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- Edvardsson Rasmussen, Jesper, 1984-
(författare)
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Inner ear proteomics and barriers : Clinical and experimental findings
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hearing is important in many aspects of life, including communication, assessing one’s surroundings, entertainment and social interaction. Hearing loss is common and according to the Global Burden of Disease Study, 5% of the global population require hearing rehabilitation (1). Pharmacological treatment options are limited, so understanding cellular mechanisms in the damaged inner ear is crucial for developing novel therapies.In this thesis, the human inner ear proteome in patients with sporadic vestibular schwannoma (VS) and its association with hearing loss were investigated. Ototoxic effects induced by furosemide were also examined, focusing on inner ear barrier function, furosemide sensitive Na-K-Cl co-transporter 1 (NKCC1), Fetuin-A, linked to tumour-associated hearing loss, and Pigment epithelium-derived factor (PEDF), potentially important for blood-endolymph barrier integrity.Translabyrinthine surgery on 35 patients, 32 with VS and three with meningioma, provided samples from perilymph, endolymph, endolymphatic sac tissue, VS biopsies and cerebrospinal fluid (CSF) for proteome analysis. Effects of furosemide on the inner ear barriers were studied in mice using 9.4Tesla MRI, and in guinea pigs using immunohistochemistry and mRNA in situ hybridisation focusing on NKCC1, Fetuin-A, and PEDF.Proteomic analysis revealed consistent sets of proteins in perilymph (91/315) and endolymph (545/1211). The proteomes of perilymph and CSF exhibited specific differences, with proteins unique to each fluid, thereby emphasizing the distinct origin of perilymph separate from CSF. Fetuin-A was inversely related to tumour-associated hearing loss, while patients with severe to profound hearing loss exhibited upregulation of complement factor H-related protein 2 (CFHR2).Furosemide compromised the blood-endolymph barrier, allowing gadolinium contrast into scala media. It affected NKCC1 of type II fibrocytes coinciding with the onset of hearing loss following high-dose furosemide, suggesting early disruption in potassium ion recirculation. Fetuin-A and PEDF were identified in the cochlea at protein and mRNA level. Their staining intensity increased in various cochlear subsites 120 minutes after furosemide administration, indicating their involvement in the cochlear response to the effects of furosemide.In summary, this thesis uncovered significant inter-individual variability in both the perilymph and endolymph proteome, alongside a consistent subset of proteins. Further, associations between hearing loss and proteome changes suggest inflammation as a potential mechanism for hearing degradation caused by vestibular schwannomas. Experimentally, impact of furosemide on blood-inner ear barriers were visualised in vivo and type II fibrocytes were identified as potential initial targets for NKCC1 blockade. Fetuin-A and PEDF were confirmed in several cell types in the cochlea and may increase in response to very high furosemide doses.
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| 3. |
- Parekh, Mrunal, 1987-, et al.
(författare)
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Arc Characteristics of Ultra-Fast Opening Switching Contacts in Hybrid Breakers
- 2021
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Ingår i: IEEE Transactions on Power Delivery. - : Institute of Electrical and Electronics Engineers (IEEE). - 0885-8977 .- 1937-4208. ; 36:5, s. 2872-2880
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Tidskriftsartikel (refereegranskat)abstract
- A mechanical switch can be used instead of a power electronic load commutation switch to reduce losses during normal power flow in standard hybrid DC breakers. The success of current commutation in such hybrid breakers depends on the arc voltage across the contacts of the mechanical switch. The behaviour of rapidly elongated arcs generated during the opening of an ultra-fast mechanical switch in the air is studied here. The voltage-current characteristics of the generated arcs are obtained for contact opening velocities of 6, 11 and 21 m/s. It is found that the arc voltage at a given current and contact separation increases with contact opening velocity. It is shown that stationary, zero-contact-velocity characteristics can not be used to accurately quantify the voltage build-up in fast elongating arcs in hybrid breakers. A best-fitting black-box the equation for the dynamic arc characteristics is presented for the tested velocities. The obtained voltage-current characteristics are used as input to simulate the current commutation process in a 12 kV hybrid DC circuit breaker case-study. Different scenarios of current commutation failure related to the arc voltage build-up are identified. It is shown that these failures scenarios can be avoided by increasing the contact opening velocity.
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