The Suppression of Ubiquitin C-Terminal Hydrolase L1 Promotes the Transdifferentiation of Auditory Supporting Cells into Hair Cells by Regulating the mTOR Pathway.

In 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.

Micelle-based fluorogenic sensing of trypsin: a sensitive method in pancreatic disease diagnosis.

Protamine-mediated micellar aggregates, featuring an AIE-based fluorescent sensor, facilitate efficient detection of trypsin activity. This method enables the detection of trypsin at exceptionally low concentrations (0.01-0.1 µg mL-1) in urine, demonstrating its potential for early clinical diagnosis of trypsin-related pancreatic diseases.

Impact of the COVID-19 pandemic on clinical and psychological aspects of temporomandibular disorders.

BACKGROUND: The Coronavirus 2019 disease (COVID-19) caused drastic changes in people's lifestyle that affected TMD characteristics through its physical and psychological influences. The aim of this study was to define the clinical and psychological characteristics of a large group of well-defined TMD patients and seek their differences between before and during the COVID-19 pandemic to establish points of care to be emphasized in the post-pandemic era. METHODS: TMD patients diagnosed by the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) aged ≥ 18 were analyzed. Samples between September, 2017 to July, 2019 (n = 455) and March, 2021 to June, 2022 (n = 338) were collected to represent before and during COVID-19, respectively. The Graded Chronic Pain Scale (GCPS) and Symptom Checklist-90-Revision (SCL-90-R) were used to evaluate disability levels and psychological status. Clinical indices were compared between COVID periods and factors related to higher pain levels were investigated according to pandemic period. RESULTS: More patients reported pain on palpation of the masticatory muscles during the pandemic (p = 0.021) while the number decreased for neck muscles (p = 0.001) and TMJ (p < 0.001) areas. Patients reporting nocturnal bruxism (23.3-29.6%) and clenching (45.1-54.7%) significantly increased during the pandemic. TMD patients with pain without disability were more common during the pandemic regardless of pain intensity (p < 0.001). The number of patients expressing interference in daily activities decreased drastically during COVID-19 regardless of disability level (p < 0.001). Factors associated with higher than moderate pain intensity (CPI ≥ 50) were insomnia (odds ratio [OR] = 1.603, p = 0.047) and somatization (OR = 1.082, p < 0.001) before the pandemic. During the pandemic, age (OR = 1.024, p = 0.007), somatization (OR = 1.070, p = 0.006), and paranoid ideation (OR = 1.117, p = 0.003) were significantly associated with higher pain intensity. CONCLUSIONS: The results of our study underline the importance of evaluating psychological profiles of TMD patients, especially somatization, paranoid ideation and psychoticism, in exceptional situations that may cause a change in individual mental status. This will lead to a better understanding of the individual TMD patient and help in planning personalized treatment strategies that will assist the patient in adjusting to changes occurring in special environments such as the COVID-19 pandemic.

Dietary intake is associated with the prevalence of uterine leiomyoma in Korean women: A retrospective cohort study.

OBJECTIVE: Uterine leiomyoma (UL), the most prevalent benign gynecologic tumor among reproductive-aged women, lacks sufficient research on the potential association between dietary intake and its occurrence in Korean women. Addressing this research gap, this study aims to evaluate the potential link between dietary intake and the prevalence of UL in Korean women. METHODS: In this cross-sectional study, a cohort of 672 women, aged 23 to 73, were enrolled, with 383 (57%) being premenopausal. Dietary intake was assessed using a validated food frequency questionnaire (FFQ), and UL presence was determined through ultrasonography. The analysis focused exclusively on items within ten categories, including vegetables/fruit, vegetables, fruits, red meat, processed meat, poultry, fish, dairy product, milk, and alcohol. Multiple logistic regression models were employed to explore the relationship between dietary intake and the prevalence of UL, calculating odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for confounding factors. RESULTS: Within the total cohort, 220 (32.7%) women were diagnosed with UL. High intakes of fish and poultry showed an association with higher UL prevalence. Odds ratios (95% CIs) for the upper quartiles compared to the lower quartiles were 1.68 (1.01-2.81; p trend = 0.05) for fish intake and 1.87 (1.11-3.17; p trend = 0.06) for poultry intake. Conversely, an inverse relationship emerged between dairy product intake and UL prevalence, with an odds ratio of 0.58 (95% CI 0.35-0.96; p trend = 0.05). Stratifying the analysis by menopausal status revealed a parallel pattern, with heightened UL prevalence with fish intake and reduced prevalence with dairy product intake. However, the link between poultry intake and UL prevalence was primarily observed among postmenopausal women. Among premenopausal women, elevated vegetable intake was linked to a decreased UL prevalence (OR 0.45, 95% CI 0.21-0.97 for top vs. bottom quartiles; p trend = 0.01). CONCLUSION: We found that high consumption of fish and poultry, coupled with low intake of dairy products, correlated with an elevated prevalence of UL. Furthermore, vegetable intake exhibited an inverse relationship with UL prevalence, particularly among premenopausal women.

Abnormal Cholesterol Metabolism and Lysosomal Dysfunction Induce Age-Related Hearing Loss by Inhibiting mTORC1-TFEB-Dependent Autophagy.

Cholesterol is a risk factor for age-related hearing loss (ARHL). However, the effect of cholesterol on the organ of Corti during the onset of ARHL is unclear. We established a mouse model for the ARHL group (24 months, n = 12) and a young group (6 months, n = 12). Auditory thresholds were measured in both groups using auditory brainstem response (ABR) at frequencies of 8, 16, and 32 kHz. Subsequently, mice were sacrificed and subjected to histological analyses, including transmission electron microscopy (TEM), H&E, Sudan Black B (SBB), and Filipin staining, as well as biochemical assays such as IHC, enzymatic analysis, and immunoblotting. Additionally, mRNA extracted from both young and aged cochlea underwent RNA sequencing. To identify the mechanism, in vitro studies utilizing HEI-OC1 cells were also performed. RNA sequencing showed a positive correlation with increased expression of genes related to metabolic diseases, cholesterol homeostasis, and target of rapamycin complex 1 (mTORC1) signaling in the ARHL group as compared to the younger group. In addition, ARHL tissues exhibited increased cholesterol and lipofuscin aggregates in the organ of Corti, lateral walls, and spiral ganglion neurons. Autophagic flux was inhibited by the accumulation of damaged lysosomes and autolysosomes. Subsequently, we observed a decrease in the level of transcription factor EB (TFEB) protein, which regulates lysosomal biosynthesis and autophagy, together with increased mTORC1 activity in ARHL tissues. These changes in TFEB and mTORC1 expression were observed in a cholesterol-dependent manner. Treatment of ARHL mice with atorvastatin, a cholesterol synthesis inhibitor, delayed hearing loss by reducing the cholesterol level and maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB. The above findings were confirmed using stress-induced premature senescent House Ear Institute organ of Corti 1 (HEI-OC1) cells. The findings implicate cholesterol in the pathogenesis of ARHL. We propose that atorvastatin could prevent ARHL by maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB during the aging process.