Clinical and genetic architecture of a large cohort with auditory neuropathy.

Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort. In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients), and 14 genes were mutated in two or more patients. Among subgroups of patients with AN, the prevalence of pathogenic and likely pathogenic variants was 54.4% and 56.2% in trios and families, while 22.9% in the cases with proband-only; 45.7% and 25.6% in the infant and non-infant group; and 33.7% and 0% in the bilateral and unilateral AN cases. Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group; other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups. In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss. The subgroups with different onset ages showed different genetic spectrums, so did bilateral and unilateral groups and sporadic and familial or trio groups.

Pure tone audiogram classification using deep learning techniques.

OBJECTIVE: Pure tone audiometry has played a critical role in audiology as the initial diagnostic tool, offering vital insights for subsequent analyses. This study aims to develop a robust deep learning framework capable of accurately classifying audiograms across various commonly encountered tasks. DESIGN, SETTING, AND PARTICIPANTS: This single-centre retrospective study was conducted in accordance with the STROBE guidelines. A total of 12 518 audiograms were collected from 6259 patients aged between 4 and 96 years, who underwent pure tone audiometry testing between February 2018 and April 2022 at Tongji Hospital, Tongji Medical College, Wuhan, China. Three experienced audiologists independently annotated the audiograms, labelling the hearing loss in degrees, types and configurations of each audiogram. MAIN OUTCOME MEASURES: A deep learning framework was developed and utilised to classify audiograms across three tasks: determining the degrees of hearing loss, identifying the types of hearing loss, and categorising the configurations of audiograms. The classification performance was evaluated using four commonly used metrics: accuracy, precision, recall and F1-score. RESULTS: The deep learning method consistently outperformed alternative methods, including K-Nearest Neighbors, ExtraTrees, Random Forest, XGBoost, LightGBM, CatBoost and FastAI Net, across all three tasks. It achieved the highest accuracy rates, ranging from 96.75% to 99.85%. Precision values fell within the range of 88.93% to 98.41%, while recall values spanned from 89.25% to 98.38%. The F1-score also exhibited strong performance, ranging from 88.99% to 98.39%. CONCLUSIONS: This study demonstrated that a deep learning approach could accurately classify audiograms into their respective categories and could contribute to assisting doctors, particularly those lacking audiology expertise or experience, in better interpreting pure tone audiograms, enhancing diagnostic accuracy in primary care settings, and reducing the misdiagnosis rate of hearing conditions. In scenarios involving large-scale audiological data, the automated classification system could be used as a research tool to efficiently provide a comprehensive overview and statistical analysis. In the era of mobile audiometry, our deep learning framework can also help patients quickly and reliably understand their self-tested audiograms, potentially encouraging timely consultations with audiologists for further evaluation and intervention.

NRF2/HO-1 pathway activation by ATF3 in a noise-induced hearing loss murine model.

BACKGROUND: Excessive oxidative stress of the inner ear as a result of high, intense noise exposure is regarded as a major mechanism underlying the development of noise-induced hearing loss (NIHL). The present study was designed to explore the effect and mechanism of activated transcription factor 3 (ATF3) in reduction/oxidation homeostasis of NIHL. METHOD: In vitro and in vivo assays were performed to investigate the functional role of ATF3 in the inner ear. Mice hearing was measured using auditory brainstem response. ATF3 short hairpin RNA (shRNA) was transfected into House Ear Institute-Organ of Corti 1 (HEI-OC1) cells to decrease ATF3 expression. Western blotting and quantitative real-time polymerase chain reaction (RT-qPCR) were performed to quantify ATF3, NRF2, HO-1 and NQO1 expression. Glutathione (GSH) assay was performed to detect intracellular GSH levels. ATF3 immunofluorescence analysis was carried out in cochlear cryosectioned samples and HEI-OC1 cells to localize ATF3 expression. Cell counting kit 8 assay and flow cytometry were performed to analyze cell viability. RESULT: ATF3 was upregulated in noise-exposed cochleae and HEI-OC1 cells treated with H2O2. NRF2 is a key factor regulated by ATF3. NRF2, HO-1, NQO1, and GSH expression was significantly downregulated in shATF3 HEI-OC1 cells. ATF3 silencing promoted reactive oxygen species accumulation and increased apoptosis and necrosis with H2O2 stimulus. CONCLUSION: ATF3 functions as an antioxidative factor by activating the NRF2/HO-1 pathway.

Presence of diabetes mellitus affects vertigo outcome in vestibular migraine.

OBJECTIVE: To investigate the association of diabetes mellitus (DM) with vertigo outcome in patients with vestibular migraine (VM). METHODS: Two hundred and thirty-four patients with VM were consecutively enrolled between October 2018 and January 2020 in a tertiary teaching medical center. Multivariable linear regression model and stratified analyses were used to explore the relationship between diabetes and vertigo outcome, which was measured by the visual analogue scale (VAS). RESULTS: Patients with diabetes were more likely to have poorer sleep quality and more severe vertigo symptoms measured by VAS at the follow-up than those without diabetes. After adjusting for potential confounders, presence of diabetes was significantly linked with poorer final vertigo VAS score (ß, 95 % confidence interval [CI]: 1.0 [0.1, 2.0]). This association was only significant for female patients with VM (ß, 95%CI: 1.2 [0.2, 2.3], p = 0.0244). CONCLUSIONS: Presence of diabetes was independently and inversely corrected with the vertigo outcome in women with VM. Our findings suggest that diabetes is likely a negative prognosticator of vertigo outcome in VM.

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population.

To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by AIFM1 variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with AIFM1 variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that AIFM1-positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with AIFM1 variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 AIFM1 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported AIFM1-positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75 ± 9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in AIFM1-related AN and affects females. In conclusion, we confirmed that AIFM1 is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of AIFM1-related AN, with females affected. Phenotypical features of AIFM1-related AN suggested that auditory dyssynchrony progressively worsened over time.

Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus.

BACKGROUND: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. METHODS: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. RESULTS: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. CONCLUSION: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

An infrared spectroscopic and theoretical study on (CH3)3N-H(+)-(H2O)(n), n = 1-22: highly polarized hydrogen bond networks of hydrated clusters.

Infrared spectra of protonated trimethylamine (TMA)-water clusters, (CH3)3N-H(+)-(H2O)n (n = 1-22) were measured in the OH stretching vibrational region by size-selective photodissociation spectroscopy. Density functional theory calculations of stable structures were performed, and temperature dependence of the isomer populations and infrared spectra was also simulated by the harmonic superposition approximation approach to analyze hydrogen bond network structures in the clusters. It was shown that the excess proton (H(+)) in this system localizes on the TMA moiety regardless of cluster size. In the small-sized clusters, many isomers coexist and their hydrogen bond networks are highly polarized to induce the large charge-dipole interaction to stabilize the excess proton. Magic number behavior is not observed at around the magic number size (n = 21) of protonated water clusters and its implication on the hydrogen bond network structures is discussed.

Relationships between the Pittsburgh Sleep Quality Index (PSQI) and vertigo outcome.

OBJECTIVE: This retrospective cohort study aimed to investigate the association of sleep characteristics measured by the Pittsburgh Sleep Quality Index (PSQI) with the vertigo outcome in vertiginous patients with comorbid cardiometabolic diseases. METHODS: Four hundred and thirteen patients with comorbid cardiometabolic diseases who consecutively visiting vertigo and dizziness clinic were enrolled between October 2018 and January 2020 in a tertiary teaching medical center. Regression analyses and stratified analyses were used to explore the relationship between PSQI and vertigo outcome, which was measured by the visual analogue scale (VAS) score. RESULTS: In the study sample, 73.8% (305/413) were defined as 'poor sleep' (PSQI>5). Participants with better recovery tended to have better baseline PSQI global score, PSQI sleep quality, PSQI sleep onset latency, PSQI daytime dysfunction, less severe baseline vertigo symptoms indicated by VAS, Vertigo Symptom Scale (VSS) and Dizziness Handicap Inventory (DHI) scores. Moreover, baseline PSQI global score and PSQI daytime dysfunction score were independently associated with the vertigo VAS scores at the last follow-up. CONCLUSION: The present results clearly indicated that poor sleep is common and inversely associated with vertigo outcome in vertiginous patients with co-morbid cardiometabolic diseases. Therefore, sleep deserves greater attention in the total medical care in specific subgroup of vertiginous patients.

Clinical features and prognosis of pediatric idiopathic sudden sensorineural hearing loss: A bi-center retrospective study.

Objective: Limited research has focused on the clinical features of sudden sensorineural hearing loss (SSNHL) in pediatric patients. This study is aimed to investigate the relationship between clinical features and the baseline hearing severity and outcomes of SSNHL in the pediatric population. Method: We conducted a bi-center retrospective observational study in 145 SSNHL patients aged no more than 18 years who were recruited between November 2013 and October 2022. Data extracted from medical records, audiograms, complete blood count (CBC) and coagulation tests have been assessed for the relationship with the severity (the thresholds of the initial hearing) and outcomes (recovery rate, hearing gain and the thresholds of the final hearing). Results: A lower lymphocyte count (P = 0.004) and a higher platelet-to-lymphocyte ratio (PLR) (P = 0.041) were found in the patient group with profound initial hearing than in the less severe group. Vertigo (ß = 13.932, 95%CI: 4.082-23.782, P = 0.007) and lymphocyte count (ß = -6.686, 95%CI: -10.919 to -2.454, P = 0.003) showed significant associations with the threshold of the initial hearing. In the multivariate logistic model, the probability of recovery was higher for patients with ascending and flat audiograms compared to those with descending audiograms (ascending: OR 8.168, 95% CI 1.450-70.143, P = 0.029; flat: OR 3.966, 95% CI 1.341-12.651, P = 0.015). Patients with tinnitus had a 3.2-fold increase in the probability of recovery (OR 3.222, 95% CI 1.241-8.907, P = 0.019), while the baseline hearing threshold (OR 0.968, 95% CI 0.936-0.998, P = 0.047) and duration to the onset of therapy (OR 0.942, 95% CI 0.890-0.977, P = 0.010) were negatively associated with the odds of recovery. Conclusions: The present study showed that accompanying tinnitus, the severity of initial hearing loss, the time elapse and the audiogram configuration might be related to the prognosis of pediatric SSNHL. Meanwhile, the presence of vertigo, lower lymphocytes and higher PLR were associated with worse severity.

Expression patterns of Ca(V)1.3 channels in the rat cochlea.

Although Ca(V)1.3 channels are known to be essential for neuronal excitation and signal transduction in the auditory system, their expression patterns in the cochlea are still not fully understood, particularly in the regions where non-sensory cells are located. We performed immunohistochemistry, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) to identify the expression and distribution of Ca(V)1.3 channels in the rat cochlea. Immunohistochemistry revealed that Ca(V)1.3 channels were localized in the outer hair cells (OHCs), inner hair cells (IHCs), limbus laminae spiralis, spiral ganglion cell, spiral ligament (SL), and stria vascularis (STV). The results of RT-PCR and western blotting demonstrated Ca(V)1.3 channels had a tissue-specific expression pattern. Ca(V)1.3 mRNA and protein were intensively expressed in the basilar membrane and spiral ganglion while moderate level of Ca(V)1.3 channels was observed in SL and STV. Our study preliminarily revealed the expression patterns of Ca(V)1.3 channels in the rat cochlea, providing a theoretical basis for further research on the role of Ca(V)1.3 channels in the periphery auditory system.

[Applying a rigid curved video laryngoscope in laryngeal microsurgery of patients with difficult laryngeal exposure].

Objective:To test the feasibility of a rigid curved video laryngoscope in laryngeal microsurgery of patients with difficult laryngeal exposure. Methods:Thirteen patients with difficult laryngeal exposure underwent microlayngeal surgery using a new-design rigid curved video laryngoscope. The clinical data were collected and analyzed. Results:In all of the 13 patients with difficult laryngeal exposure,the fully exposure rate of glottis was 100% using a new-design rigid curved laryngoscope.But only 7 precise surgeries using our rigid curved instruments were completed successfully. Conclusion:Rigid curved laryngoscope is a useful tool to in treating patients with difficult laryngeal exposure in microlaryngeal surgery. Satisfactory glottis exposure, magnified surgical field and precise maneuver of the lesions could be achieved. But manipulation of this tool is challenging, which warrants further investigation．.

New Target of Oxidative Stress Regulation in Cochleae: Alternative Splicing of the p62/Sqstm1 Gene.

We investigated oxidative stress and antioxidant response in the p62/Sqstm1-Keap1-Nrf2 pathway in C57BL/6 mice cochleae during age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL), and the function of full-length and variant p62 in the regulation of Nrf2 activation. Groups of young (2 months), old (13-14 months), control, and acoustic trauma (AT) mice were examined cochlear damage and oxidative stress as follows: auditory brainstem response and hair cell counts; malondialdehyde (MDA) levels measured by assay kit and 7,8-dihydro-8-oxoguanine (8-oxoG) detected by immunohistochemistry. Full-length and variant p62 were examined for expression in cochleae, hippocampus (HIP), and auditory cortex (AC) using immunoblotting. Keap1-Nrf2 pathway activation was based on immunoblotting of nuclear Nrf2 and quantitative real-time PCR of Nrf2 target genes HO-1/NQO-1. The oxidative function of full-length and variant p62 was examined in HEI-OC-1 cells by flow cytometry. The results showed hearing loss, and cochlear hair cell loss was associated with MDA accumulation and 8-oxoG expression during ARHL and NIHL. Nrf2 showed no obvious changes in nuclear protein. Expression levels mRNA for HO-1 and NQO1 were lower in old mice and mildly greater in AT Mice. The expression of p62 splicing variant lacking the Keap1-interacting region was greater than full-length p62 in cochleae. However, the expression of p62 splicing variant was lesser than full-length p62 in HIP and AC. For HEI-OC-1 cells, overexpression of full-length p62 decreased ROS levels induced by H2O2. Oxidative stress is closely related to ARHL and NIHL. Changing the ratio of full-length to variant p62 protein expression may be a new target to reduce the level of oxidative stress in cochleae.

Protocol for assessing auditory brainstem response in mice using a four-channel recording system.

Evaluating auditory sensitivity is critical to hearing research, particularly to that focusing on hearing impairment. Auditory brainstem response recording is frequently used in mice to assess auditory sensitivity and is an approach superior to the traditional techniques. Here, we describe a protocol for recording ABR in mice using four-channel equipment. We detail the procedures of animal preparation, the setup of the ABR recording system, the click- and tone burst-evoked ABR recordings, and data analysis.

Comparisons of Supine Roll Test and Alternative Positional Tests in HC-BPPV Lateralization.

OBJECTIVE: The purpose of the study was to evaluate the efficiency of the supine roll test (SRT) and alternative positional tests (APTs) including the bow and lean test (BLT), pseudo-spontaneous nystagmus (PSN), and lying down nystagmus (LDN) to identify the affected side in horizontal canal benign paroxysmal positional vertigo (HC-BPPV). METHODS: In our prospective study, we performed a testing profile (PSN, BLT, LDN, SRT) on 59 HC-BPPV patients using videonystagmography. We compared the accuracy and sensitivity of these tests in HC-BPPV lateralization. Data from 30 healthy patients were collected as the control group. RESULTS: When performing positional tests, the elicited nystagmus coinciding with Ewald's second law was defined as a "positive response". In 44 patients with geotropic nystagmus, the rates of positive response in LDN, PSN, and BLT were 22/44 (50%), 19/44 (43%), and 18/44 (41%), respectively, while in 15 patients with apogeotropic nystagmus, the positive response rates of these three tests were 10/15 (66.7%), 9/15 (60%), and 4/15 (27.00%), respectively. The sensitivity of LDN (54.38%) was higher than that of PSN (47.37%) and BLT (38.60%) but lower than that of SRT (89.47%). Notably, the accuracy rate of PSN (71.8%) was higher than that of the other APTs. In 6 patients with symmetrical nysgtamus during the roll test, 5 patients showed a positive response in both LDN and BLT (83.34%), whereas 4 patients showed a positive response in PSN (66.67%). CONCLUSION: All positional tests are helpful for determining the affected side of HC-BPPV, but SRT carries the highest accuracy of lateralization followed by PSN.

Development of peroxynitrite-responsive fluorescence probe for recognition of drug-induced liver injury.

Peroxynitrite (ONOO-) as an active substance, is produced during normal physiological process, which plays an important role in maintaining cell REDOX balance and cell function. Moreover, the peroxynitrite is involved in many diseases and especially can be used as a biomarker of drug-induced liver injury (DILI). Therefore, in this work, we synthesized a fluorescent probe JQ-3 for detecting ONOO-. The results showed the probe JQ-3 possessed excellent selectivity, fast response time (10 min) and low detection limit (32 nM). The probe JQ-3 is almost unaffected by pH, showing the potential application in biological systems. Moreover, the probe JQ-3 can be successfully used for the detection of exogenous and endogenous ONOO- in living cells and zebrafish. At the same time, the DILI was successfully recognized by visualizing ONOO- with JQ-3 in living cells and zebrafish. Therefore, the probe JQ-3 provides a potential tool for detecting ONOO- to understand physiological and pathology processes of disease.

Identification and Validation of Prognostic Factors of Lipid Metabolism in Obstructive Sleep Apnea.

Background: Obstructive sleep apnea (OSA) is considered to be an independent factor affecting lipid metabolism. This study explored the relationship between immune genes and lipid metabolism in OSA. Methods: Immune-related Differentially Expressed Genes (DEGs) were identified by analyzing microarray data sets from the Gene Expression Omnibus (GEO) database. Subsequently, we conducted protein-protein interaction (PPI) network analysis and calculated their Gene Ontology (GO) semantic similarity. The GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, Disease Ontology (DO), gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were employed for functional enrichment analyses and to determine the most significant functional terms. Combined with the results of boruta and random forest, we selected predictors to build a prognostic model, along with seeking out the potential TFs and target drugs for the predictive genes. Results: Immune-related DEGs included 64 genes upregulated and 98 genes downregulated. The enrichment analysis might closely associate with cell adhesion and T cell-mediated immunity pathways and there were many DEGs involved in lipid and atherosclerosis signaling pathways. The highest-ranking hub gene in PPI network have been reported lowly expressed in OSA. In line with the enrichment analysis, DO analysis reveal that respiratory diseases may be associated with OSA besides immune system disorders. Consistent with the result of the KEGG pathway, the analysis of GSVA revealed that the pro-inflammation pathways are associated with OSA. Monocytes and CD8 T cells were the predominant immune cells in adipose tissue. We built a prognostic model with the top six genes, and the prognostic genes were involved in the polarization of macrophage and differentiation of T lymphocyte subsets. In vivo experimental verification revealed that EPGN, LGR5, NCK1 and VIP were significantly down-regulated while PGRMC2 was significantly up-regulated in mouse model of OSA. Conclusions: Our study demonstrated strong associations between immune genes and the development of dyslipidemia in OSA. This work promoted the molecular mechanisms and potential targets for the regulation of lipid metabolism in OSA.

Analysis of thyroid dysfunction in patients with sudden sensorineural hearing loss.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) refers to the sudden occurrence of unexplained sensorineural hearing loss. The present study showed that different systemic diseases had different influence on the occurrence and hearing outcome of SSHL. Thyroid hormone is one of the important factors for the development of fetal ear and auditory function. However, the distribution of thyroid dysfunction in SSHL patients and the effect of thyroid dysfunction on the occurrence and hearing outcome of SSHL has not been studied. METHODS: In this study, a retrospective analysis had been done in 676 patients with SSHL. We had described the distribution of thyroid function in patients with SSHL in detail, and by the statistical method, analyzed the relationship between the hearing outcome and thyroid dysfunction, respectively. RESULTS: In all patients, 24.41% (165/676) had abnormal thyroid function testing results. The onset age of SSHL in FT3 abnormal group (including low and high group) was younger than that in normal FT3 group. Recovery group had more patients with lower-than-normal T3 level as compared to non-recovery patients. Significant associations between T3 levels and hearing outcome were observed in the subgroup with longer time elapse between symptom onset and treatment (≥14 d). CONCLUSION: The incidence of thyroid dysfunction in SSHL is significantly higher than in the general population. There was obvious relationship between T3 and FT3 item of thyroid dysfunction and the onset time and hearing outcome of SSHL, which indicated that T3 or FT3 indicator may be one of the affecting factors for the SSHL. Early screening and diagnosis of thyroid dysfunction, especial T3 level, may help to evaluate the prognosis in SSHL patients.

Expression of α2-Na/K-ATPase in C57BL/6J Mice Inner Ear and Its Relationship with Age-related Hearing Loss.

K+ cycling in the cochlea is critical to maintain hearing. Many sodium-potassium pumps are proved to participate in K+ cycling, such as Na/K-ATPase. The α2-Na/K-ATPase is an important isoform of Na/K-ATPase. The expression of α2-Na/K-ATPase in the cochlea is not clear. In this study, we used C57BL/6 mice as a model of presbycusis and implemented immunohistochemistry staining and quantitative real time-PCR, and the α2-Na/K-ATPase expression pattern was confirmed in the inner ear. It was found α2-Na/K-ATPase was expressed widely in cochlea and its mRNA and protein expression was gradually reduced with aging (4-, 14-, 26- and 48-weeks old mice). We suspected that, the down-regulation of α2-Na/K-ATPase expression might be associated with the remodeling of K+ cycling, degeneration of morphological structure and decrease of hearing function in aging C57 mice. In conclusion, we speculated that the reduction of α2-Na/K-ATPase might play an important role in the pathogenesis of age-related hearing loss.

Anticooperative effect induced by mixed solvation in H+ (CH3OH)m(H2O)n (m + n = 5 and 6): a theoretical and infrared spectroscopic study.

When a solvent molecule is replaced by another molecule with larger proton affinity, the strength of all other hydrogen bonds decreases. This is the concept of anticooperativity by successive substitution in a mixed solvation system. In the present study, this concept is demonstrated in H(+)(CH(3)OH)(m)(H(2)O)(n) (m + n = 5 and 6) mixed clusters by a joint theoretical and infrared (IR) spectroscopic approach. The observed IR spectra of the mixed clusters exhibit two high-frequency shifts of hydrogen-bonded OH stretch bands with increasing methanol content. These trends are well reproduced by first-principle IR spectra simulated by thermal averaging over a set of configurational isomers under the quantum harmonic superposition approach. Theoretical analysis on the magnitude of charge transfer from the protonated site to the solvent molecules is found to be in agreement with the spectroscopic measurement that the individual hydrogen bond in the mixed clusters is weakened with an increase of the mixing ratio of methanol to water.

Comprehensive analysis on the structure and proton switch in H+ (CH3OH)m(H2O)n (m + n = 5 and 6).

Theoretical and experimental methods were integrated to investigate the structures of H(+)(CH(3)OH)(m)(H(2)O)(n) clusters for m + n = 5 and 6. An effective theoretical approach is presented to search for extensive sets of structural isomers using an empirical model and substitution schemes. Stable isomers were then reoptimized by the B3LYP level of computations with the 6-31+G* basis set. Canonical averages of these structural isomers were analyzed by harmonic superposition approximation (HSA) to study their finite temperature behavior and enable quantitative comparisons with experimental results. Thermal energy is found to have a significant effect on the structure of these clusters. Our calculations show that cyclic isomers are preferred at low temperature, while linear and tree forms become more favorable at high temperature (>200 K). Furthermore, we found that proton can reside on both water and methanol ion cores and the proton switch is associated with morphology change. Experimental IR spectra in the free OH stretching region were also obtained and compared with calculated spectra.