Background: Mutations in the USH2A gene are strongly associated with hereditary sensorineural loss. However, the cellular mechanisms linking USH2A deficiency to cochlear hair cell vulnerability remain incompletely understood. Aims: This study aimed to investigate the effects of USH2A knockdown on Prestin expression and apoptosisrelated signaling in a cochlear hair cell model. Methods: Stable USH2A knockdown HEI-OC1 cells were generated using lentiviral shRNA transduction followed by puromycin selection (2 mu g/mL for 7 days). Gene and protein expression levels of Prestin, Bax, and Bcl-2 were assessed by RT-qPCR (2<^>(-Delta Delta Ct) method), Western blotting, and immunofluorescence. Apoptosis was evaluated by flow cytometry (Annexin V/PI), TUNEL staining, and cleaved caspase-3 immunofluorescence. Results: USH2A knockdown reduced Prestin mRNA and protein expression by approximately 60% compared with the sh-NC group (P < 0.01). Bax expression increased more than 2.5-fold, whereas Bcl-2 levels decreased by similar to 50%, indicating disruption of apoptotic balance. Flow cytometry revealed increased early apoptotic (2.16% -* 4.58%) and late apoptotic (16.3% -* 22.0%) populations. TUNEL-positive cells increased from 2.8 +/- 0.6% to 12.4 +/- 2.1% (P < 0.01), and cleaved caspase-3 fluorescence intensity was approximately threefold higher in the knockdown group. Conclusion: USH2A knockdown significantly reduces Prestin expression and promotes apoptosis through modulation of the Bax/Bcl-2 axis in HEI-OC1 cells. These findings provide mechanistic insights into how USH2A deficiency may increase cochlear hair cell vulnerability and potentially contribute to auditory dysfunction. Further in vivo validation is warranted.

Objective:Intermuscular lipoma（IL） is a rare type of deep-seated benign lipoma, accounting for approximately 0.3% of all lipomas. Its occurrence in the temporal region is particularly uncommon, and giant lesions are even rarer. We report the case of an 84-year-old male patient with a giant intermuscular lipoma in the temporal region, who had undergone two surgical excisions at an outside hospital, both followed by recurrence. The patient underwent another surgery at our hospital, during which the mass was completely excised. Postoperative histopathology confirmed the diagnosis of intermuscular lipoma, and no recurrence was observed during a 1-year follow-up. Based on the clinical presentation and treatment course of this case, combined with a review of relevant literature, the authors analyze the etiology, diagnosis and treatment, recurrence factors, and prognosis of giant intermuscular lipomas in the temporal region, aiming to improve awareness of this rare disease, emphasize intraoperative management, and reduce postoperative recurrence rates.

UNLABELLED:Hearing loss (HL) is the most common sensory disorder, with genetic factors accounting for approximately 60% of cases of congenital HL. Hearing loss is the most common sensory disorder, affecting approximately 60% of cases, which is often related to hereditary patterns. The MYO6 gene encodes the unconventional myosin VI, a protein crucial for maintaining the function of inner ear hair cells and the normal structure of stereocilia. Variants in the MYO6 have been implicated in HL at loci DFNA22 and DFNB37. Due to the high genetic heterogeneity of sensorineural HL, variants at different loci within this gene result in varying degrees of hearing impairment. This review summarizes the current understanding of MYO6-related pathogenesis, provides an overview of the structure and function of the MYO6 gene, and discusses the diseases associated with various forms of MYO6 variants. The objective is to enhance the understanding of the genotype-phenotype correlation associated with MYO6 and to explore emerging preclinical gene therapy strategies for addressing this genetically heterogeneous disorder, while also providing insights for clinical genetic counseling.

Background:Usher syndrome (USH) is an autosomal recessive disorder characterized by hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. USH2A is one of the causative genes of USH. This study is aimed at exploring the mechanism of hearing loss induced by USH2A gene knockout. Method:USH2A knockout (Ush2a-/-) mice were used, and auditory brainstem response testing was performed on WT, Ush2a-/-, and Ush2a+/- mice. Then, the cochlea tissues were used to carry out immunofluorescence staining, hematoxylin and eosin (H&E) staining, and scanning electron microscopy (SEM). The mRNA expressions were detected by RT-qPCR. Finally, the differentially expressed genes (DEGs) in cochlear tissues of Ush2a-/- and WT mice were identified by transcriptome sequencing. Results:Compared to WT mice, Ush2a-/- and Ush2a+/- mice exhibited moderate-to-severe nonprogressive hearing loss, with more pronounced deficits at low (4 kHz) and high (32/24 kHz) frequencies. HE staining and immunofluorescence staining showed that the modiolus, stria vascularis, basilar membrane, and the number of inner hair cells and outer hair cells (OHCs) in USH2A knockout mice have not changed. However, SEM results showed that severe stereociliary collapse was evident in OHCs of the Ush2a-/- group. In addition, through transcriptomic analysis, 3632 upregulated genes and 2921 downregulated genes were obtained in the Ush2a-/- mice. Among these DEGs, the most DEGs associated with hearing loss were Scn2a, Shank2, Bsn, Fcer1g, Prkce, Tgfb1, and Irf7. Conclusion:This study demonstrates that USH2A deficiency disrupts auditory function through stereociliary instability and dysregulation of genes critical for synaptic transmission and cytoskeletal dynamics.

UNLABELLED:Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are integral components of the cytoplasmic pattern recognition receptors (PRRs) family, playing a crucial role in both innate immunity and inflammatory responses. Nucleotide-binding oligomerization domain-like receptors detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), activating multiple signaling pathways, including nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK), and triggering immune responses through inflammasome activation. The NLR family contains 5 distinguishable subfamily classifications. The development and progression of multiple ear-related disorders depend significantly on NOD1, NOD2, NLRP3, and NLRX1, among other specific members of the NLR family. The analysis investigates NLRs' interactions with ear pathologies, particularly focusing on NLRP3 functions in the development of otitis media along with its effect on cholesteatoma formation and hearing loss. In addition, this review evaluates targeted therapeutic strategies derived from NLRs research by developing a theoretical foundation that suggests new ways for advancing treatments for otological diseases.

BACKGROUND:Cochlear implantation (CI) is a standard intervention for congenital severe to profound sensorineural hearing loss. However, postoperative auditory and speech outcomes vary considerably across patients, and the developmental status of the cochlear nerve is considered a major determinant of rehabilitation efficacy. OBJECTIVE:This study aimed to assess the correlation between cochlear nerve cross-sectional area (CNCSA) and outcomes after cochlear implantation (CI). METHODS:We retrospectively analyzed 136 bilateral CI recipients, comparing auditory and speech rehabilitation results over 2 years postoperatively with bilateral CNCSA. Patients were grouped based on average CNCSA. RESULTS:A significant positive correlation was observed between CNCSA and scores on the IT-MAIS, MUSS, CAP, and SIR at 2 years post-CI. Patients with bilateral CNCSA >0.87 mm2 had significantly better speech rehabilitation outcomes than those with one or both nerves below this threshold. CONCLUSIONS:CNCSA is correlated with post-CI rehabilitation outcomes in patients with severe-to-profound sensorineural hearing loss, and may serve as a predictor for auditory and speech rehabilitation success.

IntroductionWaardenburg syndrome type 1 (WS1) is a rare autosomal dominant disorder characterized by congenital sensorineural hearing loss and facial dysmorphisms. PAX3 mutations are a known genetic cause. This study investigated a novel PAX3 mutation in a Chinese Yugur family and assessed long-term auditory outcomes after cochlear implantation.Methods and ResultsWhole-exome and Sanger sequencing were used to identify causative variants, followed by bioinformatic analyses to predict pathogenicity. Auditory and speech rehabilitation were evaluated over a 7-year follow-up. A novel heterozygous frameshift mutation in PAX3 (c.788dup, p.Gln264ThrfsTer5) was identified and confirmed to be de novo. Structural modeling indicated disruption of a conserved domain, supporting its pathogenic role. The proband achieved excellent auditory and speech recovery and successfully integrated into mainstream education.DiscussionThis study expands the mutation spectrum of PAX3 and provides evidence supporting the pathogenicity of the c.788dup variant. It also confirms the long-term benefit of cochlear implantation and rehabilitation in WS1-related hearing loss.

The tectorial membrane (TM) is an essential extracellular matrix in the cochlea, integral to auditory processing by facilitating hair cell stimulation and sound transmission. Despite its vital role, the mechanisms underlying TM-related hearing loss remain unclear. This review aim to discuss the structure and functions of the TM, exploring its role in cochlear mechanics and auditory signal amplification. Abnormalities in TM composition, including disruptions in collagen, glycosaminoglycans, and non-collagenous proteins, are implicated in various forms of hearing loss, including those associated with genetic mutations and ototoxic drug exposure. We also examine the contributions of genes such as TECTA, TECTB, and CEACAM16, whose mutations disrupt TM integrity and lead to sensorineural hearing loss. Additionally, the impact of aging and thyroid hormone deficiency on TM degeneration is considered. Current diagnostic and therapeutic approaches are discussed, with an emphasis on the potential of gene therapy and stem cell therapy.

BACKGROUND:Hearing loss, a major public health issue, affects 1.33 per 1,000 live births worldwide. Genetic factors contribute to over half of congenital cases, with X-linked inheritance accounting for 1-5%. POU3F4 mutations are associated with approximately 50% of X-linked non-syndrome hearing loss cases. POU3F4 plays a critical role in cochlear development by regulating otic mesenchyme cell differentiation. The study investigates the impact of a novel POU3F4 p.E294G mutation on cochlear structure and function using cellular and animal model. METHODS:The study utilized immortalized lymphoblastoid cell lines, POU3F4 overexpressed HEK293 cells and generated Pou3f4 knock-in (Pou3f4KI) mice via CRISPR/Cas9 to introduce the p.E294G mutation. Alterations in expression and subcellular localization of POU3F4 were detected at the cellular level. Auditory function was assessed using auditory brainstem response testing. Cochlear structure was analyzed through histology, immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RNA sequencing, qPCR and Western blot were conducted to evaluate gene expression and mitochondrial function. RESULTS:The transcription of POU3F4 was abnormal and the expression was normal in lymphoblastoid cell lines. Abnormal nuclear localization of POU3F4 p.E294G was found in overexpressed HEK293 cells. Pou3f4KI mice exhibited cochlear malformations, including modiolus hypoplasia and reduced stria vascularis cell populations. Auditory testing revealed progressive hearing loss. Pou3f4 affect mitochondrial protein expression by affecting the expression of TFAM. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation (OXPHOS) complex assembly and activity, decreased ATP levels. The level of reactive oxygen species, mitochondrial fission and apoptosis in cochlea were elevated. CONCLUSIONS:The POU3F4 p.E294G resulted in abnormal nuclear localization. Pou3f4 mutant disrupts cochlear development and function, impairs mitochondrial integrity, induces oxidative stress, and promotes apoptosis, leading to progressive hearing loss. The findings enhance the understanding of POU3F4-related hearing loss mechanisms and highlight the importance of early genetic screening and audiological monitoring.

Retiform hemangioendothelioma (RH) is a rare intermediate (locally aggressive) vascular tumor that mostly affects the dermis of the trunk and limbs, but has never been reported in the inferior turbinate. A 10-year-old Chinese boy presented with recurrent epistaxis in his left nasal cavity and anemia for more than 2 years. Radiographic and electronic video laryngoscopic images showed an expansile mass in the left inferior turbinate. Endoscopic surgery and electrocautery were performed to resect the tumor beyond the macroscopic border. Histopathologically, the tissues were infiltrated by hyperplastic blood vessels arranged in a retiform pattern, and endothelial cells proliferate significantly in some areas. Immunohistochemistry showed a positive result for CD31, CD34, Fli-1, and ERG. No epistaxis, tumor recurrence, or metastasis was found on reexamination over 18 months after surgery.

Background:Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic and mitochondrial proteins. The mt-ARS genes encode the mitochondrial aminoacyl-tRNA synthetase (mt-ARSs), and variants in mt-ARS genes affect mitochondrial protein synthesis. This can impair the translation of mitochondrial proteins, adversely affecting oxidative phosphorylation and leading to related diseases. To date, 19 mt-ARS genes have been identified and found to be strongly associated with the development of mitochondrial disorders. Hearing loss (HL) is one of the most common chronic conditions in children and a leading cause of communication disorders. Genetic studies of sensorineural HL are critical to diagnosing and treating sensorineural HL. The relationship between mt-ARS genes and sensorineural HL is gradually surfacing as cases of HL phenotypes caused by variants in the mammalian mt-ARS genes continue to be reported. Seven mt-ARS genes have been reported to contribute to various hereditary sensorineural HL. Summary:This article reviews studies on mitochondrial aminoacyl-tRNA synthetase, mt-ARS genes, and variants associated with HL phenotypes. Investigating their genetic characteristics provides deeper insights into the pathophysiology and molecular mechanisms of sensorineural hearing loss. Key Messages:Disease phenotypes resulting from variants in mt-ARS genes exhibit significant clinical heterogeneity. The varying degrees of sensorineural HL phenotypes caused by mt-ARS gene variants warrant the attention of otologists and researchers. At least seven of the currently reported mt-ARS genes are associated with sensorineural HL. However, the molecular mechanisms by which these genes contribute to HL remain incompletely understood. Further studies of the mt-ARS genes still await additional case reports, as well as related model animal studies and combined functional studies.

The porous nature and structural variability of covalent organic frameworks (COFs) make them preferred for drug loading and delivery applications. However, most COF materials suffer from poor luminescent properties and inefficiency for cell uptake. Herein, we experimentally demonstrate the crucial role of long alkoxy chains in the synthesis of crystalline COF nanostructures with high cellular uptake efficiency. After luminescence integration through band engineering, the semiconducting COF exhibits an optical bandgap of 2.05 eV, an emission wavelength of 632 nm, a high quantum yield of 37 %, and excellent fluorescence stability (100 % at 3 h). Such excellent optical properties of the designed COF nanocarriers enable quantitative evaluations of cellular uptake and visual tracking of drug delivery. It was demonstrated that the cellular uptake efficiency was enhanced by orders of magnitude for the COF after the introduction of long n-octyloxy chains, which firstly delivered the anticancer camptothecin (CPT) to cell lysosomes, and then underwent "endo/lysosomal escape" to induce cell apoptosis. In vivo assay evidenced a significant enhancement in the therapeutic effect with a 96 % inhibition of tumor growth after 14 days of treatment. This progress sheds light on designing cutting-edge drug delivery nanosystems based on COF materials with integrated diagnostic and therapeutic functions.

BackgroundCochlear implants (CI) help regain perception of sound for patients with sensorineural hearing loss. The ability to recognize music pitch may be crucial for recognizing and producing speech for Mandarin. Aims/ObjectivesThis study aims to search for possible influencing factors of music perception and correlations between music perception and auditory speech abilities among prelingually deaf pediatric Mandarin-speaking CI users. Material and MethodsMusic perception of 24 pediatric CI users and 12 normal hearing children was measured using the MuSIC test. Auditory speech perception of the 24 CI users was also measured and analyzed with their music perception results. ResultsPediatric CI users performed worse than normal hearing children in pitch, rhythm and melody discrimination tests (p < .05). Significant difference in pitch and melody discrimination tests between age at implantation <5 and >5 groups was found. There were significant correlations between perception of consonants, tones, and speech in a noisy environment and perception of music pitch and melody. Conclusion and SignificancePrelingually deaf pediatric CI users who received implantation before the age of five perform better in music perception tests. Pediatric CI users with better music perception show better auditory speech perception of Mandarin.

Abstract Objective We aimed to evaluate the genotype–phenotype relationship in two Chinese family members with enlarged vestibular aqueduct (EVA). Methods We collected blood samples and clinical data from each pedigree family member. Genomic DNA was isolated from peripheral leukocytes using standard methods. Targeted next‐generation sequencing and Sanger sequencing were performed to find the pathogenic mutation in this family. Minigene assays were used to verify whether the novel intronic mutation SLC26A4c.765+4A>G influenced mRNA splicing. Results Hearing loss in the patients with EVA was diagnosed using auditory tests and imaging examinations. Two pathogenic mutations, c.765+4A>G and c.919‐2A>G were detected in SLC26A4. In vitro minigene analysis confirmed that c.765+4A>G variant could cause aberrant splicing, resulting in skipping over exon 6. Conclusions The SLC26A4c.765+4A>G mutation is the causative variant in the Chinese family with EVA. Particular attention should be paid to intronic variants.

BACKGROUND:SLC26A4 gene mutations related to hearing loss patients can obtain good hearing and speech rehabilitation effects after cochlear implantation (CI). OBJECTIVE:To explore the long-term rehabilitative outcomes of CI in patients with different SLC26A4 mutation groups. MATERIAL AND METHODS:Clinical data of 71 patients with SLC26A4 gene mutations who received CI in the Second Hospital of Lanzhou University from 2012 to 2015 were retrospectively reviewed. According to the genetic test results, use One-way ANOVA analysis to compare the differences in auditory results, categories of auditory performance (CAP) and speech intelligibility rating (SIR) index questionnaire scores and speech recognition rates among different groups in 4-5 years after CI. RESULT:Compared with other genotypes of SLC26A4, the patients with homozygous mutation of c.919-2A > G in SLC26A4 had better hearing aid threshold at 500 Hz and better recognition rates of Yangyang words than other monoallelic mutation groups after CI (p < .05). CONCLUSIONS AND SIGNIFICANCE:The most common hot spot mutation of SLC26A4 gene is c.919-2A > G. The patients with homozygous mutation of c.919-2A > G in SLC26A4 gene had partly better hearing and speech rehabilitation than other monoallelic mutation groups after CI.

Covalent organic frameworks (COFs) have emerged as promising drug carriers due to their structural variability, inherent porosity, and customizable functions. However, most COFs used in drug delivery suffer from low cellular bioavailability and poor luminescence properties. In this study, we designed a series of size-tunable, crystalline, and red-fluorescent COF nanospheres (COFNSs) for trackable anticancer drug delivery. The semiconducting COFNSs were prepared by condensations of 1,3,5-triformylbenzene (TFB) with various dihydrazide blocks through the Schiff-base reaction, resulting in red emission at 647 nm and excellent fluorescence stability (∼100% for 1 h). Such fluorescence property allowed for systematic investigation of the cellular endocytosis pathway of COFNSs, visualization of drug delivery, and observation of the cell apoptosis process. The COFNSs exhibited high cell viability (>90%), a loading capacity of 183 wt % for the anticancer drug camptothecin (CPT), and significant enhancement in inhibiting 4T1 cancers both in vitro and in vivo as the CPT nanocarrier. This progress presents a valuable approach to design COF nanocarriers with integrated fluorescent and drug delivery functions.

Objectives To evaluate the mental health of paediatric cochlear implant users and analyse the relationship between six dimensions (movements, cognitive ability, emotion and will, sociality, living habits and language) and hearing and speech rehabilitation. Methods Eighty-two cochlear implant users were assessed using the Mental Health Survey Questionnaire. Age at implantation, time of implant use and listening modes were investigated. Categories of Auditory Performance and the Speech Intelligibility Rating Scale were used to score hearing and speech abilities. Results More recipients scored lower in cognitive ability and language. Age at implantation was statistically significant ( p < 0.05) for movements, cognitive ability, emotion and will, and language. The time of implant usage and listening mode indicated statistical significance ( p < 0.05) in cognitive ability, sociality and language. Conclusion Timely attention should be paid to the mental health of paediatric cochlear implant users, and corresponding psychological interventions should be implemented to make personalised rehabilitation plans.

As the most common cause of speech disorders, the etiological study of deafness is important for the diagnosis and treatment of deafness. The mitochondrial genome has gradually become a hotspot for deafness genetic research. Mitochondria are the core organelles of energy and material metabolism in eukaryotic cells. Human mitochondria contain 20 amino acids, except for tRNALeu and tRNASer, which have 2 iso-receptors, the other 18 amino acids correspond to unique tRNAs one by one, so mutations in any one tRNA may lead to protein translation defects in mitochondria and thus affect their oxidative phosphorylation process resulting in the corresponding disease phenotype. Mitochondrial tRNAs are extensively modified with base modifications that contribute to the correct folding of tRNAs and maintain their stability. Defective mitochondrial tRNA modifications are closely associated with the development of mitochondrial diseases. The in-depth study found that modification defects of mammalian mitochondrial tRNAs are associated with deafness, especially the nucleotide modification defect of mt-tRNA-37. This article reviews the research on mitochondrial tRNAs, nucleotide modification structure of mitochondrial tRNA-37, and nuclear genes related to modification defects to provide new ideas for the etiological study of deafness.

BackgroundCongenital sensorineural hearing loss is a common congenital condition.ObjectivesThe purpose of this study was to assess the correlation between nonverbal mental development and the effect of post-cochlear implant in children.Material and methodsThe study is a retrospective analysis of the CI program implemented at the ENT in the Lanzhou University Second Hospital (China). We reviewed data of 225 children who received CI between 2015 and 2018. Finally, 115 children met the inclusion criteria. Our hospital used The Griffith mental development scales to evaluate the preoperative non-verbal intelligence. The outcome of CI was evaluated using the categories of IT-MAIS, MUSS, CAP and SIR at 2 years after surgery. The associations between the preoperative non-verbal development quotient (DQ) and the postoperative outcomes were analyzed.ResultsPreoperative non-verbal DQ correlates with the long-term postoperative result, especially the Eye-hand co-ordination and Performance DQ.Conclusions and SignificancePreoperative non-verbal intelligence would predict postoperative effect. The single postoperative scale does not fully reflect the postoperative result.

BACKGROUND:Central lucency of the bony island of the lateral semicircular canal (LSCC) is commonly found in patients with congenital severe-to-profound sensorineural hearing loss (SNHL).OBJECTIVE:Exploring the significance of bony island lucency of LSCC in congenital severe-to-profound SNHL patients.MATERIAL AND METHODS:Retrospective measurements of the inner ear structures were made on axial temporal bone CT scans from 182 (364 ears) congenital severe-to-profound SNHL patients and 50 (100 ears) tympanic membrane perforation (TMP) patients.RESULTS:The incidence of bony island lucency of LSCC was 46.7% in the congenital severe-to-profound SNHL group and 0% in the TMP group. There was a statistically significant difference in inner ear structures among congenital severe-to-profound SNHL patients with normal inner ear structure and bony island lucency of LSCC, congenital severe-to-profound SNHL patients with normal inner ear structure and no bony island lucency of LSCC, and TMP patients. The importance of the bony island lucency of LSCC was further confirmed through multiple linear regression analysis.CONCLUSIONS AND SIGNIFICANCE:Bony island lucency may have significance in congenital severe-to-profound SNHL and may be a manifestation of largely overlooked SCC malformation or hypoplasia of the inner ear.