality images can be obtained with 320-slice computed tomography (CT) with model-based iterative reconstruction (MBIR). We therefore investigated the diagnostic accuracy of 320-slice ...CT with MBIR for detecting significant coronary artery stenosis. Methods This was a retrospective study of 160 patients who underwent coronary CT and invasive coronary angiography (ICA). The first 100 consecutive patients (Group 1) underwent 320-slice CT without MBIR or small-focus scanning. The next 60 consecutive patients (Group 2) underwent 320-slice CT with both MBIR and small-focus scanning. Patients who underwent coronary artery bypass surgery were excluded. The diagnostic performance of 320-slice CT without MBIR or small-focus scanning and 320-slice CT with both of them, with ICA regarded as a reference standard, was compared to detect significant coronary artery stenosis (≥70% on CT, ≥75% on ICA). Results In a patient-based analysis, the sensitivity, specificity, and overall accuracy of detection of significant stenosis on CT against ICA were 95%, 85%, and 91% in Group 1, and 93%, 83%, and 90% in Group 2, respectively. No significant differences were observed between the two groups in the patient- and segment-based analyses. However, among cases with a severe coronary artery calcium score >400 (31 cases in Group 1 and 28 in Group 2), the specificity and overall accuracy were significantly higher (all p<0.01) in Group 2 than in Group 1 according to the segment-based analysis. Conclusion The diagnostic accuracy of the detection of coronary artery stenosis on CT was improved using 320-slice CT with MBIR.
Ras GTPase‐activating proteins negatively regulate the Ras/Erk signaling pathway, thereby playing crucial roles in the proliferation, function, and development of various types of cells. In this ...study, we identified a novel Ras GTPase‐activating proteins protein, RASAL3, which is predominantly expressed in cells of hematopoietic lineages, including NKT, B, and T cells. We established systemic RASAL3‐deficient mice, and the mice exhibited a severe decrease in NKT cells in the liver at 8 weeks of age. The treatment of RASAL3‐deficient mice with α‐GalCer, a specific agonist for NKT cells, induced liver damage, but the level was less severe than that in RASAL3‐competent mice, and the attenuated liver damage was accompanied by a reduced production of interleukin‐4 and interferon‐γ from NKT cells. RASAL3‐deficient NKT cells treated with α‐GalCer in vitro presented augmented Erk phosphorylation, suggesting that there is dysregulated Ras signaling in the NKT cells of RASAL3‐deficient mice. Taken together, these results suggest that RASAL3 plays an important role in the expansion and functions of NKT cells in the liver by negatively regulating Ras/Erk signaling, and might be a therapeutic target for NKT‐associated diseases.
We treated a female patient known to have a double-chambered right ventricle (DCRV) who presented with symptoms of an acute myocardial infarction (AMI). Emergent coronary artery catheterization ...revealed acute right coronary artery (RCA) occlusion and proximal left anterior descending (LAD) stenosis. We performed percutaneous coronary intervention (PCI) for the RCA occlusion. Right heart catheterization revealed a pressure gradient across the mid-RV of 58 mmHg. Computed tomography and magnetic resonance imaging revealed no other congenital cardiac abnormalities. She underwent surgical repair of the RV stenosis and coronary artery bypass surgery for LAD stenosis.
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