In terrestrial mammals, odorant receptors and associated sensory transduction machinery in olfactory sensory neurons (OSNs) are compartmentalized in the cilia, a critically important organelle for odor detection. The large number and length of olfactory cilia provide an extensive receptive surface for odor detection. The stability of these organelles is critical for olfactory function, as damage to olfactory cilia due to environmental factors, age, or disease impairs odor detection. However, it is unclear if there are innate structural or functional features of olfactory cilia that vary between OSN subtypes and affect the fidelity of the odorant receptive field. Using ciliary-targeted fluorescent probes, we analyzed cilia morphology in live, intact OSNs in situ from mice and rats. This unbiased approach revealed a previously unappreciated constancy of average cilia length and number in OSNs across the olfactory epithelium, measures that were also independent of animal age, sex, genetic background, and even rodent species. However, average OSN cilia length did vary with the cyclic nucleotide they use to transduce olfactory stimuli: OSNs expressing the non-canonical olfactory receptor guanylate cyclase-D, which use cGMP as the second messenger, had dramatically shorter cilia than the canonical odorant receptors M71 or I7 or the trace amine-associated receptor TAAR3, each of which instead employs the second messenger cAMP. These findings suggest that differences in cyclic nucleotide signaling are associated with cilia length in OSNs. Together, the data provide a basis for understanding structure-function relationship between cilia morphology and odorant transduction as a foundation for building a high-fidelity chemosensory organ.

Millions of people in the United States experience a reduced or distorted ability to smell or taste. Chemosensory disorders such as anosmia (the inability to smell), parosmia (distorted smell), or dysgeusia (altered taste) have major impacts on health and quality of life including difficulty sensing dangers such as fire or spoilage, a diminished palatability of food and drink that can negatively influence diet and nutrition, feelings of social isolation, and an increased incidence of frailty, anxiety, and depression. Smell or taste dysfunction can also be symptoms of other health issues, including sinonasal disease, cancer, or neurodegenerative disease. Aging adults are disproportionately affected. However, smell and taste function are not regularly assessed as a part of routine healthcare despite their prevalence and impact. This is a lost opportunity, as early detection of a chemosensory disorder would enable patients to obtain needed validation, education and support for their health challenge, could direct both patient and provider to treatment options, and may suggest underlying health issues that should be addressed. To better understand the current barriers to including chemosensory testing as a regular component of health care and to identify opportunities to overcome those barriers, the conference "Towards Universal Chemosensory Testing" was convened on November 5-7, 2023, in Philadelphia, PA. This conference brought together scientists, clinicians, patients, and other experts to discuss these issues and identify collective ways to overcome barriers to testing. This white paper-which is focused primarily on the US healthcare system-is the result of those discussions.

Growing demand for the tasty and healthy food has driven the development of low-calorie sweeteners, sweet taste modulators, and bitter masking compounds originated from natural sources. With the discovery of human taste receptors, increasing numbers of sweet taste modulators have been identified through human taste response and molecular docking techniques. However, the discovery of novel taste-active molecules in nature can be accelerated by using advanced spectrometry technologies based on structure-activity relationships (SARs). SARs explain why structurally similar compounds can elicit similar taste qualities. Given the characterization of structural information from reported data, strategies employing SAR techniques to find structurally similar compounds become an innovative approach to expand knowledge of sweeteners. This review aims to summarize the structural patterns of known natural non-nutritive sweeteners, sweet taste enhancers, and bitter masking compounds. Innovative SAR-based approaches to explore sweetener derivatives are also discussed. Most sweet-tasting flavonoids belong to either the flavanonols or the dihydrochalcones and known bitter masking molecules are flavanones. Based on SAR findings that structural similarities are related to the sensory properties, innovative methodologies described in this paper can be applied to screen and discover the derivatives of taste-active compounds or potential taste modulators.

Anosmia is common with respiratory virus infections, but loss of taste or chemesthesis is rare. Reports of true taste loss with COVID-19 were viewed skeptically until confirmed by multiple studies. Nasal menthol thresholds are elevated in some with prior COVID-19 infections, but data on oral chemesthesis are lacking. Many patients recover quickly, but precise timing and synchrony of recovery are unclear. Here, we collected broad sensory measures over 28 days, recruiting adults (18-45 years) who were COVID-19 positive or recently exposed (close contacts per U.S. CDC criteria at the time of the study) in the first half of 2021. Participants received nose clips, red commercial jellybeans (Sour Cherry and Cinnamon), and scratch-n-sniff cards (ScentCheckPro). Among COVID-19 cases who entered the study on or before Day 10 of infection, Gaussian Process Regression showed odor identification and odor intensity (two distinct measures of function) each declined relative to controls (close contacts who never developed COVID-19), but effects were larger for intensity than identification. To assess changes during early onset, we identified four COVID-19 cases who enrolled on or prior to Day 1 of their illness: this allowed for visualization of baseline ratings, loss, and recovery of function over time. Four controls were matched for age, gender, and race. Variables included sourness and sweetness (Sour Cherry jellybeans), oral burn (Cinnamon jellybeans), mean orthonasal intensity of four odors (ScentCheckPro), and perceived nasal blockage. Data were plotted over 28 days, creating panel plots for the eight cases and controls. Controls exhibited stable ratings over time. By contrast, COVID-19 cases showed sharp deviations over time. No single pattern of taste loss or recovery was apparent, implying different taste qualities might recover at different rates. Oral burn was transiently reduced for some before recovering quickly, suggesting acute loss may be missed in data collected after acute illness ends. Changes in odor intensity or odor identification were not explained by nasal blockage. Collectively, intensive daily testing shows orthonasal smell, oral chemesthesis and taste were each altered by acute COVID-19 infection, and this disruption was dyssynchronous for different modalities, with variable loss and recovery rates across modalities and individuals.

Transient loss of smell is a common symptom of influenza and other upper respiratory infections. Loss of taste is possible but rare with these illnesses, and patient reports of 'taste loss' typically arise from a taste / flavor confusion. Thus, initial reports from COVID-19 patients of loss of taste and chemesthesis (i.e., chemical somatosensation like warming or cooling) were met with skepticism until multiple studies confirmed SARS-CoV-2 infections could disrupt these senses. Many studies have been based on self-report or on single time point assessments after acute illness was ended. Here, we describe intensive longitudinal data over 28 days from adults aged 18-45 years recruited in early 2021 (i.e., prior to the Delta and Omicron SARS-CoV-2 waves). These individuals were either COVID-19 positive or close contacts (per U.S. CDC criteria at the time of the study) in the first half of 2021. Upon enrollment, all participants were given nose clips, blinded samples of commercial jellybeans (Sour Cherry and Cinnamon), and scratch-n-sniff odor identification test cards (ScentCheckPro), which they used for daily assessments. In COVID-19 cases who enrolled on or before Day 10 of infection, Gaussian Process Regression showed two distinct measures of function - odor identification and odor intensity - declined relative to controls (exposed individuals who never developed COVID-19). Because enrollment began upon exposure, some participants became ill only after enrollment, which allowed us to capture baseline ratings, onset of loss, and recovery. Data from these four cases and four age- and sex- matched controls were plotted over 28 days to create panel plots. Variables included mean orthonasal intensity of four odors (ScentCheckPro), perceived nasal blockage, oral burn (Cinnamon jellybeans), and sourness and sweetness (Sour Cherry jellybeans). Controls exhibited stable ratings over time. By contrast, COVID-19 cases showed sharp deviations over time. Changes in odor intensity or odor identification were not explained by nasal blockage. No single pattern of taste loss or recovery was apparent, implying different taste qualities might recover at different rates. Oral burn was transiently reduced for some before recovering quickly, suggesting acute loss may be missed in datasets collected only after illness ends. Collectively, intensive daily testing shows orthonasal smell, oral chemesthesis and taste were each altered by acute SARS-CoV-2 infection. This disruption was dyssynchronous for different modalities, with variable loss and recovery rates across both modalities and individuals.

Background Nasal mucus is proving to be a useful means by which to study the pathogenesis of chronic rhinosinusitis (CRS). Given the increase in publications examining nasal mucus and the lack of a review on this topic, we will focus on this noninvasive approach to studying CRS. Particular attention will be drawn towards inflammatory cytokines and biomarkers and their influence on disease severity. Methods A literature review of papers published in English pertaining to nasal mucus was performed using the PubMed database. The search utilized combinations of the following keywords: sinusitis, polyps, sample collection, nasal mucus, or nasal secretion. Studies solely on acute or bacterial sinusitis, allergic rhinitis, or cystic fibrosis were not included. Results A wide variety of materials and methods have been used to collect nasal mucus. Numerous assay types have been performed with the most common being ELISA, cytometric bead array, and proteomics. Most studies have focused on examining the levels of Th1/Th2 cytokines along with chemokines associated with type 2 immunity. Other factors identified include growth factors, senescence-associated proteins, complement, and antimicrobial defenses have also been identified. Nasal mucus cytokines have proven useful in cluster analysis and predicting postoperative improvement in Sino-nasal Outcome Test (SNOT-22) scores. One limitation of the use of nasal mucus is that some studies have suggested that nasal mucus does not always reflect the tissue microenvironment. Conclusions Nasal mucus represents a critical tool by which to examine the sinonasal microenvironment in a noninvasive manner. Unlike studies of tissue, it can be utilized in both surgically and medically managed patients and avoids the trauma of biopsies. However, studies are still needed to determine the most effective method for nasal mucus collection. Studies should also take care to confirm that nasal mucus markers do, in fact, reflect the levels of the product studied in the tissue.

PURPOSE:Many widely-used psychophysical tests of olfaction have limitations that can create barriers to adoption outside research settings. For example, tests that measure the ability to identify odors may confound sensory performance with memory recall, verbal ability, and past experience with the odor. Conversely, threshold-based tests typically avoid these issues, but are labor intensive. Additionally, many commercially available olfactory tests are slow and may require a trained administrator, making them impractical for use in a short wellness visit or other broad clinical assessment.METHODS:We tested the performance of the Adaptive Olfactory Measure of Threshold (ArOMa-T) -- a novel odor detection threshold test that employs an adaptive Bayesian algorithm paired with a disposable odor-delivery card -- in a non-clinical sample of individuals (n=534) at the 2021 Twins Day Festival in Twinsburg, OH.RESULTS:Participants successfully completed the test in under 3 min with a false alarm rate of 9.6% and a test-retest reliability of 0.61. Odor detection thresholds differed by sex (~3.2-fold) and between the youngest and oldest age groups (~8.7-fold), consistent with prior work. In an exploratory analysis, we failed to observe evidence of detection threshold differences between participants who reported a history of COVID-19 and matched controls who did not. We also found evidence for broad-sense heritability of odor detection thresholds.CONCLUSION:Together, these data indicate the ArOMa-T can determine odor detection thresholds. The ArOMa-T may be particularly valuable in clinical or field settings where rapid and portable assessment of olfactory function is needed.

Mammalian taste bud cells express receptors for numerous peptides implicated elsewhere in the body in the regulation of metabolism, nutrient assimilation, and satiety. The perturbation of several peptide signaling pathways in the gustatory periphery results in changes in behavioral and/or physiological responsiveness to subsets of taste stimuli. We previously showed that Peptide YY (PYY) - which is present in both saliva and in subsets of taste cells - can affect behavioral taste responsiveness and reduce food intake and body weight. Here, we investigated the contributions of taste bud-localized receptors for PYY and the related Neuropeptide Y (NPY) on behavioral taste responsiveness. Y1R, but not Y2R, null mice show reduced responsiveness to sweet, bitter, and salty taste stimuli in brief-access taste tests; similar results were seen when wildtype mice were exposed to Y receptor antagonists in the taste stimuli. Finally, mice in which the gene encoding the NPY propeptide was deleted also showed reduced taste responsiveness to sweet and bitter taste stimuli. Collectively, these results suggest that Y1R signaling, likely through its interactions with NPY, can modulate peripheral taste responsiveness in mice.

In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean +/- SD, C19+: -82.5 +/- 27.2 points; C19-: -59.8 +/- 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for similar to 50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings <= 2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.

Valentina Parma1, Kathrin Ohla2, , Maria G. Veldhuizen3, Masha Y. Niv4, Christine E. Kelly5, Alyssa J. Bakke6, Keiland W. Cooper7, Cédric Bouysset8, Nicola Pirastu9, Michele Dibattista10, Rishemjit Kaur11, Marco Tullio Liuzza12, , Marta Y. Pepino13, Veronika Schöpf14, Veronica Pereda-Loth15, Shannon B. Olsson16, Richard C. Gerkin17, , Paloma Rohlfs Domínguez18, Javier Albayay19, Michael C. Farruggia20, Surabhi Bhutani21, Alexander W. Fjaeldstad22, , Ritesh Kumar23, Anna Menini24, Moustafa Bensafi25, , Mari Sandell26,27, Iordanis Konstantinidis28, Antonella Di Pizio29, Federica Genovese30, Lina Öztürk3, Thierry Thomas-Danguin31, Johannes Frasnelli32, Sanne Boesveldt33, Özlem Saatci34, Luis R. Saraiva30,35, , Cailu Lin30, , Jérôme Golebiowski8, Liang-Dar Hwang36, Mehmet Hakan Ozdener30, Maria Dolors Guàrdia37, Christophe Laudamiel38, Marina Ritchie39, Jan Havlícek40, Denis Pierron41, Eugeni Roura42, , Marta Navarro42, Alissa A. Nolden43, Juyun Lim44, , Katherine L. Whitcroft45, Lauren R. Colquitt30, Camille Ferdenzi25, , Evelyn V. Brindha46, Aytug Altundag47, Alberto Macchi48, Alexia Nunez-Parra49, Zara M. Patel50, Sébastien Fiorucci8, Carl M. Philpott51, , Barry C. Smith52, , Johan N. Lundström30,53, , Carla Mucignat54, Jane K. Parker55, Mirjam van den Brink56, Michael Schmuker23, Florian Ph. S. Fischmeister57, Thomas Heinbockel58, Vonnie D. C. Shields59, Farhoud Faraji60, Enrique Santamaría61, William E.A. Fredborg62, Gabriella Morini63, Jonas K. Olofsson62, , Maryam Jalessi64, Noam Karni65, Anna D’Errico66, Rafieh Alizadeh67, , Robert Pellegrino68, Pablo Meyer69, Caroline Huart70, Ben Chen71, Graciela M. Soler72, Mohammed K. Alwashahi73, Antje Welge-Lüssen74, Jessica Freiherr75, , Jasper H. B. de Groot76, Hadar Klein4, Masako Okamoto77, Preet Bano Singh78, Julien W. Hsieh79, GCCR Group Author, Danielle R. Reed30, Thomas Hummel80, Steven D. Munger81,82 and John E.Hayes6, 1Department of Psychology, Temple University, 1701 N 13th St, Philadelphia, PA 19122, USA, 2Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Wilhelm-Johnen-Straße, 52428 Jülich, Germany, 3Department of Anatomy, Faculty of Medicine, Mersin University, Çiftlikköy Campus, Yenişehir, 33343 Mersin, Turkey, 4Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, PO Box 12, Rehovot 7610001, Israel, 5AbScent, 14 London Street, Andover, Hampshire SP10 2PA, UK, 6Department of Food Science, The Pennsylvania State University, Erickson Food Science Building, University Park, PA 16802, USA, 7Center for the Neurobiology of Learning and Memory, University of California and Qureshey Research Laboratory, 506 C Student Center, Irvine, CA 92697-0001, USA, 8Institut de Chimie de Nice, UMR CNRS 7272, Université Côte d’Azur, 28 Avenue Valrose, 06108 Nice, France, 9 Centre for Global Health Research, Usher Institute, The University of Edinburgh, Old Medical School, Teviot Place, Edinburgh EH8 9AG, UK, 10Department of Basic Medical Sciences, Neuroscience and Sensory Organs, Università degli Studi di Bari A. Moro, P.zza G. Cesare 11, Bari 70124, Italy, 11CSIR-Central Scientific Instruments Organisation, Sec 30-C, Chandigarh 160030, India, 12Department of Medical and Surgical Sciences, “Magna Graecia” University of Catanzaro, Viale Europa (Loc. Germaneto), 88100 Catanzaro, Italy, 13Department of Food Science and Human Nutrition and Division of Nutritional Sciences, University of Illinois at Urbana Champaign, 905 South Goodwin Avenue, Urbana, IL 61801, USA, 14Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria, 15Laboratoire d’Anthropologie Moléculaire et Imagerie de Synthese, UMR 5288 CNRS, Universitéde Toulouse, 31073 Toulouse, France, 16National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK Campus, Bellary Road, Bengaluru 560065, India, 17School of Life Sciences, Arizona State University, PO Box 874501, Tempe, AZ 85287, USA, 18Department of Psychology and Anthropology, University of Extremadura, Avenida de la Universidad, s/n, 10003 Cáceres, Spain, 19Department of General Psychology, University of Padova, Via Venezia 8, 35131 Padova, Italy, 20Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA, 21School of Exercise and Nutritional Sciences, 5500 Campanile Drive, San Diego State University, San Diego, CA 92182, USA, 22Flavour Clinic, Department of Otorhinolaryngology, Regional Hospital West Jutland, Central Denmark Region, Laegaardvej 12, 7500 Holstebro, Denmark, 23Biocomputation Group, Department of Computer Science, University of Hertfordshire, Hatfield AL10 9AB, UK, 24Neuroscience Area, International School for Advanced Studies, SISSA, Via Bonomea 265, 34136 Trieste, Italy, 25Neuropop Team, Lyon Neuroscience Research Center, CNRS UMR5292—INSERM U1028—University Claude Bernard Lyon 1, 95 bd Pinel, 69500 Bron, France, 26Department of Food and Nutrition, University of Helsinki, PO Box 66, FI-00014 Helsinki, Finland,

The initial step in the sensation and discrimination of ingested material is the detection of chemicals by taste receptor proteins. Taste stimuli are typically categorized based on human perceptual qualities: sweet, salty, sour, bitter or umami. Mammalian sweet, bitter and umami taste receptors are members of the large G protein-coupled receptor superfamily, while receptors for salty and sour stimuli are ion channels. Stimulation of taste receptors expressed on taste receptor cells within the oral cavity leads to signal transduction, neurotransmitter release and propagation of sensory information via afferent nerves to taste processing areas in the central nervous system.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the “Identifying Treatments for Taste and Smell Disorders” conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.

Animals use social communication to learn important information from conspecifics that can guide appropriate behavioral choices. For example, during the social transmission of food preference (STFP), conspecific semiochemicals detected by mouse olfactory sensory neurons (OSNs) expressing the atypical olfactory receptor guanylyl cyclase D (GC-D+ OSNs) promote the acquisition of food preferences in the recipient animal, mitigating the risk of ingesting food contaminated with toxins or pathogens. However, it is unclear if GC-D+ OSNs mediate preference learning outside this specific context. Here, we report that GC-D+ OSNs are required for the acquisition of odor preferences by both adult and juvenile mice, and that GC-DD-dependent preference could be formed for conditionally aversive odors. We used a two-choice olfactory behavioral test to assess odor preferences in adult Gucy2d +/+, +/- and -/- mice that encountered novel odors together with GC-D+ OSN stimuli (guanylin family peptides), during social investigation of a live conspecific, or during suckling as pups. Gucy2d +/+ and +/- mice (which express functional GC-D), but not Gucy2d -/- littermates, successfully acquire a preference for the demonstrated odor in any of these behavioral paradigms. Mice could even acquire a GC-D-dependent preference for odors to which they had recently formed a conditioned aversion. Together, these results demonstrate that GC-D+ OSNs mediate the acquisition of socially-transmitted odor preferences in different social and experiential contexts and at different life stages.