Paradisi Rese@rch

Discovery Evolution Application
Francesca Paradisi
Prof. Francesca Paradisi

Associate Professor in Biocatalysis and Enzyme Engineering

About me...

I completed my MSc in Organic Chemistry from the University of Bologna in 1998 under the supervision of Prof. Cainelli. In 2002 I completed my PhD at the same institution with a thesis on the synthesis of non-natural amino acids via diketopiperazine scaffolds. During my PhD I spent a summer in Dublin as a visiting student in Trinity College working with Prof. Thorri Gunnlaugsson and it was a fantastic experience. So after my PhD I had no doubt I wanted to go abroad and I joined the group of Prof. Paul Engel at University College Dublin as Post-Doctoral Fellow where I discovered the wonders of biocatalysis. I remained in Paul’s group until 2005 developing several projects mainly focused on amino acid dehydrogenases and their applications in the synthesis of non-natural amino acids. I owe Paul all I know about enzymes and their reaction mechanisms!

I spent then a few months in Enzolve Technologies in 2005, a spin-off company of UCD where I worked on the use of mutant dehydrogeanse enzymes for neonatal screening of metabolic disorders. In 2006 I won the lotto and was appointed College Lecturer in Chemical Biology at the UCD School of Chemistry. I was promoted in 2014 to Senior Lecturer. I was fortunate to be always surrounded by a team of excellent students that made my research always interesting, certainly challenging, and thankfully rewarding.

A had the great opportunity to spend the summer of 2015 in UC Davis in California as a visiting academic and I joined the group of Dr. Justin Siegel who gave me the possibility of expanding my research to a different class of enzymes (glycosyl hydrolyses) and getting my hands dirty in the lab again was awesome as they say.  While I was in Davis and I thought things couldn’t get any better, I was offered the position of Associate Professor in Biocatalysis and Enzyme Engineering in the School of Chemistry at the Univeristy of Nottingham. I have started this new adventure since February 2016.

Outside my work life, I have a husband and two children, Oliver and Martina, and a cat. I love skiing and swimming and travelling too.

Research Highlights

PlosOne (2017): “Engineering substrate promiscuity in halophilic alcohol dehydrogenase (HvADH2) by in silico design”

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OBC (2017): “Extreme halophilic alcohol dehydrogenase mediated highly efficient syntheses of enantiopure aromatic alcohols”

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Trends in Biotechnology (2017): “Flow Bioreactors as Complementary Tools for Biocatalytic Process Intensification”

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ChemCatChem (2017): Highly Efficient Oxidation of Amines to Aldehydes with Flow-based Biocatalysis

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Chemistry Today (2017): Mini-review “Biocatalysis takes to flow”

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Amino Acids (2017): Stabilization of Angiotensin-(1–7) by key substitution with a cyclic non-natural amino acid

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Green Chemistry (2017) : “Continuous flow biocatalysis: production and in-line purification of amines by immobilised transaminase from Halomonas elongata”

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OBC (2016) : “Stereoelectronic effects in the reaction of aromatic substrates catalysed by Halomonas elongata transaminase and its mutants”

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Latest Post

Congratulations Matteo!

Very well done to Matteo who defended his thesis on the 23rd of October! The external examiner was very impressed and the group very much enjoy celebrating together at the group meeting the following day. Benny came to visit for the occasion, and to eat delicious...

Research

Our Projects :
Flow Biocatalysis

Enzymes are amazing catalysts which effortlessly, and with extreme precision, regulate reactions of biosynthetic pathways in a biological system. We are taking enzymes from different sources, those that offer the optimal characteristics for our chemistry, and recreate artificial cascades ex-vivo using a flow reactor. Enzymes we produce, are directly and covalently immobilised onto solid supports and packed into column reactors. Each enzymatic biotransformation can be individually optimised so that the starting material is fully converted into the product by the time the flow takes it out of the column. Two, three more columns containing different enzymes can be connected sequencially, and several steps can be performed with high efficiency and fast flow.  Continuous flow biocatalysis is the ultimate evolution of continuous processing and has brought enzymes to a whole new dimension. Have a look at the enzymes we work with below.

Enzyme Toolbox

We have a special interest in enzymes from extremophilic microbes which have adapted to life in  high salt environments (Dead Sea, salterns, etc). The mechanism developed by the organisms to  withstand molar concentrations of NaCl is either by accumulation of high amounts of KCl in the cytoplasm, or by efficient production of soluble organic molecules. In both cases the enzymes expressed by these bacteria or achaea have evolved structurally to be able to perform in a water depleted system and therfore are excellent candidates for synthetic applications which normally require organic solvents.

Transaminases are a family of enzymes with high potential in biotechnological applications. They can be very useful for the enantioselective production of a series of compounds with high value such as chiral amines and enantiopure amino alcohols which find use in many chemical fields; above all, for the synthesis of biologically active compounds. The synthesis of enantiopure amines by enzymatically catalyzed reactions presents several advantages as an alternative to traditional approaches such as mild reaction conditions, high stereoselectivity, fewer synthetic steps, potential total substrate conversion and no environmental issues unlike in the case of transition metal catalysts. 

The reaction is reversible and transaminases can also be used for the mild oxidation of amines into aldehydes and ketones.

We have isolated and investigated a transaminase from Halomonas elongata (HEWT) which has shown high enantioselectivity, large substrate spectra and stability in organic solvents, HEWT a highly suitable enzyme for biotechnological applications in the production of chiral amines. For these reasons, we are currently developing different projects regarding its application, including continuous flow biotransformation and enzyme evolution to improve its catalytic performance against non natural substrates.

Redox enzymes encompass a number of different biocatalysts of great industrial interest. We have a collection of enzymes from both salt adapted and mesophilic sources such as alcohol dehydrogenases (ADHs) and ketoreductases (KR) which we have used to synthesise chiral alcohols (in the reductive direction) and in the dynamic kinetic resolution of profenic aldehydes. These enzymes pose an additional challenge as they are cofactor dependent (NAD(P)H). The cofactor cannot be used stoichiometrically as it is prohibitively expensive. We have therefore developed simple recycling strategies which are easily adaptable to flow biocatalysis.

Hydrolytic enzymes are another large family of very useful biocatalysts. We have recently expanded our research into reactions which include ester and amide hydrolysis (and eventually also synthesis) as part of an artificial enzymatic cascade. A selection of esterases and amidases are now part of our library. In a separate project six ß-glycosyl hydrolyses, all classified as GH1, have been selected to investigate how environmental adaptation affects biocatalytic properties, as well as stability at different temperatures, pHs and in the presence of solvents. Furthermore, we analysed whether the subtle differences in the active site of the proteins may indicate a pattern for a preferential substrate recognition. GH1 from Thermobaculum terrenum (Tte) and Thermus Nonproteolyticus (Tno) have been chosen as thermophilic examples, Halothermothrix orenii (Hor) and Halobacillus halophilus (Hha) as two halophilic proteins (with Hor being also thermophilic), and finally Colwellia psychrerythraea (Cps) and Marinomonas profundimaris (Mpr) as psychrophilic ones. 

Semi-synthetic enzymes

Metals are part of biological molecules and cover different roles. It is fascinating how inorganic elements are pivotal in many cases for biological activity. In collaboration with Prof. Albrecht in Switzerland we have started looking at the amino acid residues that hold in place a catalytic metal in the active site of a number of enzymes. Specifically we are investigating the role of histidine as a ligand in copper proteins such as azurin. Azurin is a bacterial blue copper protein that acts as electron shuttle in bacteria denitrification process, where its metal center undergoes oxidation-reduction between Cu(I) and Cu (II) during the electron transfer. We have taken azurin as a model to evaluate the hypothesis that carbon-metal bonding in proteins (other than nitrogen-metal bonding) could play an important role since the interconversion of histidine between the weakly π-acidic imine (N-bound form) and the strongly σ-donating C-bound carbene tautomer2 will have substantial implications on the activity and oxidation-reduction chemistry of the coordinated metal center.

Under this same heading it is worth mentioning that our ADH proteins contain a catalytic zinc in the active site which coordinates to the substrate and facilitates its biotransformation. We are interested in investigating better the role of the zinc and its role in substrate selectivity. What happens if we change the metal for a different one? Can substrates other than alcohols/carbonyls be accommodated and transformed?

Peptido-mimeticts

Peptidomimetics are widely used in medicinal chemistry as therapeutic agents to act as agonists or antagonists on receptor or enzyme targets. They are also valuable tools for investigating the relationship between peptide structure and function as they elucidate key residues that are required to achieve a desired biological response. The incorporation of cyclic structures into peptidomimetics was shown to decrease their conformational flexibility resulting in increased selectivity and affinity with their target and improved enzymatic stability and bioavailability.

While trying to synthesise the side chain of an non-natural amino acid, we serendipitously discovered a side product of our reaction which looked more interestingly than the product we wanted to make. In 2013 we published the synthesis of the non-natural δ-amino acid ACCA (cis-3-(aminomethyl)cyclobutanecarboxylic acid) (O’Reilly et al. 2013, Amino acids, 511-518). ACCA contains a cyclobutane ring that gives the molecule conformational rigidity and locks the amino and carboxylic acid group in a cis conformation.

ACCA shows structural similarity to glutamate, making it an interesting building block for the synthesis of glutamate analogues. A set of dipeptides containing ACCA and a natural amino acid (glycine, valine, phenylalanine, cysteine) have been synthesized and are evaluated for their application as glutamate analogues selectively targeting the cystine-glutamate exchanger (Xc).

Angiotensin-(1-7) is a heptapeptide hormone of the renin-angiotensin system (RAS). We are particularly interested in the potential use of Angiotensin-(1-7) in anti-cancer therapy. Its anti-angiogenic and anti-proliferative properties have been investigated Prof. Gallagher at Wake Forest University (NC, USA). A phase II clinical trial recently completed by the Wake Forest School of Medicine successfully showed its therapeutic potential as a second or third line treatment of patients with unresectable or metastatic sarcomas.

Ang-(1-7) mediates its biological responses by interacting with the G protein-coupled mas. It is readily cleaved by the dipeptidyl carboxypeptidase angiotensin-converting enzyme (ACE) resulting in short-half life. We have synthesised a series of Ang-(1-7) analogues incorporating ACCA to decrease enzymatic metabolism thereby overcoming the problem of the short half-life of the endogenous heptapeptide and improving its properties as a therapeutic agent. This work has led to a patent application (Gallagher et al. U.S. Provisional Application No. 62/266,410, 2015).

Group Members

Christian Heckmann

After already having completed my fourth year chemistry project in the Paradisi research group, I have stayed on as a PhD student on the BBSRC iCASE course. Outside of the lab I enjoy cooking, and take a keen interest in space travel.

Research area

I am working on developing transaminase catalysts that produce small chiral amines with high enantioselectivity, to the further investigate how amidases may be used to further transform these amines into their corresponding amides. Both small chiral amines and amides are common features in many agrochemicals, and are of interest to Johnson Matthey, the industrial partner of this project.

Email : christian.heckmann@nottingham.ac.uk

Larah Bruen

I graduated from National University of Ireland, Galway in 2014 with a B.Sc. in Chemistry. I am now a fourth year PhD student working in the area of protein engineering and biocatalysis in University College Dublin. In my free time, I love reading, listening to podcasts, playing piano, and watching anything to do with true crime.

Research area

My research is focused on an alcohol dehydrogenase from a halophilic archaea. I am working to expand the substrate scope of this enzyme through in-silico docking and site-directed mutagenesis. I am also working on a novel method of screening mutant libraries of alcohol dehydrogenases, as a parallel method to find superior mutants.

Email : larah.bruen@ucdconnect.ie

Eimear Hegarty

In 2016, I graduated from the University of Limerick with a B.Sc. in Industrial Biochemistry. Having developed a keen interest in molecular biology and enzymology during my undergraduate studies I joined the Paradisi group to further pursue my research interests. Outside of the lab, I enjoy travelling and spending time with family and friends.

Research area

My research focuses on the use of enzymes as catalysts in organic synthetic chemistry. At present I am exploring the application of oxidoreductases and transaminases in stereoselective transformations that are difficult to perform by chemical means. I am particularly interested in the asymmetric reaction of small cyclic ketones with the formation of high value chiral compounds which serve as important intermediates in several therapeutic drugs.

Email : eimear.hegarty@nottingham.ac.uk

Dr. Martina Contente

After my Phd in Medicinal Chemistry at the University of Milan, I joined the Paradisi group as visiting Post-Doc in Dublin and subsequently as confirmed Post-doc at the University of Nottingham. Outside my chemistry word I am passionate about ballet. I also like organizing dinner for my friends and travelling with my boyfriend.

Research area

I am very interested in Biocatalysis research in particular in using enzymes or engineered whole cells as catalysts for the preparation of important synthetic intermediates. I am currently working on the combination of immobilized “extermozymes” and flow chemistry reactor for an efficient and sustainable preparation of high value chemicals used as aromas and fragrances or building blocks for pharmaceuticals.

Email: martina.contente@nottingham.ac.uk

Lidia Delgado

I graduated from the University of Granada with a BSc in Food Sciences. Subsequently, I won a 2-year scholarship from the Spanish Ministry of Agriculture, Food and Environment working at the Quality Schemes and Organic Farming Unit in Madrid. In my spare time, I enjoy travelling, reading fantasy and historical novels.

Research area

In October 2016 I joined the PhD programme of the Centre for Doctoral Training in Sustainable Chemistry, in the Paradisi’s research group. My research is focused on the characterization of a novel family of Glycosyl-Hydrolases . My goal is to improve the efficiency of food industrial processes from a sustainable approach.

Email : lidia.delgado@nottingham.ac.uk

Almulhim Nourah

I obtained my master degree in Chemistry from the University of New Brunswick (UNB), Canada, where I focused on increasing the stability of the bio fluorescence enzyme, Luciferase. I also held a lecturing position at the King Faisal University, Saudi Arabia. Outside of the lab I have a husband and two kids, Mohammed and Daynah.

Research area

I am a 1st year PhD student who recently joined Paradisi’s groupMy project is focused on improving the activity of natural beta-thioglucosidase enzymes derived from the thermophilic bacteriumThermus Non proteolyticus. My final aim is to engineer a strain capable of hydrolyzing the sulfur-bond contained in glucosinolate.

Email : Nourah.Almulhim@nottingham.ac.uk

David Roura Padrosa

I joined Paradisi Group a year ago after finishing a MSc in Molecular Biology and Biomedicine at the University of Girona, a city up north from Barcelona in Catalunya. Before that, I studied Biology at the same University. In my free time, i enjoy movies, reading and, of course, enjoying comicbooks.

Research area

I am now starting my 2nd  year as PhD student. My project is focused on the discovery, cloning and immobilization of novel enzymes from Halomonas elongata for their use in flow chemistry reactors. My idea is to take advantage of these enzymes unique characteristics for the production of valuable chemicals in a more sustainable way.

Email : david.roura@nottingham.ac.uk

Christian Heckmann

After already having completed my fourth year chemistry project in the Paradisi research group, I have stayed on as a PhD student on the BBSRC iCASE course. Outside of the lab I enjoy cooking, and take a keen interest in space travel.

Research area

I am working on developing transaminase catalysts that produce small chiral amines with high enantioselectivity, to the further investigate how amidases may be used to further transform these amines into their corresponding amides. Both small chiral amines and amides are common features in many agrochemicals, and are of interest to Johnson Matthey, the industrial partner of this project.

Email : christian.heckmann@nottingham.ac.uk

Larah Bruen

I graduated from National University of Ireland, Galway in 2014 with a B.Sc. in Chemistry. I am now a fourth year PhD student working in the area of protein engineering and biocatalysis in University College Dublin. In my free time, I love reading, listening to podcasts, playing piano, and watching anything to do with true crime.

Research area

My research is focused on an alcohol dehydrogenase from a halophilic archaea. I am working to expand the substrate scope of this enzyme through in-silico docking and site-directed mutagenesis. I am also working on a novel method of screening mutant libraries of alcohol dehydrogenases, as a parallel method to find superior mutants.

Email : larah.bruen@ucdconnect.ie

Dr. Martina Contente

After my Phd in Medicinal Chemistry at the University of Milan, I joined the Paradisi group as visiting Post-Doc in Dublin and subsequently as confirmed Post-doc at the University of Nottingham. Outside my chemistry word I am passionate about ballet. I also like organizing dinner for my friends and travelling with my boyfriend.

Research area

I am very interested in Biocatalysis research in particular in using enzymes or engineered whole cells as catalysts for the preparation of important synthetic intermediates. I am currently working on the combination of immobilized “extermozymes” and flow chemistry reactor for an efficient and sustainable preparation of high value chemicals used as aromas and fragrances or building blocks for pharmaceuticals.

Email: martina.contente@nottingham.ac.uk

Lidia Delgado

I graduated from the University of Granada with a BSc in Food Sciences. Subsequently, I won a 2-year scholarship from the Spanish Ministry of Agriculture, Food and Environment working at the Quality Schemes and Organic Farming Unit in Madrid. In my spare time, I enjoy travelling, reading fantasy and historical novels.

Research area

In October 2016 I joined the PhD programme of the Centre for Doctoral Training in Sustainable Chemistry, in the Paradisi’s research group. My research is focused on the characterization of a novel family of Glycosyl-Hydrolases . My goal is to improve the efficiency of food industrial processes from a sustainable approach.

Email : lidia.delgado@nottingham.ac.uk

Eimear Hegarty

I have recently joined the Paradisi Research Group as a 1st year PhD student having just completed my B.Sc. in Industrial Biochemistry at the University of Limerick (Ireland). 

Research area

With a keen interest in biocatalysis and enzyme engineering my research will focus on exploiting the hyper-salinity requirements of Haloferax volcanii to the advantage of biotechnology by developing it as a new expression system for proteins of industrial relevance.


Email : eimear.hegarty@nottingham.ac.uk

David Roura Padrosa

I joined Paradisi Group a year ago after finishing a MSc in Molecular Biology and Biomedicine at the University of Girona, a city up north from Barcelona in Catalunya. Before that, I studied Biology at the same University. In my free time, i enjoy movies, reading and, of course, enjoying comicbooks.

Research area

I am now starting my 2nd  year as PhD student. My project is focused on the discovery, cloning and immobilization of novel enzymes from Halomonas elongata for their use in flow chemistry reactors. My idea is to take advantage of these enzymes unique characteristics for the production of valuable chemicals in a more sustainable way.

Email : david.roura@nottingham.ac.uk

Almulhim Nourah

I obtained my master degree in Chemistry from the University of New Brunswick (UNB), Canada, where I focused on increasing the stability of the bio fluorescence enzyme, Luciferase. I also held a lecturing position at the King Faisal University, Saudi Arabia. Outside of the lab I have a husband and two kids, Mohammed and Daynah.

Research area

I am a 1st year PhD student who recently joined Paradisi’s groupMy project is focused on improving the activity of natural beta-thioglucosidase enzymes derived from the thermophilic bacteriumThermus Non proteolyticus. My final aim is to engineer a strain capable of hydrolyzing the sulfur-bond contained in glucosinolate.

Email : Nourah.Almulhim@nottingham.ac.uk

Those that shared the journey

Dr. Kevin Devine, Senior Lecturer, London Metropolitan University, UK

Dr. Daniele Balducci

Dr. Jennifer Cassidy, Science Foundation Ireland, IE

Dr. Elena Lestini, Post Doc, Dublin City University, IE

Dr. Ann-Kathrin Liliensiek, Researcher, Federal Institute of Hydrology, Essen, DE

Dr. Maeve O’Neill, Team Leader, Biocatalysts Ltd, Cardiff, UKK

Dr. Elaine O’Reilly (2010), Assistant Professor, University of Nottingham, UK

Dr. Gabriele Gucciardo (2010), Team Leader, Almac Group, Northern Ireland, UK

Dr. Sabrina Devereux (2010), Project Manager, Horizon Pharma Ireland, IE

Dr. Leanne Timpson (2011), Novozymes,  Nottingham, UK

Dr. Daniela Quaglia (2012), Post Doctoral Researcher, Université de Montréal, Canada

Dr. Philip Conway (2012), Technical Development Chemist, GSK, Cork, IE

Dr. Lara Pes (2013), Post Doctoral Researcher, Weill Cornell Medical College, NY, USA

Dr. Keith Robertson (2013), Technical Development Chemist, GSK, Cork, IE

Dr. Diya Alsafadi (2013), Researcher, Royal Scientific Society, Jordan

Dr. Jennifer Cassidy (2015), Post Doctoral Researcher, University College Dublin, IE

Dr. Anita Wester (2016), Post Doctoral Researcher, Københavns Universiter, DK

Dr. Matteo Planchestainer (2017), Post Doctoral Researcher, University of Bern, CH

Cillin Mac Donnchadha (2009), LEO Pharma, Dublin, IE

Outputs

Journal Articles

Reviews & Book

Patents

Biotrans 2017
Read more.
June 2017: Corbella Summer School Keynote Lecture
Read more.
August 2016: Big changes ahead!
The group will shortly officially move to Nottingham, and we will have a number of new researchers joining us, so we
Read more.
ChemCatChem Cover and Cover Profiles are out!
We are very happy with the front cover of our article which comes out in the October issue, have a
Read more.
October 2016: Ben Feringa in Groningen
Pleasant surprise for Francesca e Matteo during the Novel Enzyme conference in Groningen (The Netherland) last week.   Bernard Lucas
Read more.
October 2016: Well done Anita!
Massive congratulations to Anita who successfully defended her thesis on the 4th of October 2016. Wishing you all the very
Read more.
September 2016: Leaving UCD
Emotional moment during Francesca’s leaving lecture in UCD few weeks ago. Many students, colleagues, and friends attended her fascinating summary of ten
Read more.
June 2016: The Tromsø Experience
Read more.
Congratulations Matteo!
Read more.
SIMB 2017, Annual Meeting, Denver, Colorado
Fran was an invited speaker at the Annual Meeting organised by the (American) Society of Industrial Microbiology and Biotechnology. She
Read more.
Goodbye Jenni!
Read more.
October 2016: Nott’s crew… Check!
Here we are! The group is finally complete and ready to kick off this new adventure!!        
Read more.
December 2016: Jenni’s poster astonishes at CSCB symposium
Read more.
October 2016: Shiny New Lab
Here we are! After a lot of unpacking and patience too, our lab is ready to run!      
Read more.
May 2017: Well done Larah!
Read more.
March 2017: Lab B11 road trip
Read more.

Collaborations

“A knotty puzzle may hold a scientist up for a century, when it may be that a colleague has

the solution already and is not even aware of the puzzle that it might solve.”

(Isaac Asimov, The Robots of Dawn)

Dr. Justin Siegel and Dr. Marc Facciotti, UC Davis, California, USA

Dr. Justin Siegel and Dr. Marc Facciotti, UC Davis, California, USA

Prof. Peg Gallagher and Dr. Ann Tallant

Prof. Peg Gallagher and Dr. Ann Tallant, Wake Forest University, North Carolina, USA

Dr. Cormac Murphy

Dr. Cormac Murphy, University College Dublin, Ireland

Prof. Prem Puri

Prof. Prem Puri, National Children’s Research Centre, Dublin, Ireland

Dr. Thorsten Allers

Dr. Thorsten Allers, University of Nottingham, UK

Dr. Adele Williamson

Dr. Adele Williamson, Tromso University, Norway

Prof. Martin Albrecht

Prof. Martin Albrecht, University of Bern, Switzerland

Prof. Francesco Molinari

Prof. Francesco Molinari, University of Milan, Italy

Dr. Alessandra Tolomelli

Dr. Alessandra Tolomelli, University of Bologna, Italy

Prof. Francesca Paradisi

Associate Professor in Biocatalysis and Enzyme Engineering

School of Chemistry |University of Nottingham| University Park Nottingham | NG7 2RD| UK

Phone: +44(0)115 74 86267

Email: francesca.paradisi@nottingham.ac.uk

School of Chemistry

University Park, Nottingham NG7 2RD, Regno Unito

Prof. Francesca Paradisi

5 + 13 =

Synthesis and Solid State Pharmaceutical Centre
Islamic development bank
Irish Research Council
United States Environmental Protection Agency
Science Foundation Ireland
Biotechnology and Biological Sciences Research Council (BBSRC)
European cooperation in science and technology
European cooperation in science and technology
Image Group research Paradisi

THANKS FOR VISITING US

Francesca Paradisi Research © 2016-2017  - School of Chemistry - University of Nottingham

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