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Head of Institute: Prof. Oren Tirosh

Administrative manager: Ms. Yael Fruchter

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Institute of Biochemistry, Food Science and Nutrition,
Robert H. Smith Faculty of Agriculture, Food and Environment,
The Hebrew University of Jerusalem, 
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Publications

2020
Rozner, R. ; Vernikov, J. ; Griess-Fishheimer, S. ; Travinsky, T. ; Penn, S. ; Schwartz, B. ; Mesilati-Stahy, R. ; Argov-Argaman, N. ; Shahar, R. ; Monsonego-Ornan, E. The Role of Omega-3 Polyunsaturated Fatty Acids from Different Sources in Bone Development. Nutrients 2020, 12. Publisher's VersionAbstract
N-3 polyunsaturated fatty acids (PUFAs) are essential nutrients that must be obtained from the diet. We have previously showed that endogenous n-3 PUFAs contribute to skeletal development and bone quality in fat-1 mice. Unlike other mammals, these transgenic mice, carry the n-3 desaturase gene and thus can convert n-6 to n-3 PUFAs endogenously. Since this model does not mimic dietary exposure to n-3 PUFAs, diets rich in fish and flaxseed oils were used to further elucidate the role of n-3 PUFAs in bone development. Our investigation reveals that dietary n-3 PUFAs decrease fat accumulation in the liver, lower serum fat levels, and alter fatty acid (FA) content in liver and serum. Bone analyses show that n-3 PUFAs improve mechanical properties, which were measured using a three-point bending test, but exert complex effects on bone structure that vary according to its source. In a micro-CT analysis, we found that the flaxseed oil diet improves trabecular bone micro-architecture, whereas the fish oil diet promotes higher bone mineral density (BMD) with no effect on trabecular bone. The transcriptome characterization of bone by RNA-seq identified regulatory mechanisms of n-3 PUFAs via modulation of the cell cycle and peripheral circadian rhythm genes. These results extend our knowledge and provide insights into the molecular mechanisms of bone remodeling regulation induced by different sources of dietary n-3 PUFAs.
Ofir, O. ; Buch, A. ; Rouach, V. ; Goldsmith, R. ; Stern, N. ; Monsonego-Ornan, E. Association between abdominal obesity and fragility fractures among elderly Israeli women. 2020, 32, 1459 - 1467. Publisher's VersionAbstract
Obesity has been traditionally viewed as a protective factor for fractures. Recent studies have challenged this concept, particularly regarding abdominal obesity. We aimed to investigate the association between abdominal obesity, body mass index (BMI) and fragility fractures prevalence in a sample of community-dwelling elderly Israeli women.
Antunes, B. P. ; Vainieri, M. L. ; Alini, M. ; Monsonego-Ornan, E. ; Grad, S. ; Yayon, A. Enhanced chondrogenic phenotype of primary bovine articular chondrocytes in Fibrin-Hyaluronan hydrogel by multi-axial mechanical loading and FGF18. 2020, 105, 170 - 179. Publisher's VersionAbstract
Current treatments for cartilage lesions are often associated with fibrocartilage formation and donor site morbidity. Mechanical and biochemical stimuli play an important role in hyaline cartilage formation. Biocompatible scaffolds capable of transducing mechanical loads and delivering bioactive instructive factors may better support cartilage regeneration. In this study we aimed to test the interplay between mechanical and FGF-18 mediated biochemical signals on the proliferation and differentiation of primary bovine articular chondrocytes embedded in a chondro-conductive Fibrin-Hyaluronan (FB/HA) based hydrogel. Chondrocytes seeded in a Fibrin-HA hydrogel, with or without a chondro-inductive, FGFR3 selective FGF18 variant (FGF-18v) were loaded into a joint-mimicking bioreactor applying controlled, multi-axial movements, simulating the natural movements of articular joints. Samples were evaluated for DNA content, sulphated glycosaminoglycan (sGAG) accumulation, key chondrogenic gene expression markers and histology. Under moderate loading, samples produced particularly significant amounts of sGAG/DNA compared to unloaded controls. Interestingly there was no significant effect of FGF-18v on cartilage gene expression at rest. Following moderate multi-axial loading, FGF-18v upregulated the expression of Aggrecan (ACAN), Cartilage Oligomeric Matrix Protein (COMP), type II collagen (COL2) and Lubricin (PRG4). Moreover, the combination of load and FGF-18v, significantly downregulated Matrix Metalloproteinase-9 (MMP-9) and Matrix Metaloproteinase-13 (MMP-13), two of the most important factors contributing to joint destruction in OA. Biomimetic mechanical signals and FGF-18 may work in concert to support hyaline cartilage regeneration and repair.Statement of significance Articular cartilage has very limited repair potential and focal cartilage lesions constitute a challenge for current standard clinical procedures. The aim of the present research was to explore novel procedures and constructs, based on biomaterials and biomechanical algorithms that can better mimic joints mechanical and biochemical stimulation to promote regeneration of damaged cartilage. Using a hydrogel-based platform for chondrocyte 3D culture revealed a synergy between mechanical forces and growth factors. Exploring the mechanisms underlying this mechano-biochemical interplay may enhance our understanding of cartilage remodeling and the development of new strategies for cartilage repair and regeneration.
Kalev-Altman, R. ; Hanael, E. ; Zelinger, E. ; Blum, M. ; Monsonego-Ornan, E. ; Sela-Donenfeld, D. Conserved role of matrix metalloproteases 2 and 9 in promoting the migration of neural crest cells in avian and mammalian embryos. The FASEB JournalThe FASEB JournalThe FASEB Journal 2020, 34, 5240 - 5261. Publisher's VersionAbstract
Abstract Neural crest cells (NCCs) are a unique embryonic cell population that initially reside at the dorsal neural tube but later migrate in the embryo and differentiate into multiple types of derivatives. To acquire motility, NCCs undergo epithelial-to-mesenchymal transition and invade the surrounding extracellular matrix (ECM). Matrix metalloproteases (MMPs) are a large family of proteases which regulate migration of various embryonic and adult cells via ECM remodeling. The gelatinase's subgroup of MMPs is the most studied one due to its key role in metastasis. As it is composed of only two proteases, MMP2 and MMP9, it is important to understand whether each is indispensable or redundant in its biological function. Here we explored the role of the gelatinases in executing NCC migration, by determining whether MMP2 and/or MMP9 regulate migration across species in singular, combined, or redundant manners. Chick and mouse embryos were utilized to compare expression and activity of both MMPs using genetic and pharmacological approaches in multiple in vivo and ex vivo assays. Both MMPs were found to be expressed and active in mouse and chick NCCs. Inhibition of each MMP was sufficient to prevent NCC migration in both species. Yet, NCC migration was maintained in MMP2?/? or MMP9?/? mouse mutants due to compensation between the gelatinases, but reciprocal pharmacological inhibition in each mutant prevented NCC migration. This study reveals for the first time that both gelatinases are expressed in avian and mammalian NCCs, and demonstrates their fundamental and conserved role in promoting embryonic cell migration.
Gerkin, R. C. ; Ohla, K. ; Veldhuizen, M. G. ; Joseph, P. V. ; Kelly, C. E. ; Bakke, A. J. ; Steele, K. E. ; Farruggia, M. C. ; Pellegrino, R. ; Pepino, M. Y. ; et al. Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms. Chem Senses 2020. Publisher's VersionAbstract
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.
Karni, N. ; Klein, H. ; Asseo, K. ; Benjamini, Y. ; Israel, S. ; Nimri, M. ; Olstein, K. ; Nir-Paz, R. ; Hershko, A. ; Muszkat, M. ; et al. Self-rated smell ability enables highly specific predictors of COVID-19 status: a case control study in Israel. Open Forum Infect Dis 2020. Publisher's VersionAbstract
Clinical diagnosis of COVID-19 is essential for detection and prevention of COVID-19. Sudden onset of taste and smell loss is a hallmark of COVID-19, and optimal ways for including these symptoms in the screening of patients and distinguishing COVID-19 from other acute viral diseases, should be established.We performed a case-control study on patients that were PCR-tested for COVID-19 (112 positive and 112 negative participants), recruited during the first wave (March 2020 – May 2020) of COVID-19 pandemic in Israel. Patients reported over by phone their symptoms and medical history and rated their olfactory and gustatory abilities before and during their illness on a 1-10 scale.Changes in smell and taste occurred in 68% (95% CI 60%-76%) and 72% (64%-80%), of positive patients, with 24 (11-53 range) and 12 (6-23) respective odds ratios. The ability to smell was decreased by 0.5±1.5 in negatives, and by 4.5±3.6 in positives. A penalized logistic regression classifier based on 5 symptoms has 66% sensitivity, 97% specificity and an area under the ROC curve of 0.83 (AUC) on a hold-out set. A classifier based on degree of smell change only is almost as good, with 66% sensitivity, 97% specificity and 0.81 AUC. The predictive positive value (PPV) of this classifier is 0.68 and negative predictive value (NPV) is 0.97.Self-reported quantitative olfactory changes, either alone or combined with other symptoms, provide a specific tool for clinical diagnosis of COVID-19. A simple calculator for prioritizing COVID-19 laboratory testing is presented here.
Asseo, K. ; Fierro, F. ; Slavutsky, Y. ; Frasnelli, J. ; Niv, M. Y. Tracking COVID-19 using taste and smell loss Google searches is not a reliable strategy. 2020, 10, 20527. Publisher's VersionAbstract
Web search tools are widely used by the general public to obtain health-related information, and analysis of search data is often suggested for public health monitoring. We analyzed popularity of searches related to smell loss and taste loss, recently listed as symptoms of COVID-19. Searches on sight loss and hearing loss, which are not considered as COVID-19 symptoms, were used as control. Google Trends results per region in Italy or state in the US were compared to COVID-19 incidence in the corresponding geographical areas. The COVID-19 incidence did not correlate with searches for non-symptoms, but in some weeks had high correlation with taste and smell loss searches, which also correlated with each other. Correlation of the sensory symptoms with new COVID-19 cases for each country as a whole was high at some time points, but decreased (Italy) or dramatically fluctuated over time (US). Smell loss searches correlated with the incidence of media reports in the US. Our results show that popularity of symptom searches is not reliable for pandemic monitoring. Awareness of this limitation is important during the COVID-19 pandemic, which continues to spread and to exhibit new clinical manifestations, and for potential future health threats.
Teboul, N. ; Gadri, Y. ; Berkovich, Z. ; Reifen, R. ; Peleg, Z. Genetic Architecture Underpinning Yield Components and Seed Mineral–Nutrients in Sesame. Genes 2020, 11. Publisher's VersionAbstract
Genetic dissection of yield components and seed mineral-nutrient is crucial for understanding plant physiological and biochemical processes and alleviate nutrient malnutrition. Sesame (Sesamum indicum L.) is an orphan crop that harbors rich allelic repertoire for seed mineral–nutrients. Here, we harness this wide diversity to study the genetic architecture of yield components and seed mineral–nutrients using a core-collection of worldwide genotypes and segregating mapping population. We also tested the association between these traits and the effect of seed nutrients concentration on their bio-accessibility. Wide genetic diversity for yield components and seed mineral–nutrients was found among the core-collection. A high-density linkage map consisting of 19,309 markers was constructed and used for genetic mapping of 84 QTL associated with yield components and 50 QTL for seed minerals. To the best of our knowledge, this is the first report on mineral–nutrients QTL in sesame. Genomic regions with a cluster of overlapping QTL for several morphological and nutritional traits were identified and considered as genomic hotspots. Candidate gene analysis revealed potential functional associations between QTL and corresponding genes, which offers unique opportunities for synchronous improvement of mineral–nutrients. Our findings shed-light on the genetic architecture of yield components, seed mineral–nutrients and their inter- and intra- relationships, which may facilitate future breeding efforts to develop bio-fortified sesame cultivars.
Parma, V. ; Niv, M. Y. ; Group, G. C. C. R. More Than Smell - COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis. Chemical Senses 2020, 45, 609-622. Publisher's VersionAbstract
Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19–79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (−79.7 ± 28.7, mean ± standard deviation), taste (−69.0 ± 32.6), and chemesthetic (−37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
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 ClinicalTrials.gov. 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