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Cell Jan 20212021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen-as "molecular glues" that induce neo-protein-protein...
2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen-as "molecular glues" that induce neo-protein-protein associations. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.
Topics: Biological Products; Cyclosporine; Immunosuppressive Agents; Tacrolimus
PubMed: 33417864
DOI: 10.1016/j.cell.2020.12.020 -
Clinical Neurophysiology Practice 2019Vestibular evoked myogenic potentials (VEMPs) are a useful and increasingly popular component of the neuro-otology test battery. These otolith-dependent reflexes are... (Review)
Review
Vestibular evoked myogenic potentials (VEMPs) are a useful and increasingly popular component of the neuro-otology test battery. These otolith-dependent reflexes are produced by stimulating the ears with air-conducted sound or skull vibration and recorded from surface electrodes placed over the neck (cervical VEMPs) and eye muscles (ocular VEMPs). VEMP abnormalities have been reported in various diseases of the ear and vestibular system, and VEMPs have a clear role in the diagnosis of superior semicircular canal dehiscence. However there is significant variability in the methods used to stimulate the otoliths and record the reflexes. This review discusses VEMP methodology and provides a detailed theoretical background for the techniques that are typically used. The review also outlines the common pitfalls in VEMP recording and the clinical applications of VEMPs.
PubMed: 30949613
DOI: 10.1016/j.cnp.2019.01.005 -
Cell Aug 2018Type I spiral ganglion neurons (SGNs) transmit sound information from cochlear hair cells to the CNS. Using transcriptome analysis of thousands of single neurons, we...
Type I spiral ganglion neurons (SGNs) transmit sound information from cochlear hair cells to the CNS. Using transcriptome analysis of thousands of single neurons, we demonstrate that murine type I SGNs consist of subclasses that are defined by the expression of subsets of transcription factors, cell adhesion molecules, ion channels, and neurotransmitter receptors. Subtype specification is initiated prior to the onset of hearing during the time period when auditory circuits mature. Gene mutations linked to deafness that disrupt hair cell mechanotransduction or glutamatergic signaling perturb the firing behavior of SGNs prior to hearing onset and disrupt SGN subtype specification. We thus conclude that an intact hair cell mechanotransduction machinery is critical during the pre-hearing period to regulate the firing behavior of SGNs and their segregation into subtypes. Because deafness is frequently caused by defects in hair cells, our findings have significant ramifications for the etiology of hearing loss and its treatment.
Topics: Animals; Cluster Analysis; Genetic Markers; Hair Cells, Auditory; Hearing; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred CBA; Mice, Knockout; Mutation; Neuroglia; Neurons; Sequence Analysis, RNA; Signal Transduction; Spiral Ganglion
PubMed: 30078710
DOI: 10.1016/j.cell.2018.07.008 -
Seminars in Hearing Feb 2022Evolutionary changes occur across health care, including within the hearing care delivery system. At times, the change is driven by external forces and thus elicits a... (Review)
Review
Evolutionary changes occur across health care, including within the hearing care delivery system. At times, the change is driven by external forces and thus elicits a reactive response. In contrast, developing a vision of a future state, and subsequently the strategies to achieve that vision, is a proactive and a preferred process. Using the reactive versus proactive framework, a future state built around the emergence of genetics as both an assessment tool and a treatment option is presented. In addition, a broad, consumer-centric vision for access to affordable and contemporary hearing care is presented that would result in an expanded and positive future state for hearing care services.
PubMed: 35719743
DOI: 10.1055/s-0042-1743542 -
Indian Journal of Otolaryngology and... Dec 2022Noise in human societies is unavoidable, but it tends to become a modern epidemic that induces various detrimental effects to several organs and functions in humans....
Noise in human societies is unavoidable, but it tends to become a modern epidemic that induces various detrimental effects to several organs and functions in humans. Increased cardiovascular danger, anxiety and sleep disturbance are just few of these effects. It is noteworthy that children, even neonates and their developing organism are especially vulnerable to noise-related health problems. Noise is measured with special noise-meters. These devices express results in decibels by transforming random noise to a continuous sound. This sound is characterized by equivalent acoustic energy to the random noise for a defined time interval. Human auditory apparatus is principally endangered by acute noises but also by chronic noise exposure, in the context of both occupational and recreational activities. Various mechanisms are implicated in the pathogenesis of noise-induced hearing loss that can cause either temporary or permanent damage. Among them, emphasis is given to the impairment by free radicals and inflammatory mediators, to the activation of apoptotic molecular pathways, but also to glutamate excitotoxicity. A hidden hearing loss, synaptopathy, is attributed to the latter. The irreversible nature of hearing loss, as well as the idiosyncratic sensitivity of individuals, imposes the necessity of early diagnosis of auditory impairment by noise. Super high frequency audiograms, otoacoustic emissions and electrophysiological examinations can address diagnosis. Thankfully, there is extensive research on acoustic trauma therapeutic approaches. However, until we succeed in regenerating the sensory organ of hearing, chronic noise-induced hearing loss cannot be treated. Thus, it is fundamental that society protects people from noise, by laws and regulations.
PubMed: 36742745
DOI: 10.1007/s12070-021-02797-1 -
British Journal of Anaesthesia Apr 2023The March issue contains a laboratory study of auditory perception, which is an unusual topic for this journal. A perspective is provided on how the study relates to...
The March issue contains a laboratory study of auditory perception, which is an unusual topic for this journal. A perspective is provided on how the study relates to recent research on clinical auditory alarms and displays. Techniques used in the study are explored and explained, such as enrolment of non-clinician volunteer participants, use of coordinate response measure phrase stimuli, presentation of sound loudness levels using the decibel scale, and analysis using signal detection theory. Such efforts to improve the safety, efficacy, and tolerability of modern medical device alarms are critical for improved patient safety.
Topics: Humans; Sound; Auditory Perception; Patient Safety
PubMed: 36792387
DOI: 10.1016/j.bja.2023.01.014 -
Hearing Research Jun 2017Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a... (Review)
Review
Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a growing number of auditory researchers. In addition, several research groups have become interested in developing therapeutic approaches that can reverse synaptopathy and restore hearing function. One of the major challenges to realizing the potential of synaptopathy rodent models is that current clinical audiometric approaches cannot yet reveal the presence of this subtle cochlear pathology in humans. This has catalyzed efforts, both from basic and clinical perspectives, to investigate novel means for diagnosing synaptopathy and to determine the main functional consequences for auditory perception and hearing abilities. Such means, and a strong concordance between findings in pre-clinical animal models and clinical studies in humans, are important for developing and realizing therapeutics. This paper frames the key outstanding translational questions that need to be addressed to realize this ambitious goal.
Topics: Animals; Cochlea; Diagnosis, Differential; Disease Models, Animal; Hearing Loss, Noise-Induced; Humans; Noise; Predictive Value of Tests; Prevalence; Species Specificity; Synapses; Synaptic Transmission; Translational Research, Biomedical
PubMed: 28069376
DOI: 10.1016/j.heares.2016.12.010 -
Science Advances Oct 2023We present an adaptive optical neural network based on a large-scale event-driven architecture. In addition to changing the synaptic weights (synaptic plasticity), the...
We present an adaptive optical neural network based on a large-scale event-driven architecture. In addition to changing the synaptic weights (synaptic plasticity), the optical neural network's structure can also be reconfigured enabling various functionalities (structural plasticity). Key building blocks are wavelength-addressable artificial neurons with embedded phase-change materials that implement nonlinear activation functions and nonvolatile memory. Using multimode focusing, the activation function features both excitatory and inhibitory responses and shows a reversible switching contrast of 3.2 decibels. We train the neural network to distinguish between English and German text samples via an evolutionary algorithm. We investigate both the synaptic and structural plasticity during the training process. On the basis of this concept, we realize a large-scale network consisting of 736 subnetworks with 16 phase-change material neurons each. Overall, 8398 neurons are functional, highlighting the scalability of the photonic architecture.
PubMed: 37862413
DOI: 10.1126/sciadv.adi9127