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Bar-Dolev, M. ; K., B. ; Braslavsky, I. ; P.L, D. Structure–Function of IBPs and Their Interactions with Ice. In Antifreeze Proteins ; Antifreeze Proteins ; Springer, Cham. 2020; Vol. 2. Publisher's VersionAbstract
The diversity among the dozen antifreeze proteins (AFPs) and other ice-binding proteins (IBPs) with known or robustly predicted three-dimensional structures is remarkable. Their protein folds range from single short alpha-helices to long beta-solenoids and small globular domains with mixed secondary structure. IBPs differ one from another not only in structure, but also in activity levels, affinity for different ice planes, and ice-binding site size, shape, and amino acid composition. IBPs arose from different evolutionary routes on many different occasions, and even function in different ways to protect the host organism from freeze injury. The only unifying feature of IBPs is their basic function, to bind to ice, and even this is achieved with different orientations and kinetics. This chapter covers the structural diversity of IBPs and their ice-binding sites (IBS). We discuss the correlation between IBS structure and size with activity levels, and how the structural differences are manifested in their binding characteristics. Further we discuss the protein:ice interface at the molecular level and recent mechanisms of ice recognition.
Dror, Y. ; Rimon, E. ; Vaida, R. Whole-Wheat Bread for Human Health; Springer Nature Switzerland : Cham, Switzerland, 2020. Publisher's VersionAbstract
This book examines the effect of whole-wheat bread on health, with evidence linking the consumption of whole-wheat products to a decrease in the relative risk of non-communicable diseases in comparison with products baked from refined flour. The authors focus on key areas such as milling and refining procedures, bakery products, and assessment of the present consumption of wheat products. They offer a detailed description of all available ingredients of wheat-kernel, with particular attention paid to the health benefits of wheat-kernel antioxidants and dietary fiber ingredients. Vitamins, glutathione, choline and betaine, carotenoids, sterols and stanols are covered, and the book concludes with a general overview of the effect of whole-wheat bread on colon activity and immune capacity. Methods of improving bread nutritional quality, and the potential for the upgrading of the nutritional qualities of whole-bread, are also discussed. 


Consumption of whole-wheat in Western societies, however, has either not increased or increased very slightly. The authors intend for this book to highlight the health benefits of whole-wheat bread and the factors that contribute to these benefits.

Ben Abu, N. ; Mason, P. E. ; Klein, H. ; Dubovski, N. ; Ben Shoshan-Galeczki, Y. ; Malach, E. ; Prazienkova, V. ; Maletinska, L. ; Tempra, C. ; Chamorro, V. C. ; et al. Sweet taste of heavy water. bioRxiv 2020. Publisher's VersionAbstract
Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D2O from H2O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and adds to perceived sweetness of sweeteners. In contrast, mice do not prefer D2O over H2O, indicating that they are not likely to perceive heavy water as sweet. For humans, the sweet taste of D2O is suppressed by lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3 sweet taste receptor. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and the chimeric Gα16gust44 G-protein are activated by D2O but not by H2O. The present study resolves a long-standing controversy about the taste of heavy water, confirms that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of potential sites and modes of action.Competing Interest StatementThe authors have declared no competing interest.
Asseo, K. ; Fierro, F. ; Slavutsky, Y. ; Frasnelli, J. ; Niv, M. Y. Utility and limitations of Google searches on sensory loss as markers for new COVID-19 cases. medRxiv 2020. Publisher's VersionAbstract
Evidence of smell loss in COVID-19 is growing. Researchers and analysts have suggested to use Google searches on smell loss as indicators of COVID-19 cases. However, such searches may be due to interest elicited by media coverage of the COVID-19-related smell loss, rather than attempts to understand self-symptoms. We analyzed searches related to 4 senses: smell and taste (both recently shown to be impaired in some COVID-19 patients), vision and sight (senses not currently known to be impaired in COVID-19 patients), and an additional general control (“COVID-19 symptoms”). Focusing on two countries with a large number of cases, Italy and the United States, we have compared Google Trends results per region or state to the number of new cases prevalence in that region. The analysis was performed for each of the 8 weeks ranging from March 4th till April 28th. No correlation with vision loss or sight loss searches was identified, while taste and smell loss searches were correlated with new COVID-19 cases during a limited time window, that starts when the number of weekly new cases reached for the first time 21357 cases in Italy (11-17 March) and 47553 in the US (18-24 March). Media effect on the specific symptoms searches was also analyzed, establishing a different impact according to the country. Our results suggest that Google Trends for taste loss and smell loss searches captured a genuine connection between these symptoms and new COVID-19 cases prevalence in the population. However, due to variability in correlation from week to week, and overall decrease in correlation as taste and smell loss are becoming known COVID-19 symptoms, recognized now by CDC and World Health Organization, Google Trends is no longer a reliable marker for monitoring the disease spread. The “surprise rise” followed by decrease, probably attributable to knowledge saturation, should be kept in mind for future digital media analyses of potential new symptoms of COVID-19 or future pandemics.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was supported by the ISF grant #1129/19Author DeclarationsAll relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript.YesAll necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData will be made available on GitHub
Shoshan-Galeczki], Y. [B. ; Niv, M. Y. Structure-based screening for discovery of sweet compounds. Food Chemistry 2020, 315, 126286. Publisher's VersionAbstract
Sweet taste is a cue for calorie-rich food and is innately attractive to animals, including humans. In the context of modern diets, attraction to sweetness presents a significant challenge to human health. Most known sugars and sweeteners bind to the Venus Fly Trap domain of T1R2 subunit of the sweet taste heterodimer. Because the sweet taste receptor structure has not been experimentally solved yet, a possible approach to finding sweet molecules is virtual screening using compatibility of candidate molecules to homology models of sugar-binding site. Here, the constructed structural models, docking and scoring schemes were validated by their ability to rank known sweet-tasting compounds higher than properties-matched random molecules. The best performing models were next used in virtual screening, retrieving recently patented sweeteners and providing novel predictions.
Leung, N. Y. ; Thakur, D. P. ; Gurav, A. S. ; Kim, S. H. ; Pizio], A. [D. ; Niv, M. Y. ; Montell, C. Functions of Opsins in Drosophila Taste. Current Biology 2020, 30, 1367 - 1379.e6. Publisher's VersionAbstract
Summary Rhodopsin is a light receptor comprised of an opsin protein and a light-sensitive retinal chromophore. Despite more than a century of scrutiny, there is no evidence that opsins function in chemosensation. Here, we demonstrate that three Drosophila opsins, Rh1, Rh4, and Rh7, are needed in gustatory receptor neurons to sense a plant-derived bitter compound, aristolochic acid (ARI). The gustatory requirements for these opsins are light-independent and do not require retinal. The opsins enabled flies to detect lower concentrations of aristolochic acid by initiating an amplification cascade that includes a G-protein, phospholipase Cβ, and the TRP channel, TRPA1. In contrast, responses to higher levels of the bitter compound were mediated through direct activation of TRPA1. Our study reveals roles for opsins in chemosensation and raise questions concerning the original roles for these classical G-protein-coupled receptors.
Littmann, M. ; Selig, K. ; Cohen-Lavi, L. ; Frank, Y. ; Hönigschmid, P. ; Kataka, E. ; Mösch, A. ; Qian, K. ; Ron, A. ; Schmid, S. ; et al. Validity of machine learning in biology and medicine increased through collaborations across fields of expertise. 2020, 2 18 - 24. Publisher's VersionAbstract
Machine learning (ML) has become an essential asset for the life sciences and medicine. We selected 250 articles describing ML applications from 17 journals sampling 26 different fields between 2011 and 2016. Independent evaluation by two readers highlighted three results. First, only half of the articles shared software, 64% shared data and 81% applied any kind of evaluation. Although crucial for ensuring the validity of ML applications, these aspects were met more by publications in lower-ranked journals. Second, the authors’ scientific backgrounds highly influenced how technical aspects were addressed: reproducibility and computational evaluation methods were more prominent with computational co-authors; experimental proofs more with experimentalists. Third, 73% of the ML applications resulted from interdisciplinary collaborations comprising authors from at least two of the three disciplines: computational sciences, biology, and medicine. The results suggested collaborations between computational and experimental scientists to generate more scientifically sound and impactful work integrating knowledge from both domains. Although scientifically more valid solutions and collaborations involving diverse expertise did not correlate with impact factors, such collaborations provide opportunities to both sides: computational scientists are given access to novel and challenging real-world biological data, increasing the scientific impact of their research, and experimentalists benefit from more in-depth computational analyses improving the technical correctness of work.
Di Pizio, A. ; Waterloo, L. A. W. ; Brox, R. ; Löber, S. ; Weikert, D. ; Behrens, M. ; Gmeiner, P. ; Niv, M. Y. Rational design of agonists for bitter taste receptor TAS2R14: from modeling to bench and back. Cell Mol Life Sci 2020, 77, 531-542.Abstract
Human bitter taste receptors (TAS2Rs) are a subfamily of 25 G protein-coupled receptors that mediate bitter taste perception. TAS2R14 is the most broadly tuned bitter taste receptor, recognizing a range of chemically diverse agonists with micromolar-range potency. The receptor is expressed in several extra-oral tissues and is suggested to have physiological roles related to innate immune responses, male fertility, and cancer. Higher potency ligands are needed to investigate TAS2R14 function and to modulate it for future clinical applications. Here, a structure-based modeling approach is described for the design of TAS2R14 agonists beginning from flufenamic acid, an approved non-steroidal anti-inflammatory analgesic that activates TAS2R14 at sub-micromolar concentrations. Structure-based molecular modeling was integrated with experimental data to design new TAS2R14 agonists. Subsequent chemical synthesis and in vitro profiling resulted in new TAS2R14 agonists with improved potency compared to the lead. The integrated approach provides a validated and refined structural model of ligand-TAS2R14 interactions and a general framework for structure-based discovery in the absence of closely related experimental structures.
Stoeger, V. ; Holik, A. - K. ; Hölz, K. ; Dingjan, T. ; Hans, J. ; Ley, J. P. ; Krammer, G. E. ; Niv, M. Y. ; Somoza, M. M. ; Somoza, V. Bitter-Tasting Amino Acids l-Arginine and l-Isoleucine Differentially Regulate Proton Secretion via T2R1 Signaling in Human Parietal Cells in Culture. J Agric Food Chem 2020, 68, 3434-3444.Abstract
This study aimed at identifying whether the bitter-tasting amino acids l-arginine (l-ARG) and l-isoleucine (l-ILE) differentially regulate mechanisms of gastric acid secretion in human parietal cells (HGT-1 cells) via activation of bitter taste sensing receptors (T2Rs). In a first set of experiments, involvement of T2Rs in l-ARG and l-ILE-modulated proton secretion was demonstrated by co-treatment of HGT-1 cells with T2R antagonists. Subsequent whole genome screenings by means of cDNA arrays revealed T2R1 as a prominent target for both amino acids. Next, the functional role of T2R1 was verified by means of a CRISPR-Cas9 knock-out approach. Here, the effect of l-ARG on proton secretion decreased by 65.7 ± 21.9% and the effect of l-ILE increased by 93.2 ± 24.1% in HGT-1 T2R1 ko versus HGT-1 wt cells ( < 0.05). Overall, our results indicate differential effects of l-ARG and l-ILE on proton secretion in HGT-1 cells and our molecular docking studies predict distinct binding for these amino acids in the binding site of T2R1. Further studies will elucidate whether the mechanism of differential effects involves structure-specific ligand-biased signaling of T2R1 or additional cellular targets.
Cruces-Sande, M. ; Arcones, A. C. ; Vila-Bedmar, R. ; Val-Blasco, A. ; Sharabi, K. ; Díaz-Rodríguez, D. ; Puigserver, P. ; Mayor, F. ; Murga, C. Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting. FASEB J 2020, 34, 399-409.Abstract
The liver plays a key role during fasting to maintain energy homeostasis and euglycemia via metabolic processes mainly orchestrated by the insulin/glucagon ratio. We report here that fasting or calorie restriction protocols in C57BL6 mice promote a marked decrease in the hepatic protein levels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein-coupled receptors (GPCRs) and insulin signaling. Such downregulation of GRK2 levels is liver-specific and can be rapidly reversed by refeeding. We find that autophagy, and not the proteasome, represents the main mechanism implicated in fasting-induced GRK2 degradation in the liver in vivo. Reducing GRK2 levels in murine primary hepatocytes facilitates glucagon-induced glucose production and enhances the expression of the key gluconeogenic enzyme Pck1. Conversely, preventing full downregulation of hepatic GRK2 during fasting using adenovirus-driven overexpression of this kinase in the liver leads to glycogen accumulation, decreased glycemia, and hampered glucagon-induced gluconeogenesis, thus preventing a proper and complete adaptation to nutrient deprivation. Overall, our data indicate that physiological fasting-induced downregulation of GRK2 in the liver is key for allowing complete glucagon-mediated responses and efficient metabolic adaptation to fasting in vivo.
Ben-Yacov, L. ; Ainembabazi, P. ; Stark, A. H. ; Kizito, S. ; Bahendeka, S. Prevalence and sex-specific patterns of metabolic syndrome in rural Uganda. BMJ Nutrition, Prevention & Health 2020. Publisher's VersionAbstract
{Background and aims In sub-Saharan Africa, infectious diseases are still the leading causes of mortality; however, this may soon be surpassed by non-communicable illnesses, namely hypertension, diabetes and cardiovascular disease. This study determined the prevalence and patterns of metabolic syndrome and cardio-risk factors in men and women in rural Uganda.Methods A household-based, cross-sectional survey was carried out following the WHO STEP-wise approach to surveillance. It included demographic and lifestyle questionnaires, anthropometric measurements and biochemical analyses. Of the 200 randomly recruited participants, 183 successfully completed two steps of the study and 161 provided blood samples.Results Data were collected from 183 adults, aged 18–69 years; 62% were female. Based on the National Cholesterol Education Program-Adult Treatment Panel-III criteria, the prevalence of metabolic syndrome was 19.1% (95% CI 14.0 to 22.5). Elevated fasting plasma glucose was observed in 14.2% (95% CI 9.1 to 19.3) of participants, hypertriglyceridaemia in 16.9% (95% CI 12.1 to 23.1); hypertension in 36.1% (95% CI 29.0 to 43.0) and 52.5% (95% CI 45.2 to 59.6) had low HDL (high-density lipoprotein) cholesterol. Abdominal obesity was found in 24.6% (95% CI 18.8 to 31.4) of participants. Sex disparities were significant for several risk factors. Females had significantly higher prevalence of abdominal obesity (38.6% vs 1.5% in males
Sinai, T. ; Goldberg, M. R. ; Nachshon, L. ; Amitzur-Levy, R. ; Yichie, T. ; Katz, Y. ; Monsonego-Ornan, E. ; Elizur, A. Reduced Final Height and Inadequate Nutritional Intake in Cow's Milk-Allergic Young Adults. The Journal of Allergy and Clinical Immunology: In PracticeThe Journal of Allergy and Clinical Immunology: In Practice 2019, 7 509 - 515. Publisher's VersionAbstract
BackgroundGrowth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height.BackgroundGrowth impairment was previously described in milk-allergic children but was not examined in adults on reaching final height.
Qin, C. ; Qin, Z. ; Zhao, D. ; Pan, Y. ; Zhuang, L. ; Wan, H. ; Di Pizio, A. ; Malach, E. ; Niv, M. Y. ; Huang, L. ; et al. A bioinspired in vitro bioelectronic tongue with human T2R38 receptor for high-specificity detection of N-C=S-containing compounds. Talanta 2019, 199, 131-139.Abstract
Detection and identification of bitter compounds draw great attention in pharmaceutical and food industry. Several well-known agonists of specific bitter taste receptors have been found to exhibit anti-cancer effects. For example, N-C=S-containing compounds, such as allyl-isothiocyanates, have shown cancer chemo-preventive effects. It is worth noting that human T2R38 receptor is specific for compounds containing N-C=S moiety. Here, a bioinspired cell-based bioelctronic tongue (BioET) is developed for the high-specificity isothiocyanate-induced bitter detection, utilizing human Caco-2 cells as a primary sensing element and interdigitated impedance sensor as a secondary transducer. As an intestinal carcinoma cell line, Caco-2 endogenously expresses human bitter receptor T2R38, and the activation of T2R38 induces the changes of cellular morphology which can be detected by electric cell-substrate impedance sensing (ECIS). After configuration and optimization of parameters including timing of compound administration and cell density, quantitative bitter evaluation models were built for two well-known bitter compounds, phenylthiocarbamide (PTC) and propylthiouracil (PROP). The bitter specific detection of this BioET is inhibited by probenecid and U-73122, and is not elicited by other taste modalities or bitter ligands that do not activate T2R38. Moreover, by combining different computational tools, we designed a ligand-based virtual screening (LBVS) protocol to select ligands that are likely to activate T2R38 receptor. Three computationally predicted agonists of T2R38 were selected using the LBVS protocol, and the BioET presented response to the predicted agonists, validating the capability of the LBVS protocol. This study suggests this unique cell-based BioET paves a general and promising way to specifically detect N-C=S-containing compounds that can be used for pharmaceutical study and drug development.
Di Pizio, A. ; Ben Shoshan-Galeczki, Y. ; Hayes, J. E. ; Niv, M. Y. Bitter and sweet tasting molecules: It's complicated. Neurosci Lett 2019, 700, 56-63.Abstract
"Bitter" and "sweet" are frequently framed in opposition, both functionally and metaphorically, in regard to affective responses, emotion, and nutrition. This oppositional relationship is complicated by the fact that some molecules are simultaneously bitter and sweet. In some cases, a small chemical modification, or a chirality switch, flips the taste from sweet to bitter. Molecules humans describe as bitter are recognized by a 25-member subfamily of class A G-protein coupled receptors (GPCRs) known as TAS2Rs. Molecules humans describe as sweet are recognized by a TAS1R2/TAS1R3 heterodimer of class C GPCRs. Here we characterize the chemical space of bitter and sweet molecules: the majority of bitter compounds show higher hydrophobicity compared to sweet compounds, while sweet molecules have a wider range of sizes. Importantly, recent evidence indicates that TAS1Rs and TAS2Rs are not limited to the oral cavity; moreover, some bitterants are pharmacologically promiscuous, with the hERG potassium channel, cytochrome P450 enzymes, and carbonic anhydrases as common off-targets. Further focus on polypharmacology may unravel new physiological roles for tastant molecules.
Oren, T. ; Nimri, L. ; Yehuda-Shnaidman, E. ; Staikin, K. ; Hadar, Y. ; Friedler, A. ; Amartely, H. ; Slutzki, M. ; Di Pizio, A. ; Niv, M. Y. ; et al. Recombinant Ostreolysin Induces Brown Fat-Like Phenotype in HIB-1B Cells. Mol Nutr Food Res 2019, 63, e1970012.
Arafeh, R. ; Di Pizio, A. ; Elkahloun, A. G. ; Dym, O. ; Niv, M. Y. ; Samuels, Y. RASA2 and NF1; two-negative regulators of Ras with complementary functions in melanoma. Oncogene 2019, 38, 2432-2434.
Wodak, S. J. ; Paci, E. ; Dokholyan, N. V. ; Berezovsky, I. N. ; Horovitz, A. ; Li, J. ; Hilser, V. J. ; Bahar, I. ; Karanicolas, J. ; Stock, G. ; et al. Allostery in Its Many Disguises: From Theory to Applications. Structure 2019, 27, 566-578.Abstract
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
Dagan-Wiener, A. ; Di Pizio, A. ; Nissim, I. ; Bahia, M. S. ; Dubovski, N. ; Margulis, E. ; Niv, M. Y. BitterDB: taste ligands and receptors database in 2019. Nucleic Acids Res 2019, 47, D1179-D1185.Abstract
BitterDB ( was introduced in 2012 as a central resource for information on bitter-tasting molecules and their receptors. The information in BitterDB is frequently used for choosing suitable ligands for experimental studies, for developing bitterness predictors, for analysis of receptors promiscuity and more. Here, we describe a major upgrade of the database, including significant increase in content as well as new features. BitterDB now holds over 1000 bitter molecules, up from the initial 550. When available, quantitative sensory data on bitterness intensity as well as toxicity information were added. For 270 molecules, at least one associated bitter taste receptor (T2R) is reported. The overall number of ligand-T2R associations is now close to 800. BitterDB was extended to several species: in addition to human, it now holds information on mouse, cat and chicken T2Rs, and the compounds that activate them. BitterDB now provides a unique platform for structure-based studies with high-quality homology models, known ligands, and for the human receptors also data from mutagenesis experiments, information on frequently occurring single nucleotide polymorphisms and links to expression levels in different tissues.
Sharabi, K. ; Tavares, C. D. J. ; Puigserver, P. Regulation of Hepatic Metabolism, Recent Advances, and Future Perspectives. Curr Diab Rep 2019, 19, 98.Abstract
PURPOSE OF REVIEW: The purpose of this review is to provide a brief summary of recent advances in our understanding of liver metabolism. The critical role of the liver in controlling whole-body energy homeostasis makes such understanding crucial to efficiently design new treatments for metabolic syndrome diseases, including type 2 diabetes (T2D). RECENT FINDINGS: Significant advances have been made regarding our understanding of the direct and indirect effects of insulin on hepatic metabolism and the communication between the liver and other tissues. Moreover, the catabolic functions of glucagon, as well as the importance of hepatic redox status for the regulation of glucose production, are emerging as potential targets to reduce hyperglycemia. A resolution to the long-standing question "insulin suppression of hepatic glucose production, direct or indirect effect?" is starting to emerge. New advances in our understanding of important fasting-induced hepatic metabolic fluxes may help design better therapies for T2D.
Shigemura, M. ; Lecuona, E. ; Angulo, M. ; Dada, L. A. ; Edwards, M. B. ; Welch, L. C. ; Casalino-Matsuda, M. S. ; Sporn, P. H. S. ; Vadász, I. ; Helenius, I. T. ; et al. Elevated CO regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans. Sci Rep 2019, 9 18251.Abstract
Carbon dioxide (CO) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster). We found that hypercapnia activated genes that regulate Wnt signaling in mouse lungs and skeletal muscles in vivo and in several cell lines of different tissue origin. Hypercapnia-responsive Wnt pathway homologues were similarly observed in secondary analysis of available transcriptomic datasets of hypercapnia in a human bronchial cell line, flies and nematodes. Our data suggest the evolutionarily conserved role of high CO in regulating Wnt pathway genes.