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Traditionally, the cochlea has been considered as an immunological privileged site, as the blood-labyrinth barrier provides isolation from the systemic immune system. However, the presence of immune cells in the cochlea has been recently reported, suggesting that immune-mediated processes can play a crucial role within the auditory system. In this context, both protective and detrimental T-cell functions have been linked to normal hearing and hearing loss, respectively, thereby emphasizing the dual role of T cells in cochlear health. Current knowledge also suggests that a balanced presence and activity of T cells is crucial for tissue homeostasis in the cochlea, avoiding pathologies such as age-related hearing loss and autoimmune inner ear diseases. Although cochlea-resident T cells are scarce under physiological conditions, the number of T cells appear to rise in response to acoustic trauma revealing the active recruitment of peripheral immune cells through cochlear blood vessels. In order to evaluate the induction of a peripheral inflammatory response upon noise trauma, we exposed mice to excessive noise (115 dB) for two hours. Hearing levels were determined 72 h and 1 week after noise-exposure, which revealed a substantial increase in hearing thresholds in all mice. To evaluate if the auditory stimulation would trigger a peripheral immune response we isolated splenocytes and analyzed cytokine production in different immune subsets by high parametric flow cytometry. The analyses revealed increased activation of both CD4+ and CD8+ T cells, illustrated by significant increases in the expression of INF-γ, TNF and CD44. These data suggest a peripheral component in the elevated inflammatory response following acoustic trauma. Future research will be performed to explore the link between noise-induced hearing loss, peripheral inflammation and more specifically antigen-specificity of the observed increase in activated CD4+ and CD8+ T-cell populations. [ABSTRACT FROM AUTHOR]

The c.151C>T (p.P51S) mutation in COCH is highly prevalent in the Dutch/Belgian population and causes DFNA9 (hearing loss and vestibular dysfunction) in > 1500 individuals. The initial symptoms manifest between the 3rd and 5th decade of life, which leaves ample time for therapeutic intervention. The clear non-haploinsufficiency disease mechanism indicates that blocking or reducing the p.P51S mutant cochlin protein levels may alleviate or prevent the DFNA9 phenotypes. Considering the broad expression of COCH by the fibrocytes of the inner ear, we designed "gapmer" antisense oligonucleotides (ASO) to specifically induce RNase H1-mediated degradation of COCH transcripts containing the c.151C>T mutation. We established several model systems to investigate the molecular efficacy of ASOs targeting the c. 151C>T mutation or low-frequency mutant allele-specific SNPs. Using overexpression models, we identified several ASOs that efficiently induce the degradation of mutant COCH transcripts. By introducing chemical modification to the oligonucleotide bases, we can alter the affinity and selectivity for the mutation transcript. We identified several ASOs with a strong preference for the mutant transcript in overexpression models. To investigate allele-specificity under physiological expression levels, we exposed patient-derived otic progenitor cells (iPCS-OPCs) to different ASOs for 8 days. In parallel, we developed a genetically humanized mouse model for DFNA9 in which human sequence-specific therapeutic strategies can be evaluated. Phenotypic follow-up of mice of all genotypes indicate that the genetic humanization has no adverse effects, and removal of the Cdh23ahl allele is mandatory to observe the late-onset auditory phenotype: the first signs of high-frequency hearing loss emerged at 12 months of age. Studies in iPSC-OPCs indicated that the ASOs identified in overexpression studies also effectively reduce mutant COCH transcript levels in patient-derived cells with physiological expression levels. Unfortunately, variation between replicate wells of OPC differentiation is relatively high, making it difficult to draw conclusions on allele-specificity. We selected a candidate ASO, directed against a rare mutant allele-spe-cific intronic SNP, for subsequent studies in our humanized mouse model. First intracochlear injections will be conducted in May 2024, after which we can collect the first in vivo data on gapmer ASO uptake and efficacy in fibrocytes of the mammalian inner ear. [ABSTRACT FROM AUTHOR]

The spiral ligament in the cochlea has been suggested to play a significant role in the pathophysiology of sensorineural hearing loss (SNHL). Positioned between the stria vascula-ris and the bony otic capsule, this structure contains spiral ligament fibrocytes (SLFs), categorized into five main types based on their structural characteristics, immunostaining patterns and location within the spiral ligament. Together with the stria vascularis, the SLFs maintain a positive endo-cochlear potential (EP) in the scala media via K+ recycling, which is an essential component in the transduction mechanism of the auditory pathway. It has also been suggested that the SLFs contribute to the cochlear immune response, gluta-mate homeostasis and cochlear blood flow regulation. Spiral ligament damage disrupts K+ recycling, reducing the EP and subsequently causing SNHL. Despite their pivotal roles, a lot remains unknown about the SLFs. Therefore, this systematic review about SLFs in cell culture could give an overview of the current state of the art, providing a basis for future studies trying to investigate those cells in vitro. A literature search was performed using PubMed, Web of Science and Scopus taking into account the PRISMA guidelines. Twenty-five studies were included in this review that report on SLFs in cell culture. The differences in species, sex, age, method of culturing and used antibodies for immunohis-tochemistry are discussed. The majority of these studies cultured spiral ligament fragments onto type I collagen-coated petri dishes; a protocol described by Gratton et al. in 1996, while some recent studies are focussing more on growing these cells in a 3D environment. A better understanding of the currently published methods will help us to optimize fibrocyte culture techniques, thereby allowing to investigate a variety of possibilities that can significantly increase our knowledge about SLFs. Among others, these possibilities include to discover their functional characteristics, such as growth patterns, protein expression profiles and ion channel physiology, to expose the cells to hy-poxia or other toxic conditions and to assess the resulting effects, to genetically modify SLFs, to explore drug repurposing possibilities, to evaluate potential therapies for SNHL and to investigate their capability as a source for transplantable cells. [ABSTRACT FROM AUTHOR]

BackgroundMultiple symptoms of suicide risk have been assessed based on visual and auditory information, including flattened affect, reduced movement, and slowed speech. Objective quantification of such symptomatology from novel data sources can increase the sensitivity, scalability, and timeliness of suicide risk assessment. ObjectiveWe aimed to examine measurements extracted from video interviews using open-source deep learning algorithms to quantify facial, vocal, and movement behaviors in relation to suicide risk severity in recently admitted patients following a suicide attempt. MethodsWe utilized video to quantify facial, vocal, and movement markers associated with mood, emotion, and motor functioning from a structured clinical conversation in 20 patients admitted to a psychiatric hospital following a suicide risk attempt. Measures were calculated using open-source deep learning algorithms for processing facial expressivity, head movement, and vocal characteristics. Derived digital measures of flattened affect, reduced movement, and slowed speech were compared to suicide risk with the Beck Scale for Suicide Ideation controlling for age and sex, using multiple linear regression. ResultsSuicide severity was associated with multiple visual and auditory markers, including speech prevalence (β=−0.68, P=.02, r2=0.40), overall expressivity (β=−0.46, P=.10, r2=0.27), and head movement measured as head pitch variability (β=−1.24, P=.006, r2=0.48) and head yaw variability (β=−0.54, P=.06, r2=0.32). ConclusionsDigital measurements of facial affect, movement, and speech prevalence demonstrated strong effect sizes and linear associations with the severity of suicidal ideation.