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The LRRK2-G2019S mutation attenuates repair of brain injury partially by reducing the release of osteopontin-containing monocytic exosome-like vesicles
No full textBackground: Brain injury has been suggested as a risk factor for neurodegenerative diseases. Accordingly, defects in the brain's intrinsic capacity to repair injury may result in the accumulation of damage and a progressive loss of brain function. The G2019S (GS) mutation in LRRK2 (leucine rich repeat kinase 2) is the most prevalent genetic alteration in Parkinson's disease (PD). Here, we sought to investigate how this LRRK2-GS mutation affects repair of the injured brain. Methods: Brain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes. Results: Damaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains. Conclusions: The LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury
The changing dynamics of work from home and its association with sleep disturbance through work-family conflict during the COVID-19 pandemic
Get PDFOBJECTIVES: Work from home (WFH) can increase sleep disturbances. However, only few studies have examined the connection between WFH and sleep disturbance while considering work-family conflict (WFC) and the changes brought about by the COVID-19 pandemic. This study aimed to examine the association between WFH and sleep disturbance, considering WFC, and assess how this association changed during the COVID-19 pandemic. METHODS: We used data from the fifth and sixth Korean Working Conditions Survey. WFH workers and a control group were selected using propensity score matching. Conditional logistic regression analysis was used to estimate the odds ratios (ORs) with 95% CIs for sleep disturbance in the WFH and control groups. RESULTS: The workers working from home showed significantly higher ORs for sleep disturbance before (4.26; 95% CI, 3.59-5.05) and during (1.52; 95% CI, 1.26-1.83) the COVID-19 pandemic. When stratified by WFC, the association was significant only in the workers with WFC before COVID-19. However, the association was not significant during COVID-19 among the workers with WFC. CONCLUSIONS: WFH was significantly associated with sleep disturbance among workers before COVID-19, but this association was not observed during the COVID-19 pandemic. Considering the significant role that WFC plays in this association, companies should provide a family-friendly WFH environment when adopting WFH practices
Disparities in pediatric anaphylaxis triggers and management across Asia
Get PDFBackground: The epidemiology and management of anaphylaxis are not well-reported in Asia. Methods: A regional pediatric anaphylaxis registry was established by the Asia-Pacific Research Network for Anaphylaxis (APRA), using standardized protocols for prospective data collection, to evaluate the triggers and management of anaphylaxis in the Asia-Pacific region. Pediatric patients below 18 years presenting with anaphylaxis across four Asian countries/cities (Thailand, Singapore, Hong Kong (HK), and Qingdao) were included. Allergen triggers, symptoms, anaphylaxis severity, and management were compared. Results: Between 2019 and 2022, 721 anaphylaxis episodes in 689 patients from 16 centers were identified. The mean age at anaphylaxis presentation was 7.0 years (SD = 5.2) and 60% were male. Food was the most common trigger (62%), particularly eggs and cow's milk in children aged 3 years and below. In school-age children, nut anaphylaxis was most common in HK and Singapore, but was rare in the other countries, and wheat was the top allergen in Bangkok. Shellfish anaphylaxis was most common in children aged 7–17. Adrenaline was administered in 60% of cases, with 9% given adrenaline before hospital arrival. Adrenaline devices were prescribed in up to 82% of cases in Thailand but none in Qingdao. Conclusions: The APRA identified food as the main trigger of anaphylaxis in children, but causative allergens differed even across Asian countries. Fewer than two-thirds of cases received adrenaline treatment, pre-hospital adrenaline usage was low, and adrenaline device prescription remained suboptimal. The registry recognizes an unmet need to strengthen anaphylaxis care and research in Asia-Pacific
Interrupting an IFN- 3-dependent feedback loop in the syndrome of pyogenic arthritis with pyoderma gangrenosum and acne
Get PDFObjectives To study the molecular pathogenesis of PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, a debilitating hereditary autoinflammatory disease caused by dominant mutation in PSTPIP1. Methods Gene knock-out and knock-in mice were generated to develop an animal model. THP1 and retrovirally transduced U937 human myeloid leukaemia cell lines, peripheral blood mononuclear cells, small interfering RNA (siRNA) knock-down, site-directed mutagenesis, cytokine immunoassays, coimmunoprecipitation and immunoblotting were used to study inflammasome activation. Cytokine levels in the skin were evaluated by immunohistochemistry. Responsiveness to Janus kinase (JAK) inhibitors was evaluated ex vivo with peripheral blood mononuclear cells and in vivo in five treatment-refractory PAPA patients. Results The knock-in mouse model of PAPA did not recapitulate the human disease. In a human myeloid cell line model, PAPA-associated PSTPIP1 mutations activated the pyrin inflammasome, but not the NLRP3, NLRC4 or AIM2 inflammasomes. Pyrin inflammasome activation was independent of the canonical pathway of pyrin serine dephosphorylation and was blocked by the p.W232A PSTPIP1 mutation, which disrupts pyrin-PSTPIP1 interaction. IFN-γpriming of monocytes from PAPA patients led to IL-18 release in a pyrin-dependent manner. IFN-γwas abundant in the inflamed dermis of PAPA patients, but not patients with idiopathic pyoderma gangrenosum. Ex vivo JAK inhibitor treatment attenuated IFN- 3-mediated pyrin induction and IL-18 release. In 5/5 PAPA patients, the addition of JAK inhibitor therapy to IL-1 inhibition was associated with clinical improvement. Conclusion PAPA-associated PSTPIP1 mutations trigger a pyrin-IL-18-IFN-γpositive feedback loop that drives PAPA disease activity and is a target for JAK inhibition
The Suppression of Ubiquitin C-Terminal Hydrolase L1 Promotes the Transdifferentiation of Auditory Supporting Cells into Hair Cells by Regulating the mTOR Pathway
Get PDFIn mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters’ cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway
Predicted brain age (PBA), promising surrogate indicator for neurodevelopment in preterm baby: how to predict accurately?
No full textLongitudinal Magnetic Resonance Imaging with ROS-Responsive Bilirubin Nanoparticles Enables Monitoring of Nonalcoholic Steatohepatitis Progression to Cirrhosis
No full textDespite the vital importance of monitoring the progression of nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), an efficient imaging modality that is readily available at hospitals is currently lacking. Here, a new magnetic-resonance-imaging (MRI)-based imaging modality is presented that allows for efficient and longitudinal monitoring of NAFLD and NASH progression. The imaging modality uses manganese-ion (Mn2+)-chelated bilirubin nanoparticles (Mn@BRNPs) as a reactive-oxygen-species (ROS)-responsive MRI imaging probe. Longitudinal T1-weighted MR imaging of NASH model mice is performed after injecting Mn@BRNPs intravenously. The MR signal enhancement in the liver relative to muscle gradually increases up to 8 weeks of NASH progression, but decreases significantly as NASH progresses to the cirrhosis-like stage at weeks 10 and 12. A new dual input pseudo-three-compartment model is developed to provide information on NASH stage with a single MRI scan. It is also demonstrated that the ROS-responsive Mn@BRNPs can be used to monitor the efficacy of potential anti-NASH drugs with conventional MRI. The findings suggest that the ROS-responsive Mn@BRNPs have the potential to serve as an efficient MRI contrast for monitoring NASH progression and its transition to the cirrhosis-like stage
The impact of CDCA5 expression on the immune microenvironment and its potential utility as a biomarker for PD-L1/PD-1 inhibitors in lung adenocarcinoma
Get PDFBackground: Studies have highlighted the important role of cell division cycle associated 5 (CDCA5) in tumor-associated immune dysfunction. We studied immune dysfunction based on CDCA5 expression in lung adenocarcinoma and investigated its potential as a biomarker for patients undergoing anti-programmed death protein-1/ programmed death ligand-1 (PD-1/PD-L1) inhibitor therapy. Methods: We used the CIBERSORTx algorithm to investigate the immune cell distribution based on CDCA5 and explored its potential as a biomarker for PD-1/PD-L1 therapy using Tumor Immune Dysfunction and Exclusion in three lung adenocarcinoma datasets. Thus, we validated the role of CDCA5 as a biomarker in patients treated with PD-1/PD-L1 inhibitors. We also investigated the pathways through which CDCA5 regulates PD-L1 expression in a cell line. Results: The high CDCA5 expression group showed elevated interferon gamma signature, CD274 expression, CD8+ T cell levels, tumor mutation burden, and microsatellite instability. Higher CDCA5 expression was associated with poorer prognosis in patients not treated with PD-1/PD-L1 inhibitors. However, in patients treated with PD-1/PD-L1 inhibitors, higher CDCA5 expression correlated with better response rates and prognosis. CDCA5 expression positively correlated with inhibitory immune checkpoint molecules. CDCA5 regulated the expression of PD-L1 through the ANXA/AKT pathway, and combined suppression of CDCA5 and PD-L1 synergistically inhibited cell proliferation. Conclusions: CDCA5 served as a promising biomarker for patients undergoing PD-L1/PD-1 inhibitor treatment, and co-inhibition of CDCA5 and PD-L1 could serve as an effective therapeutic strategy
Evaluation of machine learning approach for surgical results of Ahmed valve implantation in patients with glaucoma
Get PDFBackground: Ahmed valve implantation demonstrated an increasing proportion in glaucoma surgery, but predicting the successful maintenance of target intraocular pressure remains a challenging task. This study aimed to evaluate the performance of machine learning (ML) in predicting surgical outcomes after Ahmed valve implantation and to assess potential risk factors associated with surgical failure to contribute to improving the success rate. Methods: This study used preoperative data of patients who underwent Ahmed valve implantation from 2017 to 2021 at Ajou University Hospital. These datasets included demographic and ophthalmic parameters (dataset A), systemic medical records excluding psychiatric records (dataset B), and psychiatric medications (dataset C). Logistic regression, extreme gradient boosting (XGBoost), and support vector machines were first evaluated using only dataset A. The algorithm with the best performance was selected based on the area under the receiver operating characteristics curve (AUROC). Finally, three additional prediction models were developed using the best performance algorithm, incorporating combinations of multiple datasets to predict surgical outcomes at 1 year. Results: Among 153 eyes of 133 patients, 131 (85.6%) and 22 (14.4%) eyes were categorized as the success and failure groups, respectively. The XGBoost was shown as the best-performance model with an AUROC value of 0.684, using only dataset A. The final three further prediction models were developed based on the combination of multiple datasets using the XGBoost model. All datasets combinations demonstrated the best performances in terms of AUROC (dataset A + B: 0.782; A + C: 0.773; A + B + C: 0.801). Furthermore, advancing age was a risk factor associated with a higher surgical failure incidence. Conclusions: ML provides some predictive value in predicting the outcomes of Ahmed valve implantation at 1 year. ML evaluation revealed advancing age as a common risk factor for surgical failure
Multicolor Two-Photon Microscopy Imaging of Lipid Droplets and Liver Capsule Macrophages In Vivo
No full textLipid droplets (LDs) store energy and supply fatty acids and cholesterol. LDs are a hallmark of chronic nonalcoholic fatty liver disease (NAFLD). Recently, studies have focused on the role of hepatic macrophages in NAFLD. Green fluorescent protein (GFP) is used for labeling the characteristic targets in bioimaging analysis. Cx3cr1-GFP mice are widely used in studying the liver macrophages such as the NAFLD model. Here, we have developed a tool for two-photon microscopic observation to study the interactions between LDs labeled with LD2 and liver capsule macrophages labeled with GFP in vivo. LD2, a small-molecule two-photon excitation fluorescent probe for LDs, exhibits deep-red (700 nm) fluorescence upon excitation at 880 nm, high cell staining ability and photostability, and low cytotoxicity. This probe can clearly observe LDs through two-photon microscopy (TPM) and enables the simultaneous imaging of GFP+ liver capsule macrophages (LCMs) in vivo in the liver capsule of Cx3cr1-GFP mice. In the NAFLD mouse model, Cx3cr1+ LCMs and LDs increased with the progress of fatty liver disease, and spatiotemporal changes in LCMs were observed through intravital 3D TPM images. LD2 will aid in studying the interactions and immunological roles of hepatic macrophages and LDs to better understand NAFLD