INSTITUTE OF BIOLOGY, MEDICINAL CHEMISTRY & BIOTECHNOLOGY
 
  Drug Discovery
  Molecular Analysis
  Organic and Organometallic Chemistry
  Medicinal Chemistry
  Structural Biology & Chemistry
  Molecular Endocrinology
  Signal Mediated Gene Expression
  Molecular & Cellular Ageing
  Biomedical Applications
  Holistic Approaches in Health
  Chemical Carcinogenesis and Genetic Toxicology
  Metabolic Engineering-Bioinformatics
  Biotechnology
  Enzyme and Synthetic Biotechnology
  Biomimetics & Nanobiotechnology

 

Biomimetics & Nanobiotechnology

Biomimetics & Nanobiotechnology

 

The Biomimetics and Nanobiotechnology team deals with studies on the behavior of bioactives, such as peptides, enzymes, drugs, vitamins and antioxidants in model systems. The studies are focused on structural and functional aspects of the biomolecules when hosted in nano-scale environments such as nanodispersions (microemulsion or nanoemulsions) and related systems.

In such systems the coexistence of water nano-droplets in a continuous non-polar organic phase (oil) and vice versa, allows the solubilization of substances with various polarities. The lipophilic ones are localized in the oil phase and the hydrophilic ones (such as antioxidants) are encapsulated in the aqueous phase where they react through a huge interface.

 

Research Team

Research Staff
Dr. Aris Xenakis, Researcher Α'
Dr. Vassiliki Papadimitriou, Researcher B'
Dr. Maria Zoumpanioti, Research Engineer Β’

Scientific Technical Personnel
Mr. G. Sotiroudis, MSc. Pharmacist

Post Doctoral Researchers
Dr. Spyridon Avramiotis, Chemist
Dr. Maria Chatzidaki, Chemical Engineer

PhD Students
Evgenia Mitsou, Biologist, University of Ioannina, Greece
Ioanna Theochari, Chemist, University of Thessaly, Greece

Msc. Students
Fani Balkiza, Chemical Engineer
Ioanna Golfomitsou, Chemist

Bsc. students
Evdokia Vasiliadi, Department of Biological Applications, University of Ioannina, Greece
Maria Vlachou, Department of Biological Apllications, University of Ioannina, Greece
Sofia Dimou, Faculty of Biology, University of Athens, Greece

[Full List of students]

Visiting Members/ Recent collaborators (since 2012)

  • Marija N. Todosijević, Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
  • Marwa Charri, Department of Biological Engineering, National Engineering Scholl in Sfax, Tunisia
  • Ioanna Chazapi, University of Cyprus, Nicosia, Cyprus
  • Nehir Arik, Ege University, Izmir, Turkey
  • Maissa Khemakhem, Ecole Supérieure des Industries Alimentaires de Tunis, Tunis, Tunisia
  • Karen Mendeiros Gonçalves, Faculty of Pharmacy, Federal University of Rio de Janeiro, Brazil
  • Ivaldo Itabaiana Junior, Faculty of Chemistry, Federal University of Rio de Janeiro, Brazil
  • Andreia Fatima Zanette, Department of Chemical Engineering, State University of Maringa, Brazil

 

Overview of research activities

The activities developed within the Biomimetics and Nanobiotechnology group comprise:

  • Development and structural characterization of nanodispersions - nanoformulation
  • Structure and function studies of immobilised enzymes - biocatalysis.

Our lab has the expertise in formulation of nanodispersions such as microemulsions and nanoemulsions, especially on biocompatible ones, as well as enzyme immobilization and use for the synthesis of high added value products. Main aim of our group is the broadening of their applications in different aspects of life from food products to cosmetics and pharmaceuticals.

 

Formulation of water-in-oil (W/O) microemulsion [Video]

 

Current projects

Formulation of stable liquid nano-dispersions made of vegetable oils and biocompatible emulsifiers. 2 step gastrointestinal lipolysis

Colloidal systems could be applied in the food sector as products with enhanced nutritional value. An interesting type of bioactive molecules is naturally occurring antioxidants. Antioxidants of different polarities could be encapsulated in emulsions or nanoemulsions for potential use as functional foods. The scavenging effect of antioxidants found in Extra Virgin Olive Oil (ORAC, DPPH, EPR) using different in vitro techniques in homogeneous and micro-heterogeneous media are examined. Moreover, a two-step digestion model gives an insight on the relationship between colloidal dispersions and digestive enzymes.

 

Biocatalysis in microemulsions

Microemulsions are regarded as "the ultimate enzyme microreactors" for liquid catalysis. Their structure, composed by water nanodroplets dispersed in a non-polar medium, provides several benefits for their use as media for enzymatic transformations. They have the ability to overcome the solubility limitations of hydrophobic substrates, enhance the enzymatic activity (superactivity phenomenon) and stability, while providing an interface for surface-active enzymes. Of particular interest is the use of such systems to study biotransformations catalyzed by lipases and other enzymes towards the production of high added value products.

 

Biocatalysis in surfactant-free microemulsions

Weak self-assembly systems consisted by a nonpolar hydrocarbon, an alcohol and water can form macroscopically homogeneous liquid media with distinct microenvironments of varying polarity. These ternary systems are very similar to classic water in oil microemulsions although they don’t have any amphiphilic surfactant. They were thus, initially called “surfactantless” or “detergentless” microemulsions. One of the main application fields that these systems cover is the one of biocatalysis in non-conventional media, a pillar of industrial biotechnology.

 

Enzyme immobilization on gels based on natural polymers

Gels, either based on water-in-oil microemulsions (organogels) or on water (hydrogels) can be formed using various natural polymers such as gelatin, agar, chitosan or cellulose derivatives. Enzymes entrapped in such systems can keep their activity and enhance their stability within the gel matrix. The importance of these catalysts leans on their numerous potential biotechnological applications. An important example is the use of various lipase-containing systems for hydrolytic or synthetic reactions.

 

Formulation of biocompatible nanodispersions as food products replacements for increased nutritional value and stability

Food grade W/O microemulsions, based on olive oil, developed and characterized to be used in blends with sunflower oil as replacers of palm kernel oil in products like whipped cream alternatives. The replacement reduces the required energy for homogenization and the alternatives are eco-friendlier and cost less for the industry. Furthermore, the input of microemulsions and non-hydrogenated vegetable oil reduce the overall content of dietary hydrogenated fat and trans fatty acid thus increasing the nutritional value.

 

Nanodispersions enriched with olive oil, essential oils and antimicrobial substances against foodborne microorganisms

W/O microemulsions based on olive oil and essential oils formulated for the encapsulation and protection of nisin, a natural bio-preservative used for food applications.
The aim of this project is the assessment of the activity of microemulsions against foodborne microorganisms such as Listeria monocytogenes, Bacillus cereus etc. Structural characteristics of optimized microemulsions examined using dynamic light scattering (DLS) and electron paramagnetic resonance (EPR) spectroscopy. Antibacterial activity assessed using the well-diffusion assay (WDA) assay.

Microemulsions containing dittany oil has shown positive results against Lactococcus lactis, when used as nisin carriers.  Future perspectives include the development of various nisin loaded food grade microemulsions and their incorporation in a variety of emulsion-based food products.

 

Encapsulation of bioactive compound in nanodispersions to increase the nutritional value of food products.

This project is related to the formulation of food grade O/W nanoemulsions as encapsulation vehicles of lipophilic vitamins (Vitamin D, e.t.c). Vitamin D is a lipophilic vitamin, responsible for increasing intestinal absorption of calcium, iron, magnesium, phosphate, and zinc. As long as very few foods contain vitamin D, its synthesis in the skin is the major natural source of the vitamin. This procedure is mainly dependent on sun exposure. O/W nanoemulsions are formulated using high pressure homogenization. The systems are structurally characterized using DLS and EPR in order to investigate changes upon vitamin’s encapsulation and stability over time. Nanoemulsions are composed of biocompatible ingredients, as the main target is to be able to be used in food industry to enrich specific products in Vitamin D.

 

Microemulsions as carriers of potential anticancer drugs for targeted therapies.

Nanodispersions based on biocompatible, safe materials are formulated as delivery vehicles of drugs with potential anticancer activity. Most of the chemotherapeutic drugs currently available are poorly water-soluble and need to have their bioavailability improved through the development of enabled formulations and effective delivery mechanisms.

One of the most important fields of modern "translational research" is the design and development of delivery systems as carriers for chemotherapeutic drugs. Their targeted-controlled release in tumor tissues is an attempt to avoid side effects and face major clinical problems such as tumor resistance.

In this respect, (O/W) micro- and nanoemulsions are formulated as delivery vehicles of Vemurafenib analog PLX4720 which is a lipophilic antitumor drug against various cancer types (e.g melanoma) correlated with the BRAFV600E mutation. Structural characterization of the proposed systems is obtained using viscosity, dynamic light scattering (DLS), electron paramagnetic resonance (EPR) spectroscopy and cryogenic-transmission electron microscopy (Cryo-TEM).

 

Nanodispersions for intranasal delivery of bioactive compounds

The drug delivery through nasal route offers advantages including rapid absorption, avoidance of first-pass hepatic metabolism etc.. In this respect, nanodispersions based on Extra Virgin Olive Oil will be used as carriers for a variety of bioactive compounds through nasal route. Intranasal administration of nanodispersions offers a practical, non-invasive, convenient and cost-effective route of administration. The nanodispersions will be tested for their possible toxic in nasal cells. It has to be underlined that preliminary studies have not shown any toxic effect in human colon cells of the above systems even in high concentrations. The construction of a nasal epithelium that is mimicking the physiological will be constructed with the cultivation of specific cell lines in Transwell device. The artificial epithelium will be used in order to prove if the proposed systems enhance the permeability of different encapsulated compounds in nasal mucosa and if cause morphological changes in the epithelium.

 

 

Current Funded projects:

  1. Nanobiotechnology, National Hellenic Research Foundation Project 2402, 2015-2018, Budget 162.635 €. Coordinator NHRF: Dr. A. Xenakis
  2. Program Agence Nationale de Recherche (ANR), Institut Carnot, Projet Lipides pour l’industrie et la santé (LISA), France. 2013-14. «micro/nano-émulsions de type e/h biocompatibles et riches en micronutriments : préparation et caractérisation» Budget: 43.000 €. Coordinator: F.Calderon, INP Bordeaux.
  3. EU INCO FP7: Mediterranean Science, Policy, Research & Innovation Gateway (MEDSPRING), , 2013-6 Budget: 289.650 €. Coordinator NHRF: Dr A. Xenakis
  4. EU INCO FP7: EURO-MEDITERRANEAN Cooperation through ERANET joint activities and beyond (ERANETMED, 2013-6, Budget: 107.649,45 €. Coordinator NHRF: Dr A. Xenakis
  5. Program National Strategic Reference Framework, Action “Developmental Projects of Research Organisations- Kripis”2013-2015:“STHENOS”, Targeted therapeutic approaches against degenerative diseases, with special focus on cancer and ageing. Budget: 1.500.000,00 € (Biomimetics 174.773€). Coordinator Dr A. Pintzas
  6. Program ΕΣΠΑ PAVET “Application of Nanoemulsion Technology to food products based on Oil in Water Emulsions such as vegetable cream and fudge icings” Budget: 300.000,00 € Contractor: JOTIS SA Budget :61.250€ Coordinator NHRF, Dr. V. Papadimitriou

Complete list of projects

 

Collaboration with industries (since 2012)

The collaboration of our team with industries has two main axes:

  • Provision of services in order to determine properties of different types of products (use of EPR, DLS etc.)
  • Product development through common projects (food products, cosmetics etc.)

JOTIS SA

  • ΠΑΒΕΤ 2013. “Application of Nanoemulsion Technology to food products based on Oil in Water Emulsions such as vegetable cream and fudge icings” (BeNeFIC)
  • Submission ΠΑΒΕΤ 2013. “Exploitation of Greek vinery waste for the development of high added value traditional foods”.
  • Submission Greek-Germany Cooperation «Food grade surfactant-free microemulsions for healthy and safe food preparations» .


VIORYL S.A.

  • Common Programme ΕΣΠΑ “Cooperation” 2010-2. “Development of nanoemulsions as new materials for managing phytoprotective products to reduce the environmental charge”

 

Group activities – Honors

  • Scholarship from Institut Français Gréce
    Dr. M. Chatzidaki was selected by the Institut Français Gréce for a three-month Post-Doc scholarship «Séjours scientifiques de haut niveau» 2016.

  • Innovathens 2016 – Olea team
    Our team has been selected by scientists specialized in food science, economists and entrepreneurs to participate in the Business Accelerator called “Food for Business” organized by the Innovathens team- Hub of Innovation and Entrepreneurship, Technopolis city of Athens. (For more information visit: http://www.innovathens.gr/).
    “Food for Business” is a  three-month program of accelerated advisory that provides high quality information services, education and personalized mentoring/coaching in groups and startups who aspire to try the fields of foods, gastronomy and tourism.

  • Ecotrophelia competition 2015 – (µeRÅki)                                                        
    The members of the team (Chatzidaki M., Mitsou E., Sklaviadis L., Theochari I.) participated in the contest (https://ecotrophelia.org/) introducing a “smart” salad dressing based on the technology of microemulsions. More specifically, the final product was a mixture of olive oil as the continuous phase, dittany extract, raki (greek traditional alcohol beverage) and balsamic vinegar as the aqueous phase.
    The product attracted a lot of greek enterpises and resulted in a patent.



  • Ekkinisi Lab 2014
    (NanoBio Team: Papadimitriou, Zoumpanioti, Xenakis) Our team has participated in the “EkinisiLab” New Business Development Incubator that provides 6-month coaching and consulting training programs for start-ups and spin-off companies. The EkinisiLAB environment offers opportunities for development and networking, using the expertise of high-ranking executives from SEV member-businesses. It also offers market research services and data on export markets.

 

Recent patents

  • Papadimitriou K., Chatzidaki M. D., Alexandraki S., Papadimitriou V., Tsakalidou E., Xenakis A. 2015. “Water-in-oil (W/O) microemulsions as carriers of bacteriocins for the antimicrobial protection of foods” (OBI – 1008858).
  • Chatzidaki M. D., Mitsou E., Theochari I., Papadimitriou V., Xenakis A., 2015. “Edible microemulsions with encapsulated plant extracts as dressing type products” (OBI – 1008863).
  • Filippou K., Zoumpanioti M., Xenakis A. 2014. “Immobilized catalyst in a continuous flow system for the synthesis of high added value products” (OBI – 1008307).
  • Kalaitzaki A., Xenakis A., Papadimitriou V. (2013) “Biocompatible nanodispersions as media for encapsulating bioactive substances with phytoprotective activity” (OBI- 20130100305).

 

 

Selected Recent Publications

  1. Papanikolaou, N. E., Kalaitzaki, A., Karamaouna, F., Michaelakis, A., Papadimitriou, V., Dourtoglou, V., & Papachristos, D. P. Nano-formulation enhances insecticidal activity of natural pyrethrins against Aphis gossypii (Hemiptera: Aphididae) and retains their harmless effect to non-target predators. Environmental Science and Pollution Research (2017), 1-7, DOI: 10.1007/s11356-017-8596-2. (IF 2015 2.760)
  2. E. Mitsou, A. Xenakis, M. Zoumpanioti. “Oxidation catalysis by enzymes in microemulsions.” Catalysts (2017) 7, DOI: 10.3390/catal7020052 (IF2015 2.964)
  3. M. Chatzidaki, K. Papadimitriou, V. Alexandraki, E. Tsirvouli, Z. Chakim, A. Ghazel, K. Mortensen, A. Yaghmur, S. Salentinig, V. Papadimitriou, E. Tsakalidou, A. Xenakis. “Microemulsions as potential carriers of: effect of composition on the structure and efficacy” Langmuir (2016) 32, DOI: 10.1021/acs. langmuir.6b02923 (IF2015 4.457)
  4. M. Chatzidaki, E. Mateos-Diaz, F. Leal-Calderon, A. Xenakis, F. Carrière “Water-in-Oil microemulsions versus emulsions as carriers of hydroxytyrosol: an in vitro gastrointestinal lipolysis study using the pHstat technique” Food & Function (2016) 7, 2258-69. DOI: 10.1039/c6fo00361c (IF2015 2.791)
  5. Xenakis, M. Zoumpanioti, and H. Stamatis. "Enzymatic reactions in structured surfactantfree microemulsions." Current Opinion in Colloid & Interface Science (2016) 22, 41-45. DOI: 10.1016/j.cocis.2016.02.009. (IF2015 6.234) Cited 2 (0)
  6. K . Gonçalves, I.I. Junior, V. Papadimitriou, M. Zoumpanioti, I.C.R., Leal, R.O.M.A. de Souza, Y. Cordeiro, A. Xenakis. "Nanoencapsulated Lecitase Ultra and Thermomyces lanuginosus Lipase, a Comparative Structural Study." Langmuir 32.26 (2016): 6746-6756. DOI: 10.1021/acs.langmuir.6b00826. (IF2015 4.457)
  7. M. Khemakhem, V. Papadimitriou, G. Sotiroudis, P. Zoumpoulakis, C. Arbez-Gindre, N. Bouzouita, T. G. Sotiroudis “Melanin and Humic acid-like polymer complex from olive mill waste waters. Part I. Isolation and Characterization.” Food Chemistry, (2016) 203 540–547. DOI: 10.1016/j.foodchem.2016.01.110. (IF2015 4.052) Cited 1 (1)
  8. M.Khemakhem, G. Sotiroudis, E. Mitsou, S. Avramiotis, T. G. Sotiroudis, N. Bouzouita, V. Papadimitriou. Melanin and humic acid-like polymer complex from olive mill waste waters. Part II. Surfactant properties and encapsulation in W/O microemulsions. Journal of Molecular Liquids (2016). 222, 480-486. DOI: 10.1016/j.molliq.2016.07.065. (IF2015 2.740)
  9. M. Chatzidaki, N. Arik, J. Monteil, V. Papadimitriou, F. Leal-Calderon, A. Xenakis “Microemulsion versus emulsion as effective carrier of Hydroxytyrosol” Colloids and Surfaces B. Biointerfaces (2016) 137, 146-151, DOI 10.1016/j.colsurfb.2015.04.053 (IF2015 4.152). Cited 8 (2)
  10. E.Mitsou, G. Tavantzis, G. Sotiroudis, D. Ladikos, A. Xenakis, V. & Papadimitriou ”Food grade water-in-oil microemulsions as replacement of oil phase to help process and stabilization of whipped cream.” Colloids and Surfaces A: Physicochemical and Engineering Aspect s(2016), 510, 69-76.
  11. M. Chatzidaki, E. Mitsou, A. Yaghmur, A. Xenakis, V. Papadimitriou, “Formulation and characterization of food-grade microemulsions as carriers of natural phenolic antioxidants" Colloids and Surfaces A: Physichochem. Eng.Aspects, (2015) 483, 130-6. DOI 10.1016/j.colsurfa.2015.03.060 (IF2015 2.752). Cited 9 (3)
  12. A. Kalaitzaki, A. Xenakis, V. Papadimitriou “Highly Water Dilutable Microemulsions: A structural study” Colloid Polym.Sci. (2015) DOI 10.1007/s00396-014-3496-1. (IF2013 2.410)


Complete list of publications & patents

Collaborations with Industries

 

Collaborations (since 2012)

  • Cirad, Argicultural Research for Development, Montpellier, France
  • Institut de Chimie & Biologie des Membranes & des Nano-objets (CBMN), Pessac, France
  • CNRS - Centre National de la Recherche Scientifique, Marseille, France
  • University of Örebro, Örebro, Sweden
  • Technion- Israel Institue of Technology, Haifa, Israel
  • University of Copenhagen, Copenhagen, Denmark
  • Ecole Supérieure des Industries Alimentaires de Tunis, Tunis, Tunisia
  • Ege University, Izmir, Turkey
  • National Engineering School in Sfax, Sfax, Tunisia
  • Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
  • University of Cyprus, Nicosia, Cyprus
  • Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • State University of Maringa, Department of Chemical Engineering, Maringa, Brazil
  • Argicultural University of Athens, Athens, Greece
  • Department of Biological Applications & Biotechnology, University of Ioannina, Ioannina, Greece
  • Faculty of Biology, National & Kapodistrian University of Athens, Athens, Greece
  • University of Thessaly, Larissa, Greece
  • Department of Food Technology, Technological Educational Institute of Athens, Athens, Greece
  • Department of Food Technology, School of Argicultural Technology, Thessaloniki, Greece
  • Benaki Phytopathological Institute, Kifissia, Greece
  • Material Synthesis and Physical Chemistry, Theoretical & Physical Chemistry Institute, National Hellenic Research Foundation, Athens, Greece

 

Scientific equipment

Dynamic Light Scattering (DLS)

DLS is a non-invasive, well-established technique that can be used to determine the size and the size distribution of particles in the sub-micron region. Some of the DLS applications which are used in our lab are the determination of particle size, polydispersity index and z-potential of different types of emulsions such as microemulsions and nanoemulsions.

 

 

Electron Paramagnetic Resonance (EPR)/ Bruker EMX

EPR is a powerful, versatile, nondestructive and nonintrusive analytical method yielding structural and dynamical information, even from ongoing chemical or physical processes.

The Bruker EMX EPR spectometer is a research grade scientific instrument. It is capable of routine measurements, as well as sophisticated and advanced experiments.

Some of the EPR applications which are commonly used in our laboratory are listed below:


  • Study of interfacial properties and dynamic structures in different nanodispersions, using spin labels such as 5-doxyl stearic acid (5-DSA)
  • Investigation of proteins dynamics and conformation in a variety of environments by bounding an enzyme’s active site with appropriate spin-label reagents
  • Sensitive and rapid method (spin trapping) for evaluating the antioxidant activity of potential antioxidant compounds by using free radicals (Galvinoxyl, DPPH etc.)
  • Detection of paramagnetic species

Our group has expertise in EPR studies with decades of experience and plentiful bibliography (See the complete list publication archive) in a wide range of applications from biotechnology and pharmaceuticals to food applications.

 

Gas Chromatograph

A useful tool for monitoring enzymatic bioconversions

 

High-performance liquid chromatography

Used for qualitative and quantitative analysis of reaction samples

 

High Pressure Homogenizer (PANTA PLUS – GEA)

PandaPlus 1000 is a table-top laboratory unit, designed for continuous operation at high pressure, for high pressure processing of nanoparticles, nanodispersions, nanoemulsions and for cell disruption. In addition, it can be used for processing dairy products, fruit juices, liquid food, food additives and ingredients as well as cosmetic and chemical products. Tests can be run even with small sample volumes, and the results are comparable with those achieves on bigger size machines.


Probe homogenizer (UNIDRIVE X1000 homogenizer)

It is a homogenizer for general laboratory purpose with electronically stabilized speed control. The stirring medium is subjected to a combination of mechanical shearing and sonic energy. It is suitable for the formulation of emulsions, nanoemulsions and Pickering emulsions

 

Franz Diffusion Cell

Franz Diffusion Cell is generally regarded as the most common in vitro release testing method. It is often used to monitor release of active compounds from semi-solid drug products across a membrane (synthetic membrane, a tissue construct or biological sample such as cadaver skin). It is suitable for testing the release of active substances encapsulated in microemulsions or gels.

 

 

High pressure apparatus

Our high pressure apparatus is suitable for performing enzymatically catalyzed reactions under supercritical conditions. Since supercritical carbon dioxide (scCO2) has emerged as perhaps the most promising “green” solvent (apart from water) due to its being toxicologically harmless, not inflammable, readily available and inexpensive, enzymatic reactions in scCO2 are increasingly attracting interest. Using this apparatus, we aim in replacement of any organic solvent used in the conventional biocatalytic process by harmless CO2.

 

Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) System

The hybrid quadrupole / linear ion trap technology of the 3200 QTRAP System offers the ability to identify and quantitate components from complex samples in a single run. LC-MS/MS can be used for qualitative and quantitative analysis of lipid complex mixtures but also for the monitoring of chemical reactions (esterification, epoxidation).
The mass spectrometer has a wide range of applications and among others, it has been used in our lab for the identification and determination of smoking biomarkers in meconium.

 

 

 

News

Dr. A Xenakis interview in ''Ελευθεροτυπία'' Newspaper (26-5-2013)

Collaboration with Örebro, Sweden

 

 

 

 
 

 

   
       

 

 

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