UAV telephotography elucidates floristic variability and beta diversity of island cliffs under grazing interventions.

Cliffs contain one of the least known plant communities, which has been overlooked in biodiversity assessments due to the inherent inaccessibility. Our study adopted the unmanned aerial vehicle (UAV) with the telephoto camera to remotely clarify floristic variability across unreachable cliffs. Studied cliffs comprised 17 coastal and 13 inland cliffs in Gageodo of South Korea, among which 9 and 5 cliffs were grazed by the introduced cliff-dwelling goats. The UAV telephotography showed 154 and 166 plant species from coastal and inland cliffs, respectively. Inland cliffs contained more vascular plant species (P < 0.001), increased proportions of fern and woody species (P < 0.05), and decreased proportion of herbaceous species (P < 0.001) than coastal cliffs. It was also found that coastal and inland cliffs differed in the species composition (P < 0.001) rather than taxonomic beta diversity (P = 0.29). Furthermore, grazed coastal cliffs featured the elevated proportions of alien and annual herb species than ungrazed coastal cliffs (P < 0.05). This suggests that coastal cliffs might not be totally immune to grazing if the introduced herbivores are able to access cliff microhabitats; therefore, such anthropogenic introduction of cliff-dwelling herbivores should be excluded to conserve the native cliff plant communities.

p62/sequestosome-1 as a severity-reflecting plasma biomarker in Charcot-Marie-Tooth disease type 1A.

Autophagy is a self-degradation system for recycling to maintain homeostasis. p62/sequestosome-1 (p62) is an autophagy receptor that accumulates in neuroglia in neurodegenerative diseases. The objective of this study was to determine the elevation of plasma p62 protein levels in patients with Charcot-Marie-Tooth disease 1A (CMT1A) for its clinical usefulness to assess disease severity. We collected blood samples from 69 CMT1A patients and 59 healthy controls. Plasma concentrations of p62 were analyzed by ELISA, and we compared them with Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2). A mouse CMT1A model (C22) was employed to determine the source and mechanism of plasma p62 elevation. Plasma p62 was detected in healthy controls with median value of 1978 pg/ml, and the levels were significantly higher in CMT1A (2465 pg/ml, p < 0.001). The elevated plasma p62 levels were correlated with CMTNSv2 (r = 0.621, p < 0.0001), motor nerve conduction velocity (r = - 0.490, p < 0.0001) and disease duration (r = 0.364, p < 0.01). In C22 model, increased p62 expression was observed not only in pathologic Schwann cells but also in plasma. Our findings indicate that plasma p62 measurement could be a valuable tool for evaluating CMT1A severity and Schwann cell pathology.

Isoegomaketone exhibits potential as a new Mycobacterium abscessus inhibitor.

Although the incidence of Mycobacterium abscessus infection has recently increased significantly, treatment is difficult because this bacterium is resistant to most anti-tuberculosis drugs. In particular, M. abscessus is often resistant to available macrolide antibiotics, so therapeutic options are extremely limited. Hence, there is a pressing demand to create effective drugs or therapeutic regimens for M. abscessus infections. The aim of the investigation was to assess the capability of isoegomaketone (iEMK) as a therapeutic option for treating M. abscessus infections. We determined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of iEMK for both reference and clinically isolated M. abscessus strains. In addition to time-kill and biofilm formation assays, we evaluated iEMK's capability to inhibit M. abscessus growth in macrophages using an intracellular colony counting assay. iEMK inhibited the growth of reference and clinically isolated M. abscessus strains in macrophages and demonstrated effectiveness at lower concentrations against macrophage-infected M. abscessus than when used to treat the bacteria directly. Importantly, iEMK also exhibited anti-biofilm properties and the potential to mitigate macrolide-inducible resistance, underscoring its promise as a standalone or adjunctive therapeutic agent. Overall, our results suggest that further development of iEMK as a clinical drug candidate is promising for inhibiting M. abscessus growth, especially considering its dual action against both planktonic bacteria and biofilms.

Slow blood-flow in the left atrial appendage is associated with stroke in atrial fibrillation patients.

Background: Atrial fibrillation (AF) patients are at high risk of stroke with ∼90% clots originating from the left atrial appendage (LAA). Clinical understanding of blood-flow based parameters and their potential association with stroke for AF patients remains poorly understood. We hypothesize that slow blood-flow either in the LA or the LAA could lead to the formation of blood clots and is associated with stroke for AF patients. Methods: We retrospectively collected cardiac CT images of paroxysmal AF patients and dichotomized them based on clinical event of previous embolic event into stroke and non-stroke groups. After image segmentation to obtain 3D LA geometry, patient-specific blood-flow analysis was performed to model LA hemodynamics. In terms of geometry, we calculated area of the pulmonary veins (PVs), mitral valve, LA and LAA, orifice area of LAA and volumes of LA and LAA and classified LAA morphologies. For hemodynamic assessment, we quantified blood flow velocity, wall shear stress (WSS, blood-friction on LA wall), oscillatory shear index (OSI, directional change of WSS) and endothelial cell activation potential (ECAP, ratio of OSI and WSS quantifying slow and oscillatory flow) in the LA as well as the LAA. Statistical analysis was performed to compare the parameters between the groups. Results: Twenty-seven patients were included in the stroke and 28 in the non-stroke group. Examining geometrical parameters, area of left inferior PV was found to be significantly higher in the stroke group as compared to non-stroke group (p = 0.026). In terms of hemodynamics, stroke group had significantly lower blood velocity (p = 0.027), WSS (p = 0.018) and higher ECAP (p = 0.032) in the LAA as compared to non-stroke group. However, LAA morphologic type did not differ between the two groups. This suggests that stroke patients had significantly slow and oscillatory circulating blood-flow in the LAA, which might expose it to potential thrombogenesis. Conclusion: Slow flow in the LAA alone was associated with stroke in this paroxysmal AF cohort. Patient-specific blood-flow analysis can potentially identify such hemodynamic conditions, aiding in clinical stroke risk stratification of AF patients.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Targeting SARM1 improves autophagic stress-induced axonal neuropathy.

ABBREVIATIONS: AAV: adeno-associated virus; ATF3: activating transcription factor 3; ATG7: autophagy related 7; AVIL: advillin; cADPR: cyclic ADP ribose; CALC: calcitonin/calcitonin-related polypeptide; CMT: Charcot-Marie-Tooth disease; cKO: conditional knockout; DEG: differentially expressed gene; DRG: dorsal root ganglion; FE-SEM: field emission scanning electron microscopy; IF: immunofluorescence; NCV: nerve conduction velocity; PVALB: parvalbumin; RAG: regeneration-associated gene; ROS: reactive oxygen species; SARM1: sterile alpha and HEAT/Armadillo motif containing 1; SYN1: synapsin I.

Electrocardiography score based on the Minnesota code classification system predicts cardiovascular mortality in an asymptomatic low-risk population.

BACKGROUND: The use of a single abnormal finding on electrocardiography (ECG) is not recommended for stratifying the risk of cardiovascular (CV) events in low-risk general populations because of its low discriminative power. However, the value of a scoring system containing multiple abnormal ECG findings for predicting CV death has not been sufficiently evaluated. METHODS: In a prospective community-based cohort study, 8417 participants without atherosclerotic CV diseases (ASCVDs) and any related symptoms were followed for 18 years. The standard 12-lead ECGs were recorded at baseline and the ECG findings were categorized using the Minnesota code classification. CV deaths were defined as death from myocardial infarction (MI), chronic ischemic heart disease, heart failure, fatal arrhythmia, cerebrovascular event, pulmonary thromboembolism, peripheral vascular disease and sudden cardiac arrest and identified using the Korean National Statistical Office (KOSTAT) database. RESULTS: In a multivariate Cox proportional hazard (CPH) model, major and minor ST-T wave abnormalities, atrial fibrillation (AF), Q waves in the anterior leads, the lack of Q waves in the posterior leads, high amplitudes of the left and right precordial leads, left axis deviation and sinus tachycardia were associated with higher risks of CV deaths. The ECG score consisted of these findings showed modest predictive values represented by C-statistics that ranged from 0.632 to 760 during the follow-up and performed better in the early follow-up period. The ECG score independently predicted CV death after adjustment for relevant covariates in a multivariate model, and improved the predictive performance of the 10-year ASCVD risk estimator and a model of conventional risk factors including age, diabetes and current smoking. The combined ECG score (Harrell's C-index: 0.852, 95% confidence interval [CI], 0.828-0.876) composed of the ECG score and the conventional risk factors outperformed the 10-year ASCVD risk estimator (Harrell's C-index: 0.806; 95% CI, 0.780-0.833) and the model of the conventional risk factors (Harrell's C-index: 0.841, 95% CI, 0.817-0.865) and exhibited an excellent goodness of fit between the predicted and observed probabilities of CV death. CONCLUSIONS: The ECG score could be useful to predict CV death independently and may add value to the conventional CV risk estimators regarding the risk stratification of CV death in asymptomatic low-risk general populations.

The ECG score based on the Minnesota code classification can independently predict CV death and significantly improve the predictive power of the conventional CV risk estimators in asymptomatic low-risk general population.The combined ECG score comprised the ECG score, age and the presence of diabetes and current smoking predicted CV mortality more accurately than the conventional SV risk estimators.ECG may still be a viable CV risk stratification tool for population-based health screening projects.

Methylsulfonylmethane ameliorates metabolic-associated fatty liver disease by restoring autophagy flux via AMPK/mTOR/ULK1 signaling pathway.

Introduction: Metabolism-associated fatty liver disease (MAFLD) is a global health concern because of its association with obesity, insulin resistance, and other metabolic abnormalities. Methylsulfonylmethane (MSM), an organic sulfur compound found in various plants and animals, exerts antioxidant and anti-inflammatory effects. Here, we aimed to assess the anti-obesity activity and autophagy-related mechanisms of Methylsulfonylmethane. Method: Human hepatoma (HepG2) cells treated with palmitic acid (PA) were used to examine the effects of MSM on autophagic clearance. To evaluate the anti-obesity effect of MSM, male C57/BL6 mice were fed a high-fat diet (HFD; 60% calories) and administered an oral dose of MSM (200 or 400 mg/kg/day). Moreover, we investigated the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin complex 1 (mTORC1)/UNC-51-like autophagy-activating kinase 1 (ULK1) signaling pathway to further determine the underlying action mechanism of MSM. Results: Methylsulfonylmethane treatment significantly mitigated PA-induced protein aggregation in human hepatoma HepG2 cells. Additionally, Methylsulfonylmethane treatment reversed the PA-induced impairment of autophagic flux. Methylsulfonylmethane also enhanced the insulin sensitivity and significantly suppressed the HFD-induced obesity and hepatic steatosis in mice. Western blotting revealed that Methylsulfonylmethane improved ubiquitinated protein clearance in HFD-induced fatty liver. Remarkably, Methylsulfonylmethane promoted the activation of AMPK and ULK1 and inhibited mTOR activity. Conclusion: Our study suggests that MSM ameliorates hepatic steatosis by enhancing the autophagic flux via an AMPK/mTOR/ULK1-dependent signaling pathway. These findings highlight the therapeutic potential of MSM for obesity-related MAFLD treatment.

Differential Immune Responses and Underlying Mechanisms of Metabolic Reprogramming in Smooth and Rough Variants of Mycobacterium peregrinum Infections.

Mycobacterium peregrinum (Mpgm) is a rapidly growing mycobacteria that is classified as a nontuberculous mycobacterium (NTM) and is commonly found in environmental sources such as soil, water, and animals. Mpgm is considered an opportunistic pathogen that causes infection in immunocompromised individuals or those with underlying medical conditions. Although there have been clinical reports on Mpgm, reports of the immune response and metabolic reprogramming have not been published. Thus, we studied standard Mpgm-ATCC and two clinical strains (Mpgm-S and Mpgm-R) using macrophages and mouse bone marrow-derived cells. Mpgm has two types of colony morphologies: smooth and rough. We grew all strains on the 7H10 agar medium to visually validate the morphology. Cytokine levels were measured via ELISA and real-time PCR. The changes in mitochondrial function and glycolysis in Mpgm-infected macrophages were measured using an extracellular flux analyzer. Mpgm-S-infected macrophages showed elevated levels of inflammatory cytokines, including interleukin (IL)-6, IL-12p40, and tumor necrosis factor (TNF)-α, compared to Mpgm-ATCC- and Mpgm-R-infected macrophages. Additionally, our findings revealed metabolic changes in Mpgm-ATCC and two clinical strains (Mpgm-S and Mpgm-R) during infection; significant changes were observed in the mitochondrial respiration, extracellular acidification, and the oxygen consumption of BMDMs upon Mpgm-S infection. In summary, within the strains examined, Mpgm-S displayed greater virulence, triggered a heightened immune response, and induced more profound shifts in bioenergetic metabolism than Mpgm-ATCC and Mpgm-R. This study is the first to document distinct immune responses and metabolic reorganization following Mpgm infection. These findings lay a crucial foundation for further investigations into the pathogenesis of Mpgm.

Asymbiotic Seed Germination and In Vitro Seedling Development of the Endangered Orchid Species Cypripedium guttatum.

Cypripedium guttatum is a highly restricted terrestrial orchid that faces increasing endangerment owing to its habitat destruction and illegal collection. Compared to epiphytic orchids, terrestrial orchids such as C. guttatum have harder seed coats and more demanding in vitro germination conditions. This study aimed to develop an effective in vitro propagation system for C. guttatum to aid in its conservation. Seeds from mature capsules were subjected to various conditions, including sterilization using 1% sodium hypochlorite (NaOCl) and different light conditions, culture media, hormones, and organic supplements, to assess germination and early seedling development in vitro. Sterilization with 1% NaOCl significantly improved the germination rate, especially under dark conditions. Germination initiation occurred at 2 and 3 months in orchid seed sowing medium (OSM) and Murashige and Skoog (MS) medium, respectively. The addition of 1 mg/L naphthaleneacetic acid (NAA) further enhanced germination. However, the inclusion of organic supplements, such as apple and banana homogenates, in the culture medium led to substantial growth inhibition after 12 months. Notably, orchid maintenance medium (OMM) without organic additives proved to be the most suitable for seedling growth. The results of this study show that sterilization, appropriate light, and optimal NAA concentrations are beneficial for seed germination.

Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.

BACKGROUND: We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS: At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters. RESULTS: Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline. CONCLUSIONS: The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.

Fabrication of nanofibrous PbO2 electrode embedded with Pt for decomposition of organic chelating agents.

A new fabrication method of nanofibrous metal oxide electrode comprising Pt nanofiber (Pt-NF) covered with PbO2 on a Ti substrate was proposed. Pt-NF was obtained by performing sputtering deposition of Pt on the surface of electrospun poly(vinyl alcohol) (PVA) nanofiber on a Ti substrate, in which PVA was then removed by calcination (Ti/Pt-NF). Subsequently, by introducing PbO2 to the Ti/Pt-NF using the electrodeposition method, a nanofibrous Ti/Pt-NF/PbO2 electrode was finally obtained. Because the Ti substrate was covered by nanofibrous Pt, it had no environmental exposure and thus, was not oxidized during calcination. The crystal structure of the PbO2 mainly consisted of ß-form rather than α-form; the ß-form was suitable for electrochemical decomposition and remained stable even after 20 h of use. The nanofibrous Ti/Pt-NF/PbO2 electrodes showed 10% lower anode potential, 1.6 times higher current density at water decomposition potential, lower electrical resistance in the ion charge transfer resistance, and 2.27 times higher electrochemically active surface area than those of a planar-type Ti/Pt/PbO2 electrode, and demonstrated excellent electrochemical performance. As a result, compared with the planar electrode, the Ti/Pt-NF/PbO2 electrode showed more effective electrochemical decomposition toward nitrilotriacetic acid (80%) and ethylenediaminetetraacetic acid (83%), which are commonly used as chelating agents in nuclear decontamination.

Evaluation of physicochemical characteristics and centerline temperatures of Sr ceramic waste form.

When disposing of spent fuel, nuclides such as Cs-137 and Sr-90, which generate short-term decay heat, must be removed from the spent nuclear fuel for efficient storage facility utilization. The Korea Atomic Energy Research Institute (KAERI) has been developing a nuclide management process that can enhance disposal efficiency by sorting and collecting primary nuclides and a technology for separating Sr nuclides from the spent nuclear fuels using precipitation and distillation. In this study, we prepared Sr ceramic waste form, SrTiO3, using the solid-state reaction method to immobilize the Sr nuclides, and its physicochemical properties were evaluated. Moreover, the radiological and thermal characteristics of the Sr waste form were evaluated by estimating the composition of Sr nuclides considering the spent nuclear fuel history such as burn-up and cooling period. The waste form was found to be stable with good mechanical strength and leaching properties in addition to a low coefficient of thermal expansion, which would be advantageous for intermediate storage. Based on the experimental and radiological results, the centerline temperature of the waste form caused by Sr-90 nuclide was estimated using the steady-state conduction equation. The centerline temperature increased with increasing diameter of the waste form. When generating the SrTiO3 waste form using the Sr nuclide recovered after a cooling period of 10 years, the centerline temperature was estimated to exceed the melting point of SrTiO3 at a diameter of 0.275 m, under all burn-up conditions. These results provide fundamental data for the management and intermediate storage of Sr waste.

Net clinical benefit of oral anticoagulants in Korean atrial fibrillation patients with low to intermediate stroke risk: A report from the Clinical Survey on Stroke Prevention in patients with Atrial Fibrillation (CS-SPAF).

Background: The balance of stroke risk reduction and potential bleeding risk associated with antithrombotic treatment (ATT) remains unclear in atrial fibrillation (AF) at non-gender CHA2DS2-VASc scores 0-1. A net clinical benefit (NCB) analysis of ATT may guide stroke prevention strategies in AF with non-gender CHA2DS2-VASc scores 0-1. Methods: This multi-center cohort study evaluated the clinical outcomes of treatment with a single antiplatelet (SAPT), vitamin K antagonist (VKA), and non-VKA oral anticoagulant (NOAC) in non-gender CHA2DS2-VASc score 0-1 and further stratified by biomarker-based ABCD score (Age [≥60 years], B-type natriuretic peptide [BNP] or N-terminal pro-BNP [≥300 pg/mL], creatinine clearance [<50 mL/min], and dimension of the left atrium [≥45 mm]). The primary outcome was the NCB of ATT, including composite thrombotic events (ischemic stroke, systemic embolism, and myocardial infarction) and major bleeding events. Results: We included 2465 patients (age 56.2 ± 9.5 years; female 27.0%) followed-up for 4.0 ± 2.8 years, of whom 661 (26.8%) were treated with SAPT; 423 (17.2%) with VKA; and 1040 (42.2%) with NOAC. With detailed risk stratification using the ABCD score, NOAC showed a significant positive NCB compared with the other ATTs (SAPT vs. NOAC, NCB 2.01, 95% confidence interval [CI] 0.37-4.66; VKA vs. NOAC, NCB 2.38, 95% CI 0.56-5.40) in ABCD score ≥1. ATT failed to show a positive NCB in patients with truly low stroke risk (ABCD score = 0). Conclusions: In the Korean AF cohort at non-gender CHA2DS2-VASc scores 0-1, NOAC showed significant NCB advantages over VKA or SAPT with ABCD score ≥1.

The relationship between stress and sleep quality: The mediating effect of fatigue and dizziness among patients with cardiovascular disease.

Cardiovascular disease is the leading cause of non-noncommunicable disease mortality worldwide. Therefore, this study analyzes the mediating effect of dizziness and fatigue in the relationship between stress and sleep quality in patients with heart disease. This study was conducted on patients with heart disease diagnosed by a cardiologist from December 7, 2021 to August 30, 2022 at the Outpatient Department of Cardiology at Hanyang University Hospital in Guri-si, Gyeonggi-do. To verify the serial multiple mediation effect, serial multiple mediation analysis was performed using SPSS Macro Process Model 6 as the most appropriate verification method for this study. The analysis indicated that the more dizziness a participant experienced, the more severe their physical and psychological fatigue and the poorer their quality of sleep. Also, the more severe the physical fatigue, the worse the psychological fatigue and the worse the quality of sleep. In other words, the more severe the psychological fatigue, the poorer the quality of sleep. In summary, in the relationship in which stress in patients with heart disease affects sleep quality, stress is a variable that directly affects sleep quality, and this means that the stress of patients with heart disease can affect the quality of sleep through the parameters, dizziness and fatigue, sequentially; this research model can thus be considered a partial mediator model. Fatigue in patients with cardiovascular disease had a direct effect on sleep quality, and there was a mediating effect through dizziness and fatigue in the relationship between stress and sleep quality. Therefore, it is necessary to develop a sleep management program that can improve the quality of sleep in patients with cardiovascular disease as well as a nursing intervention plan that can alleviate fatigue and control stress in such patients.

Neural cell adhesion molecule 1 is a cellular target engaged plasma biomarker in demyelinating Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot-Marie-Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity. METHODS: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme-linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels. RESULTS: Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1-positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT. CONCLUSIONS: The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression.

COUP-TFII plays a role in cAMP-induced Schwann cell differentiation and in vitro myelination by up-regulating Krox20.

Schwann cells (SCs) are known to produce myelin for saltatory nerve conduction in the peripheral nervous system (PNS). Schwann cell differentiation and myelination processes are controlled by several transcription factors including Sox10, Oct6/Pou3f1, and Krox20/Egr2. Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan receptor that plays a role in the development and differentiation. However, the role of COUP-TFII in the transcriptional regulatory network of SC differentiation has not been fully identified yet. Thus, the objective of this study was to investigate the role and molecular hierarchy of COUP-TFII during cAMP-induced SC differentiation. Our results showed that dibutyryl-cAMP (db-cAMP) increased expression levels of COUP-TFII along with the expressions of Oct6, Krox20, and myelin-related genes known to be related to SC differentiation. Our mechanistic studies showed that COUP-TFII acted downstream of Hsp90/ErbB2/Gab1/ERK-AKT pathway during db-cAMP-induced SC differentiation. In addition, we found that COUP-TFII induced Krox20 expression by directly binding to Krox20-MSE8 as revealed by chromatin immunoprecipitation assay and promoter activity assay. In line with this, the expression of COUP-TFII was increased before up-regulation of Oct6, Krox20, and myelin-related genes in the sciatic nerves during early postnatal myelination period. Finally, COUP-TFII knockdown by COUP-TFII siRNA or via AAV-COUP-TFII shRNA in SCs inhibited db-cAMP-induced SC differentiation and in vitro myelination of sensory axons, respectively. Taken together, these findings indicate that COUP-TFII might be involved in postnatal myelination through induction of Krox20 in SCs. Our results present a new insight into the transcriptional regulatory mechanism in SC differentiation and myelination.

Adaptive autophagy reprogramming in Schwann cells during peripheral demyelination.

The myelin sheath is an essential structure for the rapid transmission of electrical impulses through axons, and peripheral myelination is a well-programmed postnatal process of Schwann cells (SCs), the myelin-forming peripheral glia. SCs transdifferentiate into demyelinating SCs (DSCs) to remove the myelin sheath during Wallerian degeneration after axonal injury and demyelinating neuropathies, and macrophages are responsible for the degradation of myelin under both conditions. In this study, the mechanism by which DSCs acquire the ability of myelin exocytosis was investigated. Using serial ultrastructural evaluation, we found that autophagy-related gene 7-dependent formation of a "secretory phagophore (SP)" and tubular phagophore was necessary for exocytosis of large myelin chambers by DSCs. DSCs seemed to utilize myelin membranes for SP formation and employed p62/sequestosome-1 (p62) as an autophagy receptor for myelin excretion. In addition, the acquisition of the myelin exocytosis ability of DSCs was associated with the decrease in canonical autolysosomal flux and was demonstrated by p62 secretion. Finally, this SC demyelination mechanism appeared to also function in inflammatory demyelinating neuropathies. Our findings show a novel autophagy-mediated myelin clearance mechanism by DSCs in response to nerve damage.

Verapamil-loaded supramolecular hydrogel patch attenuates metabolic dysfunction-associated fatty liver disease via restoration of autophagic clearance of aggregated proteins and inhibition of NLRP3.

BACKGROUND: Obesity, a serious threat to public health, is linked to chronic metabolic complications including insulin resistance, type-2 diabetes, and metabolic dysfunction-associated fatty liver disease (MAFLD). Current obesity medications are challenged by poor effectiveness, poor patient compliance, and potential side effects. Verapamil is an inhibitor of L-type calcium channels, FDA-approved for the treatment of hypertension. We previously investigated the effect of verapamil on modulating autophagy to treat obesity-associated lipotoxicity. This study aims to develop a verapamil transdermal patch and to evaluate its anti-obesity effects. METHODS: Verapamil is loaded in biomimetic vascular bundle-like carboxymethyl pullulan-based supramolecular hydrogel patches cross-linked with citric acid and glycerol linkages (CLCMP). The investigation was then carried out to determine the therapeutic effect of verapamil-loaded CLCMP (Vera@CLCMP) on diet-induced obese mice. RESULTS: Vera@CLCMP hydrogel patches with hierarchically organized and anisotropic pore structures not only improved verapamil bioavailability without modifying its chemical structure but also enhanced verapamil release through the stratum corneum barrier. Vera@CLCMP patches exhibit low toxicity and high effectiveness at delivering verapamil into the systemic circulation through the dermis in a sustained manner. Specifically, transdermal administration of this patch into diet-induced obese mice drastically improved glucose tolerance and insulin sensitivity and alleviated metabolic derangements associated with MAFLD. Furthermore, we uncovered a distinct molecular mechanism underlying the anti-obesity effects associated with the hepatic NLR family pyrin domain-containing 3 (NLRP3) inflammasome and autophagic clearance by the vera@CLCMP hydrogel patches. CONCLUSION: The current study provides promising drug delivery platforms for long-term family treatment of chronic diseases, including obesity and metabolic dysfunctions.