Iron silicate perovskite and postperovskite in the deep lower mantle.

Ferromagnesian silicates are the dominant constituents of the Earth's mantle, which comprise more than 80% of our planet by volume. To interpret the low shear-velocity anomalies in the lower mantle, we need to construct a reliable transformation diagram of ferromagnesian silicates over a wide pressure-temperature (P-T) range. While MgSiO3 in the perovskite structure has been extensively studied due to its dominance on Earth, phase transformations of iron silicates under the lower mantle conditions remain unresolved. In this study, we have obtained an iron silicate phase in the perovskite (Pv) structure using synthetic fayalite (Fe2SiO4) as the starting material under P-T conditions of the lower mantle. Chemical analyses revealed an unexpectedly high Fe/Si ratio of 1.72(3) for the Pv phase in coexistence with metallic iron particles, indicating incorporation of about 25 mol% Fe2O3 in the Pv phase with an approximate chemical formula (Fe2+0.75Fe3+0.25)(Fe3+0.25Si0.75)O3. We further obtained an iron silicate phase in the postperovskite (PPv) structure above 95 GPa. The calculated curves of compressional (VP) and shear velocity (VS) of iron silicate Pv and PPv as a function of pressure are nearly parallel to those of MgSiO3, respectively. To the best of our knowledge, the iron silicate Pv and PPv are the densest phases among all the reported silicates stable at P-T conditions of the lower mantle. The high ferric iron content in the silicate phase and the spin-crossover of ferric iron at the Si-site above ~55 GPa should be taken into account in order to interpret the seismic observations. Our results would provide crucial information for constraining the geophysical and geochemical models of the lower mantle.

RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation.

Ferroportin (FPN), the body's sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of 2 different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using 2 conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases.

An Accurate and Individualized Preoperative Estimation Method for the Linear Insertion Depth of Cochlear Implant Electrode Arrays Based on Computed Tomography.

OBJECTIVES: Cochlear implantation or auditory brainstem implantation is currently the only accepted method for improving severe or profound sensorineural hearing loss. The length of the electrodes implanted during cochlear implantation is closely related to the degree of hearing improvement of hearing after the surgery. We aimed to explore new methods to accurately estimate the electrode array (EA) linear insertion depth based on computed tomography (CT) images prior surgery, which could help surgeons select the appropriate EA length for each patient. DESIGN: Previous studies estimated the linear insertion depth by measuring the length of the lateral wall of the cochlea rather than the electrode's path in the cochlea duct. Here, we determined the actual position of the EA on the CT image after cochlear surgery in order to predict the path of the EA, and the length of the predicted EA path was measured by the contouring technique (CoT) to estimate the linear insertion depth of the EA. Because CoT can only measure the length of the estimated EA path on a two-dimensional plane, we further modified the measurement by weighting the height of the cochlea and the length of the EA tail (the length of the last stimulating electrode to the end, which cannot be displayed on the CT image), which we termed the modified CoT + height + tail (MCHT) measurement. RESULTS: Based on our established method, MCHT could reduce the error to the submillimeter range (0.67 ± 0.37 mm) when estimating the linear insertion depth of various kinds of EAs compared with the actual implant length. The correlation coefficient between the linear insertion depth as predicted by MCHT and the actual was 0.958. The linear insertion depth estimated by this method was more accurate than that estimated using the classical CoT technique ( R = 0.442) and using the modified Escudé's method ( R = 0.585). CONCLUSIONS: MCHT is a method based on CT images that can accurately predict the linear insertion depth of cochlear implants preoperatively. This is the first report that we are aware of a method for predicting linear insertion depth before cochlear implantation with only submillimeter errors and that is tailored to different types of EAs.

Design and application of modified CAD/CAM socket-shield preparation template in immediate implantation in the esthetic area.

OBJECTIVE: Designed and applicated a modified customized CAD-CAM socket-shield preparation guide template in immediate implant and followed up for 3 years. CLINICAL CONSIDERATIONS: Socket-shield technique could improve the esthetic effect of immediate implant restorations by preserving the labial fascicular bone-periodontal complex at the implant site. While the socket-shield technique is highly technique-sensitive. A modified customized CAD/CAM guided template was designed and fabricated by 3D printing. The movement of the carbide bur during preparing the socket-shield was limited by the socket-shield preparation template. In this case report, the socket-shield preparation template was used for preparing the socket-shield in the tooth root with irregular morphology and the case was followed up for 3 years. CONCLUSIONS: The modified CAD/CAM socket-shield preparation template effectively improved the accuracy and efficiency of preparing the socket-shield by limiting the movement of the high-speed carbide bur in both in both lip-to-palatal and crown-to-root orientation. The socket-shield with accurate morphology could effectively maintain the gingival marginal level and contour. CLINICAL SIGNIFICANCE: The modified CAD/CAM socket-shield preparation template with the depth-locking ring effectively reduced the technique sensitivity and time consumption of the socket-shield technique, especially for tooth roots with irregular morphology.

Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis.

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

Adipose mesenchymal stem cell-derived exosomes ameliorate hypoxia/serum deprivation-induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro.

Age-related skeletal changes is closely associated with imbalanced bone remodeling characterized by elevated osteocyte apoptosis and osteoclast activation. Since osteocytes are the commander of bone remodeling, attenuating increased osteocyte apoptosis may improve age-related bone loss. Exosomes, derived from mesenchymal stem cells, hold promising potential for cell-free therapy due to multiple abilities, such as promoting proliferation and suppressing apoptosis. We aimed to explore the effect of exosomes derived from adipose mesenchymal stem cell (ADSCs-exo) on osteocyte apoptosis and osteocyte-mediated osteoclastogenesis in vitro. The osteocyte-like cell line MLO-Y4 was used as a model, and apoptosis was induced by hypoxia and serum deprivation (H/SD). Our results showed that ADSCs-exo noticeably reduced H/SD-induced apoptosis in MLO-Y4 cells via upregulating the radio of Bcl-2/Bax, diminishing the production of reactive oxygen species and cytochrome c, and subsequent activation of caspase-9 and caspase-3. Additionally, ADSCs-exo lowered the expression of RANKL both at the mRNA and protein levels, as well as the ratio of RANKL/OPG at the gene level. As determined by tartrate-resistant acid phosphatase staining, reduced osteoclastogenesis was further validated in bone marrow monocytes cultured under conditioned medium from exosome-treated MLO-Y4. Together, ADSCs-exo could antagonize H/SD induced osteocyte apoptosis and osteocyte-mediated osteoclastogenesis, indicating the therapeutic potential of ADSCs-exo in age-related bone disease.

Lysophosphatidic acid enhanced the osteogenic and angiogenic capability of osteoblasts via LPA1/3 receptor.

Lysophosphatidic acid is a serum-derived growth factor that is involved in wound healing. Although in its infancy, a growing body of evidence has demonstrated that lysophosphatidic acid exerts a potentially significant role in regulating bone cell biology. However, previous studies mainly focused on the osteoinductive potential of lysophosphatidic acid, its effects on bone tissue vascularization, another essential element during bone regeneration, remains ill-defined so far. Here in this study, we examined the effects of lysophosphatidic acid on osteogenic differentiation as well as the angiogenesis-inducing capacity of pre-osteoblasts, a cell population that coordinates osteogenic and angiogenic processes in bone regenerating niche. Our results showed that treatment of MC3T3-E1 pre-osteoblastic cells with lysophosphatidic acid enhanced alkaline phosphatase activity and matrix mineralization, demonstrating in vitro osteoblastic differentiation. Of particular importance was the finding that vascular endothelial growth factor secretion also increased after lysophosphatidic acid treatment. Lysophosphatidic acid conditioned media of MC3T3-E1 cells was capable of promoting angiogenic behavior of endothelial cells, as evidenced by stimulating proliferation, migration, and tube formation. Besides, inhibition of LPA1/3 receptor abolished lysophosphatidic acid-induced elevation of the osteogenic and angiogenic capability of pre-osteoblasts. Our research demonstrated the important role of lysophosphatidic acid in coupling osteogenesis and angiogenesis during bone remodeling through orchestrating pre-osteoblast behavior, and implications therein for novel and effective treatment strategies for bone regeneration success.

Genetic associations with longevity are on average stronger in females than in males.

It is long observed that females tend to live longer than males in nearly every country. However, the underlying mechanism remains elusive. In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians. The present study's findings may partially explain the well-known male-female health-survival paradox and suggest that genetic variants may be associated with different reactions between males and females to the same vaccine, drug treatment and/or nutritional intervention. Thus, our findings provide evidence to steer away from traditional view that "one-size-fits-all" for clinical interventions, and to consider sex differences for improving healthcare efficiency. We suggest future investigations focusing on effects of interactions between sex-specific genetic variants and environment on longevity as well as biological function.

Evaluating the effect of preheating on resin composites in pit-and-fissure caries treatments with a digital intraoral scanner.

OBJECTIVE: To evaluate the effect of preheating on the microleakage and surface hardness of resin composites in the treatment of pit-and-fissure caries with various widths, as measured by an intraoral scanner. METHODS: A total of 153 L-shaped cavities with different widths (1 mm, 1.6 mm and 2 mm) were prepared on the buccal or palatal/lingual surfaces of human molars. The cavities were measured in three dimensions by a TRIOS scanner and then filled with various resins (room temperature Z350 flowable resin and room temperature and 60 â„ƒ Z350 universal resin). Microleakage and gap formation at 2 sites were evaluated by stereomicroscopy and scanning electron microscope. Resin samples were prepared, and the top surface Vickers hardness (VHNtop) of all samples was measured at 1 day and 30 days postirradiation. RESULTS: No difference were observed in the 3D scans for the cavities sizes among groups with the same width. For the 1 mm-wide cavity, the lowest microleakage was obtained with the flowable group; for the 1.6 mm-wide cavity, the nonpreheating universal group showed the highest microleakage at site 1, and the preheating group exhibited lower microleakage than that of the nonpreheating universal group at site 2; and for the 2 mm-wide cavity, the preheating group presented lower microleakage at site 2. The gap formations were consistent with the microleakage degrees. The preheating group exhibited the highest VHNtop at 1 day and 30 days postirradiation. SIGNIFICANCE: A digital intraoral scanner could be used to scan the cavities in three dimensions. Preheating technology could reduce the microleakage of Z350 universal resin and enhance its surface hardness.

Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis.

Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines. Currently, whether and how metformin protects the kidney remains unclear. In this study, among longevity drugs, including metformin, nicotinamide, resveratrol, rapamycin, and senolytics, we unexpectedly found that metformin, even at low doses, exacerbated experimentally-induced acute kidney injury (AKI) and increased mortality in mice. By single-cell transcriptomics analysis, we found that death of renal parenchymal cells together with an expansion of neutrophils occurs upon metformin treatment after AKI. We identified programmed cell death by ferroptosis in renal parenchymal cells and blocking ferroptosis, or depleting neutrophils protects against metformin-induced nephrotoxicity. Mechanistically, upon induction of AKI, ferroptosis in renal parenchymal cells initiates the migration of neutrophils to the site of injury via the surface receptor CXCR4-bound to metformin-iron-NGAL complex, which results in NETosis aggravated AKI. Finally, we demonstrated that reducing iron showed protective effects on kidney injury, which supports the notion that iron plays an important role in metformin-triggered AKI. Taken together, these findings delineate a novel mechanism underlying metformin-aggravated nephropathy and highlight the mechanistic relationship between iron, ferroptosis, and NETosis in the resulting AKI.

Causal Effects of Circulating Lipid Traits on Epithelial Ovarian Cancer: A Two-Sample Mendelian Randomization Study.

Ovarian cancer (OC), and particularly epithelial OC (EOC), is an increasing challenge for women. Circulating lipids play different roles in the occurrence and development of OC, but no causal relationship has been confirmed. We used two-sample Mendelian randomization (MR) to evaluate the genetic effects of circulating Apolipoprotein A1 (APOA1), Apolipoprotein B (APOB), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyc-erides (TG) on EOC risks based on summary data obtained from the UK Biobank and the Ovarian Cancer Association Consortium. We used the inverse-variance weight as the main statistical method and the MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. A 1-SD increment in HDL gave odds ratios (OR) and 95% confidence intervals (CI) of OR = 0.80 (95% CI: 0.69-0.93), OR = 0.77 (95% CI: 0.66-0.90), and OR = 0.76 (95% CI: 0.63-0.90) for low malignant potential OC (LMPOC), low-grade low malignant OC (LGLMSOC), and low malignant serous OC (LMSOC), respectively. Genetic liability due to TG was associated with an increased risk of LGLMSOC and LGSOC and a suggestive association with an increased risk of LMSOC (p = 0.001, p = 0.007, and p = 0.027, respectively). Circulating HDL was negatively associated with the risk of LMPOC, LGLMSOC, and LMSOC, while elevated circulating TG levels genetically predicted an increased risk of LGLMSOC and LGSOC. Further research is needed to investigate the causal effects of lipids on EOC and potential intervention and therapeutic targets.

Causal Associations of Circulating Lipids with Osteoarthritis: A Bidirectional Mendelian Randomization Study.

Osteoarthritis (OA) imposes an increasing social burden due to global activity limitations, especially among the aged. Links between circulating lipids and OA have been reported; however, confounding data from observational studies have hindered causal conclusions. We used Mendelian randomization (MR) approach to evaluate the genetic causal effects of circulating apolipoproteins and lipoprotein lipids on OA risk. Genetic instruments at the genome-wide significance level (p < 5 × 10−8) were selected from genome-wide association studies (n = 393,193−441,016 individuals). Summary-level OA data were obtained from the UK Biobank (39,427 cases, 378,169 controls). Bidirectional two-sample Mendelian randomization (MR) analyses used MR-Egger, weighted median, and MR-PRESSO for sensitivity analysis. Genetic predisposition to 1-SD increments of Apolipoprotein B (APOB), and low-density lipoprotein (LDL) was associated with a decreased risk of knee or hip OA (KHOA) (odds ratio (OR) = 0.925, 95% confidence interval (95% CI): 0.881−0.972, p = 0.002; OR = 0.898, 95% CI: 0.843−0.957, p = 0.001) and hip OA (HOA) (OR = 0.894; 95% CI: 0.832−0.961, p = 0.002; OR = 0.870 95% CI: 0.797−0.949, p = 0.002). Genetically predicted APOB showed an association with knee OA (KOA) (OR per SD increase, 0.930, 95% CI: 0.876−0.987, p = 0.016). The OR of KOA was 0.899 (95% CI: 0.835−0.968, p = 0.005) for a 1-SD increase in LDL. Apolipoprotein A1, high-density lipoprotein, and triglycerides showed no association. Inverse MR showed no causal effect of KOA, HOA, or KHOA on these serum lipids. Distinct protective genetic-influence patterns were observed for APOB and LDL on OA, offering new insights into relationships between lipids and OA risk and a better understanding of OA etiology.

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma.

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo. Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.

Genetic trade-offs between complex diseases and longevity.

Longevity was influenced by many complex diseases and traits. However, the relationships between human longevity and genetic risks of complex diseases were not broadly studied. Here, we constructed polygenic risk scores (PRSs) for 225 complex diseases/traits and evaluated their relationships with human longevity in a cohort with 2178 centenarians and 2299 middle-aged individuals. Lower genetic risks of stroke and hypotension were observed in centenarians, while higher genetic risks of schizophrenia (SCZ) and type 2 diabetes (T2D) were detected in long-lived individuals. We further stratified PRSs into cell-type groups and significance-level groups. The results showed that the immune component of SCZ genetic risk was positively linked to longevity, and the renal component of T2D genetic risk was the most deleterious. Additionally, SNPs with very small p-values (p ≤ 1x10-5 ) for SCZ and T2D were negatively correlated with longevity. While for the less significant SNPs (1x10-5  < p ≤ 0.05), their effects on disease and longevity were positively correlated. Overall, we identified genetically informed positive and negative factors for human longevity, gained more insights on the accumulation of disease risk alleles during evolution, and provided evidence for the theory of genetic trade-offs between complex diseases and longevity.

Optimal timing of salvage intratympanic steroids in idiopathic sudden sensorineural hearing loss.

Background: Salvage intratympanic steroids (ITS) works in patients with idiopathic sudden sensorineural hearing loss (ISSNHL) after failure of initial therapy, but optimal timing of administration is unknown. Methods: Two hundred and seventy patients with ISSNHL were included. Among them, 180 were treated with ITS and standard medical treatment (SMT) and the other 90 received SMT along. The hearing threshold before and after salvage treatment were compared. The relationship between the salvage starting time and hearing recovery was analyzed. Results: The hearing of ITS group improved more than that of the SMT group in all frequency bands. The effect of both strategies decreases with the delay of the starting time. ITS can improve hearing even if being administrated 5 weeks after onset while SMT failed after 3 weeks. Conclusion: Patients with profound ISSNHL can obtain extra hearing recovery from salvage ITS. The earlier salvage starts, the greater the patient benefits.

A population-based study of precision health assessments using multi-omics network-derived biological functional modules.

Recent technological advances in multi-omics and bioinformatics provide an opportunity to develop precision health assessments, which require big data and relevant bioinformatic methods. Here we collect multi-omics data from 4,277 individuals. We calculate the correlations between pairwise features from cross-sectional data and then generate 11 biological functional modules (BFMs) in males and 12 BFMs in females using a community detection algorithm. Using the features in the BFM associated with cardiometabolic health, carotid plaques can be predicted accurately in an independent dataset. We developed a model by comparing individual data with the health baseline in BFMs to assess health status (BFM-ash). Then we apply the model to chronic patients and modify the BFM-ash model to assess the effects of consuming grape seed extract as a dietary supplement. Finally, anomalous BFMs are identified for each subject. Our BFMs and BFM-ash model have huge prospects for application in precision health assessment.

Intratympanic gentamicin injection for refractory ménière's disease (MD) has potential effect in preventing contralateral MD occurrence.

BACKGROUND: Ménière's disease (MD), characterized by episodic vertigo attacks and fluctuating progressive hearing loss, is treated by low-dose intratympanic gentamicin (ITG) injections. Whether ITG causes hearing loss is controversial, and knowledge about its effects on the contralateral hearing and vestibular function is lacking. AIMS/OBJECTIVES: We aimed to evaluate the effect of ITG on bilateral auditory and otolith organ function in patients with unilateral refractory MD. MATERIAL AND METHODS: The data of 30 patients was collected, including history, and pure tone audiometry and vestibular-evoked myogenic potentials (VEMPs) results before and one month after ITG treatment. Changes in vertigo were assessed at a two-year follow-up. RESULTS: One month after ITG injection, auditory thresholds between 125 Hz and 8 kHz on the injection side remained unchanged but have improved on the contralateral side at 125 Hz, 250 Hz, 1 kHz. The cervical and ocular VEMP solicitation rates on the injection side were lower than before the injection. Two years after treatment, vertigo was improved in 88.5% and complete controlled in 76.7% patients respectively. CONCLUSIONS AND SIGNIFICANCE: The intractable vertigo of MD can be effectively controlled by ITG injection. This can improve the low and medium frequency hearing level in the contralateral ear, suggesting that it might help prevent contralateral MD occurrence.

Tinnitus Is Associated With Extended High-frequency Hearing Loss and Hidden High-frequency Damage in Young Patients.

OBJECTIVES: To analyze the results of extended high-frequency (EHF) and high-frequency hearing tests in young patients with tinnitus who show normal response in conventional pure-tone audiometry (PTA), and to explore the correlation between tinnitus and hearing loss (HL). STUDY DESIGN: A case-control study. SETTING: A Tertiary Eye Ear Nose & Throat Hospital of China. PARTICIPANTS: Patients with tinnitus, aged 18 to 35 years old, and with normal conventional PTA (125 Hz-8 kHz) were enrolled in the tinnitus group. Volunteers without tinnitus of the same age were enrolled in the control group. MAIN OUTCOME MEASURES: The incidence of EHF-HL and the hearing thresholds at each frequency, as well as the distribution of maximum HL frequency and edge frequency in all participants were compared. RESULTS: In total, 28 cases (43 ears) were enrolled in the tinnitus group and 34 cases (68 ears) in the control group. The incidence of EHF-HL, average hearing threshold of each frequency ranging from 4 to 16 kHz, and the maximum hearing threshold were significantly higher in the tinnitus group. The edge frequency in the tinnitus group was lower than that in the control group (10.4 ±â€Š3.1 kHz versus 12.3 ±â€Š2.5 kHz, p = 0.010). The dominant tinnitus pitch in cases whose EHF was impaired was positively correlated with the hearing-level loudness of tinnitus (r = 0.627, p < 0.001). CONCLUSION: Patients with tinnitus and normal hearing in conventional PTA showed signs of EHF-HL and hidden damage in the high-frequencies more easily. EHF hearing tests and the follow-up of HF hearing tests are recommended to facilitate early detection of hearing impairment for timely intervention.

Metal transporter Slc30a1 controls pharyngeal neural crest differentiation via the zinc-Snai2-Jag1 cascade.

The pharyngeal arch (PA) is a neural crest (NC)-derived organ that is transiently developed during embryogenesis and is required for the subsequent development of various tissues. However, the role of zinc during PA differentiation from NC progenitor cells is unknown. Here, we found that the metal transporters Slc30a1a and Slc30a1b mediate zinc homeostasis during PA differentiation. Slc30a1-deficient zebrafish develop zinc accumulation in NC cells, with increased expression of stemness markers and PA dorsal genes, and SMART-seq analyses revealed that the genes snai2 and jag1b may serve as downstream targets. Furthermore, functional studies showed that knocking down either snai2 or jag1b rescues PA development in Slc30a1-deficient zebrafish. Notably, we identified the double zinc-finger domain in the transcription factor Snai2 as a zinc-responsive element that regulates jag1b expression. Our findings indicate that the Slc30a1/zinc-snai2-jag1b axis is an essential regulatory network controlling PA differentiation, shedding new light on the function of zinc homeostasis in maintaining NC cell stemness and multipotency in vertebrates.