Unresolved excess accumulation of myelin-derived cholesterol contributes to scar formation after spinal cord injury

Background: Spinal cord injury triggers complex pathological cascades, resulting in destructive tissue damage and incomplete tissue repair. Scar formation is generally considered as a barrier for regeneration in central nervous system (CNS), while the intrinsic mechanism of scar-forming after spinal cord injury has not been completed deciphered. Methods: We assessed cholesterol hemostasis in spinal cord lesions and injured peripheral nerves using confocal reflection microscopy and real-time PCR analyses. The involvement of the proteins, which were predicted to promote cholesterol efflux in spinal cord lesions, were assessed with Liver X receptor (LXR) agonist and Apolipoprotein E (APOE) deficiency. The role of reverse cholesterol transport (RCT) in cholesterol clearance was examined in APOE KO mice injured sciatic nerves and myelin-overloaded macrophages in vitro. Finally, we determined the consequence of excess cholesterol accumulation in CNS by transplantation of myelin into neonatal spinal cord lesions. Results: We found that excess cholesterol accumulates in phagocytes and is inefficiently removed in spinal cord lesions in young-adult mice. Interestingly, we observed that excessive cholesterol also accumulates in injured peripheral nerves, but is subsequently removed by RCT. Meanwhile, preventing RCT led to macrophage accumulation and fibrosis in injured peripheral nerves. Furthermore, the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids, and able to heal without excess cholesterol accumulation. We found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation, persistent macrophage activation and fibrosis, indicating myelin-derived cholesterol plays a critical role in impaired wound healing

PANoptosis-related molecular subtype and prognostic model associated with the immune microenvironment and individualized therapy in pancreatic cancer

BackgroundPANoptosis is an inflammatory type of programmed cell death regulated by PANopotosome. Mounting evidence has shown that PANoptosis could be involved in cancer pathogenesis and the tumor immune microenvironment. Nevertheless, there have been no studies on the mechanism of PANoptosis on pancreatic cancer (PC) pathogenesis.MethodsWe downloaded the data on transcriptomic and clinical features of PC patients from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Additionally, the data on copy number variation (CNV), methylation and somatic mutations of genes in 33 types of cancers were obtained from TCGA. Next, we identified the PANoptosis-related molecular subtype using the consensus clustering analysis, and constructed and validated the PANoptosis-related prognostic model using LASSO and Cox regression analyses. Moreover, RT-qPCR was performed to determine the expression of genes involved in the model.ResultsWe obtained 66 PANoptosis-related genes (PANRGs) from published studies. Of these, 24 PC-specific prognosis-related genes were identified. Pan-cancer analysis revealed complex genetic changes, including CNV, methylation, and mutation in PANRGs were identified in various cancers. By consensus clustering analysis, PC patients were classified into two PANoptosis-related patterns: PANcluster A and B. In PANcluster A, the patient prognosis was significantly worse compared to PANcluster B. The CIBERSORT algorithm showed a significant increase in the infiltration of CD8+ T cells, monocytes, and naïve B cells, in patients in PANcluster B. Additionally, the infiltration of macrophages, activated mast cells, and dendritic cells were higher in patients in PANcluster A. Patients in PANcluster A were more sensitive to erlotinib, selumetinib and trametinib, whereas patients in PANcluster B were highly sensitive to irinotecan, oxaliplatin and sorafenib. Moreover, we constructed and validated the PANoptosis-related prognostic model to predict the patient’s survival. Finally, the GEPIA and Human Protein Atlas databases were analyzed, and RT-qPCR was performed. Compared to normal tissues, a significant increase in CXCL10 and ITGB6 (associated with the model) expression was observed in PC tissues.ConclusionWe first identified the PANoptosis-related molecular subtypes and established a PANoptosis-related prognostic model for predicting the survival of patients with PC. These results would aid in exploring the mechanisms of PANoptosis in PC pathogenesis

Changes in foreign direct investment (FDI) policies in South Korea : implications and effects on the business environment

This dissertation provides an analysis of the role FDI played in the development of Korea's economy after the economic crisis of 1997.Master of Business Administration (Marketing

Low-intensity pulsed ultrasound promotes mesenchymal stem cell transplantation-based articular cartilage regeneration by inhibiting the TNF signaling pathway

Mesenchymal stem cell (MSC) transplantation therapy is highly studied for the regenerative repair of cartilage defects. Low-intensity pulsed ultrasound (LIPUS) has the potential to promote chondrogenic differentiation of MSCs, which is hopeful to facilitate the transplantation therapy. However, its underlying mechanism remains unclear. Here, we investigated the promoting effects and mechanisms of LIPUS stimulation on the chondrogenic differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs) and further evaluated its regenerative application value in articular cartilage defects in rats. In vitro, the suitable sound intensity of LIPUS for differentiation promotion was screened, and the key signal pathway of LIPUS-induced differentiation was clarified. In vivo, defective articular cartilage rat models were established for further validating LIPUS stimulation and hUC-MSC transplantation-based cartilage regeneration therapy. The results showed that LIPUS stimulation with specific parameters effectively promoted the expression of mature cartilage-related genes and proteins, inhibited TNF-{\alpha} gene expression in hUC-MSCs, and exhibited anti-inflammation in C28/I2 cells. In addition, the articular cartilage defects of rats were significantly repaired after hUC-MSC transplantation and LIPUS stimulation. Taken together, our study demonstrated that LIPUS stimulation could realize articular cartilage regeneration due to the inhibition of TNF signaling pathway especially TNF-{\alpha} gene expression down-regulation, which is of clinical value for the relief of osteoarthritis.Comment: 22 pages, 7 figures, 2 table

Security risks in teleworking: a review and analysis

© 2013 The authorsTeleworking as an innovative working practice attracts organizations to apply it throughout whole organizations, with providing plenty of benefits. However, the related information security risks generated in teleworking threaten organizations to implement it. This paper aims to ascertain information security risks arising from teleworking based on literature. The contributions of this paper are addressing most challenging security risks that existed in teleworking for companies to be concerned, providing security controls for avoiding these mentionable risks that are identified, generally discussing which component of the risks are more crucial for the risk control, and indicating intangible security risks not mentioned in literature. These risks are aligned with teleworking business goals

Ceramide Production Mediates Aldosterone-Induced Human Umbilical Vein Endothelial Cell (HUVEC) Damages.

Here, we studied the underlying mechanism of aldosterone (Aldo)-induced vascular endothelial cell damages by focusing on ceramide. We confirmed that Aldo (at nmol/L) inhibited human umbilical vein endothelial cells (HUVEC) survival, and induced considerable cell apoptosis. We propose that ceramide (mainly C18) production might be responsible for Aldo-mediated damages in HUVECs. Sphingosine-1-phosphate (S1P), an anti-ceramide lipid, attenuated Aldo-induced ceramide production and following HUVEC damages. On the other hand, the glucosylceramide synthase (GCS) inhibitor PDMP or the ceramide (C6) potentiated Aldo-induced HUVEC apoptosis. Eplerenone, a mineralocorticoid receptor (MR) antagonist, almost completely blocked Aldo-induced C18 ceramide production and HUVEC damages. Molecularly, ceramide synthase 1 (CerS-1) is required for C18 ceramide production by Aldo. Knockdown of CerS-1 by targeted-shRNA inhibited Aldo-induced C18 ceramide production, and protected HUVECs from Aldo. Reversely, CerS-1 overexpression facilitated Aldo-induced C18 ceramide production, and potentiated HUVEC damages. Together, these results suggest that C18 ceramide production mediates Aldo-mediated HUVEC damages. MR and CerS-1 could be the two signaling molecule regulating C18 ceramide production by Aldo