Recent advances and future challenges in gene therapy for hearing loss

Hearing loss is the most common sensory deficit experienced by humans and represents one of the largest chronic health conditions worldwide. It is expected that around 10% of the world's population will be affected by disabling hearing impairment by 2050. Hereditary hearing loss accounts for most of the known forms of congenital deafness, and over 25% of adult-onset or progressive hearing loss. Despite the identification of well over 130 genes associated with deafness, there is currently no curative treatment for inherited deafness. Recently, several pre-clinical studies in mice that exhibit key features of human deafness have shown promising hearing recovery through gene therapy involving the replacement of the defective gene with a functional one. Although the potential application of this therapeutic approach to humans is closer than ever, substantial further challenges need to be overcome, including testing the safety and longevity of the treatment, identifying critical therapeutic time windows and improving the efficiency of the treatment. Herein, we provide an overview of the recent advances in gene therapy and highlight the current hurdles that the scientific community need to overcome to ensure a safe and secure implementation of this therapeutic approach in clinical trials

Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation

In the adult auditory organ, mechanoelectrical transducer (MET) channels are essential for transducing acoustic stimuli into electrical signals. In the absence of incoming sound, a fraction of the MET channels on top of the sensory hair cells are open, resulting in a sustained depolarizing current. By genetically manipulating the in vivo expression of molecular components of the MET apparatus, we show that during pre-hearing stages the MET current is essential for establishing the electrophysiological properties of mature inner hair cells (IHCs). If the MET current is abolished in adult IHCs, they revert into cells showing electrical and morphological features characteristic of pre-hearing IHCs, including the re-establishment of cholinergic efferent innervation. The MET current is thus critical for the maintenance of the functional properties of adult IHCs, implying a degree of plasticity in the mature auditory system in response to the absence of normal transduction of acoustic signals

Multi-model evaluation of short-lived pollutant distributions over East Asia during summer 2008

The ability of seven state of the art chemistry-aerosol models to reproduce distributions of tropospheric ozone and its precursors, as well as aerosols over eastern Asia in summer 2008 is evaluated. The study focuses on the performance of models used to assess impacts of pollutants on climate and air quality as part of the EU ECLIPSE project. Models, run using the same ECLIPSE emissions, are compared over different spatial scales to in-situ surface, vertical profile and satellite data. Several rather clear biases are found between model results and observations including overestimation of ozone at rural locations downwind of the main emission regions in China as well as downwind over the Pacific. Several models produce too much ozone over polluted regions which is then transported downwind. Analysis points to different factors related to the ability of models to simulate VOC limited regimes over polluted regions and NOx limited regimes downwind. This may also be linked to biases compared to satellite NO2 indicating overestimation of NO2 over and to the north of the northern China Plain emission region. On the other hand, model NO2 is too low to the south and east of this region and over Korean/Japan. Overestimation of ozone is linked to systematic underestimation of CO particularly at rural sites and downwind of the main Chinese emission regions. This is likely to be due to enhanced destruction of CO by OH. Overestimation of Asian ozone and its transport downwind implies that radiative forcing from this source may be overestimated. Model-observation discrepancies over Beijing do not appear to be due to emission controls linked to the Olympic Games in summer 2008. With regard to aerosols, most models reproduce the satellite-derived AOD patterns over eastern China. Our study nevertheless reveals an overestimation of ECLIPSE model-mean surface BC and sulphate aerosols in urban China in summer 2008. The effect of the short-term emission mitigation in Beijing is too weak to explain the differences between the models. Our results rather point to an overestimation of SO2 emissions, in particular, close to the surface in Chinese urban areas. However, we also identify a clear underestimation of aerosol concentrations over northern India, suggesting that the rapid recent growth of emissions in India, as well as their spatial extension, is underestimated in emission inventories. Model deficiencies in the representation of pollution accumulation due to the Indian monsoon may also be playing a role. Comparison with vertical aerosol lidar measurements highlights a general underestimation of scattering aerosols in the boundary layer associated with overestimation in the free troposphere pointing to modeled aerosol lifetimes that are too long. This is likely linked to a too strong vertical transport and/or insufficient deposition efficiency during transport or export from the boundary layer, rather than chemical processing (in the case of sulphate aerosols). Underestimation of sulphate in the boundary layer implies potentially large errors in simulated aerosol-cloud interactions, via impacts on boundary-layer clouds. This evaluation has important implications for accurate assessment of air pollutants on regional air quality and global climate based on global model calculations. Ideally, models should be run at higher resolution over source regions to better simulate urban-rural pollutant gradients/chemical regimes, and also to better resolve pollutant processing and loss by wet deposition as well as vertical transport. Discrepancies in vertical distributions requires further quantification and improvement since this is a key factor in the determination of radiative forcing from short-lived pollutants

Corporate Social Responsibility and Islamic Financial Institutions (IFIs): Management Perceptions from IFIs in Bahrain

Islamic finance is gaining greater attention in the finance industry, and this paper analyses how Islamic financial institutions (IFIs) are responding to the welfare needs of society. Using interview data with managers and content analysis of the disclosures, this study attempts to understand management perceptions of corporate social responsibility (CSR) in IFIs. A thorough understanding of CSR by managers, as evident in the interviews, has not been translated fully into practice. The partial use of IFIs’ potential role in social welfare would add further challenges in the era of financialisation

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Hearing relies on rapid, temporally precise, and sustained neurotransmitter release at the ribbon synapses of sensory cells, the inner hair cells (IHCs). This process requires otoferlin, a six C2-domain, Ca2+-binding transmembrane protein of synaptic vesicles. To decipher the role of otoferlin in the synaptic vesicle cycle, we produced knock-in mice (Otof Ala515,Ala517/Ala515,Ala517) with lower Ca2+-binding affinity of the C2C domain. The IHC ribbon synapse structure, synaptic Ca2+ currents, and otoferlin distribution were unaffected in these mutant mice, but auditory brainstem response wave-I amplitude was reduced. Lower Ca2+ sensitivity and delay of the fast and sustained components of synaptic exocytosis were revealed by membrane capacitance measurement upon modulations of intracellular Ca2+ concentration, by varying Ca2+ influx through voltage-gated Ca2+-channels or Ca2+ uncaging. Otoferlin thus functions as a Ca2+ sensor, setting the rates of primed vesicle fusion with the presynaptic plasma membrane and synaptic vesicle pool replenishment in the IHC active zone

A roadmap to estimating agricultural ammonia volatilization over Europe using satellite observations and simulation data

Ammonia (NH3) is one of the most important gases emitted from agricultural practices. It affects air quality and the overall climate and is in turn influenced by long-term climate trends as well as by short-term fluctuations in local and regional meteorology. Previous studies have established the capability of the Infrared Atmospheric Sounding Interferometer (IASI) series of instruments, aboard the Metop satellites, to measure ammonia from space since 2007. In this study, we explore the interactions between atmospheric ammonia, land and meteorological variability, and long-term climate trends in Europe. We investigate the emission potential (Γsoil) of ammonia from the soil, which describes the soil–atmosphere ammonia exchange. Γsoil is generally calculated in-field or in laboratory experiments; here, and for the first time, we investigate a method which assesses it remotely using satellite data, reanalysis data products, and model simulations. We focus on ammonia emission potential in March 2011, which marks the start of growing season in Europe. Our results show that Γsoil ranges from 2 × 103 to 9.5 × 104 (dimensionless) in fertilized cropland, such as in the North European Plain, and is of the order of 10–102 in a non-fertilized soil (e.g., forest and grassland). These results agree with in-field measurements from the literature, suggesting that our method can be used in other seasons and regions in the world. However, some improvements are needed in the determination of mass transfer coefficient k (m s−1), which is a crucial parameter to derive Γsoil. Using a climate model, we estimate the expected increase in ammonia columns by the end of the century based on the increase in skin temperature (Tskin), under two different climate scenarios. Ammonia columns are projected to increase by up to 50 %, particularly in eastern Europe, under the SSP2-4.5 scenario and might even double (increase of 100 %) under the SSP5-8.5 scenario. The increase in skin temperature is responsible for a formation of new hotspots of ammonia in Belarus, Ukraine, Hungary, Moldova, parts of Romania, and Switzerland.</p

Efferent Control of the Electrical and Mechanical Properties of Hair Cells in the Bullfrog's Sacculus

Background: Hair cells in the auditory, vestibular, and lateral-line systems respond to mechanical stimulation and transmit information to afferent nerve fibers. The sensitivity of mechanoelectrical transduction is modulated by the efferent pathway, whose activity usually reduces the responsiveness of hair cells. The basis of this effect remains unknown. Methodology and Principal Findings: We employed immunocytological, electrophysiological, and micromechanical approaches to characterize the anatomy of efferent innervation and the effect of efferent activity on the electrical and mechanical properties of hair cells in the bullfrog’s sacculus. We found that efferent fibers form extensive synaptic terminals on all macular and extramacular hair cells. Macular hair cells expressing the Ca 2+-buffering protein calretinin contain half as many synaptic ribbons and are innervated by twice as many efferent terminals as calretinin-negative hair cells. Efferent activity elicits inhibitory postsynaptic potentials in hair cells and thus inhibits their electrical resonance. In hair cells that exhibit spiking activity, efferent stimulation suppresses the generation of action potentials. Finally, efferent activity triggers a displacement of the hair bundle’s resting position. Conclusions and Significance: The hair cells of the bullfrog’s sacculus receive a rich efferent innervation with the heaviest projection to calretinin-containing cells. Stimulation of efferent axons desensitizes the hair cells and suppresses their spiking activity. Although efferent activation influences mechanoelectrical transduction, the mechanical effects on hair bundles ar

Dynamic assembly of ribbon synapses and circuit maintenance in a vertebrate sensory system

Ribbon synapses transmit information in sensory systems, but their development is not well understood. To test the hypothesis that ribbon assembly stabilizes nascent synapses, we performed simultaneous time-lapse imaging of fluorescently-tagged ribbons in retinal cone bipolar cells (BCs) and postsynaptic densities (PSD95-FP) of retinal ganglion cells (RGCs). Ribbons and PSD95-FP clusters were more stable when these components colocalized at synapses. However, synapse density on ON-alpha RGCs was unchanged in mice lacking ribbons (ribeye knockout). Wildtype BCs make both ribbon-containing and ribbon-free synapses with these GCs even at maturity. Ribbon assembly and cone BC-RGC synapse maintenance are thus regulated independently. Despite the absence of synaptic ribbons, RGCs continued to respond robustly to light stimuli, although quantitative examination of the responses revealed reduced frequency and contrast sensitivity

Structure and Function of the Hair Cell Ribbon Synapse

Faithful information transfer at the hair cell afferent synapse requires synaptic transmission to be both reliable and temporally precise. The release of neurotransmitter must exhibit both rapid on and off kinetics to accurately follow acoustic stimuli with a periodicity of 1 ms or less. To ensure such remarkable temporal fidelity, the cochlear hair cell afferent synapse undoubtedly relies on unique cellular and molecular specializations. While the electron microscopy hallmark of the hair cell afferent synapse — the electron-dense synaptic ribbon or synaptic body — has been recognized for decades, dissection of the synapse’s molecular make-up has only just begun. Recent cell physiology studies have added important insights into the synaptic mechanisms underlying fidelity and reliability of sound coding. The presence of the synaptic ribbon links afferent synapses of cochlear and vestibular hair cells to photoreceptors and bipolar neurons of the retina. This review focuses on major advances in understanding the hair cell afferent synapse molecular anatomy and function that have been achieved during the past years

Role for a Novel Usher Protein Complex in Hair Cell Synaptic Maturation

The molecular mechanisms underlying hair cell synaptic maturation are not well understood. Cadherin-23 (CDH23), protocadherin-15 (PCDH15) and the very large G-protein coupled receptor 1 (VLGR1) have been implicated in the development of cochlear hair cell stereocilia, while clarin-1 has been suggested to also play a role in synaptogenesis. Mutations in CDH23, PCDH15, VLGR1 and clarin-1 cause Usher syndrome, characterized by congenital deafness, vestibular dysfunction and retinitis pigmentosa. Here we show developmental expression of these Usher proteins in afferent spiral ganglion neurons and hair cell synapses. We identify a novel synaptic Usher complex comprised of clarin-1 and specific isoforms of CDH23, PCDH15 and VLGR1. To establish the in vivo relevance of this complex, we performed morphological and quantitative analysis of the neuronal fibers and their synapses in the Clrn1−/− mouse, which was generated by incomplete deletion of the gene. These mice showed a delay in neuronal/synaptic maturation by both immunostaining and electron microscopy. Analysis of the ribbon synapses in Ames waltzerav3J mice also suggests a delay in hair cell synaptogenesis. Collectively, these results show that, in addition to the well documented role for Usher proteins in stereocilia development, Usher protein complexes comprised of specific protein isoforms likely function in synaptic maturation as well