The ototoxic drug cisplatin localises to stress granules altering their dynamics and composition.

Cisplatin is an effective platinum-based chemotherapeutic with several side effects, including ototoxicity. Cochlear cells have low rates of proliferation yet are highly susceptible to cisplatin. We hypothesised that cisplatin ototoxicity might be caused by cisplatin-protein interactions rather than cisplatin-DNA interactions.

An emerging role for stress granules in neurodegenerative disease and hearing loss.

Stress granules (SGs) are membrane-less cytosolic assemblies that form in response to stress (e.g., heat, oxidative stress, hypoxia, viral infection and UV).

Targeted deletion of the RNA-binding protein Caprin1 leads to progressive hearing loss and impairs recovery from noise exposure in mice.

Cell cycle associated protein 1 (Caprin1) is an RNA-binding protein that can regulate the cellular post-transcriptional response to stress. It is a component of both stress granules and neuronal RNA granules and is implicated in neurodegenerative disease, synaptic plasticity and long-term memory formation. Our previous work suggested that Caprin1 also plays a role in the response of the cochlea to stress.

An Analysis of US Academic Medical Center Websites: Usability Study.

Background: Health care organizations are tasked with providing web-based health resources and information. Usability refers to the ease of user experience on a website. In this study, we conducted a usability analysis of academic medical centers in the United States, which, to the best of our knowledge, has not been previously carried out.

Differential regulation of mammalian and avian ATOH1 by E2F1 and its implication for hair cell regeneration in the inner ear.

The mammalian inner ear has a limited capacity to regenerate its mechanosensory hair cells. This lack of regenerative capacity underlies the high incidence of age-related hearing loss in humans. In contrast, non-mammalian vertebrates can form new hair cells when damage occurs, a mechanism that depends on re-activation of expression of the pro-hair cell transcription factor Atoh1.

Functional P2X Receptors in the Auditory Nerve of Hearing Rodents Localize Exclusively to Peripheral Glia.

P2X receptors (P2XRs) are associated with numerous pathophysiological mechanisms, and this promotes them as therapeutic targets for certain neurodegenerative conditions. However, the identity of P2XR-expressing cells in the nervous system remains contentious. Here, we examined P2XR functionality in auditory nerve cells from rodents of either sex, and determined their functional and anatomic expression pattern.

COVID-19 Status, Symptom Burden, and Characteristics of Dialysis Patients Residing in Areas of Community Transmission: Research Letter.

Background: Routine testing of hemodialysis patients for COVID-19 (outside of those identified as "at risk" based on regional practice) is not universally recommended. However, there is variability in the clinical presentation of COVID-19; patients may experience symptoms that do not meet regional criteria for testing and some patients with active infection may be asymptomatic. To avoid missing individuals who are infected, consideration could be made for regular screening, particularly among those residing in areas with evidence of community spread.

Bioinspired Multiresonant Acoustic Devices Based on Electrospun Piezoelectric Polymeric Nanofibers.

Cochlear hair cells are critical for the conversion of acoustic into electrical signals and their dysfunction is a primary cause of acquired hearing impairments, which worsen with aging. Piezoelectric materials can reproduce the acoustic-electrical transduction properties of the cochlea and represent promising candidates for future cochlear prostheses. The majority of piezoelectric hearing devices so far developed are based on thin films, which have not managed to simultaneously provide the desired flexibility, high sensitivity, wide frequency selectivity, and biocompatibility.

Homeostatic maintenance and age-related functional decline in the Drosophila ear.

Age-related hearing loss (ARHL) is a threat to future human wellbeing. Multiple factors contributing to the terminal auditory decline have been identified; but a unified understanding of ARHL - or the homeostatic maintenance of hearing before its breakdown - is missing. We here present an in-depth analysis of homeostasis and ageing in the antennal ears of the fruit fly Drosophila melanogaster.

Multiphoton NAD(P)H FLIM reveals metabolic changes in individual cell types of the intact cochlea upon sensorineural hearing loss.

An increasing volume of data suggests that changes in cellular metabolism have a major impact on the health of tissues and organs, including in the auditory system where metabolic alterations are implicated in both age-related and noise-induced hearing loss. However, the difficulty of access and the complex cyto-architecture of the organ of Corti has made interrogating the individual metabolic states of the diverse cell types present a major challenge. Multiphoton fluorescence lifetime imaging microscopy (FLIM) allows label-free measurements of the biochemical status of the intrinsically fluorescent metabolic cofactors NADH and NADPH with subcellular spatial resolution.

Drug-induced Stress Granule Formation Protects Sensory Hair Cells in Mouse Cochlear Explants During Ototoxicity.

Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death.

Perinatal Ischemia Alters Global Expression of Synaptosomal Proteins Critical for Neural Plasticity in the Developing Mouse Brain.

Ischemic perinatal stroke (IPS) affects 1 in 2,300-5,000 live births. Despite a survival rate >95%, approximately 60% of IPS infants develop motor and cognitive impairments. Given the importance of axonal growth and synaptic plasticity in neurocognitive development, our objective was to identify the molecular pathways underlying IPS-associated synaptic dysfunction using a mouse model.

Intercellular Ca signalling in the adult mouse cochlea.

Key Points: Intercellular Ca waves are increases in cytoplasmic Ca levels that propagate between cells. Periodic Ca waves have been linked to gene regulation and are thought to play a crucial role in the development of our hearing epithelium, the organ of Corti and the acquisition of hearing. We observed regular periodic intercellular Ca waves in supporting cells of an ex vivo preparation of the adult mouse organ of Corti, and these waves were found to propagate independently of extracellular ATP and were inhibited by the gap junction blockers 1-octanol and carbenoxolone.

Protecting Mammalian Hair Cells from Aminoglycoside-Toxicity: Assessing Phenoxybenzamine's Potential.

Aminoglycosides (AGs) are widely used antibiotics because of their low cost and high efficacy against gram-negative bacterial infection. However, AGs are ototoxic, causing the death of sensory hair cells in the inner ear. Strategies aimed at developing or discovering agents that protect against aminoglycoside ototoxicity have focused on inhibiting apoptosis or more recently, on preventing antibiotic uptake by the hair cells.

Generation of sensory hair cells by genetic programming with a combination of transcription factors.

Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. Elucidation of the transcriptional networks regulating HC fate determination and differentiation is crucial not only to understand inner ear development but also to improve cell replacement therapies for hearing disorders. Here, we show that combined expression of the transcription factors Gfi1, Pou4f3 and Atoh1 can induce direct programming towards HC fate, both during in vitro mouse embryonic stem cell differentiation and following ectopic expression in chick embryonic otic epithelium.

Cellular glutathione content in the organ of Corti and its role during ototoxicity.

Glutathione (GSH) is the major scavenger of reactive oxygen species (ROS) inside cells. We used live confocal imaging in order to clarify the role of GSH in the biology of the organ of Corti, the sensory epithelium of the cochlea, before, during and after the onset of hearing and in ~1 year old mice. GSH content was measured using monochlorobimane (MCB), a non-fluorescent cell permeant bimane that reacts with GSH, forming a fluorescent adduct through a reaction catalyzed by glutathione-S-transferase.

Regulation of the orphan nuclear receptor Nr2f2 by the DFNA15 deafness gene Pou4f3.

Hair cells are the mechanotransducing cells of the inner ear that are essential for hearing and balance. POU4F3--a POU-domain transcription factor selectively expressed by these cells--has been shown to be essential for hair cell differentiation and survival in mice and its mutation in humans underlies late-onset progressive hearing loss (DFNA15). The downstream targets of POU4F3 are required for hair cell differentiation and survival.

Separating NADH and NADPH fluorescence in live cells and tissues using FLIM.

NAD is a key determinant of cellular energy metabolism. In contrast, its phosphorylated form, NADP, plays a central role in biosynthetic pathways and antioxidant defence. The reduced forms of both pyridine nucleotides are fluorescent in living cells but they cannot be distinguished, as they are spectrally identical.

Epithelial repair is a two-stage process driven first by dying cells and then by their neighbours.

Epithelial cells maintain an essential barrier despite continuously undergoing mitosis and apoptosis. Biological and biophysical mechanisms have evolved to remove dying cells while maintaining that barrier. Cell extrusion is thought to be driven by a multicellular filamentous actin ring formed by neighbouring cells, the contraction of which provides the mechanical force for extrusion, with little or no contribution from the dying cell.

Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: evidence against cis-inhibition.

The formation of the salt-and-pepper mosaic of hair cells and supporting cells in the sensory epithelia of the inner ear is regulated by Notch signalling and lateral inhibition, but the dynamics of this process and precise mode of action of delta-like 1 (Dll1) in this context are unclear. Here, we transfected the chicken inner ear with a fluorescent reporter that includes elements of the mammalian Hes5 promoter to monitor Notch activity in the developing sensory patches. The Hes5 reporter was active in proliferating cells and supporting cells, and Dll1 expression was highest in prospective hair cells with low levels of Notch activity, which occasionally contacted more differentiated hair cells.

Live-cell delamination counterbalances epithelial growth to limit tissue overcrowding.

The development and maintenance of an epithelium requires finely balanced rates of growth and cell death. However, the mechanical and biochemical mechanisms that ensure proper feedback control of tissue growth, which when deregulated contribute to tumorigenesis, are poorly understood. Here we use the fly notum as a model system to identify a novel process of crowding-induced cell delamination that balances growth to ensure the development of well-ordered cell packing.

Caprin-1 is a target of the deafness gene Pou4f3 and is recruited to stress granules in cochlear hair cells in response to ototoxic damage.

The POU4 family of transcription factors are required for survival of specific cell types in different sensory systems. Pou4f3 is essential for the survival of auditory sensory hair cells and several mutations in human POU4F3 cause hearing loss. Thus, genes regulated by Pou4f3 are likely to be essential for hair cell survival.

Planar polarization of the atypical myosin Dachs orients cell divisions in Drosophila.

Tissues can grow in a particular direction by controlling the orientation of cell divisions. This phenomenon is evident in the developing Drosophila wing epithelium, where the tissue becomes elongated along the proximal-distal axis. We show that orientation of cell divisions in the wing requires planar polarization of an atypical myosin, Dachs.