Biology subjects

Firestein, S.

Publications and source records attributed to Firestein, S..

3 recordsLinked to original sources

bioRxiv2021

Disruption of nuclear architecture as a cause of COVID-19 induced anosmia

Olfaction relies on a coordinated partnership between odorant flow and neuronal communication. Disruption in our ability to detect odors, or anosmia, has emerged as a hallmark symptom of infection with SARS-CoV-2, yet the mechanism behind this abrupt sensory deficit remains elusive. Here, using molecular evaluation of human olfactory epithelium (OE) from subjects succumbing to COVID-19 and a hamster model of SARS-CoV-2 infection, we discovered widespread downregulation of olfactory receptors (ORs) as well as key components of their signaling pathway. OR downregulation likely represents a non-cell autonomous effect, since SARS-CoV-2 detection in OSNs is extremely rare both in human and hamster OEs. A likely explanation for the reduction of OR transcription is the striking reorganization of nuclear architecture observed in the OSN lineage, which disrupts multi-chromosomal compartments regulating OR expression in humans and hamsters. Our experiments uncover a novel molecular mechanism by which a virus with a very selective tropism can elicit persistent transcriptional changes in cells that evade it, contributing to the severity of COVID-19.

neuroscience↗

bioRxiv2019

Widespread Receptor Driven Modulation in Peripheral Olfactory Coding

We utilized swept confocally aligned planar excitation (SCAPE) microscopy to measure odor-driven activity simultaneously in many (>10,000) olfactory sensory neurons distributed over large areas of intact mouse olfactory epithelium. This approach allowed us to investigate the responses to mixtures or blends of odors and their components, a more realistic stimulus than monomolecular odors. In up to 38% of responding cells, responses to a mixture of odors were different - absent, smaller or larger - than what would be expected from the sum of the individual components. Further investigation revealed instances of both antagonism and allosteric enhancement in the primary olfactory sensory neurons. All 10 of the odor compounds tested were found to act as both agonists and antagonists at different receptors. We present a hypothetical scheme for how modulation at the peripheral receptors increases the capability of the olfactory system to recognize patterns of complex odor mixtures. The widespread modulation of primary sensory receptors argues against a simple combinatorial code and should motivate a search for alternative coding strategies.

neuroscience↗

bioRxiv2019

Bioisosterism reveals new structure-odor relationships

The question of structure-odor relationship (SOR) has inspired numerous studies into chemical odorants via their perceptual similarities. Much of this data comes from psychophysical studies on humans, precluding the possibility of direct measurements of receptor or receptor neuron activation. Remarkably, we find that many of the perceptual classifications used by human subjects translate well enough to mouse that we can apply cellular methods to better understand the molecular mechanism, that leads to odor discrimination and perception. Using a well studied and well recognizable odor percept of bitter almond, we have tested an odorant panel of aldehydes and ketones that were reported to share such perceptual qualities. These odorants include aromatic and aliphatic, as well as cyclic and allylic features. When parsing these odorants using chemical descriptors, we have a clear separation of molecules possessing these various features. However, here we show that OSN responses better recapitulate the physiological percept. Using these odorants, we also provide a proof-of-concept for non-classical bioisosterism at work in the olfactory system.

neuroscience↗