Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2). To determine whether these new compounds exert similar protective effects on HCs, we treated mouse cochlear explant cultures with the new compounds together with gentamycin. There was a severe loss of HCs in the organ of Corti after gentamycin exposure, while co-treatment with the new compounds significantly protected against gentamycin-induced HC loss. H3K4me2 levels in the nuclei of HCs decreased after exposure to gentamycin, but H3K4me2 levels were maintained in the presence of the new compounds. Apoptosis is also involved in the injury process, and the new compounds protected the inner ear HCs against apoptosis by reducing caspase-3 activation. Together, our findings demonstrate that our new compounds prevent gentamycin-induced HC loss by preventing the demethylation of H3K4me2 and by inhibiting apoptosis, and these results might provide the theoretical basis for novel drug development for hearing protection.
Abstract Motivated by some problems arising from multiclinic trials, we consider stratified two-sample designs. Nonparametric effects are defined and nonparametric hypotheses are formulated in a design where treatment, centers (strata), and interactions are assumed to be fixed factors. The interpretation of the nonparametric effects and hypotheses is analyzed in two classes of semiparametric models: the linear models and models with Lehmann alternatives. The case where centers and interactions are assumed to be random factors, the so-called mixed model, is also considered. Nonparametric effects and hypotheses are defined for general models, and their properties are analyzed in corresponding linear models and in models with Lehmann alternatives. The nonparametric effects are estimated by linear rank statistics where the ranks over all centers are used. The mixed model for repeated (baseline and endpoint) observations is briefly considered, and rank procedures are also proposed for this model. All procedures are related to the nonparametric effects and are not restricted to the two classes of semiparametric models, which are used only for interpretation of the nonparametric effects. Moreover, we do not assume continuity of the underlying distribution functions of the observations, to be as general as possible. We exclude only the trivial case where the distribution function arises from a point mass; that is, a "one-point distribution." Thus, not only data coming from continuous distribution functions, but also data with ties—especially discrete ordinal data—can be handled with the proposed procedures. In all cases, the results are derived for unbalanced designs so that there are no restrictions for practical applications. The small-sample properties of the proposed statistics are investigated by simulation studies, and the relevant asymptotic distribution theory is considered. Applications of the proposed procedures are demonstrated by means of examples related to multicenter clinical trials. Key Words: Asymptotic normalityFixed-effect modelMixed modelRank testsRepeated measurementsTiesTwo-factor designsUnbalanced designs
Rural preschool teachers are an important part of rural education, and the construction of rural preschool teachers is the time. At present, the rural preschool teachers in Zigong City have some problems, such as unbalanced title structure, less training opportunities, single supplement channels and lack of local feelings. In order to accelerate the construction of preschool education legislation, improve the training of rural preschool teachers, expand the supplementary mechanism of rural preschool teachers, and cultivate rural preschool teachers' local feelings, we should promote the construction of rural preschool teachers.
Recent evidence suggests that stem cell differentiation can be regulated by modulation of the cell’s biomechanics. The cytoskeletal structures and arrangements in stem cells undergoing differentiation are dramatically altered, and these alterations vary by lineage. The complexity of events associated with the transformation of these precursor cells leaves many questions unanswered about morphological, structural, proteomic, and functional changes in differentiating stem cells. A thorough understanding of stem cell behavior, both experimentally and computationally, would allow for the development of more effective approaches to the expansion of stem cells in vitro and for the regulation of their commitment to a specific phenotype.
In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21 Cip1 and p27 Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line.
Abstract This work sought to determine the crosstalk between the Notch and Wnt signaling pathways in regulating supporting cell (SC) proliferation and hair cell (HC) regeneration in mouse utricles. We cultured postnatal day (P)3 and P60 mouse utricles, damaged the HCs with gentamicin, and treated the utricles with the γ-secretase inhibitor DAPT to inhibit the Notch pathway and with the Wnt agonist QS11 to active the Wnt pathway. We also used Sox2-CreER, Notch1-flox (exon 1), and Catnb-flox (exon 3) transgenic mice to knock out the Notch pathway and activate the Wnt pathway in Sox2+ SCs. Notch inhibition alone increased SC proliferation and HC number in both undamaged and damaged utricles. Wnt activation alone promoted SC proliferation, but the HC number was not significantly increased. Here we demonstrated the cumulative effects of Notch inhibition and Wnt activation in regulating SC proliferation and HC regeneration. Simultaneously inhibiting Notch and overexpressing Wnt led to significantly greater SC proliferation and greater numbers of HCs than manipulating either pathway alone. Similar results were observed in the transgenic mice. This study suggests that the combination of Notch inhibition and Wnt activation can significantly promote SC proliferation and increase the number of regenerated HCs in mouse utricle.
By applying an objective method to evaluate its sustainability, a certain country could make proper plans and policies for further development.However, subjective and complicated problems have been found in the current methods and index systems.Therefore, researchers set up a composite model that it can evaluate the sustainability for a certain country in a more objective way, in comparison with other methods.Researchers propose a method for evaluating sustainability for a certain country, which solves problems concerning strong subjectivity and complicity in current models.Researchers choose 17 representative core indicators based on the index system of UNCSD and divide them into two catalogues --Nature Indicators and Operate Indicators.First, Means Clustering Algorithm of k-means (an unsupervised learning method) divides the data into three categories.Then, researchers obtain those indicators, using regression analysis, and build an objective evaluation model.When researchers make policies for a country to allocate resources reasonably, researchers maximize the improvement of the ability of sustainable development based on "along the gradient direction ascend the fastest".In this paper, researchers conduct simulations experiment, using data of 96 countries in the World Bank.After analyzing the deviations and sensitivity of the model, the theoretical results are verified experimentally.
Abstract Objective Tinnitus is a highly prevalent hearing disorder, and the burden of tinnitus diagnosis and treatment is very heavy, especially in China. In order to better benefit the majority of tinnitus patients, we developed a new mobile app based on our patented invention – named the Fudan Tinnitus Relieving System (FTRS) – for tinnitus management. The FTRS app aims to alleviate patients’ tinnitus symptoms using customized sound therapy, to evaluate the treatment effect, to provide a doctor-patient communication platform, and to support tinnitus rehabilitation and auditory health. Methods In this study, we introduced the major functions of the FTRS app, analyzed the geographical distribution of users around China, and performed an analysis on the demographic and clinical characteristics of patients with tinnitus, including age and tinnitus position, duration, frequency, and severity in both men and women based on the user information collected by the FTRS. The data for 22,867 participants (males: 13,715; females: 9,152) were included in the statistical analysis. Results The FTRS app has been popular with tinnitus patients since its launch in May 2018 with its integrated pitch-matching test, individualized sound therapy, follow-up assessment, and provision of easy-to-understand science and education for tinnitus. The users were located throughout Mainland China but primarily concentrated in Shanghai, Jiangsu, Zhejiang, Guangdong, and Shandong provinces. We observed gender differences regarding age and tinnitus frequency, severity, and position among the app’s users. The FTRS has not only facilitated patients’ access to treatment at times and places that are convenient for them, but also provides a large amount of data based on user feedback in order to support clinical tinnitus research. Conclusions Compared with traditional face-to-face medical treatment, the FTRS greatly reduced medical costs and enabled patients with tinnitus to arrange their own treatment times. At the same time, the FTRS has provided standardized tinnitus data that have laid a foundation for clinical research on tinnitus. However, because of differences in the popularity and utilization of smart devices, FTRS user data might only reflect the situation of tinnitus patients who can effectively use smart devices. Therefore, the findings of this study need to be interpreted with caution.
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