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The special AT-rich sequence-binding (SATB) protein DVE-1 is widely recognized for its pivotal involvement in orchestrating the retrograde mitochondrial unfolded protein response (mitoUPR) in C. elegans. In our study of downstream factors contributing to lifespan extension in sensory ciliary mutants, we find that DVE-1 is crucial for this longevity effect independent of its canonical mitoUPR function. Additionally, DVE-1 also influences lifespan under conditions of dietary restriction and germline loss, again distinct from its role in mitoUPR. Mechanistically, while mitochondrial stress typically prompts nuclear accumulation of DVE-1 to initiate the transcriptional mitoUPR program, these long-lived mutants reduce DVE-1 nuclear accumulation, likely by enhancing its cytosolic translocation. This observation suggests a cytosolic role for DVE-1 in lifespan extension. Overall, our study implies that, in contrast to the more narrowly defined role of the mitoUPR-related transcription factor ATFS-1, DVE-1 may possess broader functions than previously recognized in modulating longevity and defending against stress., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Angiotensin-II (Ang-II) production is driven by deviations in blood volume and osmolality, and serves the role of regulating blood pressure and fluid intake to maintain cardiovascular and hydromineral homeostasis. These actions are mediated by Ang-II acting on its type 1a receptor (AT1aR) within the central nervous system and periphery. Of relevance, AT1aR are expressed on sensory afferents responsible for conveying cardiovascular information to the nucleus of the solitary tract (NTS). We have previously determined that optical excitation of neurons and vagal afferents within the NTS that express AT1aR (referred to as NTS AT1aR ) mimics the perception of increased vascular stretch and induces compensatory responses to restore blood pressure. Here, we test whether NTS AT1aR are also involved in the modulation of water and sodium intake. We directed the light-sensitive excitatory channelrhodopsin-2 (ChR2) or inhibitory halorhodopsin (Halo) to Agtr1a-containing neurons and measured water and sodium chloride (NaCl) intake in the presence and absence of optical stimulation within the NTS during various challenges to fluid homeostasis. Optical perturbation of NTS AT1aR modulates NaCl intake, such that excitation attenuates, whereas inhibition increases intake. This effect is only observed in the water-deprived condition, suggesting that NTS AT1aR are involved in the regulation of sodium intake during an imbalance in both the intracellular and extracellular fluid compartments. Furthermore, optical excitation of NTS AT1aR increases c-Fos expression within oxytocinergic neurons of the paraventricular nucleus of the hypothalamus (PVN), indicating that the regulation of sodium intake by NTS AT1aR may be mediated by oxytocin. Collectively, these results reveal that NTS AT1aR are sufficient and necessary to modulate sodium intake relative to perceived changes in vascular stretch., (Copyright © 2024. Published by Elsevier Inc.)

Distinct basolateral amygdala (BLA) cell populations influence emotional responses in manners thought important for anxiety and anxiety disorders. The BLA contains numerous cell types which can broadcast information into structures that may elicit changes in emotional states and behaviors. BLA excitatory neurons can be divided into two main classes, one of which expresses Ppp1r1b (encoding protein phosphatase 1 regulatory inhibitor subunit 1B) which is downstream of the genes encoding the D1 and D2 dopamine receptors ( drd1 and drd2 respectively). The role of drd1+ or drd2+ BLA neurons in learned and unlearned emotional responses is unknown. Here, we identified that the drd1 + and drd2 + BLA neuron populations form two parallel pathways for communication with the ventral striatum. These neurons arise from the basal nucleus of the BLA, innervate the entire space of the ventral striatum, and are capable of exciting ventral striatum neurons. Further, through three separate behavioral assays, we found that the drd1 + and drd2 + parallel pathways bidirectionally influence both learned and unlearned emotional states when they are activated or suppressed, and do so depending upon where they synapse in the ventral striatum - with unique contributions of drd1 + and drd2 + circuitry on negative emotional states. Overall, these results contribute to a model whereby parallel, genetically-distinct BLA to ventral striatum circuits inform emotional states in a projection-specific manner., Competing Interests: Conflict of interest statement: The authors declare no competing financial interests.

Olfaction is essential for complex social behavior in insects. To discriminate complex social cues, ants evolved an expanded number of odorant receptor ( Or ) genes. Mutations in the obligate odorant co-receptor gene orco lead to the loss of ~80% of the antennal lobe glomeruli in the jumping ant Harpegnathos saltator . However, the cellular mechanism remains unclear. Here, we demonstrate massive apoptosis of odorant receptor neurons (ORNs) in the mid to late stages of pupal development, possibly due to ER stress in the absence of Orco. Further bulk and single-nucleus transcriptome analysis shows that, although most orco -expressing ORNs die in orco mutants, a small proportion of them survive: They express ionotropic receptor ( Ir ) genes that form IR complexes. In addition, we found that some Or genes are expressed in mechanosensory neurons and nonneuronal cells, possibly due to leaky regulation from nearby non- Or genes. Our findings provide a comprehensive overview of ORN development and Or expression in H. saltator .

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.

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NG AT1aR ) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a -Cre mice and Cre-dependent AAVs to direct tdTomato to NG AT1aR , neuroanatomical studies revealed that NG AT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NG AT1aR , we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a -containing neurons. Two-photon intravital imaging in Agtr1a -GCaMP6s mice revealed that NG AT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NG AT1aR at their soma or axon terminals within the caudal NTS of Agtr1a -ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NG AT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NG AT1aR and suggest that such neurons may be exploited to discern and relieve hypertension., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional complexes, prevalent in inflammatory bowel diseases and irritable bowel syndrome, compromise barrier integrity and often lead to the notorious "leaky gut" syndrome. Critical to the maintenance of the intestinal barrier is a finely orchestrated network of intrinsic and extrinsic factors that modulate the expression, composition, and functionality of junctional complexes. This review navigates through the composition of key junctional complex components and the common methods used to assess intestinal permeability. It also explores the critical intracellular signaling pathways that modulate these junctional components. Lastly, we delve into the complex dynamics between the junctional complexes, microbial communities, and environmental chemicals in shaping the intestinal barrier function. Comprehending this intricate interplay holds paramount importance in unraveling the pathophysiology of gastrointestinal disorders. Furthermore, it lays the foundation for the development of precise therapeutic interventions targeting barrier dysfunction.

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., Competing Interests: Declaration of Competing Interest SDM, JEH, and RCG each hold equity in Redolynt, LLC, which they co-founded in 2021. This financial interest has been reviewed by the Individual Conflict of Interest Committee at each of their respective universities and is being actively managed by each university. None of the other authors have any conflicts to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

As a universal mechanical cue, shear stress plays essential roles in many physiological processes, ranging from vascular morphogenesis and remodeling to renal transport and airway barrier function. Disrupted shear stress is commonly regarded as a major contributor to various human diseases such as atherosclerosis, hypertension, and chronic kidney disease. Despite the importance of shear stress in physiology and pathophysiology, our current understanding of mechanosensors that sense shear stress is far from complete. An increasing number of candidate mechanosensors have been proposed to mediate shear stress sensing in distinct cell types, including G protein-coupled receptors (GPCRs), G proteins, receptor tyrosine kinases, ion channels, glycocalyx proteins, and junctional proteins. Although multiple types of mechanosensors might be able to convert shear stress into downstream biochemical signaling events, in this review, we will focus on discussing the mechanosensitive GPCRs (angiotensin II type 1 receptor, GPR68, histamine H1 receptor, adhesion GPCRs) and ion channels (Piezo, TRP) that have been reported to be directly activated by shear stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Living organisms possess the ability to respond to environmental cues and adapt their behaviors and physiologies for survival. Eusocial insects, such as ants, bees, wasps, and termites, have evolved advanced sociality: living together in colonies where individuals innately develop into reproductive and non-reproductive castes. These castes exhibit remarkably distinct behaviors and physiologies that support their specialized roles in the colony. Among ant species, Harpegnathos saltator females stand out with their highly plastic caste phenotypes that can be easily manipulated in a laboratory environment. In this protocol, we provide detailed instructions on how to generate H. saltator ant colonies, define castes based on behavioral and physiological phenotypes, and experimentally induce caste switches, including the transition from a non-reproductive worker to a reproductive gamergate and vice versa (known as reversion). The unusual features of H. saltator make it a valuable tool to investigate cellular and molecular mechanisms underlying phenotypic plasticity in eusocial organisms. Key features H. saltator is one of few ant species showing remarkable caste plasticity with striking phenotypic changes, being a useful subject for studying behavioral plasticity. Caste switches in H. saltator can be easily manipulated in a controlled laboratory environment by controlling the presence of reproductive females in a colony. The relatively large size of H. saltator females allows researchers to dissect various tissues of interest and conduct detailed phenotypic analyses., Competing Interests: Competing interestsThe authors have no competing interests to declare., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY-NC license.)

Nicotine is an addictive drug whose popularity has recently increased, particularly among adolescents, because of the availability of electronic nicotine devices (i.e., "vaping") and nicotine e-liquids containing additives with rich chemosensory properties. Some efforts to understand the role of these additives in nicotine reward suggest that they increase nicotine reward and reinforcement, but the sensory contributions of additives, especially in their vapor forms, are largely untested. Here, to better understand how a fruit-flavored (i.e., strawberry) additive influences nicotine reward and aversion, we used a conditioned place preference (CPP) procedure in which nicotine and a strawberry additive were delivered as a vapor to male and female adolescent mice. We found that nicotine vapor alone can lead to a dose-dependent CPP when using a biased design. The strawberry additive did not produce CPP on its own, and we did not observe an effect of the strawberry additive on nicotine vapor-induced reward. Nevertheless, mice exposed to nicotine plus strawberry additive vapor had higher plasma cotinine concentrations, which did not appear to reflect altered nicotine metabolism. Instead, by directly measuring vapor sampling through respiration monitoring, we uncovered an increase in the amount of sniffing toward strawberry-containing nicotine vapor compared with nicotine vapor alone. Together these data indicate that chemosensory-rich e-liquid additives may enhance the perceived sensory profile of nicotine vapors rather than the reward value per se, which leads to overall increased nicotine exposure., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Patten et al.)

Background: Disorders of the sense of smell have received greater attention because of the frequency with which they occur as a symptom of SARS-CoV-2 infection. Olfactory dysfunction can lead to profound reduction in quality of life and may arise from many different causes., Methods: A selective literature review was conducted with consideration of the current version of the guideline issued by the Association of the Scientific Medical Societies in Germany., Results: The cornerstones of diagnosis are the relevant medical history and psychophysical testing of olfactory function using standardized validated tests. Modern treatment strategies are oriented on the cause of the dysfunction. While treatment of the underlying inflammation takes precedence in patients with sinunasal dysosmia, olfactory training is the primary treatment option for other forms of the disorder. The prognosis is determined not only by the cause of the olfactory dysfunction and the patient's age, but also by the olfactory performance as measured at the time of diagnosis., Conclusion: Options for the treatment of olfactory dysfunction are available but limited, depending on the cause. It is therefore important to carry out a detailed diagnostic work-up and keep the patient informed of the expected course and prognosis.

Primary cilia are cellular appendages critical for diverse types of Signaling. They are found on most cell types, including cells throughout the CNS. Cilia preferentially localize certain G-protein-coupled receptors (GPCRs) and are critical for mediating the signaling of these receptors. Several of these neuronal GPCRs have recognized roles in feeding behavior and energy homeostasis. Cell and model systems, such as Caenorhabditis elegans and Chlamydomonas , have implicated both dynamic GPCR cilia localization and cilia length and shape changes as key for signaling. It is unclear whether mammalian ciliary GPCRs use similar mechanisms in vivo and under what conditions these processes may occur. Here, we assess two neuronal cilia GPCRs, melanin-concentrating hormone receptor 1 (MCHR1) and neuropeptide-Y receptor 2 (NPY2R), as mammalian model ciliary receptors in the mouse brain. We test the hypothesis that dynamic localization to cilia occurs under physiological conditions associated with these GPCR functions. Both receptors are involved in feeding behaviors, and MCHR1 is also associated with sleep and reward. Cilia were analyzed with a computer-assisted approach allowing for unbiased and high-throughput analysis. We measured cilia frequency, length, and receptor occupancy. We observed changes in ciliary length, receptor occupancy, and cilia frequency under different conditions for one receptor but not another and in specific brain regions. These data suggest that dynamic cilia localization of GPCRs depends on properties of individual receptors and cells where they are expressed. A better understanding of subcellular localization dynamics of ciliary GPCRs could reveal unknown molecular mechanisms regulating behaviors like feeding., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Brewer et al.)

Background: Sensory perception is profoundly shaped by attention. Attending to an odor strongly regulates if and how it is perceived - yet the brain systems involved in this process are unknown. Here we report integration of the medial prefrontal cortex (mPFC), a collection of brain regions integral to attention, with the olfactory system in the context of selective attention to odors., Methods: First, we used tracing methods to establish the tubular striatum (TuS, also known as the olfactory tubercle) as the primary olfactory region to receive direct mPFC input in rats. Next, we recorded (i) local field potentials from the olfactory bulb (OB), mPFC, and TuS, or (ii) sniffing, while rats completed an olfactory selective attention task., Results: Gamma power and coupling of gamma oscillations with theta phase were consistently high as rats flexibly switched their attention to odors. Beta and theta synchrony between mPFC and olfactory regions were elevated as rats switched their attention to odors. Finally, we found that sniffing was consistent despite shifting attentional demands, suggesting that the mPFC-OB theta coherence is independent of changes in active sampling., Conclusions: Together, these findings begin to define an olfactory attention network wherein mPFC activity, as well as that within olfactory regions, are coordinated based upon attentional states., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sodium (Na + ) is crucial for numerous homeostatic processes in the body and, consequentially, its levels are tightly regulated by multiple organ systems. Sodium is acquired from the diet, commonly in the form of NaCl (table salt), and substances that contain sodium taste salty and are innately palatable at concentrations that are advantageous to physiological homeostasis. The importance of sodium homeostasis is reflected by sodium appetite, an "all-hands-on-deck" response involving the brain, multiple peripheral organ systems, and endocrine factors, to increase sodium intake and replenish sodium levels in times of depletion. Visceral sensory information and endocrine signals are integrated by the brain to regulate sodium intake. Dysregulation of the systems involved can lead to sodium overconsumption, which numerous studies have considered causal for the development of diseases, such as hypertension. The purpose here is to consider the inverse-how disease impacts sodium intake, with a focus on stress-related and cardiometabolic diseases. Our proposition is that such diseases contribute to an increase in sodium intake, potentially eliciting a vicious cycle toward disease exacerbation. First, we describe the mechanism(s) that regulate each of these processes independently. Then, we highlight the points of overlap and integration of these processes. We propose that the analogous neural circuitry involved in regulating sodium intake and blood pressure, at least in part, underlies the reciprocal relationship between neural control of these functions. Finally, we conclude with a discussion on how stress-related and cardiometabolic diseases influence these circuitries to alter the consumption of sodium.

Olfactory sensory neurons (OSNs) form embryonically and mature perinatally, innervating glomeruli and extending dendrites with multiple cilia. This process and its timing are crucial for odor detection and perception and continues throughout life. In the olfactory epithelium (OE), differentiated OSNs proceed from an immature (iOSN) to a mature (mOSN) state through well-defined sequential morphological and molecular transitions, but the precise mechanisms controlling OSN maturation remain largely unknown. We have identified that a GTPase, ARL13B, has a transient and maturation state-dependent expression in OSNs marking the emergence of a primary cilium. Utilizing an iOSN-specific Arl13b-null murine model, we examined the role of ARL13B in the maturation of OSNs. The loss of Arl13b in iOSNs caused a profound dysregulation of the cellular homeostasis and development of the OE. Importantly, Arl13b null OSNs demonstrated a delay in the timing of their maturation. Finally, the loss of Arl13b resulted in severe deformation in the structure and innervation of glomeruli. Our findings demonstrate a previously unknown role of ARL13B in the maturation of OSNs and development of the OE., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Olfactory cilia are the obligate transducers of the odorant signal, and thus their study has been a focus of investigation in the olfactory field. Various methodologies have been established to visualize the cilia of olfactory sensory neurons; however, these approaches are limited to static imaging and often lack the ability to resolve individual cilia projecting from solitary neurons in the postnatal mouse. Here we detail a procedure of the visualization of olfactory cilia by ectopic expression of fluorescently tagged proteins. The procedure can be used for the observation and manipulation of the olfactory cilia and ciliary proteins in both static and dynamic conditions., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Sniffing is a commonly displayed behavior in rodents, yet how this important behavior adjusts throughout development to meet the sensory demands of the animals has remained largely unexplored. In this issue of Chemical Senses, Boulanger-Bertolus et al. investigates the ontogeny of odor-evoked sniffing through a longitudinal study of rats engaged in several olfactory paradigms from infancy to adulthood. The results of this study yield a cohesive picture of sniffing behavior across three developmental stages, while also providing direct comparisons within subjects between these timepoints. As we discuss herein, these results advance the field in relation to existing literature on the development of odor-evoked sniffing behavior in several important ways., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

In most organisms, reproduction is correlated with shorter life span. However, the reproductive queen in eusocial insects exhibits a much longer life span than that of workers. In Harpegnathos ants, when the queen dies, workers can undergo an adult caste switch to reproductive pseudo-queens (gamergates), exhibiting a five-times prolonged life span. To explore the relation between reproduction and longevity, we compared gene expression during caste switching. Insulin expression is increased in the gamergate brain that correlates with increased lipid synthesis and production of vitellogenin in the fat body, both transported to the egg. This results from activation of the mitogen-activated protein kinase (MAPK) branch of the insulin signaling pathway. By contrast, the production in the gamergate developing ovary of anti-insulin Imp-L2 leads to decreased signaling of the AKT/forkhead box O (FOXO) branch in the fat body, which is consistent with their extended longevity.

Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet-Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration. Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of inositol polyphosphate-5-phosphatase E (INPP5E) restored cilia length and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2/F-actin-dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan-therapeutic intervention targets for the treatment of ciliopathies.

The olfactory sensory neurons (OSNs) of the olfactory epithelium (OE) exhibit a remarkable regenerative capability, which protects the population against environmental insult and enables adjustment to new odors. The lifespan of OSNs is still open to question, with estimates ranging from 1 month to at least 1 year. However, the estimates come with some caveats, including low labeling efficiency and a focus solely on newborn neurons. We revisited the issue via the use of OMP-tTA; TetO-Cre; Rosa26-fl(stop)-Tdtomato (OMP-tTA;TdT) mice, which allowed us to selectively label ∼95% of the OMP(+) OSN population that reach maturity by a given time and, by switching to doxycycline chow, to "chase" this preexisting OSN population. Two loading protocols were used: conception to 2 months old and conception to 4.5 months old. Surviving OSNs were common up to 6 months chase time in both groups, but more neurons survived when loading for 4.5 months as compared with 2 months. A spatial difference was evident: higher percentages of OSNs survived in the dorsomedial OE as compared with ventrolateral and in posterior versus anterior OE regions. Finally, proliferation rates anticorrelated with the spatial differences in OSN survival; higher proliferation rates were observed ventrally. Together, these results demonstrate spatial and temporal differences in OSN survival, highlighting it as a dynamic system that can be studied for factors affecting neuronal survival., (© 2022 Wiley Periodicals LLC.)

While rates of smoking combustible cigarettes in the United States have trended down in recent years, use of electronic cigarettes (e-cigarettes) has dramatically increased, especially among adolescents. The vast majority of e-cigarette users consume "flavored" products that contain a variety of chemosensory-rich additives, and recent literature suggests that these additives have led to the current "teen vaping epidemic." This review, covering research from both human and rodent models, provides a comprehensive overview of the sensory implications of e-cigarette additives and what is currently known about their impact on nicotine use. In doing so, we specifically address the oronasal sensory contributions of e-cigarette additives. Finally, we summarize the existing gaps in the field and highlight future directions needed to better understand the powerful influence of these additives on nicotine use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Johnson, Patten, Ma, De Biasi and Wesson.)

Brain-derived 17β-estradiol (E2) confers rapid effects on neural activity. The tubular striatum (TuS, also called the olfactory tubercle) is both capable of local E2 synthesis due to its abundant expression of aromatase and is a critical locus for odor-guided motivated behavior and odor hedonics. TuS neurons also contain mRNA for estrogen receptors α, β, and the G protein-coupled estrogen receptor. We demonstrate here that mRNA for estrogen receptors appears to be expressed upon TuS dopamine 1 receptor-expressing neurons, suggesting that E2 may play a neuromodulatory role in circuits which are important for motivated behavior. Therefore, we reasoned that E2 in the TuS may influence attraction to urinary odors which are highly attractive. Using whole-body plethysmography, we examined odor-evoked high-frequency sniffing as a measure of odor attaction. Bilateral infusion of the aromatase inhibitor letrozole into the TuS of gonadectomized female adult mice induced a resistance to habituation over successive trials in their investigatory sniffing for female mouse urinary odors, indicative of an enhanced attraction. All males displayed resistance to habituation for female urinary odors, indicative of enhanced attraction that is independent from E2 manipulation. Letrozole's effects were not due to group differences in basal respiration, nor changes in the ability to detect or discriminate between odors (both monomolecular odorants and urinary odors). Therefore, de novo E2 synthesis in the TuS impacts females' but not males' attraction to female urinary odors, suggesting a sex-specific influence of E2 in odor hedonics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The lipid composition of the primary cilia membrane is emerging as a critical regulator of cilia formation, maintenance and function. Here, we show that conditional deletion of the phosphoinositide 5'-phosphatase gene Inpp5e, mutation of which is causative of Joubert syndrome, in terminally developed mouse olfactory sensory neurons (OSNs), leads to a dramatic remodeling of ciliary phospholipids that is accompanied by marked elongation of cilia. Phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], which is normally restricted to the proximal segment redistributed to the entire length of cilia in Inpp5e knockout mice with a reduction in phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] and elevation of phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P3] in the dendritic knob. The redistribution of phosphoinositides impaired odor adaptation, resulting in less efficient recovery and altered inactivation kinetics of the odor-evoked electrical response and the odor-induced elevation of cytoplasmic Ca2+. Gene replacement of Inpp5e through adenoviral expression restored the ciliary localization of PI(4,5)P2 and odor response kinetics in OSNs. Our findings support the role of phosphoinositides as a modulator of the odor response and in ciliary biology of native multi-ciliated OSNs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Iron is indispensable for normal body functions across species because of its critical roles in red blood cell function and many essential proteins and enzymes required for numerous physiological processes. Regulation of iron homeostasis is an intricate process involving multiple modulators at the systemic, cellular, and molecular levels. Interestingly, emerging evidence has demonstrated that many modulators of iron homeostasis contribute to organismal aging and longevity. On the other hand, the age-related dysregulation of iron homeostasis is often associated with multiple age-related pathologies including bone resorption and neurodegenerative diseases such as Alzheimer's disease. Thus, a thorough understanding on the interconnections between systemic and cellular iron balance and organismal aging may help decipher the etiologies of multiple age-related diseases, which could ultimately lead to developing therapeutic strategies to delay aging and treat various age-related diseases. Here we present the current understanding on the mechanisms of iron homeostasis. We also discuss the impacts of aging on iron homeostatic processes and how dysregulated iron metabolism may affect aging and organismal longevity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Bardet-Biedl syndrome (BBS) is a hereditary genetic disorder that results in numerous clinical manifestations including olfactory dysfunction. Of at least 21 BBS-related genes that can carry multiple mutations, a pathogenic mutation, BBS1M390R, is the single most common mutation of clinically diagnosed BBS outcomes. While the deletion of BBS-related genes in mice can cause variable penetrance in different organ systems, the impact of the Bbs1M390R mutation in the olfactory system remains unclear. Using a clinically relevant knock-in mouse model homozygous for Bbs1M390R, we investigated the impact of the mutation on the olfactory system and tested the potential of viral-mediated, wildtype gene replacement therapy to rescue smell loss. The cilia of olfactory sensory neurons (OSNs) in Bbs1 M390R/M390R mice were significantly shorter and fewer than those of wild-type mice. Also, both peripheral cellular odor detection and synaptic-dependent activity in the olfactory bulb were significantly decreased in the mutant mice. Furthermore, to gain insight into the degree to which perceptual features are impaired in the mutant mice, we used whole-body plethysmography to quantitatively measure odor-evoked sniffing. The Bbs1 M390R/M390R mice showed significantly higher odor detection thresholds (reduced odor sensitivity) compared to wild-type mice; however, their odor discrimination acuity was still well maintained. Importantly, adenoviral expression of Bbs1 in OSNs restored cilia length and re-established both peripheral odorant detection and odor perception. Together, our findings further expand our understanding for the development of gene therapeutic treatment for congenital ciliopathies in the olfactory system., (© 2021 Federation of American Societies for Experimental Biology.)

Cilia on neurons play critical roles in both the development and function of the central nervous system (CNS). While it remains challenging to elucidate the precise roles for neuronal cilia, it is clear that a subset of G-protein-coupled receptors (GPCRs) preferentially localize to the cilia membrane. Further, ciliary GPCR signaling has been implicated in regulating a variety of behaviors. Melanin concentrating hormone receptor 1 (MCHR1), is a GPCR expressed centrally in rodents known to be enriched in cilia. Here we have used MCHR1 as a model ciliary GPCR to develop a strategy to fluorescently tag receptors expressed from the endogenous locus in vivo. Using CRISPR/Cas9, we inserted the coding sequence of the fluorescent protein mCherry into the N-terminus of Mchr1. Analysis of the fusion protein ( mCherry MCHR1) revealed its localization to neuronal cilia in the CNS, across multiple developmental time points and in various regions of the adult brain. Our approach simultaneously produced fortuitous in/dels altering the Mchr1 start codon resulting in a new MCHR1 knockout line. Functional studies using electrophysiology show a significant alteration of synaptic strength in MCHR1 knockout mice. A reduction in strength is also detected in mice homozygous for the mCherry insertion, suggesting that while the strategy is useful for monitoring the receptor, activity could be altered. However, both lines should aid in studies of MCHR1 function and contribute to our understanding of MCHR1 signaling in the brain. Additionally, this approach could be expanded to aid in the study of other ciliary GPCRs., (© 2021 Wiley Periodicals LLC.)

Proteotoxic stress is a common challenge for all organisms. Among various mechanisms involved in defending such stress, the evolutionarily conserved unfolded protein responses (UPRs) play a key role across species. Interestingly, UPRs can occur in different subcellular compartments including the endoplasmic reticulum (UPR ER ), mitochondria (UPR MITO ), and cytoplasm (UPR CYTO ) through distinct mechanisms. While previous studies have shown that the UPRs are intuitively linked to organismal aging, a systematic assay on the temporal regulation of different type of UPRs during aging is still lacking. Here, using Caenorhabditis elegans (C. elegans) as the model system, we found that the endogenous UPRs (UPR ER , UPR MITO , and UPR CYTO ) elevate with age, but their inducibility exhibits an age-dependent decline. Moreover, we revealed that the temporal requirements to induce different types of UPRs are distinct. Namely, while the UPR MITO can only be induced during the larval stage, the UPR ER can be induced until early adulthood and the inducibility of UPR CYTO is well maintained until mid-late stage of life. Furthermore, we showed that different tissues may exhibit distinct temporal profiles of UPR inducibility during aging. Collectively, our findings demonstrate that UPRs of different subcellular compartments may have distinct temporal mechanisms during aging., (© 2020 Wiley Periodicals LLC.)

Eusocial insects, such as bees, ants, and wasps of the Hymenoptera and termites of the Blattodea, are able to generate remarkable diversity in morphology and behavior despite being genetically uniform within a colony. Most eusocial insect species display caste structures in which reproductive ability is possessed by a single or a few queens while all other colony members act as workers. However, in some species, caste structure is somewhat plastic, and individuals may switch from one caste or behavioral phenotype to another in response to certain environmental cues. As different castes normally share a common genetic background, it is believed that much of this observed within-colony diversity results from transcriptional differences between individuals. This suggests that epigenetic mechanisms, featured by modified gene expression without changing genes themselves, may play an important role in eusocial insects. Indeed, epigenetic mechanisms such as DNA methylation, histone modifications and non-coding RNAs, have been shown to influence eusocial insects in multiple aspects, along with typical genetic regulation. This review summarizes the most recent findings regarding such mechanisms and their diverse roles in eusocial insects.

Functional characterization of mammalian olfactory receptors (ORs) remains a major challenge to ultimately understanding the olfactory code. Here, we compare the responses of the mouse Olfr73 ectopically expressed in olfactory sensory neurons using AAV gene delivery in vivo and expressed in vitro in cell culture. The response dynamics and concentration-dependence of agonists for the ectopically expressed Olfr73 were similar to those reported for the endogenous Olfr73, however the antagonism previously reported between its cognate agonist and several antagonists was not replicated in vivo. Expressing the OR in vitro reproduced the antagonism reported for short odor pulses, but not for prolonged odor exposure. Our findings suggest that both the cellular environment and the stimulus dynamics shape the functionality of Olfr73 and argue that characterizing ORs in 'native' conditions, rather than in vitro, provides a more relevant understanding of ligand-OR interactions.

Phenotypic plasticity allows organisms to respond to changing environments throughout their lifetime, but these changes are rarely reversible. Exceptions occur in relatively long-lived vertebrate species that exhibit seasonal plasticity in brain size, although similar changes have not been identified in short-lived species, such as insects. Here, we investigate brain plasticity in reproductive workers of the ant Harpegnathos saltator . Unlike most ant species, workers of H. saltator are capable of sexual reproduction, and they compete in a dominance tournament to establish a group of reproductive workers, termed 'gamergates'. We demonstrated that, compared to foragers, gamergates exhibited a 19% reduction in brain volume in addition to significant differences in behaviour, ovarian status, venom production, cuticular hydrocarbon profile, and expression profiles of related genes. In experimentally manipulated gamergates, 6-8 weeks after being reverted back to non-reproductive status their phenotypes shifted to the forager phenotype across all traits we measured, including brain volume, a trait in which changes were previously shown to be irreversible in honeybees and Drosophila . Brain plasticity in H. saltator is therefore more similar to that found in some long-lived vertebrates that display reversible changes in brain volume throughout their lifetimes.

Olfactory perception is a complicated process involving multiple cortical and subcortical regions, of which the underlying brain dynamics are still not adequately mapped. Even in the definition of the olfactory primary cortex, there is a large degree of variation in parcellation templates used for investigating olfaction in neuroimaging studies. This complicates comparison between human olfactory neuroimaging studies. The present study aims to validate an olfactory parcellation template derived from both functional and anatomical data that applies structural connectivity (SC) to ensure robust connectivity to key secondary olfactory regions. Furthermore, exploratory analyses investigate if different olfactory parameters are associated with differences in the strength of connectivity of this structural olfactory fingerprint. By combining diffusion data with an anatomical atlas and advanced probabilistic tractography, we found that the olfactory parcellation had a robust SC network to key secondary olfactory regions. Furthermore, the study indicates that higher ratings of olfactory significance were associated with increased intra- and inter-hemispheric SC of the primary olfactory cortex. Taken together, these results suggest that the patterns of SC between the primary olfactory cortex and key secondary olfactory regions has potential to be used for investigating the nature of olfactory significance, hence strengthening the theory that individual differences in olfactory behaviour are encoded in the structural network fingerprint of the olfactory cortex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fjaeldstad, Stiller-Stut, Gleesborg, Kringelbach, Hummel and Fernandes.)

Social behavior is one of the most fascinating and complex behaviors in humans and animals. A fundamental process of social behavior is communication among individuals. It relies on the capability of the nervous system to sense, process, and interpret various signals (e.g., pheromones) and respond with appropriate decisions and actions. Eusocial insects, including ants, some bees, some wasps, and termites, display intriguing cooperative social behavior. Recent advances in genetic and genomic studies have revealed key genes that are involved in pheromone synthesis, chemosensory perception, and physiological and behavioral responses to varied pheromones. In this review, we highlight the genes and pathways that regulate queen pheromone-mediated social communication, discuss the evolutionary changes in genetic systems, and outline prospects of functional studies in sociobiology., (© 2021 Yan and Liebig; Published by Cold Spring Harbor Laboratory Press.)

As an ancient cellular co-factor ubiquitously present in all domains of life, nearly all iron-sulfur ([Fe-S]) clusters are assembled in the mitochondrion. Although multiple mitochondrion-derived signalings are known to be key players in longevity regulation, whether the mitochondrial [Fe-S] cluster assembly machinery modulates lifespan is previously unknown. Here, we find that ISCU-1, the C. elegans ortholog of the evolutionarily conserved iron-sulfur cluster (ISC) assembly machinery central protein ISCU, regulates longevity and stress response. Specifically, ISCU-1 accelerates aging in the intestine. Moreover, we identify the Nrf2 transcription factor SKN-1 and a nuclear hormone receptor NHR-49 as the downstream factors of ISCU-1. Lastly, a mitochondrial outer membrane protein phosphatase PGAM-5 appears to link ISCU-1 to SKN-1 and NHR-49 in lifespan regulation. Together, we have identified a novel function of mitochondrial ISC assembly machinery in longevity modulation and stress response.

Amino acid substitutions within the conserved polypeptide sequence of the insect olfactory receptor co-receptor (Orco) have been demonstrated to influence its pharmacological properties. By sequence analysis and phylogenetic investigation, in the Lepidopteran subgroup Ditrysia we identified a fixed substitution in the intracellular loop-3 (ICL-3) of a conserved histidine to glutamine. By means of HEK293 cells as a heterologous system, we functionally expressed Orco from the Ditrysian model Cydia pomonella (CpomOrco) and compared its functional properties with a site-directed mutagenized version where this ICL-3-glutamine was reverted to histidine (CpomOrco Q417H ). The mutagenized CpomOrco Q417H displayed decreased responsiveness to VUAA1 and reduced response efficacy to an odorant agonist was observed, when co-transfected with the respective OR subunit. Evidence of reduced responsiveness and sensitivity to ligands for the mutagenized Orco suggest the fixed glutamine substitution to be optimized for functionality of the cation channel within Ditrysia. In addition, contrary to the wild type, the mutagenized CpomOrco Q417H preserved characteristics of VUAA-binding when physiologic conditions turned to acidic. Taken together, our findings provide further evidence of the importance of ICL-3 in forming basic functional properties of insect Orco- and Orco/OR-channels, and suggest involvement of ICL-3 in the potential functional adaptation of Ditrysian Orcos to acidified extra-/intracellular environment.

Temperature is a universal cue and regulates many essential processes ranging from enzymatic reactions to species migration. Due to the profound impact of temperature on physiology and behavior, animals and humans have evolved sophisticated mechanisms to detect temperature changes. Studies from animal models, such as mouse, Drosophila , and C. elegans , have revealed many exciting principles of thermosensation. For example, conserved molecular thermosensors, including thermosensitive channels and receptors, act as the initial detectors of temperature changes across taxa. Additionally, thermosensory neurons and circuits in different species appear to adopt similar logic to transduce and process temperature information. Here, we present the current understanding of thermosensation at the molecular and cellular levels. We also discuss the fundamental coding strategies of thermosensation at the circuit level. A thorough understanding of thermosensation not only provides key insights into sensory biology but also builds a foundation for developing better treatments for various sensory disorders.

The unique traits of eusocial insects, such as social behavior and reproductive division of labor, are controlled by their genetic system. To address how genes regulate social traits, we have developed mutant ants via delivery of CRISPR complex into young embryos during their syncytial stage. Here, we provide a protocol of CRISPR-mediated mutagenesis in Harpegnathos saltator, a ponerine ant species that displays striking phenotypic plasticity. H. saltator ants are readily reared in a laboratory setting. Embryos are collected for microinjection with Cas9 proteins and in vitro synthesized small guide RNAs (sgRNAs) using home-made quartz needles. Post-injection embryos are reared outside the colony. Following emergence of the first larva, all embryos and larvae are transported to a nest box with a few nursing workers for further development. This protocol is suitable for inducing mutagenesis for analysis of caste-specific physiology and social behavior in ants, but may also be applied to a broader spectrum of hymenopterans and other insects.

Some fungal epithiodiketopiperazine alkaloids display α,β-polysulfide bridges alongside diverse structural variations. However, the logic of their chemical diversity has rarely been explored. Here, we report the identification of three new (2, 3, 8) and five known (1, 4-7) epithiodiketopiperazines of this subtype from a marine-derived Penicillium sp. The structure elucidation was supported by multiple spectroscopic analyses. Importantly, we observed multiple nonenzymatic interconversions of these analogues in aqueous solutions and organic solvents. Furthermore, the same biosynthetic origin of these compounds was supported by one mined gene cluster. The dominant analogue (1) demonstrated selective cytotoxicity to androgen-sensitive prostate cancer cells and HIF-depleted colorectal cells and mild antiaging activities, linking the bioactivity to oxidative stress. These results provide crucial insight into the formation of fungal epithiodiketopiperazines through chemical interconversions., (© 2020 Wiley-VCH GmbH.)

Olfactory GPCRs (ORs) in mammalian olfactory receptor neurons (ORNs) mediate excitation through the Gα s family member Gα olf . Here we tentatively associate a second G protein, Gα o , with inhibitory signaling in mammalian olfactory transduction by first showing that odor evoked phosphoinositide 3-kinase (PI3K)-dependent inhibition of signal transduction is absent in the native ORNs of mice carrying a conditional OMP-Cre based knockout of Gα o . We then identify an OR from native rat ORNs that are activated by octanol through cyclic nucleotide signaling and inhibited by citral in a PI3K-dependent manner. We show that the OR activates cyclic nucleotide signaling and PI3K signaling in a manner that reflects its functionality in native ORNs. Our findings lay the groundwork to explore the interesting possibility that ORs can interact with two different G proteins in a functionally identified, ligand-dependent manner to mediate opponent signaling in mature mammalian ORNs., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Olfactory dysfunction is a common disorder in the general population. There are multiple causes, one of which being ciliopathies, an emerging class of human hereditary genetic disorders characterized by multiple symptoms due to defects in ciliary biogenesis, maintenance, and/or function. Mutations/deletions in a wide spectrum of ciliary genes have been identified to cause ciliopathies. Currently, besides symptomatic therapy, there is no available therapeutic treatment option for olfactory dysfunction caused by ciliopathies. Multiple studies have demonstrated that targeted gene replacement can restore the morphology and function of olfactory cilia in olfactory sensory neurons and further re-establish the odor-guided behaviors in animals. Therefore, targeted gene replacement could be potentially used to treat olfactory dysfunction in ciliopathies. However, due to the potential limitations of single-gene therapy for polygenic mutation-induced diseases, alternative therapeutic targets for broader curative measures need to be developed for olfactory dysfunction, and also for other symptoms in ciliopathies. Here we review the current understanding of ciliogenesis and maintenance of olfactory cilia. Furthermore, we emphasize signaling mechanisms that may be involved in the regulation of olfactory ciliary length and highlight potential alternative therapeutic targets for the treatment of ciliopathy-induced dysfunction in the olfactory system and even in other ciliated organ systems., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives/hypothesis: The association between smoking and olfactory loss remains a conundrum. Prior studies have found negative and positive effects of smoking on olfactory function in the general population. However, smoking cessation seems to improve both rated and measured olfactory function. The purpose of this study was to investigate the olfactory function and smoking habits in patients with olfactory loss caused by different etiologies to unveil underlying patterns related to smoking., Study Design: Retrospective observational study., Methods: Patients were included from two specialized taste and smell centers. Patients underwent olfactory testing, clinical examination including rhinoscopy, and the underlying etiology was identified. Patterns of olfactory test scores, demographics, and etiologies were analyzed., Results: In total, 3,900 patients with olfactory loss were included. Of these, 521 were current smokers, and 316 were former smokers. Patients with a history of smoking did not have significantly lower olfactory function. Current smokers were more often affected by posttraumatic olfactory loss, but not sinonasal, postviral, or idiopathic olfactory loss., Conclusions: Current smoking, but not former smoking, was associated with posttraumatic olfactory loss. In relation to measured olfactory function, a history of smoking was not associated to lower olfactory scores. Our findings suggest that the general recommendations of smoking cessation for patients with olfactory loss are especially relevant for patients with posttraumatic olfactory loss. The nature of this association between current smoking and posttraumatic olfactory loss has yet to be elucidated., Level of Evidence: 2b Laryngoscope, 131:E8-E13, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

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 ~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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)