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Head of Institute: Prof. Oren Froy

Administrative manager: Ms. Yael Fruchter

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

2019
Croote, D. ; Braslavsky, I. ; Quake, S. R. Addressing Complex Matrix Interference Improves Multiplex Food Allergen Detection by Targeted LC–MS/MS. Analytical ChemistryAnalytical Chemistry 2019. Publisher's VersionAbstract
The frequent use of precautionary food allergen labeling (PAL) such as “may contain” frustrates allergic individuals who rely on such labeling to determine whether a food is safe to consume. One technique to study whether foods contain allergens is targeted liquid chromatography-tandem mass spectrometry (LC–MS/MS) employing scheduled multiple reaction monitoring (MRM). However, the applicability of a single MRM method to many commercial foods is unknown as complex and heterogeneous interferences derived from the unique composition of each food matrix can hinder quantification of trace amounts of allergen contamination. We developed a freely available, open source software package MAtrix-Dependent Interference Correction (MADIC) to identify interference and applied it with a method targeting 14 allergens. Among 84 unique food products, we found patterns of allergen contamination such as wheat in grains, milk in chocolate-containing products, and soy in breads and corn flours. We also found additional instances of contamination in products with and without PAL as well as highly variable soy content in foods containing only soybean oil and/or soy lecithin. These results demonstrate the feasibility of applying LC–MS/MS to a variety of food products with sensitive detection of multiple allergens in spite of variable matrix interference.The frequent use of precautionary food allergen labeling (PAL) such as “may contain” frustrates allergic individuals who rely on such labeling to determine whether a food is safe to consume. One technique to study whether foods contain allergens is targeted liquid chromatography-tandem mass spectrometry (LC–MS/MS) employing scheduled multiple reaction monitoring (MRM). However, the applicability of a single MRM method to many commercial foods is unknown as complex and heterogeneous interferences derived from the unique composition of each food matrix can hinder quantification of trace amounts of allergen contamination. We developed a freely available, open source software package MAtrix-Dependent Interference Correction (MADIC) to identify interference and applied it with a method targeting 14 allergens. Among 84 unique food products, we found patterns of allergen contamination such as wheat in grains, milk in chocolate-containing products, and soy in breads and corn flours. We also found additional instances of contamination in products with and without PAL as well as highly variable soy content in foods containing only soybean oil and/or soy lecithin. These results demonstrate the feasibility of applying LC–MS/MS to a variety of food products with sensitive detection of multiple allergens in spite of variable matrix interference.
Abu Ahmad, N. ; Raizman, M. ; Weizmann, N. ; Wasek, B. ; Arning, E. ; Bottiglieri, T. ; Tirosh, O. ; Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline–deficient rats. The FASEB Journal 2019, fj.201802683R. Publisher's VersionAbstract
Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline?deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet?induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ?-oxidation: fibroblast growth factor 21 and peroxisome proliferator?activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ?-oxidation in liver and the effects on PL metabolism in brain.?Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline?deficient rats.Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline?deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet?induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ?-oxidation: fibroblast growth factor 21 and peroxisome proliferator?activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ?-oxidation in liver and the effects on PL metabolism in brain.?Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline?deficient rats.
Berkovich, B. - E. ; Stark, A. H. ; Eliakim, A. ; Nemet, D. ; Sinai, T. Rapid Weight Loss in Competitive Judo and Taekwondo Athletes: Attitudes and Practices of Coaches and Trainers. International Journal of Sport Nutrition and Exercise Metabolism 2019, 1 - 7. Publisher's VersionAbstract
Fasting, skipping meals, and dehydration are common methods of rapid weight loss used prior to competition in weight category sports. This study examines coaches? attitudes, perceptions, and practices regarding rapid weight loss among judo and taekwondo athletes. A convenience sample of experienced coaches and trainers (n?=?68) completed structured questionnaires. Participants in this study were 33.8?±?9.3 years old; 57 were males and 11 were females; and 59% were certified coaches, with 71% reporting over 20 years of involvement in sports and 68% having more than 10 years of teaching experience. The majority (90%) reported that they usually supervised athletes through the weight loss process. Interventions for weight loss began at 12.7?±?1.9 years of age, with a recommended precompetition weight loss duration of 16.2?±?8.2 days and an average reduction of 1.5?±?0.7 kg. The majority of the responders (92%) recommended that their athletes practice gradual weight loss methods using a combination of dehydration or increased physical activity (80.3%), sweat suits (50.8%), restricted fluid intake (39.3%), training in heated rooms (27%), and sauna (26.2%). Recommendations of spitting (27.8%) or using laxatives, diuretics, diet pills, or vomiting (21.3%) were also reported. Coaches and trainers often encouraged athletes to cut weight before competition. The methods recommended are potentially harmful with severe health risks, including compromised nutritional status and diminished athletic performance. This is of particular concern in young athletes who are still growing and developing physically. Enhancing knowledge and awareness for coaches, athletes, and parents regarding potential dangers, along with improved nutrition education, is critical for reducing the magnitude and misuse of rapid weight loss methods.Fasting, skipping meals, and dehydration are common methods of rapid weight loss used prior to competition in weight category sports. This study examines coaches? attitudes, perceptions, and practices regarding rapid weight loss among judo and taekwondo athletes. A convenience sample of experienced coaches and trainers (n?=?68) completed structured questionnaires. Participants in this study were 33.8?±?9.3 years old; 57 were males and 11 were females; and 59% were certified coaches, with 71% reporting over 20 years of involvement in sports and 68% having more than 10 years of teaching experience. The majority (90%) reported that they usually supervised athletes through the weight loss process. Interventions for weight loss began at 12.7?±?1.9 years of age, with a recommended precompetition weight loss duration of 16.2?±?8.2 days and an average reduction of 1.5?±?0.7 kg. The majority of the responders (92%) recommended that their athletes practice gradual weight loss methods using a combination of dehydration or increased physical activity (80.3%), sweat suits (50.8%), restricted fluid intake (39.3%), training in heated rooms (27%), and sauna (26.2%). Recommendations of spitting (27.8%) or using laxatives, diuretics, diet pills, or vomiting (21.3%) were also reported. Coaches and trainers often encouraged athletes to cut weight before competition. The methods recommended are potentially harmful with severe health risks, including compromised nutritional status and diminished athletic performance. This is of particular concern in young athletes who are still growing and developing physically. Enhancing knowledge and awareness for coaches, athletes, and parents regarding potential dangers, along with improved nutrition education, is critical for reducing the magnitude and misuse of rapid weight loss methods.
Shiff, Y. E. ; Reif, S. ; Marom, R. ; Shiff, K. ; Reifen, R. ; Golan-Gerstl, R. MiRNA-320a is less expressed and miRNA-148a more expressed in preterm human milk compared to term human milk. Journal of Functional Foods 2019, 57, 68 - 74. Publisher's VersionAbstract
ObjectivesTo investigate whether there is a difference in the profile of miRNAs between human milk (HM) from mothers of preterm versus HM from mothers of full-term infants. Second goal is to assess biological functions or implication related to those differences in miRNAs expression. Methods Four of the highly expressed miRNAs in milk were detected by qRT-PCR. Milk derived exosomes were incubated with cells. The expression of miRNAs and target gene were detected by qRT-PCR. Results MiRNA-320 was more highly expressed in the colostrum of fullterm than in preterm HM. The expression of MiRNA-148 was higher in preterm mother's milk than of full-term colostrum. MiRNA-320 and MIRNA-148a expression were upregulated in cells incubated with milk exosomes, which lead to a decrease in their target genes FASN1 and DNMT1 respectivilly. Conclusions Alterations in miRNAs expression in HM can affect biologic function in infants and may serve as a nutritional therapeutic target.
Curzon, A. Y. ; Chandrasekhar, K. ; Nashef, Y. K. ; Abbo, S. ; Bonfil, D. J. ; Reifen, R. ; Bar-el, S. ; Avneri, A. ; Ben-David, R. Distinguishing between Bread Wheat and Spelt Grains Using Molecular Markers and Spectroscopy. Journal of Agricultural and Food Chemistry 2019, 67, 3837 - 3841. Publisher's VersionAbstract
The increasing demand for spelt products requires the baking industry to develop accurate and efficient tools to differentiate between spelt and bread wheat grains. We subjected a 272-sample spelt-bread wheat set to several potential diagnostic methods. DNA markers for γ-gliadin-D (GAG56D), γ-gliadin-B (GAG56B), and the Q-gene were used, alongside phenotypic assessment of ease-of-threshing and near-infrared spectroscopy (NIRS). The GAG56B and GAG56D markers demonstrated low diagnostic power in comparison to the Q-gene genotyping, which showed full accordance with the threshing phenotype, providing a highly accurate distinction between bread wheat and spelt kernels. A highly reliable Q classification was based on a three-waveband NIR model [Kappa (0.97), R-square (0.93)], which suggested that this gene influences grain characteristics. Our data ruled out a protein concentration bias of the NIRS-based diagnosis. These findings highlight the Q gene and NIRS as important, valuable, but simple tools for distinguishing between bread wheat and spelt.The increasing demand for spelt products requires the baking industry to develop accurate and efficient tools to differentiate between spelt and bread wheat grains. We subjected a 272-sample spelt-bread wheat set to several potential diagnostic methods. DNA markers for γ-gliadin-D (GAG56D), γ-gliadin-B (GAG56B), and the Q-gene were used, alongside phenotypic assessment of ease-of-threshing and near-infrared spectroscopy (NIRS). The GAG56B and GAG56D markers demonstrated low diagnostic power in comparison to the Q-gene genotyping, which showed full accordance with the threshing phenotype, providing a highly accurate distinction between bread wheat and spelt kernels. A highly reliable Q classification was based on a three-waveband NIR model [Kappa (0.97), R-square (0.93)], which suggested that this gene influences grain characteristics. Our data ruled out a protein concentration bias of the NIRS-based diagnosis. These findings highlight the Q gene and NIRS as important, valuable, but simple tools for distinguishing between bread wheat and spelt.
Di Pizio, A. ; Ben Shoshan-Galeczki, Y. ; Hayes, J. E. ; Niv, M. Y. Bitter and sweet tasting molecules: It's complicated. Neuroscience Letters 2019, 700, 56 - 63. Publisher's VersionAbstract
“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.
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. Cellular and Molecular Life Sciences 2019. Publisher's VersionAbstract
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.
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. Publisher's VersionAbstract
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.
Thawabteh, A. ; Lelario, F. ; Scrano, L. ; Bufo, S. A. ; Nowak, S. ; Behrens, M. ; Di Pizio, A. ; Niv, M. Y. ; Karaman, R. Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies. Chemical Biology & Drug Design 2019, 93, 262 - 271. Publisher's VersionAbstract
Abstract A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.
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. Publisher's Version
Qutob, N. ; Masuho, I. ; Alon, M. ; Emmanuel, R. ; Cohen, I. ; Di Pizio, A. ; Madore, J. ; Elkahloun, A. ; Ziv, T. ; Levy, R. ; et al. Author Correction: RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells. Scientific Reports 2019, 9 4523. Publisher's VersionAbstract
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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. Publisher's VersionAbstract
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.
Guttman, Y. ; Nudel, A. ; Kerem, Z. Polymorphism in Cytochrome P450 3A4 Is Ethnicity Related. Front. Genet., 2019, 10, 224. Publisher's VersionAbstract
Can mutations in cytochrome P450 3A4 (CYP3A4), the major food- and drug-metabolizing enzyme, serve as biomarkers for personalized precise medicine? Classical genetic studies provide only limited data regarding the frequencies of CYP3A4 mutations and their role in food-drug interactions. Here, in an analysis of one large database of 141,456 individuals, we found 856 SNPs (single nucleotide polymorphism), of which 312 are missense mutations, far more than the previously reported dozens. Analyzing the data further, it is demonstrated that the frequency of mutations differs among ethnic groups. Hierarchical clustering divided the mutations into seven groups, each corresponding to a specific ethnicity. To the best of our knowledge, this is the first comprehensive analysis of CYP3A4 allele frequencies in distinct ethnic groups. We suggest ethnicity based classification of CYP3A4 SNPs as the first step towards precise diet and medicine. Understanding which and when polymorphism might have clinical significance is a tremendously complex task. Using a modeling approach, we could predict changes in the binding poses of ligands in the active site of single variants. These changes might imply clinical effects of the overlooked protein-altering CYP3A4 mutations, by modifying drug metabolism and FDI. It may be concluded that dietary habits, and hence FDI, are matters of ethnicity. Consequently, ethnic-related polymorphism in CYP3A4 and diet may be one underlying mechanism of response to medical regimes. The approaches presented here have the power to highlight mutations of clinical relevance in any gene of interest, thus to complement the arsenal of classic genetic screening tools.
Ofer, L. ; Dean, M. N. ; Zaslansky, P. ; Kult, S. ; Shwartz, Y. ; Zaretsky, J. ; Griess-Fishheimer, S. ; Monsonego-Ornan, E. ; Zelzer, E. ; Shahar, R. A novel nonosteocytic regulatory mechanism of bone modeling. PLOS Biology 2019, 17, e3000140 -. Publisher's VersionAbstract
Bone’s ability to change its morphology in response to load is widely attributed to osteocytes. A study of fish shows that bone can respond to load even in the absence of osteocytes, using a molecular mechanism that is conserved across vertebrates, albeit with different cellular effectors.
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 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. Objectives To investigate the dietary intake and final stature of young adults with IgE-mediated cow's milk allergy (IgE-CMA) as compared with nonallergic controls. Methods Eighty-seven patients with IgE-CMA, median age 19.5 years (interquartile range [IQR], 17.3-22.7), and 36 control participants without food allergies, median age 22.7 years (IQR, 18.9-26.1), were studied. Anthropometric and nutritional data were collected. Age and gender z-scores were determined according to the Centers for Disease Control and Prevention growth charts. Nutrient intake assessment was based on dietary records. Individuals with conditions or treatments affecting bone metabolism or growth, other than asthma, were excluded. Results Mean values of height z-scores were significantly reduced in CMA subjects compared with controls (−0.64 ± 0.9 vs −0.04 ± 0.7, P = .001). In contrast, no differences were found between the 2 groups in weight and body mass index z-scores. Patients with CMA had significantly lower intake of protein, and several essential vitamins (A, B12, and riboflavin) and minerals (calcium, potassium, phosphorus, magnesium, and zinc) compared with controls (P < .05), but the intakes of calories, carbohydrate, and fat were not significantly different between the 2 groups. Differences between actual and expected (based on midparental height) height z-scores were comparable in CMA subjects with or without asthma and between those with and without additional food allergies. Conclusions Young adults who have CMA from infancy are at risk of not reaching their growth potential. Growth and nutritional monitoring and appropriate dietary intervention are of particular importance in these at-risk individuals.
Ghate, V. ; Zelinger, E. ; Shoyhet, H. ; Hayouka, Z. Inactivation of Listeria monocytogenes on paperboard, a food packaging material, using 410 nm light emitting diodes. Food Control 2019, 96, 281 - 290. Publisher's VersionAbstract
Light emitting diodes of wavelength 410 nm were used to inactivate Listeria monocytogenes stains on paperboard, an increasingly popular food packaging material. The integrity of the cell membranes was examined using differential fluorescent staining. Scanning electron microscopy (SEM) was used to obtain a deeper understanding of L. monocytogenes stain formation on paperboard and the damage caused to the cells by the LEDs. While the planktonic L. monocytogenes population could be completely inactivated following a brief lag phase that lasted about 20 min, the illumination of the sessile population left some persisters despite immediate commencement of the inactivation. Planktonic populations of inocula sized 3, 5 and 7 log CFU/mL were reduced below the detection limit in 54, 80 and 84 min respectively, whereas it took 120 and 390 min to reach constancy in the sessile populations of inocula sized 5 and 7 log CFU/cm2. The number of membrane-damaged cells was seen to increase with the illumination time. SEM images provided evidence of the protection conferred by the stain on the underlying cells. This study demonstrates that blue LEDs have the potential to reduce the risk of L. monocytogenes contamination from paperboard cartons under refrigeration.
Weintraub, Y. ; Cohen, S. ; Chapnik, N. ; Ben-Tov, A. ; Yerushalmy-Feler, A. ; Dotan, I. ; Tauman, R. ; Froy, O. Clock Gene Disruption is an Initial Manifestation of Inflammatory Bowel Disease. Clinical Gastroenterology and Hepatology 2019. Publisher's VersionAbstract
Background & AimsSleep disruption modifies the immune system and can trigger flares of inflammatory bowel diseases (IBD). Changes in expression of clock genes have been reported in patients with IBD. We investigated whether a change in the circadian clock is an early event in development of IBD. Methods We performed a prospective study of patients younger than 21 years old who underwent diagnostic endoscopies at the pediatric and adult gastroenterology units at the Tel Aviv Sourasky Medical Center from August 2016 through August 2017. Questionnaires were completed by 32 patients with IBD (8–21 years old) and 18 healthy individuals (controls) that provided data on demographics, sleep, disease activity scores. We also obtained data on endoscopic scores, anthropometric parameters, blood level of C-reactive protein (CRP), and fecal level of calprotectin. Peripheral blood and intestinal mucosa samples were analyzed for expression levels of clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1, and PER2). Results Levels of CRP and fecal calprotectin were significantly higher in patients with IBD compared with controls (P<.05). Expression levels of clock genes (CLOCK, CRY1, CRY2, PER1, and PER2) were significantly lower in inflamed intestinal mucosa from patients compared with intestinal mucosa from controls (P<.05). Expression levels of all clock genes except for PER2, were also significantly lower in non-inflamed intestinal mucosal tissues from patients compared with controls (P<.05). Expression levels of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) were lower in white blood cells from patients with IBD compared with controls. This reduction was greater in white blood cells from patients with ulcerative colitis than in patients with Crohn's disease. Conclusion Young, newly diagnosed, untreated patients with IBD have reduced expression of clock genes in inflamed and non-inflamed intestinal mucosal samples, and also in blood cells, compared with healthy individuals. Alterations in expression of clock genes might be an early event in IBD pathogenesis. ClinicalTrials.gov Identifier: NCT03662646
Tal, Y. ; Chapnik, N. ; Froy, O. Non-obesogenic doses of fatty acids modulate the functionality of the circadian clock in the liver. Cellular and Molecular Life Sciences 2019, 76, 1795 - 1806. Publisher's VersionAbstract
Saturated fatty acids, such as palmitate, lead to circadian disruption in cell culture. Moreover, information regarding the effects of unsaturated fatty acids on circadian parameters is scarce. We aimed at studying the effects of low doses of saturated as well as unsaturated fatty acids on circadian metabolism in vivo and at deciphering the mechanism by which fatty acids convey their effect. Mice were fed non-obesogenic doses of palm or olive oil and hepatocytes were treated with palmitate and oleate. Mice fed non-obesogenic doses of palm oil showed increased signaling towards fatty acid synthesis, while olive oil increased signaling towards fatty acid oxidation. Low doses of palmitate and oleate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins. Palmitate, but not oleate, counteracted the reduction in lipid accumulation and BMAL1-induced expression of mitochondrial genes involved in fatty acid oxidation. Palmitate was also found to interfere with the transcriptional activity of CLOCK:BMAL1 by preventing BMAL1 deacetylation and activation. In addition, palmitate, but not oleate, reduced PER2-mediated transcriptional activation and increased REV-ERBα-mediated transcriptional inhibition of Bmal1. The inhibition of PER2-mediated transcriptional activation by palmitate was achieved by interfering with PER2 nuclear translocation. Indeed, PER2 reduced fat accumulation in hepatocytes and this reduction was prevented by palmitate. Herein, we show that the detrimental metabolic alteration seen with high doses of palmitate manifests itself early on even with non-obesogenic levels. This is achieved by modulating BMAL1 at several levels abrogating its activity and expression.
Michael, C. ; Ido, B. Ice-binding proteins and the applicability and limitations of the kinetic pinning model. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 2019, 377, 20180391. Publisher's Version
Guy Preis, S. ; Chayet, H. ; Katz, A. ; Yashunsky, V. ; Kaner, A. ; Ullman, S. ; Braslavsky, I. Labyrinth ice pattern formation induced by near-infrared irradiation. Science Advances 2019, 5 eaav1598. Publisher's VersionAbstract
Patterns are broad phenomena that relate to biology, chemistry, and physics. The dendritic growth of crystals is the most well-known ice pattern formation process. Tyndall figures are water-melting patterns that occur when ice absorbs light and becomes superheated. Here, we report a previously undescribed ice and water pattern formation process induced by near-infrared irradiation that heats one phase more than the other in a two-phase system. The pattern formed during the irradiation of ice crystals tens of micrometers thick in solution near equilibrium. Dynamic holes and a microchannel labyrinth then formed in specific regions and were characterized by a typical distance between melted points. We concluded that the differential absorption of water and ice was the driving force for the pattern formation. Heating ice by laser absorption might be useful in applications such as the cryopreservation of biological samples.