Radiant ignition of a reactive solid with in-depth absorption

An asymptotic analysis of the limit of large activation energy is presented for radiant ignition of a solid that experiences a one-step Arrhenius reaction in the condensed phase. Both constant and time-dependent radiant-energy fluxes arc considered, and the complete range of values is covered for the absorption coefficient ji. It is shown that as » increases, the structure of the transition stage, which follows the inert heat-conduction stage, passes from a thermal explosion without heat conduction, to a single transient heat-conduction zone with distributed chemical heat release, to a two-zone structure composed of a reactive-diffusive-absorptive zone near the surface and a transient-diffusive zone in the interior. For very high values of u, the reactive-diffusive-absorptive zone further splits into a surface absorption zone and an interior reactive-diffusive zone, thereby reproducing results obtained previously for ignition by a surface-applied energy flux. The analysis shows that contrary to earlier expectation, the nondimensional absorption coefficient must be at least as large as the nondimensional activation energy for in-depth absorption to affect the ignition time negligibly

Programmed cell death recruits macrophages into the developing mouse cochlea

Programmed cell death (PCD) plays a critical role in the development and maturation of the cochlea. Significant remodeling occurs among cells of the greater epithelial ridge (GER) of Kölliker\u27s organ, leading to tissue regression and formation of the inner sulcus. In mice, this event normally occurs between postnatal days 5-15 (P5-15) and is regulated by thyroid hormone (T3). During this developmental time period, the cochlea also contains a large population of macrophages. Macrophages are frequently involved in the phagocytic clearance of dead cells, both during development and after injury, but the role of macrophages in the developing cochlea is unknown. This study examined the link between developmental cell death in the GER and the recruitment of macrophages into this region. Cell death in the basal GER begins at P5 and enhanced numbers of macrophages were observed at P7. This pattern of macrophage recruitment was unchanged in mice that were genetically deficient for CX3CR1, the receptor for fractalkine (a known macrophage chemoattractant). We found that injection of T3 at P0 and P1 caused GER cell death to begin at P3, and this premature PCD was accompanied by earlier recruitment of macrophages. We further found that depletion of macrophages from the developing cochlea (using CX3CR

Age-related hearing loss: Unraveling the pieces.

Age-related hearing loss (ARHL) is the most common cause of hearing loss in the world. The development of ARHL in each individual is multifactorial, involving both intrinsic and extrinsic factors. This review highlights several of the key findings in the ARHL literature and discusses future directions. Level of Evidence:NA

Age-related hearing loss: biological aspects

Presbycusis is one of the more prevalent neurodegenerative disease of aging. There are many studies about the influence of environmental and genetic factors. Age-related hearing loss is caused by changes in peripheral (cell loss in organ of Corti, spiral ganglion and stria vascularis) and central auditory systems (consequent to peripheral modifications or for changes in the neurobiologic activity underlying central processing of auditory informations) [1]. Consequences are reduced sensitivity, tuning sharpness, compression, and reduced signal-to-noise ratios, deficits in auditory discrimination, temporal processing, processing of degraded auditory signals or when embedded in competing acoustic signals. Approaching biology of age-related hearing loss is complex: it needs to clarify some peripheral aspects with different cochlear structure and cellular type affected, and some others central auditory processing aspects. There are some peripherally induced central effects and others direct neurodegenerative changes in the brain. Moreover biochemical and mechanical injury in life course can represent a risk factor for auditory function particularly for organ of Corti. This complicates the attempt of separate pure presbycusis from socioacusis. Research indicated some "longevity genes" and longevity-promoting life-styles (obesity and correlated conditions like hyperlipidemia, hypercholesterolemia, hypertension, hyperhomocysteinemia and cardiovascular disease, smoking, diet and diabetes [2,3]. Age-related hearing loss seems to occur more frequently in industrial population than in non-industrial [4]. The relation between alleles pro or against-aging and environment maybe play a determinant role in the evolution of hearing with aging. Until such genes are identified, the best strategy is to reduce environmental risk factors (noise exposure, ototoxic drugs, industrial solvents or combinations of these)

No dramatic age-related loss of hair cells and spiral ganglion neurons in Bcl-2 over-expression mice or Bax null mice

Age-related decline of neuronal function is associated with age-related structural changes. In the central nervous system, age-related decline of cognitive performance is thought to be caused by synaptic loss instead of neuronal loss. However, in the cochlea, age-related loss of hair cells and spiral ganglion neurons (SGNs) is consistently observed in a variety of species, including humans. Since age-related loss of these cells is a major contributing factor to presbycusis, it is important to study possible molecular mechanisms underlying this age-related cell death. Previous studies suggested that apoptotic pathways were involved in age-related loss of hair cells and SGNs. In the present study, we examined the role of Bcl-2 gene in age-related hearing loss. In one transgenic mouse line over-expressing human Bcl-2, there were no significant differences between transgenic mice and wild type littermate controls in their hearing thresholds during aging. Histological analysis of the hair cells and SGNs showed no significant conservation of these cells in transgenic animals compared to the wild type controls during aging. These data suggest that Bcl-2 overexpression has no significant effect on age-related loss of hair cells and SGNs. We also found no delay of age-related hearing loss in mice lacking Bax gene. These findings suggest that age-related hearing loss is not through an apoptotic pathway involving key members of Bcl-2 family

Vesicular glutamatergic transmission in noise-induced loss and repair of cochlear ribbon synapses

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3

Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion

Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells. We used a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX(3)CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea. SIGNIFICANCE STATEMENT It is known that damage to the inner ear leads to recruitment of inflammatory cells (macrophages), but the chemical signals that initiate this recruitment and the functions of macrophages in the damaged ear are unclear. Here we show that fractalkine signaling regulates macrophage recruitment into the cochlea and also promotes the survival of cochlear afferents after selective hair cell lesion. Because these afferent neurons carry sound information from the cochlea to the auditory brainstem, their survival is a key determinant of the success of cochlear prosthetics. Our data suggest that fractalkine signaling in the cochlea is neuroprotective, and reveal a previously uncharacterized interaction between cells of the cochlea and the innate immune system

Progressive hearing loss in mice carrying a mutation in Usp53

UNLABELLED: Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins TJP1 and TJP2 in polarized epithelial cells, suggesting that USP53 is part of the tight junction complex. The barrier properties of tight junctions of the stria vascularis appeared intact in a biotin tracer assay, but the endocochlear potential is reduced in adult mambo mice. Hair cell degeneration in mambo mice precedes endocochlear potential decline and is rescued in cochlear organotypic cultures in low potassium milieu, indicating that hair cell loss is triggered by extracellular factors. Remarkably, heterozygous mambo mice show increased susceptibility to noise injury at high frequencies. We conclude that USP53 is a novel tight junction-associated protein that is essential for the survival of auditory hair cells and normal hearing in mice, possibly by modulating the barrier properties and mechanical stability of tight junctions. SIGNIFICANCE STATEMENT: Hereditary hearing loss is extremely prevalent in the human population, but many genes linked to hearing loss remain to be discovered. Forward genetics screens in mice have facilitated the identification of genes involved in sensory perception and provided valuable animal models for hearing loss in humans. This involves introducing random mutations in mice, screening the mice for hearing defects, and mapping the causative mutation. Here, we have identified a mutation in the Usp53 gene that causes progressive hearing loss in the mambo mouse line. We demonstrate that USP53 is a catalytically inactive deubiquitinating enzyme and a novel component of tight junctions that is necessary for sensory hair cell survival and inner ear homeostasis

Oncomodulin, an EF-hand Ca2+ buffer, is critical for maintaining cochlear function in mice

UNLABELLED: Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses. Thus, Ocm is not critical for cochlear development but does play an essential role for cochlear function in the adult mouse. SIGNIFICANCE STATEMENT: Numerous proteins act as buffers, sensors, or pumps to control calcium levels in cochlear hair cells. In the inner ear, EF-hand calcium buffers may play a significant role in hair cell function but have been very difficult to study. Unlike other reports of genetic disruption of EF-hand calcium buffers, deletion of oncomodulin (Ocm), which is predominately found in outer hair cells, leads to a progressive hearing loss after 1 month, suggesting that Ocm critically protects hearing in the mature ear