Mechanism underlying synergic activation of Tyrosinase promoter by MITF and IRF4

Background: The transcription factor interferon regulatory factor 4 (IRF4) was identified to be involved in human pigmentation by genome-wide association studies (GWASs). The rs12203592-[T/C], which is located in intron 4 of IRF4, shows the strongest link to these pigmentation phenotypes including freckling, sun sensitivity, eye and hair color. Previous studies indicated a functional cooperation of IRF4 with Microphthalmia-associated transcription factor (MITF), a causing gene of Waardenburg syndrome (WS), to synergistically trans-activate Tyrosinase (TYR). However, the underlying mechanism is still unknown. Methods: To investigate the importance of DNA binding in the synergic effect of IRF4. Reporter plasmids with mutant TYR promoters was generated to locate the IRF4 DNA binding sites in the Tyrosinase minimal promoter. By building MITF and IRF4 truncated mutations plasmids, the necessary regions of the synergy functions of these two proteins were also located. Results: The cooperative effect between MITF and IRF4 was specific for TYR promoter. The DNA-binding of IRF4 was critical for the synergic function. IRF4 DNA binding sites in TYR promoter were identified. The Trans-activation domains in IRF4 (aa134-207, aa300-420) were both important for the synergic function, whereas the auto-mask domain (aa207-300) appeared to mask the synergic effect. Mutational analysis in MITF indicated that both DNA-binding and transcriptional activation domains were both required for this synergic effect. Conclusions: Here we showed that IRF4 potently synergized with MITF to activate the TYR promoter, which was dependent on DNA binding of IRF4. The synergic domains in both IRF4 and MITF were identified by mutational analysis. This identification of IRF4 as a partner for MITF in regulation of TYR may provide an important molecular function for IRF4 in the genesis of melanocytes and the pathogenic mechanism in WS

Short-term effects of intravenous batroxobin in treatment of sudden sensorineural hearing loss: a propensity score-matched study

BackgroundSudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains to be determined. This study aimed to compare the short-term efficacy of therapy combined with intravenous batroxobin and that without intravenous batroxobin in SSNHL patients.MethodsThis retrospective study harvested the data of SSNHL patients hospitalized in our department from January 2008 to April 2021. The hearing levels on the admitted day (before treatment) and the discharge day were considered pre-treatment hearing and post-treatment hearing, respectively. The hearing gain was the difference value of pre-treatment hearing and post-treatment hearing. We used Siegel's criteria and the Chinese Medical Association of Otolaryngology (CMAO) criteria to evaluate hearing recovery. The complete recovery rate, overall effective rate, and hearing gain at each frequency were considered outcomes. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the batroxobin group and the non-batroxobin group. Sensitivity analysis was carried out in flat-type and total-deafness SSNHL patients.ResultsDuring the study period, 657 patients with SSNHL were admitted to our department. Among them, a total of 274 patients met the enrolled criteria of our study. After PSM, 162 patients (81 in each group) were included in the analysis. Once the hospitalized treatment was completed, the patients would be discharged the next day. Logistic regression analysis of the propensity score-matched cohort indicated that both the complete recovery rates [Siegel's criteria, OR: 0.734, 95% CI: 0.368–1.466, p = 0.381; CMAO criteria, OR: 0.879, 95% CI: 0.435–1.777, p = 0.720] and the overall effective rates [Siegel's criteria and CMAO criteria, OR: 0.741, 95% CI: 0.399–1.378, p = 0.344] were not significantly different between the two treatment groups. Sensitivity analysis has shown similar results. For flat-type and total-deafness SSNHL patients, no significant difference was found in post-treatment hearing gain at each frequency between the two groups after PSM.ConclusionThere was no significant difference in short-term hearing outcomes between treatment with batroxobin and treatment without batroxobin in SSNHL patients by Siegel's and CMAO criteria after PSM. Future studies for better therapy regimens of SSNHL are still needed

Profiles of inflammation factors and inflammatory pathways around the peri-miniscrew implant

Background. Peri-miniscrew implant is a temporary assistant armamentarium for the treatment of severe malocclusion and complex tooth movement, the inflammation around it is the main reason for the failure of orthodontic treatment due to the implant loosening and falling out. Inflammation around the peri-miniscrew implant is associated with the release of proinflammatory cytokines. These pro-inflammatory cytokines, in turn, recruit immune cells (such as macrophages, dendritic cells, T cells, and B cells), which can produce and release inflammatory biomarkers, regulate the interaction between immune cells, periodontal ligament cells, osteoblasts, and so on. However, there is currently no effective clinical treatment plan to prevent inflammation around implants. Purpose. To investigate the potentially essential factors in the inflammatory response around the periminiscrew implant and explore the signaling pathways involved. Methods. Here, we review the studies focused on inflammatory biomarkers (Interleukins, tumor necrosis factor-α (TNF-α), receptor activator of NF-κB ligand (RANKL), matrix metalloproteinases (MMPs), and cellular adhesion molecules (CAMs)) in peri-miniscrew implant crevicular fluid (PMICF), as well as inflammatory signaling pathways (Wnt5a, JNK, Erk1/2, NF-κBp65 and TAB/TAK) in periodontal cells from 1998 to 2020. Results. A literature search revealed TLR-2, TLR-4, LOX-1, and BMPs are involved in regulating ILs (IL-1β, IL-6, IL-8, and IL-17), TNF-α, RANKL, MMP-2, MMP-9 expression via JNK, Erk1/2, Wnt5a, NF-κBp65, OPN, and TAB/TAK signaling pathways. Among them, IL-1β and IL-6 are the critical inflammation factors in the signaling pathways inducing the inflammatory reaction surrounding implants. Besides, CAM-1 was also regulated by MMP-9 and IL-17. Conclusion. There are considerable potential factors involving regulating inflammatory biomarkers on downstream signaling pathways in peri-minisrew implant crevicular fluid. Clinical significance. This review provides the substantiation of these cell factors and signaling pathways around peri-miniscrew implants, proposes more practical clinical therapeutic ideas and schemes for improving the stability and clinical efficacy of periminiscrew implants

Studies on Pathogenesis of Waardenburg Syndrome Type II and Tietz Syndrome Resulting from MITF Gene Mutations

AbstractMicrophthalmia-associated transcription factor (MITF) controls melanocyte survival and differentiation through directly regulating the expression of the tyrosinase(TYR)and tyrosinase-related proteins 1 and 2(TYRP1 and TYRP2)genes.MITFmutations have been reported to result in an abnormal melanocyte development and lead to Waardenburg syndrome type 2 (WS2), characterized by variable degrees of sensorineural hearing loss and patchy regional distribution of hypopigmentation. Recently,MITFwas also indicated as a causative gene for a more severe syndrome, the Tietz Syndrome (TS), characterized by generalized hypopigmentation and complete hearing loss. However, few functional studies have been performed to compare the diseases-causing mutations. Here, we analyzed thein vitroactivity of two recent identified WS2-associated mutation (p.R217I and p.T192fsX18) and one TS-associated mutation p.N210K. The R217I MITF retained partial activity, normal DNA-binding ability and nuclear distribution, whereas the T192fsX18MITFfailed to activateTYRpromoter due to loss of DNA-binding activity, and aberrant subcellular localization. The aberrant subcellular localization of T192fsX18 MITF may be caused by deletion of a putative nuclear localization signal (NLS) at aa 213-218 (ERRRRF). Indeed, MITF with deletion of the NLS fragment failed to translocate into the nucleus and activated theTYRpromoter. Tagging this NLS to GFP promoted the green fluorescence protein (GFP) translocated into the nucleus. The surprising finding of our study is that a TS-associatedMITFmutation, N210K, showed comparablein vitroactivity as WT. Thus, the possible involvement ofMITFin TS and its underlying mechanisms still need further investigation

Sirtuin 1 in osteoarthritis: Perspectives on regulating glucose metabolism

Osteoarthritis (OA) is a degenerative disease characterised by articular cartilage destruction, and its complex aetiology contributes to suboptimal clinical treatment outcomes. A close association exists between glucose metabolism dysregulation and OA pathogenesis. Owing to the unique environment of low oxygen and glucose concentrations, chondrocytes rely heavily on their glycolytic capacity, exhibiting distinct spatiotemporal differences. However, under pathological stimulation, chondrocytes undergo excessive glycolytic activity while mitochondrial respiration and other branches of glucose metabolism are compromised. This metabolic change induces cartilage degeneration by reprogramming the inflammatory responses. Sirtuins, a highly conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, regulate glucose metabolism in response to energy fluctuations in different cellular compartments，alleviating metabolic stress. SIRT1, the most extensively studied sirtuin, participates in maintaining glucose homeostasis in almost all key metabolic tissues. While actively contributing to the OA progression and displaying diverse biological effects in cartilage protection, SIRT1’s role in regulating glucose metabolism in chondrocytes has not received sufficient attention. This review focuses on discussing the beneficial role of SIRT1 in OA progression from a metabolic regulation perspective based on elucidating the primary characteristics of chondrocyte glucose metabolism. We also summarise the potential mechanisms and therapeutic strategies targeting SIRT1 in chondrocytes to guide clinical practice and explore novel therapeutic directions

A Combined Fuzzy Optimization Model for the Location of an Intelligent Energy-Efficient Manufacturing Industrial Park

With the background of implementing carbon peaking and carbon neutralization, identifying methods to realize energy-saving and carbon reduction effectively has become an important issue in the intelligent energy-conservation manufacturing industry. During the process of achieving this goal, determining an optimal location for a low-carbon and intelligent manufacturing industrial park is a foremost decision-making problem for manufacturing corporations’ energy-efficient development. The article established a multi-criteria decision framework to assist manufacturing companies when selecting suitable industrial park sites. To begin with, an evaluation criteria framework is confirmed by literature search. Then, a fuzzy optimization model, which combines the fuzzy Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) and the fuzzy VlseKriterijumska Optimizacija I Kompromisno Resenje (VIKOR) is presented, where fuzzy TOPSIS is used to determine the decision-maker criteria weights. Then, criteria weights are calculated by the optimization model with construction of a Lagrange function. Moreover, the fuzzy VIKOR method is applied to sort alternatives and choose the best alternative location. In addition, five alternative sites for a manufacturing company are evaluated and ranked according to the values of the ranking index as a numerical case to demonstrate the proposed framework’s application. Finally, a comprehensive analysis of diverse methods and sensitivity analyses for the volatility in criteria weights and decision-maker weights is illustrated to confirm that the framework is practicable for the problem of intelligent and sustainable manufacturing industrial park-site selection

A Combined Fuzzy Optimization Model for the Location of an Intelligent Energy-Efficient Manufacturing Industrial Park

With the background of implementing carbon peaking and carbon neutralization, identifying methods to realize energy-saving and carbon reduction effectively has become an important issue in the intelligent energy-conservation manufacturing industry. During the process of achieving this goal, determining an optimal location for a low-carbon and intelligent manufacturing industrial park is a foremost decision-making problem for manufacturing corporations’ energy-efficient development. The article established a multi-criteria decision framework to assist manufacturing companies when selecting suitable industrial park sites. To begin with, an evaluation criteria framework is confirmed by literature search. Then, a fuzzy optimization model, which combines the fuzzy Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) and the fuzzy VlseKriterijumska Optimizacija I Kompromisno Resenje (VIKOR) is presented, where fuzzy TOPSIS is used to determine the decision-maker criteria weights. Then, criteria weights are calculated by the optimization model with construction of a Lagrange function. Moreover, the fuzzy VIKOR method is applied to sort alternatives and choose the best alternative location. In addition, five alternative sites for a manufacturing company are evaluated and ranked according to the values of the ranking index as a numerical case to demonstrate the proposed framework’s application. Finally, a comprehensive analysis of diverse methods and sensitivity analyses for the volatility in criteria weights and decision-maker weights is illustrated to confirm that the framework is practicable for the problem of intelligent and sustainable manufacturing industrial park-site selection