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Radboud Honours Academy

FNWI

Yearbook

2013‐2014

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 1


FNWI

Yearbook

2013‐2014

C o n t a c t

2 R H A ‐ F NW I

RHA FNWI Contact

Programme Director:

Drs Hay Geurts

Tel: 024‐3652575

E‐mail: [email protected]

Secretary:

Nicolette Poelen

Tel: 024‐3653313

E‐mail: [email protected]

Postal address:

RHA FNWI

Faculty of Science

Radboud University Nijmegen

PO Box 9010

6500 GL Nijmegen

Visiting address:

Heyendaalseweg 135

6525 AJ Nijmegen

Website:

http://www.ru.nl/rha/fnwi/

V o o r w o o r d

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 3

Voorwoord

Met grote trots bieden we U het jaarboek aan van Disciplinaire programma van de Radboud

Honours Academy aan de faculteit Natuurwetenschappen, Wiskunde, en Informatica: het

RHA FNWI Year Book 2013 ‐ 2014. Het is intussen ons vijfde Honours jaar, hetgeen op 24

oktober a.s. met gepaste aandacht zal worden gevierd! Met onze disciplinaire RHA biedt de

faculteit haar 25 meest getalenteerde en gemotiveerde bachelor studenten een uitdagend,

interdisciplinair academisch programma van twee jaar aan. Op deze manier maken de RHA

studenten al vroeg in hun studie kennis met het belang van het werken in teamverband in

modern interdisciplinair natuurwetenschappelijk onderzoek. De studenten leren daarnaast

om kritisch te reflecteren op natuurwetenschappelijke vraagstellingen, en op het belang en

de impact daarvan voor grote maatschappelijke vraagstukken.

In het eerste jaar van het programma werken de studenten onder begeleiding van een

mentor in vijf interdisciplinair samengestelde groepjes aan een zelfgekozen

natuurwetenschappelijk vraagstuk. Halverwege het jaar gaan de studenten op excursie om

bij internationaal gerenommeerde laboratoria meer te weten te komen over hun specifieke

onderwerp. In maart van dit jaar is de groep naar Oxford geweest, wat een groot succes was.

Dit jaarverslag presenteert de vijf verschillende onderzoeksprojecten van cohort 2013 in

korte samenvattingen van elk twee pagina’s. U zult hieruit onmiddelijk de grote breedte en

reikwijdte van de projecten kunnen appreciëren: van biomedische vragen rondom specifieke

neurologische of stofwisselingsziekten, of het belang van man‐vrouw verschillen bij

medicijnonderzoek, tot de zoektocht naar duurzame oplossingen voor het energieprobleem.

In het tweede RHA jaar gaan de studenten elk hun eigen weg om een individueel,

zelfgekozen onderzoeksproject uit te voeren, samen met een gerenommeerde onderzoeker

(de ‘meester’). In dit jaarverslag zijn de samenvattingen van de 22 onderzoeksprojecten van

cohort 2012 gebundeld.

Als voorzitter van de Programmaraad ben ik bevoorrecht om het enthousiasme en de

creatieve geesten van onze meest getalenteerde studenten van nabij mee te mogen maken

(ook in Oxford mocht ik er bij zijn!), en verder helpen te ontplooien. Het bewijs van het

succes van ons programma treft U op de hierna volgende pagina’s aan.

Veel leesplezier toegewenst,

Prof. dr. John van Opstal

Voorzitter Programmaraad RHA FNWI

P r e f a c e

4 R H A ‐ F NW I

Preface

With due pride we present to you the yearbook of the disciplinary programme of the

Radboud Honours Academy at the Faculty of Science, Mathematics and Information

Sciences: the RHA FNWI Yearbook 2013 ‐ 2014. This is our fifth year running, an occasion

that will be marked on the 24th of October this year with a lustrum symposium. Through our

disciplinary RHA the Faculty offers an ambitious, and foremost fascinating academic

programme of two years to 25 of our most talented and motivated bachelor students.

Already in an early stage of their study the students learn the importance of working in

interdisciplinary teams in the natural sciences. Moreover, they learn how to critically reflect

on research questions that arise from the natural sciences, and on the importance and

impact of this research for society.

In the first year of their RHA programme the students work under the supervision of a

mentor on a self‐chosen research problem. Halfway through the year the students visit

laboratories of international renown to inform themselves further on the specific subject. In

March this year the group visited Oxford which was a great success. This yearbook presents

the five different research projects from cohort 2013 in short two‐page summaries. The

reader can immediately appreciate the enormous range of topics: from biomedical research

questions concerning particular neurological or metabolic diseases, to the search for a

sustainable energy source to solve the global energy problem.

In their second RHA year each of the students defines his/her own research project, to

be performed under the guidance of a renowned researcher. This yearbook bundles the 22

summaries of the research projects from cohort 2012.

As the chairman of the Programme Committee I feel privileged to be so close to the

enthusiastic and creative minds of our most talented students (this year I was able to join in

the visit to Oxford!) and to to help them to develop their scientific ambitions. I am sure that

the next pages will demonstrate the success of our programme.

I hope you will enjoy reading this yearbook,

Prof. dr. John van Opstal

Chairman Programme Committee RHA FNWI

C o n t e n t s

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 5

Inhoud/Contents

Voorwoord .............................................................................................................................................. 3

Preface .................................................................................................................................................... 4

Acknowledgements ................................................................................................................................. 6

The Radboud Honours Programme of the Science Faculty .................................................................... 7

Het Radboud Honours Programma FNWI ............................................................................................... 9

1st Year ................................................................................................................................................... 11

Het gemeenschappelijke deel van het honoursprogramma FNWI in het tweede studiejaar .......... 12

1st Year RHA FNWI Research Projects ............................................................................................... 17

Excerpts from the jury review reports of the 2013 ‐2014 Faculty of Science Honours Projects ...... 28

2nd Year .................................................................................................................................................. 29

Het individuele deel van het honoursprogramma FNWI in het derde studiejaar ............................ 30

2nd Year RHA Research Projects ........................................................................................................ 33

Scientific Output .................................................................................................................................... 57

Leden RHA Programma Raad 2012‐2013 .............................................................................................. 59

About this yearbook

This yearbook is about the Radboud Honours Academy of the Science faculty and concerns

students who have started the Science Honours programme in the 2012‐2013 academic year

(cohort 2012) and those who have started in the 2013‐2014 Academic year (cohort 2013). All

project proposals and research projects are written in English but include an abstract in

Dutch. An overview of the Radboud Honours Programme of the Science faculty is given both

in English as well as in Dutch and the detailed description of both the 1st and 2nd year of the

programme is in Dutch only.

Dr Ernst R.H. van Eck

A c k n ow l e d g em e n t s

6 R H A ‐ F NW I

Acknowledgements

Without the help of a lot of people, this programme would not be the programme it is now.

The RHA FNWI would therefore like to acknowledge all the researchers and research groups

who have helped our first year RHA students with their projects, be it in giving advice or in

enabling preliminary experiments to be performed. The research groups in England who

have so kindly received our students this year, have showed them around their facilities and

had fruitful discussions with them to help them along with their projects are also thanked

warmly (and thanks Muriel for the report). The efforts of the jury members who have so

expertly judged the 1st year RHA research projects and examined the students during the

RHA 1st year symposium are deeply appreciated. Our 2nd year honours students have spent

time abroad as part of their programme. We are indebted to the research groups and people

that have welcomed them and thus made their time abroad an enervating experience.

Finally all the academic supervisors who guided the honours students throughout the

programme (the ‘mentors’ and “meesters’) are recognised for their efforts.

R H A – F NW I P r o g r amm a

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 7

The Radboud Honours Programme of the Science Faculty

The Radboud Honours Programme of the Science Faculty of the Radboud University

Nijmegen is a programme of excellence for 2nd and 3rd year Science Bachelor students. The

top students of the Science faculty (Faculteit der Natuurwetenschappen, Wiskunde in

Informatica, FNWI) are offered the opportunity to enroll in this programme in addition to

the programme of their 2nd and 3rd year Bachelor degree. Selection and admission to this

programme is based on the marks attained in the first year in addition to their intrinsic

motivation and ambition. The workload of the programme is 30 ECTS spread out over 2

years (for comparison: 1 years’ worth of study is 60 ECTS). During these 2 years students

participate in the honours programme in addition to their regular Bachelor programme, both

of which should be completed at the end of their 3rd year. Having successfully finished the

Science Honours programme the students will receive a special certificate: the so‐called

“honoursbul” (honours diploma)

The Science honours programme aims to cater to the desires and ambitions of excellent and

motivated students who wish to be challenged above and beyond their regular degree

programme. They are expected to enrich themselves within their own discipline as well as

within the context of the sciences in general. Attention is also given to the acquisition of

concomitant academic skills. The ultimate goal is to enable students who excel in their

studies to develop to their full potential during their degree programme. Here we strive to

reach a level, already at the Bachelor phase, where students can participate in scientific

research and in some cases, even in publications in the peer reviewed scientific literature.

A dm i s s i o n t o t h e h o n o u r s p r o g r amme

( F i r s t y e a r B S c )

Based on the results attained in the first semester of their Bachelor degree the best 25% of

the students of each Science degree are invited by the rector magnificus of the university to

apply for a place in the Science honours programme. Selection and admission to this

programme is competitive and based on their motivation and ambition, which they have to

show in a letter of motivation followed by an interview. Only 25 places are available in this

programme. Students that have been selected are asked to give suggestions for a research

project/theme. Ultimately access is granted if the first year of their Bachelor degree

(propedeuse) is attained within 1 year.

1 s t y e a r h o n o u r s p r o g r amme : I n t e r d i s c i p l i n a r y r e s e a r c h p r o j e c t .

( S e c o n d y e a r B S c )

In the first year of the FNWI honours programme, the process of writing of a joint research

proposal is central to that year, meriting 12 ECTS. The students will work together in small

groups (4‐5 students) and in the end produce a research proposal. Students of various

R H A – F NW I P r o g r amm a

8 R H A ‐ F NW I

scientific disciplines collaborate, investigating an interdisciplinary research theme. Each of

the students contributes from the perspective of their own degree programme. An

experienced member of the academic research staff will supervise the group. During regular

progress meetings each group will report to all other groups and the programme committee.

Part of the programme is a visit to a foreign top university/institute where leading experts

on their chosen subject will be consulted. This year is also used to develop their academic

skills and the students will receive training in giving presentations, scientific writing etcetera.

At the end of this year each group writes their research proposal, which should include a

suggested course of investigation and in certain cases some preliminary experiments. The

proposals will be sent to an expert jury who will judge the proposals on their merit. The

students will be given the opportunity to present their proposal and will be questioned by

the jury panel who will give the groups feedback on their contribution. All reporting, in

writing or orally, is expected to be in English.

2 n d y e a r h o n o u r s p r o g r amme : I n d i v i d u a l r e s e a r c h p r o j e c t .

( T h i r d y e a r B S c )

During this year the students will do the individual part of the honours programme: a

research project and extra courses totaling 18 ECTS. The student will choose a research

group and will be supervised by an academic researcher. Usually the internship is combined

with the regular Bachelor research internship, effectively doubling the time that can be

spend on a specific topic, allowing the student to fully engage in academic research. A stay

abroad, for research, for attending a conference or taking part in a course is part of this

internship. At the end of the internship a written report is produced and a presentation to

the research group is given and assessed. The 2nd year honours programme is finalised with a

symposium which is open to the general public. Here, every student will pitch their honours

research in just 2 minutes preceding a poster session where discussions ensue. The

symposium concludes with the awarding of the “honours bul” to the students.

P r o g r amme c o u n c i l

The board of the Science faculty has established the RHA FNWI programme council to

develop and execute the honours programme within the Science faculty as well as for

continual improvement and quality assurance of the programme. Members of the council

also partake in the board of examiners which who audit the compliance of individual

students with the guidelines of the programme.

R H A – F NW I P r o g r amm e

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 9

Het Radboud Honours Programma FNWI

De beste bachelorstudenten van de faculteit Natuurwetenschappen, Wiskunde en

Informatica (FNWI) wordt de mogelijkheid geboden om in het tweede en derde jaar van hun

bacheloropleiding een disciplinair excellentieprogramma te volgen: het honoursprogramma

FNWI. Selectie voor toelating tot dit programma vindt plaats op basis van studieresultaten

behaald in het eerste studiejaar, in combinatie met motivatie en ambitie. De totale omvang

van het tweejarige excellentieprogramma bedraagt 30 EC. Studenten volgen dit programma

naast hun reguliere bacheloropleiding. Daarbij is het uitgangspunt dat de deelnemende

studenten zowel hun honoursprogramma als hun reguliere bachelorprogramma in drie jaar

afronden. Studenten die het honoursprogramma FNWI succesvol doorlopen, ontvangen

hiervoor een speciale bul, de honoursbul.

Het honoursprogramma FNWI beoogt in te spelen op de wensen en ambities van excellente

en gemotiveerde studenten die zoeken naar extra uitdagingen. Het gaat hierbij om

verdieping binnen zowel de eigen discipline als binnen een interdisciplinaire bètacontext.

Daarnaast is er aandacht voor het verwerven van de bijbehorende academische

vaardigheden. Uiteindelijk doel is om excellente studenten in staat te stellen om zich

gedurende hun opleiding zo goed mogelijk te ontwikkelen. Daarbij is het streven om al in de

bachelorfase een niveau te bereiken waarbij participatie in ‐ en soms ook publiceren van ‐

wetenschappelijk onderzoek mogelijk is

H e t e e r s t e s t u d i e j a a r : d e s e l e c t i e

Op basis van de studieresultaten gedurende het eerste semester worden de beste studenten

van de verschillende opleidingen van FNWI door de rector magnificus van de universiteit

uitgenodigd om te solliciteren naar deelname aan het honoursprogramma FNWI. Selectie

vindt plaats op grond van motivatie en ambitie via een schriftelijke en mondelinge

selectieronde. De geselecteerde studenten wordt gevraagd om zelf met suggesties te

komen voor een bepaald onderzoeksthema of onderzoeksgebied. Voorwaarde om

uiteindelijk deel te mogen nemen aan het honoursprogramma FNWI is dat de propedeuse in

1 jaar behaald wordt.

H e t t w e e d e s t u d i e j a a r : d e i n t e r d i s c i p l i n a i r e o n d e r z o e k s v r a a g

In het tweede studiejaar staat het gemeenschappelijke onderzoeksvoorstel/project met een

omvang van 12 ec op het programma. Studenten van verschillende opleidingen werken in

kleine projectgroepen (4‐5 studenten) samen aan een interdisciplinaire probleemstelling,

waarbij ieder vanuit zijn eigen discipline bijdragen levert. Een ervaren wetenschappelijk

onderzoeker treedt op als mentor en begeleidt een dergelijke projectgroep. Tijdens

voortgangsavonden geeft iedere projectgroep gedurende het jaar een update van de stand

van zaken. Een gezamenlijk werkbezoek aan een buitenlandse topuniversiteit maakt deel uit

R H A – F NW I P r o g r amm e

10 R H A ‐ F NW I

van het programma. Daarnaast zijn er trainingen, gericht op het verder ontwikkelen van een

aantal academische vaardigheden. Aan het eind van het jaar wordt per projectgroep een

verslag geschreven van het onderzoeksproject, inclusief voorstellen voor nader onderzoek.

Over dit verslag wordt een mondelinge presentatie gegeven op een afsluitend symposium.

Hierbij krijgen de groepen feedback van een jury van externe experts op het gebied van de

thema's. Alle verslaglegging en presentaties vinden plaats in het Engels.

Een uitgebreide beschrijving van het gemeenschappelijk deel van het honoursprogramma

FNWI in het tweede studiejaar staat in het gedeelte van het 1ste jaars honourprogramma.

H e t d e r d e s t u d i e j a a r : d e i n d i v i d u e l e v e r d i e p i n g

Tijdens het derde studiejaar doorloopt de student het individuele onderzoeksproject met

een omvang van 18 ec. Dit bestaat uit een inhoudelijke verdieping binnen een zelfgekozen

onderzoeksrichting in de vorm van een onderzoeksproject. De student kiest hiervoor zelf een

onderzoeksgroep en een begeleider, de "meester". De student wordt aangeraden dit

onderzoeksproject te combineren met de reguliere bachelorstage om zo voldoende omvang

voor een verdiepend onderzoek te verkrijgen. Een verblijf in het buitenland, voor onderzoek,

congresbezoek of een cursus, maakt deel uit van dit gedeelte.

Een uitgebreide beschrijving van het individuele deel van het honoursprogramma FNWI in

het derde studiejaar staat in het gedeelte van het 2de jaars honourprogramma.

P r o g r amma r a a d

Het faculteitsbestuur heeft een programmaraad ingesteld om de opzet en uitvoering van het

honoursprogramma FNWI vorm te geven en toe te zien op de kwaliteit van het programma.

Leden van deze programmaraad treden ook op als examencommissie, die toetst of het

programma van individuele studenten voldoet aan de richtlijnen.

1 s t Y e a r R H A – F NW I

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 11

1st Year


FNWI

1 s t Y e a r R H A – F NW I D e s c r i p t i o n

12 R H A ‐ F NW I

Het gemeenschappelijke deel van het honoursprogramma FNWI in

het tweede studiejaar

Het tweede studiejaar bestaat uit gemeenschappelijke onderzoeksvoorstel/project met een

omvang van 12 ec, waarvan 10 ec toegekend worden aan het onderzoeksvoorstel en 2 ec

aan het onderdeel academische vorming. De start van het programma bestaat uit een

verplicht introductieblok in de week direct voorafgaand aan het begin van het tweede

studiejaar. Binnen deze introductie van drie dagen komen onder meer aan de orde:

kennismaking (studenten, mentoren, leden programmaraad)

informatie over opzet en inhoud van de verschillende programma‐onderdelen

inleiding en eerste afbakening van de te kiezen onderzoeksthema's (mentoren)

kennismaking met toegepast multidisciplinair onderzoek (lezingen en excursie TNO

Soest)

sessies waarin de studenten samen met de mentoren werken aan keuze van de

thema's en de indeling van de multidisciplinaire projectgroepen

eerste inhoudelijke verkenning en werkafspraken (projectgroep en mentor)

sociaal programma

H e t g eme e n s c h a p p e l i j k e o n d e r z o e k s v o o r s t e l / p r o j e c t

Binnen het gemeenschappelijke onderzoeksproject werken studenten in een

multidisciplinaire groep gezamenlijk aan de uitwerking van een uitdagende

wetenschappelijke vraagstelling. Het dient hierbij te gaan om een thema waarbij voor de

uitwerking een interdisciplinaire bèta‐aanpak noodzakelijk is. De groepen hebben een

omvang van ongeveer vijf studenten, afkomstig van verschillende opleidingen. De uitwerking

van het thema in de vorm van een gezamenlijk onderzoeksproject vindt plaats in de periode

van september tot juni van het tweede studiejaar. Indien mogelijk kunnen experimenten

deel uit maken van het project. Met het oog op een effectieve en doelmatige aanpak kent

deze periode een aantal ondersteunende vaardigheidstrainingen en voortgangsrapportages.

Onderdelen die bij de vaardigheidstrainingen (2 ec) aan de orde komen zijn:

presentatie‐ en debating‐technieken

professioneel samenwerken in multidisciplinaire groepen

projectmatig werken

Tijdens de voortgangsrapportages geven de projectgroepen een overzicht van hun

vorderingen, zodat de programmaraad het verloop van ieder onderzoeksproject kan

beoordelen aan de hand van tussenresultaten of "milestones".


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 13

Op z e t e n v o o r t g a n g

De programmaraad beoogt aan de hand van enkele algemene richtlijnen de voortgang van

de onderzoeksprojecten te ondersteunen. Bij de voortgangsrapportages hanteert de

programmaraad als milestone de volgende criteria:

Tijdens de eerste voortgangsrapportage in oktober presenteert elke projectgroep

hoe het oorspronkelijke thema is afgebakend tot een onderwerp met duidelijke

vraagstelling en doelstelling.

Tijdens de tweede voortgangsrapportage in december presenteert elke projectgroep

een helder overzicht van wat bekend is uit de relevante literatuur met betrekking tot

hun onderzoeksvraagstelling en bijbehorende aanpak.

Tijdens de derde voortgangsrapportage in april biedt elke projectgroep een eerste

overzicht van de behaalde resultaten inclusief voorstellen tot vervolgonderzoek en

eventuele aanbevelingen.

We r k b e z o e k b u i t e n l a n d

In het voorjaar van het tweede studiejaar wordt er gezamenlijk een tweedaags werkbezoek

gebracht aan een buitenlandse topuniversiteit (afgelopen jaren respectievelijk Oxford,

Cambridge, de ETH in Zürich, Berlijn). Het is de bedoeling dat dit bezoek de afzonderlijke

projecten ondersteunt en daarom dienen de projectgroepen met hun mentor vooraf contact

te leggen met een afdeling of instituut ter

plekke, waarvan het onderzoek goed

aansluit bij de vraagstelling van het project.

Het spreekt voor zich dat een gedegen

voorbereiding (o.a. het opstellen van

duidelijke vragen aan de afdeling/instituut)

voorwaarde is voor een succesvol bezoek.

Dit jaar werd Oxford bezocht, waar

natuurlijk Oxford University werd bezocht

naast uitstapjes naar King’s College London

en de University of Cambridge.

H e t e i n d p r o d u c t

Het gemeenschappelijke onderzoeksproject leidt tot een werkstuk met raakvlakken aan

meerdere wetenschapsgebieden binnen de natuurwetenschappen, vanuit een duidelijke

wetenschappelijke probleemstelling alsmede een aantoonbare maatschappelijke relevantie.

In het werkstuk wordt een helder overzicht gegeven van de stand van zaken in de literatuur.

Daarnaast dient ook de creativiteit van de groep zichtbaar te zijn o.a. doordat voorstellen

worden gedaan voor specifieke maatregelen of verder onderzoek. Het niveau en de stijl van

het werkstuk komen overeen met die van een wetenschappelijke notitie. Men kan denken

aan een projectvoorstel voor NWO of STW, of een wetenschappelijk onderbouwd advies, et

Oxford, March 2014: RHA students and accompanying staff pose

inside of St Johns college.


14 R H A ‐ F NW I

cetera. De taal is Engels, net zoals bij alle andere officiële producten van het

honoursprogramma FNWI. Omvang van het werkstuk: 10 tot maximaal 25 pagina's.

B e o o r d e l i n g e n a f s l u i t i n g

Het werkstuk wordt beoordeeld door een lid van de programmaraad en een externe

deskundige. Het gemeenschappelijke gedeelte van het RHA programma wordt afgesloten

met een symposium in juni. Daarin presenteren de projectgroepen hun resultaten aan een

breed, niet per se wetenschappelijk publiek (o.a. ouders/vrienden/medestudenten) en een

(externe) jury. De taal van de presentaties is Engels. Na afloop van deze presentatie zal de

jury met de groepsleden van gedachten wisselen, waarbij gericht vragen gesteld kunnen

worden aan individuele studenten. Na afloop zal de voorzitter van de jury voor elke groep

het jury‐rapport voorlezen.

Group picture of the 2013 cohort and their supervisors. The picture was taken at the 3 day introduction period to the FNWI RHA.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 15

Research Visit to Oxford

Each year in early spring all students in their first year of the RHA get the chance to visit research

groups in and experience a world‐renown academic centre. Each RHA‐group arranged meetings with

research departments that were doing research related to their own project. In these meetings we

exchange thoughts with the researchers and ask them questions about their subjects. This year the

destination of the research visit was Oxford, UK.

Thursday the 6th of March the journey started early in the morning

when we left Schiphol by plane to London Heathrow and

subsequently by bus to Oxford. This day was full of different

experiences of university life at the colleges. Our first destination

was one of the larger colleges of Oxford: St. John’s College. We

were kindly greeted by our tour guides who both live and study in

St. John’s. They showed us the gardens, library (with books from

the 15th century as well as modern scientific books) and dinner‐

halls and talked about student life in Oxford and the colleges. The

oldest buildings of the college were built in the 15th century. It was

a beautiful college to look at and

learning about the system of

universities in England was also

very interesting. The tour was

followed by a lecture given by

professor Grahame Lock, professor of philosophy, in which he

explained the system of the University of Oxford with regard to the

application procedure and the use of colleges to educate the

students. Another talk was given by Charlotte Koolstra, president

of the NWS Oxford (a society for Dutch students abroad), about

the general process of studying abroad, with a particular emphasis

on Oxford and practicalities of admittance and doing a master. In

the evening we got the chance to join a formal dinner at St John’s

College, where the students and professors wore their traditional

gowns. This was a

very impressive experience and also a very good

dinner. The day was concluded by a nice evening at

Chequers, where we could meet some other Dutch

students studying in Oxford organized by NWS.

On the Friday each group of students discussed their

projects with one or multiple research groups doing

research on related topics. In two cases, the day

brought us outside of Oxford; the group of Paul

Kouwer travelled to King’s College London (Institute

of Pharmaceutical Science), after a morning visit to

the Chemical Biology group in Oxford, and the group Nicole and Marijn presenting the project of Nicole van

Dam’s group

Group of Paul Kouwer enjoying London

Formal dinner in St. John’s college.


16 R H A ‐ F NW I

of Alexandra de Silva spent the entire day at the University of Cambridge (Department of Plant

Science). During the visits, we presented our project to the researchers and had informal discussions

with professors, post‐docs and PhD students.

Often, the discussion about the research proposals led to

an eye‐opener. Our visit made us realize that the process

to come up with a research proposal is harder than it

seems and you’ll have to adjust your research question

often to come to final one. Of course, much information

was gathered regarding the topics. In one of the visits, our

host immediately after our presentation began drawing a

concept, something very much along the lines of our idea,

but with the actual expertise of someone working in the

field. Things we had thought about, but weren’t sure were

actually possible, were made explicit, molecules and

mechanisms named instead of staying conceptual. With seven heads thinking about the same

problems, solutions and ideas came quite quickly. She seemed to

enjoy it as much as we all did. We also had the opportunity to look

around in the labs and research facilities and heard about which

research is being done: we managed to see research that hasn’t

even been published. All in all the visits were really instructive and

much fun. After the visits and before travelling back on the

saturday there was some time to look around in Oxford (and for

the group of Paul Kouwer also in London).

In general, we all had a great time visiting Oxford. We enjoyed all of

these experiences that we otherwise would have never had. It

definitely helped us with our research proposal by introducing us to

new methods and helping us with problems we otherwise might

not have solved.

Group of Uli Zeitler in an informal

discussion with prof. Armstrong

Group of Gerard Martens waiting for their visit

1 s t Y e a r R H A – R e s e a r c h P r o j e c t s

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 17

1st Year RHA FNWI Research Projects

Flux‐balance analysis of vinblastine production

Nicole van Buuringen Sharon Janssen

Marijn Man Lisa Noorlander

Supervisor: Prof. Dr. Nicole van Dam

Medicine release mechanisms in artificial organs applied to the administration of insulin

Roel Maas Eline Meijer

Roel Oldenkamp Jelle Piepenbrock

Lonneke Slenders

Supervisor: Dr. Paul Kouwer

Sex‐specific metabolism and effect of

Yvonne Bartels Charlotte Hoogstraten

Krijn Reijnders Felix Tönisen

Lina Wübbeke

Supervisor: Prof. Dr. Gerard Martens

SALMON – Superformulas And L‐systems: MOdelling Nature

Joery den Hoed Stijn Peeters

Bren Schaap Noor Smal

Luuk Verhoeven

Supervisor: Alexandra Silva

Improving CMC electrodes for use in enzymatic fuel cells

Gijs Franken Alexandra Hohnen

Sander Lemmens Ferdia Sherry

Berend Visser

Supervisor: Dr Uli Zeitler


18 R H A ‐ F NW I

Abstract: Vinblastine is a compound of a medicine that is frequently used to treat cancer and is produced in the

plant Catharanthus roseus. For this purpose, vindoline and catharanthine get extracted and isolated out of C.

roseus and are transformed into vinblastine. Unfortunately, this is still an expensive process. At this point, the

process of research can be made far more efficient. We propose to make a genome scale model of the pathway

of vinblastine/vindoline and catharanthine. After some research we decided to use flux balance analysis (FBA)

to analyse the model. This method can help us to determine the most promising sites for modification in the

pathway. The model will be made by using an already existing model of the primary metabolism of Arabidopsis

thaliana. On top of this model the secondary metabolism of C. roseus will be build. When constraints are

brought on and the model is interpreted, the best places of alteration can be found.. This allows us to

genetically modify the plant efficiently and perform knockouts to increase the produced amount of vindoline

and catharanthine.

Samenvatting: Vinblastine is een veelgebruikt medicijn voor de behandeling van verschillende type kanker. Deze

stof wordt geproduceerd in de plant Catharanthus Roseus. Helaas is de productie hiervan nog erg duur. Ons

onderzoeksvoorstel heeft dan ook als doel de productiehoeveelheid van vinblastine te verhogen. Dit willen we

doen met behulp van een model van de pathway van de voorlopers van vinblastine: vindoline en catharanthine.

Na het bouwen van het model gebruiken we flux balance analysis (FBA) om veelbelovende plaatsen in de

pathway te vinden voor modificatie. We beginnen met een al bestaand model van het primaire metabolisme

van de plant Arabidopsis thaliana en bouwen hier bovenop het secundaire C. roseus model. Met het model

kunnen de beste plekken voor veranderingen aan de plant worden gevonden en kan er met behulp van

genetische veranderingen de productie van vindoline en catharantine verhoogd worden.

Introduction: In our society, cancer is a huge problem. Not every type of cancer can be treated and the

medicines that do exist are very expensive. One of these medicines contains the substance vinblastine. It is

widely used in treatments against lymphomas, leukemia’s and solid tumors. Vinblastine is an alkaloid produced

by the plant Catharanthus roseus, better known as the Madagascar Periwinkle.

In order to be able to use vinblastine in medicines,

it has to be extracted from the plant. Figure 1

shows the ‐ rather simplified ‐ last part of the

pathway of vinblastine in Catharanthus roseus. A

pathway is a chain of chemical reactions that

occur within a cell, often with a certain end

product. In this case, you can see that vinblastine

is created from the substances vindoline and

catharanthine. These two substances are available

in larger quantities in the plant than vinblastine,

so vindoline and catharanthine are extracted from

the plant and in the laboratory transformed into

Flux‐balance analysis of vinblastine

production

Nicole van Buuringen, Sharon Janssen, Marijn Man, Lisa

Noorlander

Supervisor: Prof. Dr. Nicole van Dam

Figure 1: The important steps of the biosynthesis of vinblastine and vincristine (Schröder 2010).

From left to right: Lisa Noorlander, Marijn Man, Sharon Janssen and Nicole van Buuringen


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 19

vinblastine. Still, naturally, one plant does not produce a large amount of vindoline and catharanthine. It would

therefore be convenient if there was a way to increase the amount of vinblastine that the plant produces.

Research Proposal: The main goal of the experiment is to increase the amount of vindoline and catharanthine

in the plant Catharanthus roseus. To achieve this, we have proposed to make a flux‐balance model of the

secondary metabolism of C. roseus. The model will be made on top of an already existing model of the primary

metabolism of Arabidopsis thaliana from Cheung et al. (Cheung and others 2014) This model is the most recent

and takes the day‐night cycle of the plant into account, which is important for the production of certain

metabolites. The reactions of the pathway of vinblastine are obtained from the database CathaCyc

(www.cathacyc.org) and added to the model, including all other pathways that are connected to that of

vinblastine. Then the model will be made more realistic by adding constraints to the model, such as the input

and the output. These constraints can be found in literature, can be measured or – as a last option ‐ educated

guesses can be made.

The reconstructed model can then be analysed by simulating knock‐outs of genes. Certain gene knock‐outs will

change the fluxes in the plant and we can investigate which knock‐outs lead to the highest production of

vindoline and catharanthine. There are three major methods to simulate these knockouts: FBA, ROOM

(Regulatory On/Off Minimization) or MOMA (Minimization Of Metabolic Adjustment). With FBA it is possible to

model knock‐outs by constraining the value of the reaction speed. The computer then calculates the new flux‐

distribution by maximising the fluxes again. MOMA is based on the same constraints as FBA, but it assumes

that the new flux distribution, after the knock‐out, remains as close as possible to the wild‐type distribution.

(Segre and others 2002) At last, ROOM minimizes the total number of significant flux changes from the wild‐

type flux vector, under the same constraints as FBA and MOMA. (Shlomi and others 2005) For our research we

propose to use MOMA, because it is not reasonable that genetically modified organisms function optimal:

these mutants are not subjected to the same evolutionary pressure that shaped the wild type. (Segre, Vitkup et

al. 2002) It is also the method that is most used with models of plants.

After the analysis has been done and the best places for alteration in the pathway are known, C.

roseus can be genetically modified to efficiently increase the amount of produced vindoline. There are different

ways by which the genes of C. roseus can be silenced. One way to do this is the use of RNA interference (RNAi),

a permanent method. (Hannon 2002) Another technique for silencing is called Virus induced gene silencing

(VIGS), a transient method. (Lu and others 2003).

Outlook: This model seems a promising method to efficiently improve medicine production. Now the model

needs to be made and tested with in vivo results. With this information, the model can be made more accurate

and hopefully improve the efficiency of research.

References

Cheung CM, Poolman MG, Fell D, Ratcliffe RG, Sweetlove LJ. 2014. A diel flux‐balance model captures interactions between

light and dark metabolism during day‐night cycles in C3 and CAM leaves. Plant Physiology:pp. 113.234468.

Hannon GJ. 2002. RNA interference. Nature 418(6894):244‐251.

Lu R, Martin‐Hernandez AM, Peart JR, Malcuit I, Baulcombe DC. 2003. Virus‐induced gene silencing in plants. Methods

30(4):296‐303.

Schröder J. 2010. Fig. 1 Overview of the pathway to the bisindole alkaloids vinblastine and vincristine. . In: The bisindoles

vinblastine and vincristine amiVaV, editor.

Segre D, Vitkup D, Church GM. 2002. Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci

U S A 99(23):15112‐7.

Shlomi T, Berkman O, Ruppin E. 2005. Regulatory on/off minimization of metabolic flux changes after genetic perturbations.

Proc Natl Acad Sci U S A 102(21):7695‐700.


20 R H A ‐ F NW I

Medicine release mechanisms in artificial

organs applied to the administration of

insulin

Roel Maas, Eline Meijer, Roel Oldenkamp, Jelle

Piepenbrock and Lonneke Slenders

Supervisor: Dr. Paul Kouwer

Abstract: Artificial organs create the possibility to restore lost organ functions, for instance by regulating the

concentrations of hormones, proteins or other important molecules. The goal of this research project was to

design a generic structure or system that can act as a template for treatment. The insulin production system in

the human body was used as a model system. After consideration of various artificial organ compositions, we

propose a mechanism involving a polymer membrane encapsulating a source of insulin, carbon nanotubes, a

rotaxane acting as a gate molecule and a non‐enzymatic glucose sensor. This system, in principle, seems to be

a promising treatment for diabetes type 1. We propose further research in this field.

Samenvatting: Kunstmatige organen maken het mogelijk om verloren orgaanfuncties te herstellen. Het doel

van dit onderzoeksproject was het ontwerpen van een kunstmatig orgaan dat gebruikt kan worden als een

blauwdruk voor het behandelen van verscheidene ziektes die ontstaan door de absentie van regulatie van een

bepaalde molecuulconcentratie in het bloed. Na het in beschouwing nemen van verscheidene samenstellingen

van kunstmatige organen, stellen wij een mechanisme voor met een polymeermembraan dat een insulinebron

omsluit, carbon nanotubes, een rotaxaan dat dienst doet als poortmolecuul en een niet‐enzymatische

glucosesensor. Dit lijkt in principe een veelbelovende manier om diabetes type 1 te behandelen. Wij stellen

verder onderzoek hiernaar voor.

Introduction: The demand for the replacement of defect organs has steeply increased in recent years. The loss

of function can be the cause of different diseases by the creation of insufficient or dysfunctional proteins. To

overcome this, a donor organ replaces this dysfunction.

Although transplantation sounds promising, this procedure faces many problems. The most challenging issue is

the initiation of an immune response by the host. This will ultimately lead to the degradation of the whole

implanted organ. A lot of research has been done on the prevention of this immune response, but a successful

organ implantation still requires chronic immunosuppression.

The immune response can be prevented by microencapsulation of cells. Microencapsulation is a process that

envelops cells in a selectively permeable membrane, creating an “artificial organ”. The membrane prevents the

host’s adaptive immune system from initiating an immune response by preventing the influx of

immunoglobulins and antibodies into the interior cells. In our research, we will focus upon what we have

identified as the main bottleneck: a release mechanism to accompany functional cell microencapsulation. This

mechanism releases a pharmaceutical product in an appropriate concentration, for instance insulin release,

proportional to the glucose concentration. The main research question is the following: In what way can a

controlled insulin release mechanism be created, that can stay in the human body for prolonged periods of time

and release insulin proportional to the blood glucose level?

Research Proposal: To make such an artificial organ function properly, three different components are needed.

The first component is responsible for the production of insulin. To make this possible, we want to encapsulate

insulin producing cells in a hydrogel [1]. The second component is responsible for the survival of these cells,

providing a way to control the matrix in which cells can thrive and to control the influx and efflux of nutrients

London, March 7th 2014. From left to right: Eline Meijer (Chemistry), Roel Maas (MLS), Roel Oldenkamp (Biology), Jelle Piepenbrock (MLS), Lonneke Slenders (Biology)


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 21

and waste products. The latter function is important to let the cells produce insulin on a long‐term base. Cell

protection is governed by a combination of a polymer membrane and carbon nanotubes. The last component

is the controlled release mechanism, a way to release insulin at a concentration proportional to the glucose

concentration. This mechanism itself can be divided into two subcomponents. The first of these is the actual

mechanism of release, a gate molecule [2]. The second subcomponent is a sensor which can measure the

glucose concentration and produces a signal proportional to the glucose concentration [3]. This sensor is

therefore responsible for the controlled release of insulin.

Our proposed release mechanism consists of a bistable

[2]rotaxane that changes conformation through a redox

reaction. The electrons for this reaction are supplied by

a glucose sensor.

A bistable [2]rotaxane consists of two different π‐

electron rich groups. Next to these, it contains an

electron‐deficient ring. This ring prefers binding to one

of the electron rich groups over the other one. When

this preferred group is oxidized, the ring switches to the

other π‐electron rich group due to the Coulombic

repulsion between the oxidized group with the ring.

After reducing the oxidized group the ring slowly moves

back to the originally preferred group [2]. This shuttling

mechanism can be used to open and close a carbon

nanotube channel that is fixed in a polymer membrane.

Outlook: Theoretically, this mechanism could prove very useful in fighting various diseases. Preliminary

literature research suggests it is viable, but precisely how useful it is in practical applications needs to be

determined in a large scale research trajectory, carefully reviewing and modulating each single component and

in a second stage all components together.

References

[1] Murua, A., A. Portero, et al. (2008). "Cell microencapsulation technology: towards clinical application." Journal of

Controlled Release 132(2): 76‐83.

[2] Dey, S. K., A. Coskun, et al. (2011). "A redox‐active reverse donor–acceptor bistable [2] rotaxane." Chemical Science 2(6):

1046‐1053.

[3] Jiang, Y., S. Yu, et al. (2013). "Improvement of sensitive Ni (OH)2 nonenzymatic glucose sensor based on carbon

nanotube/polyimide membrane." Carbon 63: 367‐375.

Figure 1: A schematic overview of the setup of our

proposed membrane. (A) multi‐walled carbon

nanotubes, (B) single‐walled carbon nanotubes, (C)

polymer membrane, (D) insulin molecules and (E)

molecular valve which shuttles position when electrons


22 R H A ‐ F NW I

Abstract: Drugs are differently handled by male and female bodies, but surprisingly little attention is paid to this

phenomenon in research on and the prescription of drugs. Therefore, in this research proposal we aim to

explore the sex‐specific differences in the pharmacokinetics of drugs. An unbiased genome‐wide study will

examine which mRNAs and proteins are sex‐specifically expressed in human hepatocytes from males and

females. Further experiments, in vitro and in vivo, will be performed to examine these differences more

specifically. These results will be used to build a computational model. Together, our results may lead to an

improvement of the efficiency and efficacy of drug use.

Samenvatting: Het lichaam van een man reageert anders op medicijnen dan het lichaam van een vrouw, maar

hier wordt verrassend weinig rekening mee gehouden bij het doen van onderzoek naar en het voorschrijven van

medicijnen. Daarom zullen wij onderzoek doen naar de sekse‐specifieke verschillen in de farmacokinetiek. Er zal

een studie naar het gehele genoom worden gedaan, waarbij geen verwachtingen mee zullen spelen, om te

bepalen welke mRNA’s en eiwitten verschillend tot expressie komen in levercellen van mannen en vrouwen.

Verdere experimenten, in vitro en in vivo, zullen worden gedaan om deze verschillen beter in kaart te brengen.

Met deze resultaten zal een model worden gebouwd, welke kan leiden tot een verhoogde efficiëntie en

werkzaamheid van de medicijnen.

Introduction: Sex‐related differences in pharmacokinetics of the liver contribute to differences in drug efficacy

and toxicity profiles in men and women [1]. Drug metabolism in the liver has been well studied and appears to

consist of three phases. The first phase is the phase of oxidation, which is brought about by the substrate‐

oxidizing enzyme cytochrome P450 (CYP450). The second phase is a phase of conjugation reactions, which are

effected by transferases. The last phase is the phase of excretion, in which drug efflux transporters excrete the

drugs. All three phases and the contribution of CYP450 have been well studied. [2] However, the contributions

of proteins other than CYP450 to the sex‐related differences in pharmacokinetics have not been described yet.

Therefore, the aim of our proposed research is to determine the differences in sexual dimorphic gene

expression in the liver that may explain the sex‐specific differences in pharmacokinetics.

Research proposal: Our study design is

unbiased because we will first perform

genome‐wide expression analysis to

determine which mRNAs and proteins

are sex‐specifically expressed in vitro in

human hepatocytes from males and

females. In addition, we will analyze

human hepatocytes from males and

females treated with various

concentrations of different hormones

(growth hormone, estradiol,

testosterone) and with the

immunosuppressant drug cyclosporin,

which is mainly metabolized in the liver.

From left to right: Felix Tönisen, Lina Wübbeke, Krijn Reijnders, Yvonne Bartels and Charlotte Hoogstraten

Sex‐specific metabolism and effect of

Yvonne Bartels, Charlotte Hoogstraten, Krijn Reijnders, Felix

Tönisen, Lina Wübbeke

Supervisor: Prof. Dr. Gerard Martens

Figure 1:Model of drug metabolism in the liver. K1, k2 and k3 represent the different rate values for the various steps. K1 is a constant rate value, and k2 and k3 are Michaelis‐Menten rate values; c is cyclosporin.

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1 s t Y e a r R H A F NW I R e s e a r c h P r o j e c t s

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 23

The top list of differentially expressed genes will be validated, and selected genes will be further analyzed in

mice with transplanted human ectopic artificial livers (HEALs). [3] In these humanized mice, also the plasma

clearance of cyclosporin will be measured using liquid chromatography‐mass spectrometry. Short hairpin RNAs

will be used in vitro to downregulate the sex‐specifically expressed top‐list genes in order to determine the

effect of their downregulation on the cyclosporin clearance efficiency between human hepatocytes from male

and female. To evaluate the validity of the mouse model, we will measure the clearance of cyclosporin in male

and female human blood samples as well. Finally, based on our experimental results we will build a

computational model (see figure 1) to predict the sex‐specific pharmacokinetics of cyclosporin and other drugs

in the liver.

Outlook: The outcome of this research project may improve the efficiency and efficacy of the use of drugs.

Increased efficiency and efficacy are important to reduce adverse effects and improve overall medication and

thus the healthiness of patients. However, it also reduces costs on drug use as well as on treating adverse

effects. Furthermore, it will lead to lower drug usage.

References

[1] Franconi F, Campesi I. 2014. Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological

differences between men and women. Br. J. Pharmacol.

[2] Anzenbacher P, Anzenbacherova E. 2001. Cytochromes P450 and metabolism of xenobiotics.

[3] Chen AA, Thomas DK, Ong LL, Schwartz RE, Golub TR, Bhatia SN. 2011. Humanized mice with ectopic artificial liver

tissues. Proc. Natl. Acad. Sci. U. S. A.

1 s t Y e a r R H A R e s e a r c h P r o j e c t s

24 R H A ‐ F NW I

Abstract: This project aims to unify two potent methods of describing shapes in nature, namely L‐systems and

the Superformula. Combining these models will yield a powerful way of modelling and describing shapes as they

complement each other beautifully, L‐systems being very good at representing branches and branchlike

structures and the Superformula being excellent at floral and leaf like shapes. We will approach this unification

from two angles. We will try to include key properties of L‐systems in the capabilities of the Superformula by

making the Superformula time dependent and extending it to cover branching structures. We will also

investigate the possibilities of incorporating the Superformula into the existing framework that L‐systems

provide.

Samenvatting: In dit project proberen we twee methodes voor het bestuderen van natuurlijke vormen te

combineren. Deze twee methoden zijn het L‐systeem en de Superformule. De L‐systemen zijn erg geschikt om

vertakte structuren te beschrijven, terwijl de Superformule erg geschikt is om de vorm van bloemen en bladeren

weer te geven. Het verenigen van deze twee methoden zullen we op twee manieren aanpakken. Aan de ene

kant zullen we proberen om de belangrijkste eigenschappen van L‐systemen over te brengen op de

Superformule. Aan de andere kant zullen we onderzoeken wat de mogelijkheden zijn om de Superformule in het

huidige systeem van L‐systemen te gebruiken.

Introduction: For centuries mankind has been intrigued by the enormous variety of patterns and shapes in

nature. Flowers, snowflakes and starfish are examples of symmetrical shapes. Some succulent plants, shells and

horns show spiral patterns. Honeycombs, scales and peels form tiling patterns and water surfaces and deserts

show wave patterns. This diversity of complex shapes and patterns creates an urge to comprehend them.

Different disciplines use different approaches to obtain a better understanding. Biology explains this wealth of

patterns and shapes with the theory of evolution. Millions of years of natural selection have created many

intricate patterns and shapes. A chemical approach to understand patterns is to look at morphogens, special

signalling molecules responsible for pattern formation. Mathematicians and physicists study all kinds of

abstract and natural shapes and are therefore also interested in those we find in nature. Relatively new is the

discipline of Computer Science, which tries to capture patterns and shapes in computational models.

Figure 1: Different patterns and shapes found in nature (source: Google images)

Significant events in the history of studying patterns and shapes in nature are, among others, the following. In

1952, Alan Turing published The Chemical Basis of Morphogenesis. Turing was a mathematician and described a

mechanism that can explain a great variety of patterns, like stripes and spots, based on diffusing and reacting

morphogens [1]. In 1967, Mandelbrot published an article that discusses fractals, self‐similar shapes we also

find in nature (e.g. snowflakes, crystals and flowers) [2]. In 1968, Aristid Lindenmayer developed the L‐system,

SALMON – Superformulas And L‐systems:

MOdelling Nature

Joery den Hoed, Stijn Peeters, Bren Schaap, Noor Smal,

Luuk Verhoeven

Supervisor: Alexandra Silva From left to right: Bren Schaap, Stijn Peeters, Alexandra Silva, Joery den Hoed, Luuk Verhoeven and Noor Smal


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 25

a model to recreate branching patterns and to describe plant growth [3]. And finally in 2003, Johan Gielis

invented the Superformula to model closed shapes, like flowers, leaves and starfish [4].

Research Proposal: In this proposal, we will present a plan for the combination of two existing formalisms for

modelling shapes into one, more powerful, formalism. One of these formalisms is the Lindenmayer system, a

computational method that is already very prevalent in biological research and provides an intuitive and simple

way for the modelling of branching structures. However, this method is not very well suited to model closed

shapes like flowers and leaves. The other one is the Superformula, a mathematical formula that can describe an

incredibly wide variety of shapes with a very limited number of parameters.

L‐systems and the Superformula are two formalisms with different properties that are important for a good

model. Combining these formalisms will yield a powerful model, as they complement each other’s strengths.

However, achieving this combination is a difficult task. In order to complete it we shall focus on the following

mutually related research goals:

G1: Ageing Gielis’ Superformula: time‐dependent modelling.

Modelling the development of plants over time is a challenging task. The difficulty in modelling biological

systems, and in particular growth, stems from their complexity and diversity. We explored the capability of the

Superformula to model shapes over time and its advantages and disadvantages in comparison with L‐systems.

By modelling the same shape with both an L‐system and a time dependent Superformula, we expect to draw

parallels between both L‐system and Superformula. These parallels could provide insights on how to unify the

distinct model systems.

G2: Branching meets Buds: incorporating Superformulas in an L‐system.

L‐systems are good in describing branching structures. However, a shortcoming of L‐systems is that modelling

closed shapes like leaves and flowers with L‐systems is a laborious task and requires complicated methods.

Therefore we proposed to implement the possibility of drawing Superformulas within L‐systems by expanding

existing software so scientists and other users will be able to use the Superformula in an L‐system in an easy

and convenient way.

G3: Branching the Superformula: incorporating L‐system properties into Superformular shapes.

One of the greatest weaknesses of the Superformula compared to L‐systems is its inability to capture

branching. Therefore, to incorporate this important feature into the Superformula, we have explored the

possibility of extending it by combining different Superformulas into one single shape with the aid of R‐

functions.

Outlook: Combining the two formalisms into one biological model will create a new bridge between Biology,

Computer Science and Mathematics. The new model could be used to more accurately replicate the shapes of

biological systems, especially plants, for research purposes and to improve existing computer graphics in both

realism and storage efficiency.

References

[1] Turing, A. M. (1952). The chemical basis of morphogenesis. Bulletin of mathematical biology, 52(1):153–197.

[2] Mandelbrot, B. B. (1967). How long is the coast of britain. Science, 156(3775):636–638.

[3] Prusinkiewicz, P. and Lindenmayer, A. (1990). The Algorithmic Beauty of Plants. Springer‐Verlag New York, Inc., New

York, NY, USA.

[4] Gielis, J. (2003). A generic geometric transformation that unifies a wide range of natural and abstract shapes. American

journal of botany, 90(3):333–338.


26 R H A ‐ F NW I

Abstract: Compacted mesoporous carbon (CMC) electrodes have applications in enzymatic fuel cells, where they

can be used to, among other things, greatly increase the effective surface area of electrodes. We propose an

experiment which is a first step towards optimising CMC electrodes for use in enzymatic fuel cells. For this, we

describe a method for varying the pore size of CMC electrodes and testing the effect that this variation has on

the power output and lifetime of a fuel cell which uses these electrodes.

Samenvatting: In biologische brandstofcellen worden redox‐reacties die een elektrisch vermogen kunnen

leveren gekatalyseerd door organisch materiaal. Biologische brandstofcellen kunnen grofweg worden

opgedeeld in microbiële en enzymatische brandstofcellen. Wij hebben ons gericht op enzymatische

brandstofcellen, omdat onze interesses lagen in toepassingen op kleine schaal (bijvoorbeeld in het lichaam) en

deze soort brandstofcel daarvoor bijzonder geschikt is. De twee belangrijkste nadelen van enzymatische

brandstofcellen is hun relatief lage vermogen en hun korte levensduur, die wordt veroorzaakt door de inherente

instabiliteit van enzymen. Recent onderzoek [1] heeft aangetoond dat het gebruik van een bepaalde soort

elektrode, de compacted mesoporous carbon (CMC) elektrode, kan leiden tot een groter vermogen. In dit

onderzoek zijn CMC elektrodes gebruikt met een standaard poriegrootte. Wij stellen daarom voor om de invloed

van de poriegrootte op de prestatie van de brandstofcellen (zowel de levensduur als het vermogen) te

onderzoeken door CMC elektrodes te maken met verschillende poriegroottes en de verschillen in prestatie waar

te nemen.

Introduction: Enzymatic fuel cells are an interesting alternative energy source. Because of the substrate

specificity of enzymes, membranes are not always necessary, which implies that cells can be miniaturised and

can be made at lower costs than comparable fuel cells which do not use enzymatic catalysts. However there

are limitations to the use of enzymatic fuel cells. The two main issues are the short lifetimes of enzymes and

relatively low power output density. The first issue is caused by a large number of different factors and seems

to be the most difficult to overcome. The power output density of enzymatic fuel cells is limited by the electron

transfer rate of enzymes, which is related to the

geometry of the enzymes. A straightforward way of

increasing power output density of these cells could

be to increase the effective surface area of the

electrodes.

We propose to explore the use of compacted

mesoporous carbon (CMC) electrodes, which may

provide a partial solution to both of the main issues.

The main goal of the proposal, however, is to suggest

a method for increasing the power output density of

enzymatic fuel cells which use CMC electrodes. To

achieve this goal, we suggest looking at the effect of

the pore size of the mesoporous carbon which is used

in the CMC electrodes.

Improving CMC electrodes for use in

enzymatic fuel cells

Gijs Franken, Alexandra Hohnen, Sander Lemmens, Ferdia

Sherry, Berend Visser

Supervisor: Dr Uli Zeitler

Figure 1: A schematic diagram of a fuel cell

From left to right: Uli Zeitler, Berend Visser, Sander Lemmens, Alexandra Hohnen, Ferdia Sherry, Gijs Franken

1 s t Y e a r R H A F NW I R e s e a r c h P r o j e c t s

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 27

Research Proposal: In order to investigate

the effects of pore size on the lifetime and

power output, we will have to create

mesoporous carbon with different pore

sizes. Using the method described in [2]

we can relatively easily create graphitised

mesoporous carbon with different pore

sizes. We would like to investigate pore

sizes in the region between 5 and 25 nm.

When we have successfully

synthesised and measured our

mesoporous carbon with the desired pore

sizes we will turn the material into fuel

cells. The mesoporous carbon can be made

into an electrode and [NiFe] Hydrogenase‐

1 enzymes extracted from a certain strain

of E. coli can be loaded onto the electrode. This enzyme is used because of its extraordinary oxygen tolerance.

This electrode will be used as the anode and for consistent comparisons a platinum electrode will be used as

the cathode. The electrodes are mounted inside a chamber which is kept at an atmosphere of 80% H2 to 20%

normal air. The reactions powering the cell are oxidation of hydrogen at the anode and reduction of oxygen at

the cathode. Using LabVIEW the power outputs and lifetimes of the fuel cells with the CMC electrodes with

different pore sizes can be monitored. This allows us to decide what pore size is optimal.

Outlook: After the experiment we can compare our findings to those of Xu and Armstrong [1], and also to

platinum fuel cells, which are already in a state of practical application. If we can get the power output of an

EFC to be comparable to that of a platinum cell, whilst still retaining a somewhat respectable lifetime, that

would imply that commercial applications are viable in situations where the size of a fuel cell is of importance.

We will therefore after the experiment attempt to create a fuel cell with optimised pore size that can compete

with a commercial platinum fuel cell.

References

[1] Lang Xu and Fraser A. Armstrong. “Optimizing the power of enzyme‐based membrane‐less hydrogen fuel cells for

hydrogen‐rich H2–air mixtures”. In: Energy & Environmental Science 6 (2013), pp. 2166–2171.

[2] Haifeng Yang et al. “A Simple Melt Impregnation Method to Synthesize Ordered Mesoporous Carbon and Carbon

Nanofiber Bundles with Graphitized Structure from Pitches”. In: Journal of Physical Chemistry B 108 (2004), pp. 17320–

17328.

Figure 2: A schematic diagram of the experimental setup


28 R H A ‐ F NW I

Excerpts from the jury review reports of the 2013 ‐2014 Faculty of

Science Honours Projects

Flux‐balance analysis of vinblastine production; Nicole van Buuringen, Sharon Janssen, Marijn Man, Lisa

Noorlander, group van Dam:

This proposal aims at making a flux model for alkaloid biosynthesis in the medicinal plant Catharanthus roseus,

with the ultimate aim to use it for optimizing the production of valuable compounds such as the anti‐cancer

agent vinblastine. The proposal has a relatively short incomplete introduction of the biological model. The

exact biological model to be used is not defined, but appears to be plants. Most of all, it is not made clear how

a flux model will contribute exactly to the goal, i.e. production of more vinblastine.

Jury member: Prof. Dr. J. Memelink Institute of Biology Leiden University

Medicine release mechanisms in artificial organs. Applied to the administration of insulin; Roel Maas, Eline

Meijer, Roel Oldenkamp, Jelle Piepenbrock, Lonneke Slenders, group Kouwer:

By being maybe a bit too ambitious the proposal has lost a bit of focus which could possibly have been avoided

by immediately taking the proposed research out of its direct context and concentrate on an adaptive release

device for insulin. Having said that I still regard this proposal very good showing where opportunities for

research projects are on the way towards the higher goal of artificial organs to improve healthcare.

Jury member: Dr. D.W.P.M. Löwik Bio‐organic Chemistry Radboud Unversity

Sex‐specific metabolism and effects of drugs; Yvonne Bartels, Charlotte Hoogstraten, Krijn Reijnders, Felix

Tönisen, Lina Wübbeke, group Martens

One of the remarks: I have my doubts about the value of the in vivo model with HEAL mice. To use such a

rather invasive and drastic model there should be a better motivation to use this model. Nevertheless, I

consider this a very good research proposal that, after some modifications, might be even successful in grant

application programmes.

Jury member: Prof. Dr. B.Blaauboer Institute for Risk Assessment Sciences University of Utrecht

SALMON: Superformulas and L‐systems modeling nature; Joery den Hoed, Stijn Peeters, Bren Schaap, Noor

Smal, Luuk Verhoeven, Group da Silva

Well‐written research project with many challenges. One of the difficulties is that it goes beyond mainstream

mathematics (and mainstream / biological) thinking. On the other hand, when successful, this may or will

result in various technological applications and can certainly result or expanded into a number of papers. The

project benefits from the interplay of students with various backgrounds. The presentation and defense was

very good. The following comments may help the students in refine and shape their thoughts further.

Jury member: Dr. J.Gielis University of Antwerp

Improving CMC electrodes for use in enzymatic fuel cells; Gijs Franken, Alexandra Hohnen, Sander Lemmens,

Ferdia Sherry, Berend Visser, Group Zeitler

The proposal is well written but I would expect more detail especially on the enzyme‐containing fuel cells.

Some schemes and examples would help the reader. In addition I would like to see paragraphs on feasibility

and societal relevance of the proposal.

Jury member: Dr. H.J.M. op den Camp Microbiology Radboud University

2 n d Y e a r R H A – F NW I

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 29

2nd Year


FNWI

2 n d Y e a r R H A – F NW I D e s c r i p t i o n

30 R H A ‐ F NW I

Het individuele deel van het honoursprogramma FNWI in het derde

studiejaar

In het derde studiejaar maakt iedere student tijdens het individuele deel actief kennis met

het wetenschappelijk onderzoek binnen een afdeling of onderzoeksgroep van FNWI of (met

toestemming van de examencommissie) daarbuiten. Hiertoe kiest de student in de loop van

zijn tweede studiejaar een wetenschappelijk begeleider, de "meester". Student en meester

komen in onderling overleg tot de inrichting van het individuele onderzoeksproject; een en

ander wordt vastgelegd in een Persoonlijk Opleidingsplan, dat moet worden goedgekeurd

door de examencommissie van het honoursprogramma FNWI . Voor dit opleidingsplan is dit

formulier beschikbaar.

P e r s o o n l i j k Op l e i d i n g s p l a n

Het Persoonlijk Opleidingsplan voor het honoursprogramma FNWI van het derde studiejaar

omvat 18 ec en beschrijft de verschillende onderdelen met hun omvang en een tijdpad:

Een projectvoorstel voor een onderzoeksproject met daarin opgenomen een

uitgewerkt overzicht van de voor het project relevante literatuur; omvang 3 ec.

Een onderzoeksproject met een omvang van minimaal 9 ec. Uitbreiding van het

onderzoeksproject met de reguliere bachelorstage is met het oog op de diepgang aan

te bevelen.

Een overzicht van te volgen cursussen op het gebied van de specialisatie tot een

maximum van 6 ec.

Een invulling van de buitenlandcomponent, bijvoorbeeld in de vorm van (een deel

van) het onderzoeksproject, een cursus, een summer school, een congres of een

werkbezoek.

Een tijdpad waarin de diverse honoursactiviteiten/cursussen, alsmede de onderdelen

van het reguliere bachelorcurriculum, vermeld staan.

Eventuele aanvullende werkafspraken. Gedurende het project maakt de student deel

uit van de onderzoeksgroep met de bijbehorende rechten en plichten (o.a. deelname

aan werkbesprekingen, colloquia).

H e t o n d e r z o e k s p r o j e c t

Het zwaartepunt van het individuele deel is een wetenschappelijk onderzoeksproject met

veel ruimte voor eigen initiatief, zelfstandigheid en creativiteit. Projectdoelen moeten

dusdanig geformuleerd worden dat zij met relatief geringe achtergrondkennis en van de

andere kant veel inzet en creativiteit haalbaar zijn. De overige onderdelen (onderwijs,

buitenlandcomponent) worden afgestemd op het onderzoeksproject. Met het oog op een

doelmatige studieplanning kunnen voor projectvoorstel, cursussen en buitenlandcomponent

ook al de zomermaanden tussen het tweede en derde studiejaar benut worden.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 31

U i t b r e i d i n g me t b a c h e l o r s t a g e

Bij een combinatie van het onderzoeksproject met de bachelorstage wordt de omvang van

het project met 12 tot 15 studiepunten uitgebreid (afhankelijk van de omvang van de

bachelorstage bij de reguliere opleiding). De beoordeling van het bachelorverslag of de

bachelorscriptie zal dan plaatsvinden op basis van het gehele project. Over het

onderzoeksproject uitgebreid met de bachelorstage dient één eindverslag geschreven te

worden, in het Engels.

C u r s u s s e n

Deze cursussen mogen geen deel uitmaken van het reguliere bachelorprogramma. Bij de

extra cursussen kan wel gedacht worden aan doelgerichte uitbreiding van reguliere

cursussen in overleg tussen student, meester en de docent van de betreffende cursus.

B u i t e n l a n d

Een verblijf in het buitenland maakt deel uit van het individuele programma. De student

bezoekt in overleg met de meester een relevante wetenschappelijke bijeenkomst in het

buitenland (bijvoorbeeld een conferentie) of doet (een deel van) de onderzoekstage in het

buitenland.

De student regelt de aanvraag en organisatie, alsmede de financiële en administratieve

afhandeling van het buitenlandverblijf met (de afdeling van) de meester en dient zich zelf

ook in te spannen om subsidies te verkrijgen voor de buitenlandcomponent. Hij stuurt ter

informatie een begroting van de kosten naar het secretariaat van de programmaraad.

E i n d p r o d u c t

Het eindproduct dient te bestaan uit een geschreven verslag van het onderzoek, conform de

criteria voor wetenschappelijke publicaties. Daarnaast dient het resultaat van het onderzoek

op de een of andere manier naar buiten kenbaar te worden gemaakt, bijvoorbeeld in de

vorm van een poster op een conferentie, een voordracht op een summer school, een

bijdrage aan een extern colloquium, of een artikel in een populair‐wetenschappelijk

tijdschrift. In een aantal gevallen kan het onderzoeksproject leiden tot een

wetenschappelijke publicatie.

A f s l u i t i n g e n Ho n o u r s b u l

Het individuele onderzoeksproject wordt afgesloten met een gezamenlijk symposium van

alle honoursstudenten FNWI. Op dit symposium geeft elke student een korte presentatie

van de resultaten van zijn onderzoeksproject. Deze presentatie is gericht op een breed

publiek. Daarnaast presenteert de student een poster, waarop de wetenschappelijke

resultaten centraal staan. Tijdens het symposium wordt ook de honoursbul uitgereikt.


32 R H A ‐ F NW I

C o n t a c t t u s s e n RHA s t u d e n t e n

Op verzoek van de studenten worden ook tijdens het derde studiejaar avondbijeenkomsten

georganiseerd waar academische vaardigheden centraal staan. In het voorjaar presenteren

de studenten hun vorderingen aan hun medestudenten, de programmaraad en de meesters.

Verder kunnen de studenten zelf initiatieven nemen voor gezamenlijke activiteiten; de

programmaraad zal deze waar mogelijk faciliteren.

On September 17 2014: the Honours diplomas were awarded to the 2ndyear RHA Science students (cohort 2012)

2 n d Y e a r R H A R e s e a r c h P r o j e c t s

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 33

2nd Year RHA Research Projects

Marloes van den Akker bi Dr. Marnix H.A.G. Gorissen Organismale dierfysiologie

Janine Arts mlw Prof. dr. Gert Jan J.C. Veenstra Molecular Developmental Biology,

Koen van Asseldonk sci Dr. Anouk M. Rijs Molecular and Biophysics

Marilen Benner bi Dr. J. van der Vlag Nierziekten

Maarten Broekman bi Prof dr. H. Siepel Dierecologie en ecofysiologie

Lotte Eilander mlw Prof. dr. Ger Pruijn Biomolecular Chemistry

Lisanne Gommers bi Prof.dr. Iris D. Nagtegaal Pathologie UMCN

Carolin Heller bi Dr. Leonie M. Kamminga, Molecular Biology

Niels Hesp na&st Dr. Alix McCollam High Field Magnet Laboratory

Wouter Hetebrij wi, na&st Prof. dr. Hans D.M. Maassen Toegepaste Stochastiek,

Serge Horbach wi Dr. Bernd Souvignier Algebra & Topologie

Shauni Keller sk Dr. Daniela Wilson Bio‐organic Chemistry

Luc van Kessel na&st Dr. Jörg R. Hörandel Astrophysics

Alex Kolmus sk Dr. Bas Y.T. van de Meerakker, Molecular and Laser Physics

Yvonne Lasarzewski bi Dr. Jo Huiqing Zhou Molecular Developmental Biology

Niels Neumann wi, na&st Dr. Walter D. van Suijlekom, Mathematical Physics

Elias Post sk Prof. dr. Floris P.J.T. Rutjes Synthetic Organic Chemistry

Christian Pruefert sk Dr. Martin C. Feiters Synthetic Organic Chemistry,

Freek Roelofs na&st Prof. dr. Heino D.E. Falcke Astrophysics

Suzanne Timmermans mlw Prof. dr. Wilhelm T.S. Huck Physical Organic Chemistry

Milo Vermeulen na&st Prof. dr. Wim J. van der Zande Molecular and Biophysics

Rebecca Wallrafen mlw Dr Dirk Schubert CNS donders


34 R H A ‐ F NW I

Figure 2:. In‐situ hybridisation of lepa and NKA (which marks the ionocytes) in gills of SW acclimated

Atlantic salmon (parr). No overlay could be observed in the merged image.

Abstract: During saltwater acclimatisation of fish an adjustment of ion‐transporters in the gills takes place. For

this process a lot of glucose is needed. In this experiment the role of leptin in the energy regulation associated

with the regulation of osmosis in the Atlantic salmon is demonstrated.

Samenvatting: Tijdens zoutwater acclimatie vindt er een aanpassing van iontransporters in de kieuwen plaats,

waarvoor veel glucose nodig is. In dit experiment is de betrokkenheid van leptine in de energie regulatie

aangetoond tijdens het proces van osmoregulatie in de Atlantische zalm.

Leptin is a key hormone in regulation of feeding behaviour, energy homeostasis and high energy consuming

processes, like osmoregulation. In this study, we examined the potential role of leptin in energy (re)distribution

in liver and gills after an acute hyperosmotic challenge in smolt stage Atlantic salmon. During such a challenge,

the environmental salinity increases which influences the internal ion balance. By changing their

osmoregulatory system (e.g. different ion transporters), salmon are able to maintain homeostasis.

Atlantic salmon were acclimated to fresh water and transferred to salt water, or to fresh water as a

control. Fish were sampled at 0, 1.5, 4, 12, 24 and 72 h after transfer. qPCR analyses on lepa1, lepa2, lepr1 and

lepr2 were performed on gill and liver samples. In‐situ hybridisation with lepa and NKA was performed for

cellular localisation of lepa expression in the gills.

Figure 1. mRNA expression levels of (A) gill lepa1 and (B) liver lepa2 relative to elf1αa/20S of anadromous Atlantic salmon (smolts)

followed over time after fresh water – fresh water transfer (closed circles) and fresh water – salt water transfer (open circles). Values are

means ± SE (n=8). An asterisk indicates a significant difference between fresh water and salt water treatment at a given time as

determined by a Student’s t test. Different small and capital letters indicate significant differences between time points in respectively fresh

water and salt water treated salmon as determined by a one‐way ANOVA and a pairwise Tukey test. The significance level for all statistical

tests was P<0.05.

Plasma osmolality increased till 24 h after FW‐SW transfer, as did the expression of branchial lepa1 mRNA (transiently at 1‐3 h) and hepatic lepa2 mRNA (transiently at 4‐12 h). By in‐situ hybridisation we localised lepa1 in glycogen‐rich cells adjacent to ionocytes (mitochondrion‐rich cells). Gill lepa expression site and time of mRNA upregulation suggest involvement in glycogenolysis of the glycogen rich cells for energy supply during osmoregulation.

Leptin and energy regulation during seawater acclimation in

Atlantic salmon, salmo salar

Marloes van den Akker

Supervisor: M. Gorissen, department of animal physiology, Radboud University

0 20 40 60 800.0

0.2

0.4

0.6

0.8

FWFW

FWSW*

a/A

a/BC

a/B

a/AB

a/A

a/AC

Time (hours)

lepa

1ex

pres

sion

relat

ive to

elf1a

/20S

0 20 40 60 800.0

0.2

0.4

0.6

0.8 FWFW

FWSW

**

a/A

a/Aa/B

a/BC

a/C

a/BC

time (hours)

lepa

2ex

pres

sion

relat

ive to

elf1a

/20S


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 35

TBP TBP2

Figure 1: Schematic representation

of gene expression change. Red

downregulated genes, blue

upregulated genes.

Abstract: During development specific gene expression is required, directed by transcription factors TBP and

TBP2. We have assessed the genome‐wide dependence on TBP and TBP2 in early Xenopus laevis embryos.

Genes dependent only on TBP, only on TBP2 and on both transcription factors were identified and give insight in

the role of the two factors during developmental gene expression.

Samenvatting: Het erfelijke materiaal – het DNA – is in iedere cel hetzelfde, maar in tijdens de ontwikkeling

komen in iedere cel op ieder moment andere genen tot expressie. Dit wordt gedirigeerd door

transcriptiefactoren zoals TBP en TBP. Sommige genen worden specifiek door een van deze twee factoren

aangezet en andere genen door beide. Dit onderzoek geeft inzicht in deze twee basale factoren tijdens de

ontwikkeling van kikkerembryos (Xenopus laevis).

The development of a single cell embryo into a complex multicellular organism requires coordinated gene

expression, where transcription factors play an important role. The basal transcription factor TATA‐box Binding

Protein (TBP) directs the assembly of the transcription machinery. A vertebrate specific paralog called TBP2

(TRF3) was found [1]. Although the two factors have a different expression pattern both factors are required in

the early embryo. A specialized role and a functional redundancy were proposed for the two factors [1,2,3].

By combining an antisense directed knockdown approach with next

generation sequencing, we have investigated the genome‐wide dependence on

TBP and TBP2 during early frog (Xenopus laevis) embryogenesis (NF stage 10.5).

TBP knockdown embryos (TBP > 90 %; TBP2 70 %) show a gastrulation

arrested phenotype as described before [1,2,3]. In figure 1 all genes

significantly changed more than fourfold are depicted on the y‐axis, red colors

mean downregulation, while blue colors mean higher expression in knockdown

embryos. Expression change for both TBP as well as TBP2 knockdown is shown.

Genes dependent on TBP, TBP2 or both factors were identified.

Although Jacobi et al [3] did TBP and TBP2 knockdown experiments, till now no

genome‐wide study was performed. Here we show specialized and redundant

roles for the two transcription factors with a genome‐wide approach. Future

works directed towards a double knockdown experiment or overexpression

studies with both transcription factors will yield more knowledge to systematically dissect developmental gene

regulation at the level of basal transcription factors.

References

[1] Jallow, Z.; Jacobi, U.; Weeks, D.; Dawid, I.; Veenstra, G.; Specialized and Redundant Roles of TBP and a Vertebrate‐Specific TBP Paralog in Embryonic Gene Regulation in Xenopus, PNAS (2004) 101: 13525‐13530 [3] Veenstra, G.; Weeks, D.; Wolffe, A.; Distinct Roles for TBP and TBP‐Like Factor in Early Embryonic Gene Transcription in Xenopus, Science (2000) 290: 2312‐2315 [3] Jacobi, U.; Akkers, R.; Pierson, E.; Weeks, D.; Dagle, J.; Veenstra, G.; TBP Paralogs Accommodate Metazoan‐ and Vertebrate‐Specific Developmental Gene Regulation, EMBO (2007) 26: 3900‐3909

TBP‐Family Members and their Role in Gene Expression during Early Xenopus laevis Development

Janine Arts

Supervisors: Sarita S Paranjpe, Gert Jan C Veenstra Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen


36 R H A ‐ F NW I

Abstract: Energy for most processes in living cells is supplied by ATP hydrolysis, catalyzed by proteins called

ATPases. Their general mechanism is studied thoroughly, but details on the atomic scale remain speculative. We

studied gas‐phase ATPase active site mimics to elucidate how ATP is selectively recognized by ATPases against

other biomolecules, and how the local structure of the ATPase active site is affected upon ATP hydrolysis.

Samenvatting: Levende cellen hebben energie nodig voor de processen die erin plaatsvinden. Deze energie is

afkomstig van ATP‐moleculen die gehydrolyseerd worden door enzymen genaamd ATPases. Hoe dit plaatsvindt,

is in grote lijnen bekend, maar details op het niveau van individuele atomen zijn nog niet opgehelderd. In ons

onderzoek hebben we de werking van ATPases op deze schaal onderzocht door bindingssterktes en lokale

structuren te bestuderen van complexen van ATP met modellen van het actieve centrum van F1‐ATPase.

Hydrolysis of adenosine 5’‐triphosphate (ATP) in the active sites of

ATPases is a vital process, yet poorly understood at the atomic level [1‐2].

In our study, we explored gas‐phase local structure and binding

characteristics of complexes consisting of ATP bound to mimics of the F1‐

ATPase active site. The complexes were fragmented in a quadrupole ion

trap using collision‐induced dissociation and infrared multiple‐photon

dissociation. All complexes show fragmentation channels in which the

non‐covalent interactions between mimic and ATP are broken; the

doubly charged anionic complex of our monopeptide arginine mimic with

ATP exhibits an additional, hydrolysis‐like fragmentation channel in which

ATP loses its γ‐phosphate in the form of PO3− (fig. 1).

Bond strengths of the complexes, determined by measuring

breakdown diagrams (fig. 2), indicate that (i) ATP binds more strongly to

our monopeptide arginine mimic than ADP and G6P, (ii) the bond strength

Figure 1: Mass spectrum of simple dissociation (purple) and hydrolysis‐like fragmentation (blue) of the doubly charged ATP monopeptide arginine complex (red).

between ATP and different mimics depends on the charge and the structures of the mimics, and (iii) in the

doubly charged anionic complex of monopeptide arginine with ATP, the β‐γ phosphate bond of ATP is weaker

than the non‐covalent interactions between ATP and arginine. A structural explanation for the latter was sought

Figure 2: Breakdown diagrams of several complexes.

employing IR spectroscopy, but the obtained IR spectra of

this complex and its fragment after PO3− release should be

improved and compared with DFT calculations in order to

identify local structural features.

Besides exploring complexes in the ion trap set‐up,

the isolated gas‐phase structure of the neutral tripeptide

mimic Ac‐Glu‐Phe‐Lys‐NH2 was determined in a molecular

beam set‐up employing IR‐UV ion dip spectroscopy [3]. At least two conformers were discovered. Their

experimental IR spectra were compared with DFT calculations and both conformers were structurally assigned.

References

[1] Boyer, P.D. Biochim. Biophys. Acta, 1140(3), 215–250, 1993.

[2] Weber, J. and Senior, A.E. Biochim. Biophys. Acta, 1458(2‐3), 300–309, 2000.

[3] Jaeqx, S., Oomens, J. and Rijs, A.M. Phys. Chem. Chem. Phys., 15(38), 16341–16352, 2013.

Exploring structures and binding characteristics of gas‐

phase complexes of ATP with ATPase active site mimics

Koen K.W. van Asseldonk

Supervisors: dr. Anouk M. Rijs, IMM, Radboud University Nijmegen &

dr. Isabelle Compagnon, Institut Lumière Matière, Université Lyon 1.

m/z


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 37

Abstract: The effect of knocking out heparanase in mouse models for anti‐GBM and LPS‐induced

glomerulonephritis was studied.

Samenvatting: De expressie van het enzym heparanase is verhoogd tijdens bepaalde nierziektes. We hebben

gekeken welk effect het heeft als we muizen twee verschillende nierziektes induceren terwijl deze muizen geen

heparanase tot expressie kunnen brengen.

Proteins are restrained from entering the urine by the glomerular filtration barrier (GFB). The GFB is composed

of fenestrated glomerular endothelial cells covered by the glycocalyx, the glomerular basement membrane

(GBM) and podocytes with interdigitating foot processes. When one of these layers is affected, albumin can

leak into the urine. Albuminuria is an independent risk factor for progressive renal diseases [1]. Heparan

sulphate (HS) is a negatively charged polysaccharide abundantly expressed in

the GFB. Loss of glomerular HS negatively correlates with the extend of

proteinuria [2]. HS is cleaved by heparanase (HPSE), which has been shown to

be essential for the development of proteinuria in experimental diabetic

nephropathy [3].

To evaluate the role of HPSE on the development of proteinuria in other

glomerular diseases, we induced anti‐GBM and LPS‐induced

glomerulonephritis in wildtype (WT) and Hpse‐deficient mice. We collected

their kidneys, urine and blood and determined proteinuria, renal function,

HPSE expression and influx of inflammatory cells in these mice. HPSE

expression was increased in anti‐GBM and LPS‐induced nephritis in WT mice.

LPS and anti‐GBM‐induced nephritis both increased albuminuria and blood urea nitrogen (BUN) levels. Hpse KO

mice showed a better renal as they developed less albuminuria and lower BUN levels compared to the WT

mice. Fibrinogen deposition was increased in time after induction of anti‐GBM nephritis, but was lower in Hpse

KO mice compared to WT mice. Glomerular granulocyte influx was increased during anti‐GBM and LPS‐induced

nephritis, with no differences between Hpse‐deficient mice and WT mice. Significantly lower numbers of

macrophages were observed in Hpse KO mice compared to WT mice. The expression of tumor necrosis factor

alpha (TNF‐α), a pro‐inflammatory cytokine, was increased in both models, but significantly lower in Hpse‐

deficient mice compared to WT mice. The reduced TNF‐α expression of the Hpse KO mice may be attributed to

the decreased glomerular macrophage influx, as macrophages produce TNF‐α. TNF‐α also stimulates HPSE,

which in turn activates macrophages creating a positive feedback loop. Therefore, we conclude that HPSE‐

deficiency protects against the development of proteinuria and renal damage, possibly by creating a less pro‐

inflammatory milieu.

[1] Singh, A. and S.C. Satchell, Microalbuminuria: causes and implications. Pediatr Nephrol, 2011. 26(11): p. 1957‐65. [2] Vandenborn, J., et al., Distribution of GBM heparan‐sulfate proteoglycan core protein and side‐chains in human

glomerular‐diseases. Kidney International, 1993. 43(2): p. 454‐463. [3] Gil, N., et al., Heparanase is essential for the development of diabetic nephropathy in mice. Diabetes, 2012. 61(1):

p. 208‐16.

The Role of Heparanase in Experimental Glomerulo‐

nephritis and LPS‐nephritis

Marilen Benner

Supervisor: Johan van der Vlag, Department of Experimental

Nephrology, Radboud University Nijmegen

Figure 1: 2 hours after induction of anti‐GMB nephritis leukocytes infiltrate theglomerulus. This is reduced in Hpse KOmice


38 R H A ‐ F NW I

Abstract: In De Peel habitat fragmentation led to the existence of only two small isolated populations of the

endangered smooth snake (Coronella austriaca). These remaining populations are probably too small to prevent

future effects of inbreeding and decreasing genetic variation. Therefore, smooth snake populations in De Peel

have a high risk of extinction.

Samenvatting: De Peel was ooit een groot hoogveengebied waarvan nu nog slechts enkele kleinere gebieden

over zijn. De bedreigde gladde slang (Coronella austriaca) komt hierdoor nog maar in twee van elkaar

gescheiden populaties voor. Deze populaties zijn waarschijnlijk te klein om de negatieve effecten van inteelt en

het verlies van genetische variatie te voorkomen. De Gladde slangen populaties in De Peel hebben daarom een

grote kans op uitsterven

The smooth snake (Coronella austriaca) (figure 1) is an

endangered snake species that lives in most parts of Europe

and the west part of Asia [1]. De Peel is a peatland area in the

south of the Netherlands and one of the areas where this

species lives. However, a large part of this big peatland area

disappeared due to drainage for peat extraction. Now only

two areas are left where this species still occurs. It was

hypothesized that this habitat fragmentation forms an

important threat for this species, as this could lead to small

and isolated populations. Small and isolated populations are

at risk of extinction because the resulting inbreeding and loss of genetic variation can severely impact these

populations [2].

In this research the influence of habitat fragmentation on smooth snake populations in De Peel was

studied. A DNA analysis was performed to look at the degree of isolation, the loss of genetic variation and the

amount of inbreeding. To estimate the population size, a capture‐mark‐recapture (CMR) analysis was used,

accounting for the imperfect detectability of this species [3].

The results of these analyses showed that the two remaining populations are isolated from each other,

but that there is currently no loss of genetic variation nor inbreeding. However, the population size of one of

the populations was estimated to lay between the 100 and 200 individuals. This population size is too small to

prevent the negative effects of inbreeding and loss of genetic variation [4]. These effects are therefore likely to

arise in the future and could eventually led to the extinction of these populations. It is thus concluded that

smooth snake populations in De Peel have a high risk of extinction.

References

[1] Spellerberg, I.F., Phelps, T. Biology, general ecology and behaviour of the smooth snake, Coronella austriaca Laurenti.

Biological Journal of the Linnean Society, 9(2), 133‐164, 1977

[2] Frankham R. Conservation genetics. Annual review of genetics, 29(1), 305‐327, 1995

[3] Williams, B., Nichols, J., Conroy, M. Analysis and management of animal populations. Academic Press, New York, 2002

[4] Franklin, I. “Evolutionary change in small populations”, Conservation Biology: An evolutionary perspective, 1980, pp 135‐

149

The influence of habitat fragmentation on smooth

snake (Coronella austriaca) populations in De Peel

Maarten Broekman

Supervisor: Prof. dr. Henk Siepel, Department of Animal ecology and

Ecophysiology, Radboud University Nijmegen

Figure 1: the smooth snake (Coronella austriaca)


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 39

Abstract: This study has established the association of the SNP rs10175798 with rheumatoid arthritis (RA) and

has investigated the possible regulatory function of the region wherein the SNP is located.

Samenvatting: Dit onderzoek heeft het verband tussen de aanwezigheid van een veelvoorkomende mutatie in

het DNA, rs10175798, en het hebben van reumatïode artritis vastgesteld. Er is ook gekeken naar de gevolgen

van de mutatie voor de productie van eiwitten.

Rheumatoid arthritis is an autoimmune disease that affects about 1% of the worldwide population. It causes the inflammation of the joints. At the moment, the diagnosis of RA depends on the symptoms of the patients and the presence of two biomarkers: rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA). Both of these biomarkers are far from perfect (1). Therefore, a new biomarker is welcome. This research has used the T‐Plex PCR assay (2) to determine whether the presence of one of the alleles at the locus of the rs10175798 in the cell‐free DNA of patients can be used as a biomarker of RA. It has also looked into the functional role of rs10175798 in the pathogenesis of RA. SNPs, like rs10175798, can be either linked or causative in relation to a disease. Causative genes can be located in coding or non‐coding, regulatory regions. Whether or not a SNP is indeed located in a regulatory element can be determined by a luciferase assay. This assay shows differences in expression depending on the allele that is present.

The results of the T‐Plex PCR assay (fig. 2 and 3) show that the AG genotype and the A allele are more common amongst RA patients.

During this research, the rs10175798 locus in the cfDNA of healthy controls, RA patients and RRMS patients has been genotyped. Although there seems to be an association of the AG genotype and the A allele, this is not significant.

References

[1] Scott, D. L., Wolfe, F., Huizinga, T. W. J. (2010) Rheumatoid arthritis. Lancet, 376, 1094‐1108. [2] Baris, I., Etlik, O., Koksal, V., Ocak, Z., & Baris, S. T. (2013). SYBR green dye‐based probe‐free SNP genotyping: Introduction of T‐Plex real‐time PCR assay. Analytical biochemistry, 441(2), 225‐231. [3] http://learn.genetics.utah.edu/content/pharma/snips/, retrieved on 14‐9‐2014

rs10175798 as a possible biomarker for rheumatoid

arthritis

Lotte Eilander

Supervisors: dr. M. Dunaeva and prof. dr. G.J. Pruijn,

Biomolecular Chemistry, Radboud University

Figure 2: The different kinds of SNPs in relation to disease.

Figure 3: The genotype distribution among controls (blue),all RA patients (red) and RRMS patients (green). The oddsratio (OR) calculated for the different genotypes indicatethat AG is associated with RA, while GG is the protectivegenotype. None of these results however, are significant.

Figure 3: The allele frequencies among the controls, all RA patients and RRMS patients. The OR shows that the A allele might be associated to both RA and RRMS. These results are not significant.


40 R H A ‐ F NW I

Abstract: This study showed by use of immunohistochemistry that p53 expression is commonly abnormal in pancreatic ductal adenocarcinoma (PDAC), suggesting mutated TP53. However, p53 expression seemed to be normal in all patient cases of chronic pancreatitis (CP), indicating a possible discriminating factor. This difference could be used to improve clinical decision‐making. Samenvatting: Deze studie laat door middel van immunohistochemie zien dat p53 expressie vaak afwijkend is in pancreaskanker, als gevolg van een gemuteerd TP53 gen. Aan de andere kant wordt er in alle patientencasussen met chronische pancreatitis geen afwijkend p53 expressiepatroon waargenomen. Dit zou mogelijk een onderscheidende factor kunnen zijn tussen beide ziekten. Dit resultaat kan worden gebruikt om diagnosis beter en sneller te kunnen stellen.

Pancreatic ductal adenocarcinoma (PDAC)

has one of the worst prognoses of all

cancer types with only a 5‐years survival of

3‐5%. Many risk factors for pancreatic

carcinogenesis have been found of which

chronic pancreatitis (CP), an inflammatory

disease of the pancreas, is suggested as an

important factor for this development [1].

Four driver mutations are associated with

PDAC: KRAS, CDKN2A/P16, TP53 and

SMAD4 [2]. This study focused on the

prevalence of these driver mutations in patients with PDAC and CP in order to facilitate differential diagnosis.

A PALGA search identified 23 patients with PDAC and 7 patients with CP on the availability of formalin‐fixed

paraffin embedded (FFPE) tissue and corresponding clinicopathological data. Immunohistochemistry was used

to analyze the prevalence of p53 and p16 expression in both diseases. Additional DNA isolation of all patient

samples was performed for sequencing analysis. The results showed that abnormal p53 expression can be

found in 82.6% (p=0.002) in PDAC and 0% in CP respectively. Normal p16 expression is observed in 100% of the

cases in PDAC and CP. In conclusion, the prevalence of TP53 mutations might be useful in differentiating PDAC

from CP. More molecular insights in the interactions between CP and pancreatic ductal adenocarcinoma are

needed to facilitate differential diagnosis and to improve clinical decision‐making.

References [1] Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 Inactivation in

pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol

2003;27(12):1495‐501. [2] Yachida S, White CM, Naito Y, Zhong Y, Brosnan JA, Macgregor‐Das AM, Morgan RA, Saunders T, Laheru DA, Herman JM

and others. Clinical Significance of the Genetic Landscape of Pancreatic Cancer and Implications for Identification of

Potential Longterm Survivors. Clinical Cancer Research 2012;18(22):6339‐6347.

Prevalence of TP53, CDKN2A/P16 mutations useful in Pancreatic Adenocarcinoma and Chronic Pancreatitis differential diagnosis Lisanne Gommers

Supervisors: Prof. dr. Iris Nagtegaal, Monica van Zanten,

Department of Pathology, Radboudumc

Figure 4: Immunohistochemical analysis of p53 in PDAC and CP.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 41

Abstract: Using ChIPseq and RIPseq methods we investigate the possible role of RNAs during the recruitment of

Polycomb repressive complex 2 (PRC2), an epigenetic regulator involved in development.

Samenvatting: Het eiwit PRC2 onderdrukt genen, met name gedurende de vroege ontwikkeling van embryo’s.

In dit onderzoek kijken we met moderne moleculaire technieken, hoe PRC2 hun doelwit genen kan vinden.

How do cells maintain their identity? During development cells specify into different tissues and subsequently

this has to be maintained. Disruptions in this process are likely to cause malformations and loss of tissue

function. All cells in a multicellular body originate from a single cell, the zygote, and mainly have the same DNA

content. Due to this fact there have to be mechanisms that control the activation and repression of tissue and

cell specific gene sets. This happens on an epigenetic level of regulation. Epigenetics regulate gene expression

without changing the underlying DNA sequence.

Polycomb repressive complex 2

(PRC2) plays an important role in the

epigenetic regulation during

development and has histone

methyltransferase activity. Mutations

in this gene lead to early lethality in

vertebrates and cancer. Ezh2, as the

catalytic active subunit of PRC2, places

the repressive H3K27me3 mark on the

genome. A central question regarding

PRC2 is, how it is recruited to its

target genes. [1] [2]

Chromatin Immunoprecipitation

sequencing (ChIPseq) is a method

identifying all locations on the genome to which a certain protein binds. Here we adapt the ChIP protocol for

zebrafish, making it more efficient by reducing the number of embryos and finding a correct antibody for

zebrafish Ezh2. Furthermore we take the first steps to apply RNA Immunoprecipitation sequencing (RIPseq) in

zebrafish, giving all the RNAs interacting with Ezh2. By combining these two methods we can find Ezh2 binding

loci and the Ezh2 interacting RNAs to elucidate how PRC2 is recruited to the genome. Furthermore we

investigate the role of Ezh2 at the mid blastula transition in a maternal paternal zygotic nonsense mutant and

find a shift in expression of genes around MBT. This findings and earlier reports imply a model in which Ezh2

can sense the expression state of a gene by its nascent RNA transcript and repress these.

References

[1] Margueron, R. & Reinberg, D. (2011) The Polycomb complex and its mark in life. Nature, 469(7330), 343‐349

[2] Surface, L. E., Thorton, S.R., Boyer, L.A. (2010). Polycomb group proteins set the stage for early lineage commitment.

Cell Stem Cell, 7(3), 288‐298

Recruitment of Polycomb Repressive complex 2 by

RNAs in zebrafish

Carolin Heller

Supervisor: Dr. Leonie M. Kamminga, Dept. Molecular Biology, RIMLS

Figure 1: Ezh2 and H3K27me3 ChIP qPCR. 1 to 3 are known H3K27me3 targets, 4 and5 are Czb1 and ZOzb1 enhancers and 6 the irx3 promoter. Neq1 and neg2 are negative controls.


42 R H A ‐ F NW I

Abstract: PrOs4Sb12 belongs to the class of strongly correlating electron systems. In this class of materials, the

complexity of the electronic behaviour gives rise to novel and unusual electronic and magnetic properties. In this

study, we have performed experiments at high magnetic fields to examine the strength and evolution of the

electronic interactions.

Samenvatting: In bepaalde materialen hebben de elektronen sterke interacties met elkaar. Hierdoor kunnen

interessante fenomenen als supergeleiding optreden. Echter, door de complexiteit van deze interacties is het

lastig om deze materialen volledig te begrijpen. In dit onderzoek zijn we door middel van hoge magneetvelden

meer te weten gekomen over de werking van PrOs4Sb12 , dat ook tot deze groep materialen behoort.

Strongly correlated electron systems are one of the most interesting

classes of materials, since they often exhibit intriguing phenomena such

as unconventional superconductivity, different types of magnetism and

heavy fermion behaviour. Today, there is still much unknown about the

mechanisms responsible for these phenomena, although complex

interactions between the electrons are considered to play a major role.

Since 2002, PrOs4Sb12 has been studied actively because of the presence

of unconventional superconductivity [1], an antiferro‐quadrupolar (AFQ)

ordered phase [2], and heavy fermion behaviour. The combination of

these features makes this material an interesting model to study, hoping

that it can provide more insight into similar materials.

We have performed an extensive torque magnetometry study of

PrOs4Sb12 in high magnetic fields, consisting of measurements at

different sample orientations and temperatures. Using torque

magnetometry (see figure 1), one can measure small changes in the

magnetisation of a sample. We have used this technique to measure

quantum oscillations in the magnetisation, from which the quasipaticle

masses can be determined.

These masses have been determined at high magnetic fields up to

33 T, where it was found that these masses do not change significantly

as a function of the magnetic field, see figure 2. Therefore this suggests

that the multipole fluctuations in the AFQ phase do not contribute to the

mass enhancement of the quasiparticles, as was previously suggested.

In addition to this result, we have found in one of the samples a

magnetic transition at 21 T, suggested to be a spin‐flop transition, see

figure 3. This could mean that there is antiferromagnetism present in

PrOs4Sb12 at high magnetic fields, something that may help towards a

better understanding of the various features this material exhibits.

References

[1] Bauer, E. D. et al. Superconductivity and heavy fermion behavior in PrOs4Sb12. Physical Review B, 65: 100506, 2002.

[2] Kohgi, M. et al. Evidence for magnetic‐field‐induced quadrupolar ordering in the heavy‐fermion superconductor

PrOs4Sb12. Journal of the Physical Society of Japan, 72: 1002–1005, 2003.

Torque Magnetometry Study of PrOs4Sb12 in High

Magnetic Fields

Niels Hesp

Supervisor: Dr. Alix McCollam, High Field Magnet Laboratory (IMM),


20 22 24 26 28 300

1

2

3

4

5

6

Magnetic field (T)

Eff

ecti

ve m

ass

(me)

18

β

α

Figure 2: Quasiparticle masses as functionof the magnetic field.

Magnetic field (T)

°-4°°°°°°°°

°

(i)

(ii)

(iii)

Figure 3: Measured torque as function of themagnetic field. The broad peak at 21 T issuggested to be a spin‐flop transition.

400 μm

Figure 5: One of our samples mounted on acantilever used for torque magnetometry.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 43

Figure 1: The non‐additivity, below 0, as function of p

Abstract: The additivity of the capacity of two quantum channels was one of the oldest problems in quantum

theory probability, which is equivalent with the additivity of the minimal output von Neumann entropy of

quantum channels. It has been shown that for the generalization, the minimal output Rényi p‐entropy, the

additivity conjecture is false for all p greater than 1, and eventually also for p=1. It will be shown that there is a

certain p0 below 1, which can be explicitly found, such that for all p>p0 the additivity conjecture for the minimal

output Rényi p‐entropy is false.

Samenvatting: In de kwantumversie van de kansrekening, waarbij kansverdelingen worden vervangen door

speciale matrices, namelijk dichtheidsmatrices, geven al deze dichtheidsmatrices een waarde aan de minimale

output Rényi p‐entropie. Deze waarde geeft als het ware aan in hoeverre een niet‐verstrengelde vector

verstrengeld raakt wanneer de dichtheidsmatrix op deze vector werkt. Er was een vermoeden dat zei wanneer

je twee dichtheidsmatrices neemt, en de minimale output Rényi p‐entropie van beide matrices bij elkaar optelt,

dat dit gelijk is aan de minimale output Rényi p‐entropie van de matrix die je krijgt wanneer je de ene matrix als

het ware invult in de andere matrix. Nu blijkt dit niet zo te zijn voor bepaalde waarden van p, waar een grens

wordt gegeven waarvan zeker is dat voor alle waarden boven deze grens die twee waarden verschillen.

Quantum information theory deals mainly about the

different properties of quantum channels, positive semi‐

definite matrices with trace 1. One of those properties is

the minimal output Rényi p‐entropy of a quantum

channel, which is derived from the Rényi p‐entropy. The

entropy itself defines a lower bound for the average

amount of bits used to encrypt a message, which still

allows a unique decoding. The output entropy can be seen

as how much a pure stat, becomes mixed as the quantum

channel acts on the pure state. The question which arose

together with the minimal output Rényi p‐entropy was

whether the quantity is additive under tensor products.

It was soon discovered that, in general, this is not the case, which was eventually brought back to non‐

additivity for all p≥1. However, using [1] together with [2], we showed that the bound of 1 can be lowered to

around 0.9964, see figure 1. To do so, the dimension of the output of the quantum channel were taken to

infinity, which made it possible to calculate a value for p0, instead of mere existence.

However, it might be possible to get an even lower bound by using [3], where the value of one half

would be the most interesting case, as it has an equivalence with the Arveson norm. However, at this time it is

not clear whether there is additivity or not for the value of p is one half.

References

[1] Guillaume Aubrun, Stanislaw Szarek, and Elisabeth Werner. Hastings additivity counterexample via Dvoretzky’s theorem.

Communications in Mathematical Physics, 305(1): 85‐97, 2011.

[2] Motohisa Fukada, Christopher King, and David K Moser. Comments on Hastings additivity counterexamples.

Communications in Mathematical Physics, 296(1): 111‐143, 2010.

[3] Patrick Hayden. The maximal p‐norm multiplicativity conjecture is false. arXiv preprint arXiv:0707.3291, 2007.

Non‐additivity of Rényi p‐entropy for p>p0

Wouter Hetebrij

Supervisor: Prof. Dr. J.D.M. Maassen, department of Applied Stochastics,

Radboud University


44 R H A ‐ F NW I

Abstract: In this research we propose two new protocols in group‐based cryptography. These protocols employ

either different one‐way functions or different groups than the currently available protocols in group‐based

cryptography.

Samenvatting: In ons onderzoek stellen we nieuwe vormen van cryptografie voor. Dit met de bedoeling om een

alternatief te bieden op de huidige vormen van cryptografie die veelvuldig gebruikt worden in verscheidene

maatschappelijke toepassingen.

Traditionally cryptography is the science of writing in secret code. Its main objective is to enable

communication between two or more parties without eavesdroppers being able to intercept this

communication. Presently there is an increasing demand for secure cryptosystems due to the enormous

increase in the interest for Internet shopping, electronic financial transfers, etcetera.

The basic idea of cryptography is the use of a so‐called one‐way‐

function or trapdoor‐function: an action which is easy to perform but

hard to invert, except if one is in the position of having some ‘extra’

knowledge. In this case it should again be easy to invert to process, as

is explained in figure 1.

Over the past decades, attempts have been made in order to create

secure cryptographic protocols, based on several mathematical

structures. From these, the protocols based on number theoretic

issues have been most widely used and form the core of nearly all

contemporarily used cryptographic protocols.

In our research we have attempted to set up protocols based on the structure of non‐abelian groups and

thereby contribute to the research called group‐based cryptography. [1]

A group is a mathematical structure consisting of a set of objects and an operation on these objects, which is

invertable. Examples of groups used in our research are groups of matrices, SL(4,p), and permutation groups,

Sn.

In our research, we have designed two new protocols

based on group theoretic issues. In one of the protocols,

the novelty is that we introduce a new one‐way‐function,

conjugacy of subgroups, while in the other protocol we

use a standard one‐way‐function but implement it on a

novel class of groups which has not been used for

cryptographic purposes before.

References

[1] Myasnikov A., Shpilrain B., Ushakov A., Group‐based Cryptography. Advanced Courses in Mathematics, CRM Barcelona,

2007.

Group‐based Cryptography

Serge Horbach

Supervisor: Dr. B. Souvignier, IMAPP, Radboud University

Figure 6: trapdoor function

Figure 7: Cryptographic device


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 45

Figure 8, Transmission electron microscopy image of azide‐functionalized polymer stomatocyte.

Abstract: The aim of this research was to prepare polymer stomatocytes, bowl‐shaped polymeric vesicles,

modified on the outer surface with a temperature responsive polymer to be able to open and close the

structure. To this end, dual‐functionalized polymer stomatocytes were prepared containing azide‐ and amine‐

functionalities and poly‐N‐isopropyl acryl amide was successfully synthesized using single electron transfer –

living radical polymerization.

Samenvatting: Het doel van dit onderzoek was om nanostructuren te maken die de vorm van een kommetje

hebben waarop een temperatuur gevoelige component aan vast gemaakt kan worden om de structuur te

openen en the sluiten. Hiervoor zijn nanostructuren gemaakt die aan de binnen en buitenkant verschillend zijn

en zijn er temperatuur gevoelige componenten gesynthetiseerd

Polymer stomatocytes, bowl‐shaped polymeric vesicles, are interesting structures for biomedical applications

and have recently been investigated as nanomotors. Their bowl‐like shape enables them to capture catalytic

platinum nanoparticles which catalyze the decomposition reaction of hydrogen peroxide into water and

propelling oxygen.[1]‐[3] Temperature‐dependent stimulus responsive polymers attached to the surface of

polymer stomatocytes were expected to allow further control over their structure and function upon a

temperature stimulus. Such a temperature‐dependent structure is achieved by self‐assembling amphiphilic

block copolymers into polymersomes followed by an induced osmotic shock to transform the shape into a

polymer stomatocyte. Functional handles were introduced to the polymers to enable further modification of

the stomatocytes with the temperature‐responsive polymer poly‐N‐isopropyl acryl amide, poly‐NIPAM.

Dual‐functionalized polymer stomatocytes were prepared by reducing

the outer surface of azide‐functionalized polymer stomatocytes into

amines. These structures were analysed using transmission electron

microscopy, figure 1, zeta‐potential measurements and fluorescence

measurements. These experiments confirmed that polymer

stomatocytes were formed and that there were amines present on the

surface of the stomatocytes.

Poly‐NIPAM was successfully synthesized using single electron transfer

– living radical polymerization, SET‐LRP [4]. Kinetics experiments were

used to determine the optimal conditions for this synthesis, which are

at 0 °C using Cu(I)Br as a catalyst.

These two parts are currently in progress to prepare poly‐NIPAM modified polymer stomatocytes.

References

[1] Wilson, D.A., Nolte, R, J. M., van Hest, J.C.M. Nature Chem. 2012, 4, 268‐274. b) Wilson, D.A., Nolte, R, J. M., van Hest,

J.C.M. J. Am. Chem. Soc., 134, 9894, (2012).

[2] Wilson, D.A., de Nijs, B., van Blaaderen, A., Nolte, R, J. M., van Hest, J.C.M., Nanoscale, 2013, 5, 1315.

[3] Abdelmohsen, L. K. E. A., Peng, F., Tu, Y. Wilson, D. A.*, J. Mater. Chem. B., 2014, DOI: 10.1039/C3TB21451F.

[4] B. M. Rosen, V. Percec, Chemical Reviews, 109, p5069‐5119, 2009.

Opening and Closing of Polymer Stomatocytes

using Temperature‐Dependent Stimulus Responsive

Polymers

Shauni Keller

Supervisor: Dr. D. A. Wilson and L. K. E. A. Abdelmohsen, Department of

Bio‐Organic Chemistry, Radboud University Nijmegen


46 R H A ‐ F NW I

Abstract: LORA is a scintillation detector array detecting cosmic rays. LORA can reconstruct some important

shower parameters for each shower: arrival angle, core position and the number of particles. In this project, the

reconstruction uncertainties for these parameters have been determined by simulation.

Samenvatting: LORA is een meetopstelling die aan kosmische straling meet. Dat zijn deeltjes uit de ruimte, die,

als ze de atmosfeer bereiken, een hele cascade aan nieuwe deeltjes maken. LORA kan bepaalde eigenschappen

van zo'n cascade meten. In dit project zijn de onzekerheden in zo'n meting bepaald.

Cosmic rays are highly energetic (energies range from 108 to 1021 eV) charged particles travelling through the

Universe. When a cosmic ray interacts with the Earth's atmosphere, a number of new particles are created.

Each of these can create yet more particles, causing a cascade, or “air shower”.

LORA can reconstruct a number of shower parameters. These include the core position, arrival angle and the

number of charged particles. Previously, the uncertainties for such reconstructions have only been determined

by measurement, see [1]. In this project, they were determined by simulation.

LORA can reconstruct a number of shower parameters. These include the core position, arrival angle and

the number of charged particles. Previously, the uncertainties for such reconstructions have only been

determined by measurement. In this project, they were determined by simulation.

First, air showers were simulated with CORSIKA. The output of this simulation is a set of particles at

ground level. These were then fed into a simulation of the LORA detector set‐up in GEANT4. The result from

this simulation is the total energy deposit per detector, along with times of arrival.

The output from the GEANT4 simulation was

then given to the existing reconstruction

algorithm for LORA measurements. The output

from this reconstruction algorithm was then

compared to the initial values provided by

CORSIKA.

The result of this analysis can be found in Table 1. In this table, the simulated uncertainties are compared to

the measured values. For the uncertainties in core position and arrival angle, the simulation and measurement

agree very well. However, the simulated uncertainty for the number of charged particles is much lower than

the measurement.

The reason for this discrepancy is currently unknown, though we have a suspicion. In order to save

processing time, CORSIKA does not simulate full showers. Instead, some particles are left out and others are

given a weight factor. In undoing this “thinning” procedure, care is usually taken to keep average distributions

the same [2]. However, natural fluctuations in the shower may be flattened. Due to the large amount of

computing power required, it was not possible to verify this possibility.

References

[1] S. Thoudam. Propagation of Cosmic Rays in the Galaxy and their measurements at very high energies with LORA. PhD

thesis, Radboud University Nijmegen, June 2012.

[2] B.T. Stokes, R. Cady, D. Ivanov, J.N. Matthews, and G.B. Thomson. Dethinning extensive air shower simulations.

Astroparticle Physics, 35(11):759‐766, 2012.

The reconstruction uncertainties of the Lofar

Radboud Air Shower Array – LORA

Luc van Kessel

Supervisor: Dr Jörg Hörandel, department of Astrophysics, Radboud

Quantity Simulated Measured [1]

Core position (m) 5.4 ± 0.3 5 ± 0.5

Arrival direction (°) 0.9 ± 0.1 0.8 ± 0.2

Particle number (%) 11 ± 3 27 ± 2

Table 1: Reconstruction uncertainties for LORA


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 47

Abstract: Improving upon our understanding of chemical reactions, that is the underlying goal of measuring

spikes, also known as resonances, in the interaction probability between two molecules in the gas phase.

Simulations indicate that measuring these resonances is possible when using a particular setup. During the

characterization of this particular setup a critical component exhibited weird behaviour. A closer look into this

behaviour revealed that the molecular beam generator is bouncing. This bouncing prevented a full

characterization of the setup. Future studies should be able to complete the characterization and measure the

resonances, after repair or replacement of the beam generator.

Samenvatting: Wat gebeurt er exact met moleculen in een vlam? Fysici en chemici weten dit nog niet. Om dit

beter te begrijpen wordt er gekeken naar resonanties, plotselinge toenames in reactiesnelheden, in

molecuulbotsingen bij lage temperaturen. Het observeren van deze resonanties erg lastig. Tijdens mijn stage

heb ik met behulp van simulaties bewezen dat we onder de juiste omstandigheden deze resonanties kunnen

waarnemen en een opstelling gebouwd en (deels) gekarakteriseerd waarmee het mogelijk moet zijn om

resonanties te kunnen meten.

Our understanding of chemistry at low temperatures, in

combustion processes and outer space is lacking.

Resonances in molecule – molecule collisions can be a

stepping stone to further our understanding [1]. These

resonances are a direct consequence of quantum

mechanical effects on the potential between the two

molecules. A theoretical study shows that for NH3 and H2

collisions, resonances occur below collision energies of 50

cm‐1 (10‐21 Joule) [2], see figure 1. To be able to measure

these resonances three things are required: simulations to

prove the feasibility of the experiment, an apparatus

which can collide at sufficiently low energies and the

characterization of this apparatus.

Simulations indicated that collision energies as

low as 24 cm‐1 can be reached while keeping the

resolution sufficient to observe the resonances. The

critical component in the apparatus is the Even‐Lavie valve: a small gas container which can create very neat

gas pulses at temperatures of 4 K. During the characterization of the Even‐Lavie valve, it did not function

properly. After elaborate testing it appeared that the valve was bouncing; instead of producing one single

pulse, it produced several pulses. This bouncing prevents us from having full control over the experiment and

could potentially destroy the setup when operating at low temperatures.

In conclusion, initial steps have been made to observe resonances in the NH3 – H2 system. If the valve

is repaired and can be cooled down to sufficiently low temperatures, resonances will be measured.

References

[1]. Chandler, D. W. (2010) Cold and ultracold molecules: Spotlight on orbiting resonances. The journal of Chemical physics,

132(11), 110901

[2]. Personal communications with Ad van der Avoird and Paul Dagdigian.

Towards resolving resonances in cold collisions

Alex Kolmus

Supervisor: Dr. Bas van de Meerakker, Department of Molecular and

Laser Physics, Radboud University Nijmegen

Figure 9: Top: the cross section between NH3 and H2. Thehorizontal axis is the collision energy and the vertical axis represents the cross section, a measure for interaction probability. Each strong peak indicates a resonance. Bottom left: the post‐collision angles when a resonance occurs. Bottom right: the post‐collision angles when the collision is not on a peak.[2]


48 R H A ‐ F NW I

Abstract: To study early embryonic development in vitro the technology of human induced pluripotent stem

cells (iPSC) can be used. In this project gene regulation during epithelial differentiation in an iPSC model was

studied. Since differentiation of iPSCs towards keratinocytes is heterogeneous, single cell RNA‐Seq was used to

profile gene expression in iPSCs.

Samenvatting: “Induced pluripotent stem cells” zijn cellen die op embryonale stam cellen lijken. De cellen

kunnen gebruikt worden om vroege embryonale ontwikkeling te studeren. In dit project heb ik iPSC gebruikt om

de rol van genen in de ontwikkeling van de huid te onderzoeken.

The research question addressed in this project is to understand gene regulation of epithelial differentiation

using an iPSC model. Two objectives were addressed in this project, to establish epithelial differentiation of

iPSCs and to establish single‐cell RNA‐Seq to profile gene expression in iPSCs. To study epithelial development

iPSCs can be differentiated into keratinocytes [1]. In this

work, differentiation of human iPSCs was induced with

KSFM medium supplemented with retinoic acid and

BMP4. As seen in Figure 1 cells showed soon after

induction of differentiation cobblestone morphology

which is characteristic for keratinocytes (Figure 1, A).

Expression of the early differentiation markers for

epithelial differentiation K8, K18 and Pax6 was clearly

induced. Expression of p63 and K14 that are mature

epithelial markers was slightly induced. However, cell

morphology changed when the cells were growing more

densely, and differentiation gave rise to a heterogeneous

cell population (Figure 1, B).

To be able to study the underlying gene regulation in this heterogeneous cell

population, the use of single cell RNA‐Seq is thus necessary. In this project

single iPSCs were prepared for sequencing [2]. Single cells were picked by

mouth pipetting (Figure 2) and lysed. After reverse transcription and second

strand synthesis cDNA was amplified by PCR. Then cDNA was prepared for

sequencing. Bioinformatic analysis of the RNA‐Seq data will give insight in

the underlying molecular mechanisms of epithelial differentiation.

References

[1] Itoh, M.; Kiuru, M.; Cairo, M. S.; Christiano, A. M., Generation of keratinocytes from normal and recessive

dystrophic epidermolysis bullosa‐induced pluripotent stem cells. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (21), 8797‐8802

[2] Tang, F. C., Barbacioru, C., Wang, Y., Nordman, E., Lee, C., Xu, N., Wang, X., Bodeau, J., Tuch, B.B., Siddiqui, A., Lao,

K., Surani, M.A., mRNA‐Seq whole‐transcriptome analysis of a single cell. Nature Methods 2009.

Figure 10: Morphology of cells at day 5 and 13 of the differentiation experiments. Cells show the cobblestone morphology soon after differentiation was initiated. However, cell morphology becomes more heterogeneous when cells grew more densely.

Day 5 Day 13

A B

Epithelial differentiation of human induced pluri‐

potent stem cells and single cell RNA‐Sequencing

Yvonne Lasarzewski

Supervisor: Dr Jo Huiqing Zhou, Department of Molecular Developmental

Biology, Radboud University Nijmegen

External Supervisor: Dr Fuchou Tang, Biodynamic Optical Imaging Center,

Peking University

Scale bar: 30µmFigure 11: Single cells prepared for picking with a micro‐pipette.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 49

Abstract: In our research we focussed on a mathematical structure defined in the context of non‐commutative

geometry. We tried to understand the structure and apply it to the Standard Model of Particle Physics.

Samenvatting: De kleinste deeltje die er bestaan op de wereld kunnen we wiskundig beschrijven. Samen met

mijn begeleider heb ik geprobeerd om deze beschrijving beter te begrijpen en daarna te verrijken.

Geometry is an ancient part of mathematics which can be traced back to the ancient Greeks and further. Euclides and Newton used geometry in their work and Einstein used geometry for his famous theory of gravity. In order to develop his general theorem of relativity he had to use some kind of geometry, more specifically Einstein used Riemannian geometry. In this way, Einstein’s theory could describe gravity. The other three fundamental forces, the weak and strong nuclear force and the electromagnetic force, could not yet be described by it despite many effort. Many have tried to generalize Einstein’s theory, but it was Alain Connes in the twentieth century who found a generalization that allows for the inclusion of the other forces as well. The result was non‐commutative geometry and it generalizes Riemannian geometry. With this generalization it was also possible to describe the Standard Model of Particle Physics at least at the classical level. In 2013 an article was published in which non‐commutative geometry was further generalized by the disposal of one of the conditions, namely the first order condition [2].

We tried to understand this generalization better. In order to do so we concretely determined the perturbation semigroup for some simple examples, after which we determined the perturbation semigroup of all matrix algebras. After this we looked at the general structure of this perturbation semigroup and how it behaved under mathematical operations, such as the direct sum and the tensor product. We also looked at the perturbation semigroup of smooth functions over an algebra. With this results combined we could determine

the perturbation semigroup of the Standard Model of Particle Physics, which can be seen in figure 2.

Eventhough this expression looks

hideous, it is in fact quite

beautiful. The entire Standard

Model is encoded in this

expression. In fact, one can even

find the famous Higgs‐boson in

this expression.

References

[1] A. Connes. Gravity coupled with matter and the foundation of non‐commutative geometry. Comm. Math. Phys.,

182(1):155–176, 1996.

[2] A.H. Chamseddine, A. Connes, and W.D. van Suijlekom. Inner fluctuations in non‐commutative geometry without the

first order condition. J. Geom. Phys., 73:222–234, 2013.

Perturbation semigroup for matrix algebras

Niels Neumann

Supervisor: Dr. W.D. van Suijlekom, department of Mathematics, IMAP,


Figure 12: The Standard Model of Particle Physics

Figure 2: The Standard Model of Particle Physics in terms of the perturbation semigroup


50 R H A ‐ F NW I

Abstract: All the reaction steps in the synthetic procedure for synthesizing [n]‐ladderanes were optimized for

the use in a flow setup to make way for large scale production.

Samenvatting: Er is getracht een ladderaan, een laddervormig molecuul, te synthetiseren door elke reactie stap

te optimaliseren en toepasbaar te maken voor flow chemie, een nieuwe synthese techniek.

After the discovery that ladderanes (figure 1), ladder‐like molecules that consist of multiple fused cyclobutane

rings, are prevalent in nature, research into this molecule increased drastically. Multiple synthetic procedures

were proposed because of the scarce availability of ladderanes. However no procedure to date has been very

successful, they either have very low yields or are time consuming. Therefor this research report proposes a

different method of synthesizing ladderanes, namely with the use of flow chemistry (figure 2), an up and

coming synthetic approach that makes large scale synthesis easily attainable.

Several steps in the synthetic procedure had to be optimized: The ozonolysis

reaction, the Wittig reaction, the [2+2] cycloaddition reaction and the

reduction of an ester to an aldehyde. The optimisation entailed that all

reagents and side products had to be soluble in the same organic solvent for

each reaction step. All the side products also had to be easily purified using

aqueous extraction. Once this is achieved any size ladderane is attainable

because the cyclic setup of the synthetic procedure.

Multiple reducing agents for the ozonolysis reaction were attempted

but not a single one was both soluble in an organic solvent after oxidation and removable by aqueous

extraction. For the Wittig reaction multiple phosphine ylides were attempted, decreasing the length of the

carbon chains attached to the phosphine atom increased its reactivity drastically and increased the solubility of

the phosphine oxide byproduct in water. The negative side to making the carbon chains too short is that the

ylide becomes too reactive and easily gets hydrolyzed. The [2+2] cycloaddition reaction was only successful

when performed on a completely pure sample, making removal of the side

products mandatory. Also the cyclized product’s stereochemistry is not

influenced by which stereoisomer is used as a reagent because the

reagent isomerizes during the illumination period. For the reduction of

ester to aldehyde both LDBBA and DIBAL were used as an reducing agent

but both were unsuccessful at multiple reaction temperatures, apparently

the ester is very unreactive.

Possible alterations to the synthetic procedure could be to use tripropylphosphine as a reducing agent for the

ozonolysis reaction and as reagent for a new ylide because it is likely that tripropylphosphine oxide can be

removed with aqueous extraction. Another alternation that could make the procedure more efficient would be

remove the ozonolysis step and start differently such as with a Diels‐Alder reaction or with a metathesis

reaction.

References

[1] Xiuchun Gao, Tomislav Friscic and Leonard R. MacGillivray, Angew. Chem. (2004), 23, 232–236.

[2] Future Chemistry Home Page.

Multistep Ladderane Synthesis in Flow

Elias Post

Supervisor: Dr. Daniel Blanco Ania, Department of Synthetic Organic

Chemistry, Radboud University Nijmegen.

Figure 13: Schematic representationof a [n]‐ladderane. [1]

Figure 2: Schematic representation of aflow setup. [2]


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 51

Abstract: This project aimed the isolation and purification of intermediate protein complexes that are present

during the assembly cascade of the nitrogenase protein complex. This complex stabilisation was done using

ADP•AlF4‐ as substrate instead of ATP. After a manifold of column purification steps the intermediate protein

complex was set up for microbatch crystallisation. After weeks of rest, three set‐ups resulted in crystal

formation.

Samenvatting: Enzymen volbrengen in de natuur chemische reacties met een ongelooflijke efficiëntie. Als

scheikundige wil je hier achter elk detail komen om de methode in het vervolg op andere gebieden kunnen

toepassen. In mijn onderzoek zijn de enzymen zodanig verandert dat men met behulp van kristallografie hier

een “Foto” van kan maken. Deze informatie kun je dan gebruiken om processen af te leiden.

Nitrogenase provides the bio‐catalytic machinery that allows nitrogen fixation under ambient conditions. Nitrogenase achieves this reaction by employing certain gene products that hold iron‐sulphur‐clusters as their active centre, see figure 1. Detailed description of the assembly steps are still under investigation. Crystallography, a cornerstones of protein function investigation, was applied to nitrogenase and elucidated the structures of all the gene products, however not of all intermediates that are present during this assembly.

This work focuses on stabilising the NifEN1‐Iron‐complex, an intermediate of the nitrogenase assembly, crystallise the complex and prepare it for further crystallographic analysis. The first step for this investigation is the production of nitrogenase assembly related proteins in sufficient qualities and quantities. This was done by culturing a Azotobacter vinelandii strain for 24hours. After that a 6 day long cascade of purification and analytical steps were done in order to achieve these requirements. This included Ion‐exchange, size‐exclusion and salt‐gradient columns. SDS‐PAGE and Bradford assays were used to determine quality and quantity of the proteins. Now, the actual reaction of the different complex components was accomplished by

For this the complexation matrix was provided with ADP•AlF4‐ substrate, where the gamma‐phosphate is

replaced by an AlF4‐ moiety, which cannot deliver the gamma‐hydrolysis energy for dissociation of the

intermediate protein‐complex. Therefore this intermediate is stabilised and can be prepared for subsequent studies.

For the cyrstallisation screening various buffer exchanges were performed. These included alterations in matrix composition and pH values of the buffer. For each individual set‐up a 10μL batch was used to mix mother solution and protein solution. This set‐up the rested for weeks at room temperature.

The results showed, that a complete protein‐solution matrix and high protein concentrations delivered crystals and microcrystals, see figure 2. The crystals are going to be harvested and analysed, in order to derived structural information of the protein complex. References

[1] ‐ Hu, Fay, Lee, Wiig, and Ribbe. Dual functions of NifEN insights into the evolution and mechanism of nitrogenase. Dalton Trans, 39:2964–2971, 2009. [2] ‐ Ribbe. Nitrogen Fixation. Humana Press, 2011.

1 A nitrogenase gene product associated with the EN‐protein expression.

Employment of altered Substrates for Stabilisation of Nitrogenase Assembly Intermediates for Crystallographic Characterization Christian Prüfert Supervisors: MC Feiters, IMM, Radboud University, Nijmegen

MW Ribbe, MBB, University of California, Irvine

Figure 14: Majorcatalytic centre forthe nitrogen fixa‐tion reaction.

Figure 2: A single crystal surrounded by microcrystals


52 R H A ‐ F NW I

Figure 1: Average image of all

movie frames

Figure 2: Result of observing the

movie for eight days with the EHT

Abstract: The Event Horizon Telescope (EHT) is a Very Long Baseline Interferometry (VLBI) array aiming to

image Sagittarius A* (Sgr A*), the radio source associated with the supermassive black hole at the center of the

Milky Way, on event horizon scales. General relativistic magnetohydrodynamic (GRMHD) simulations show that

radio emission from Sgr A* exhibits variability on timescales of minutes, whereas VLBI observations typically

take several hours. One of the key assumptions needed for radio interferometry to theoretically work is that the

source does not change during the observations, which is clearly violated for Sgr A*. In this research project,

simulated EHT observations of a GRMHD movie of Sgr A* (made by Hotaka Shiokawa) have shown that an

image of the average quiescent emission, featuring the characteristic black hole shadow and photon ring

predicted by general relativity, can nonetheless be obtained.

Samenvatting: De Event Horizon Telescope is een project waarbij radiotelescopen over de hele wereld

gecombineerd worden tot een telescoop die effectief ongeveer even groot is als de aarde. Hiermee kan een

resolutie bereikt worden die hoog genoeg is om een foto te maken van Sgr A*, het superzware zwarte gat in het

centrum van de Melkweg. Dit zwarte gat is voor onze telescopen te zien door de (radio)straling die ontstaat

door materie die het zwarte gat in valt. Echter, deze straling is variabel op een tijdschaal van minuten, terwijl

een meting met de radiotelescopen een paar uur duurt. In dit project is een methode ontwikkeld om alsnog een

foto van het zwarte gat te kunnen maken.

EHT observations of Sgr A* have been simulated with the MIT Array

Performance Simulator (MAPS). This package generates interferometric

data sets (complex visibilities) from an input brightness distribution (the

model movie of Sgr A*) and some observational parameters, such as the

locations and properties of the antennas and the observing time and

duration. The visibilities can then be used to reconstruct an image of the

source under observation.

It has been shown that for Sgr A* the reconstruction quality

increases as it is observed for multiple days, over which the visibilities are

averaged. Also, it is necessary to normalize the visibilities by the total flux

density of the currently observed movie frame. Furthermore, the image

quality increases as a smoothing algorithm (a moving average with Gaussian

weight function) is applied to the complex visibilities as a function of time.

This method can be combined with an existing method to mitigate the

effects of interstellar scattering [1].

Figure 1 shows the average image of all movie frames, which is

what one would see in an ideal situation. Figure 2 shows the result of the

simulated EHT observation of the movie, made with eight telescopes over a

period of eight days. It still shows the black hole shadow and photon ring as

predicted by the GRMHD simulations, despite the variability of the source.

References

[1] V. L. Fish et al. Imaging an event horizon: mitigation of scattering toward

Sagittarius A*. Submitted to The Astrophysical Journal, June 2014.

Observing time‐variable black holes with the Event

Horizon Telescope

Freek Roelofs

Supervisor: Prof. dr. Heino Falcke, Dept. of Astronomy, RU Nijmegen


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 53

Abstract: In this project a 3D hMSC culture system was developed comprising strain‐stiffening hydrogels

consisting of fibrinogen and polyisocyanopeptide (PIC) and this system was used to evaluate the effect of strain‐

stiffening properties on hMSC behaviour in 3D. It was found that the relative amount of round cells increased

with increasing PIC:fibrinogen ratio.

Samenvatting: In dit project is een systeem ontwikkeld om (stam)cellen te kweken in 3D gels. De gels bestonden

uit twee materialen die harder worden naarmate er meer kracht op wordt uitgeoefend door bijvoorbeeld de

erin aanwezige cellen. Er is gebleken dat het veranderen van de verhouding van de twee gel‐componenten ertoe

leidt tot een verandering in het aantal ronde en gespreide cellen.

Human mesenchymal stem cells (hMSCs) are known to respond to physical cues from their extracellular

environment in determining what lineage to commit to during differentiation [1]. Much of the work that has

been done in investigating the role of physical parameters on cellular behaviour has been done on linearly

elastic systems with cells being cultured on top of a hydrogel. Such systems are far from the natural

environment of most cells, including hMSCs, as their in vivo environment is made out of a 3D network of strain‐

stiffening fibres, called the extracellular matrix (ECM). So a system in which hMSCs are being cultured and

studied inside a 3D hydrogel that is composed of strain‐stiffening materials would mimic the in vivo

environment more closely and could lead to new insights into a stem cell’s natural behaviour. Therefore, the

aim of my project was to develop such a system using fibrinogen and polyisocyanopeptide (PIC) [2] and to use

it to evaluate the effect of strain‐stiffening properties on hMSC behaviour in 3D.

To develop a protocol for 3D culture and evaluation of hMSCs, first a suitable cell concentration, hydrogel

thickness, hydrogel formation rate and cell staining procedure were evaluated using NIH 3T3 fibroblasts. Next,

the proposed protocol was validated using hMSCs to find out whether individual hMSCs could be visualised

throughout multiple layers of the hydrogel and to make sure that hMSCs were viable inside their 3D

environment.

Using the newly established protocol, the effect of strain‐stiffening properties on hMSC behaviour was

evaluated by analysis of the morphology of these cells after 24 hours inside PIC‐fibrinogen hydrogels of

different compositions. It was found that the relative amount of rounded cells increased with increasing

PIC:fibrinogen ratio. This could be caused by either a decrease in the fibrinogen concentration or an increase in

the critical strain or both, caused by the increase of the PIC:fibrinogen ratio. So further experiments are needed

to find out which of both factors plays a role.

While further research is needed to unravel the mechanisms through which physical cues of the

extracellular environment can affect cellular behaviour in 3D, an interesting dependency of hMSC morphology

on hydrogel composition has been found. So it would be interesting to look further into the physical cues

underlying this process and to focus more on other processes, like hMSC differentiation, that might also be

affected by hydrogel composition in the 3D system used here.

References

[1] Engler, A.J., et al. Matrix elasticity directs stem cell lineage specification. Cell, 126: 677‐689, 2006

[2] Kouwer, P.H.J, et al. Responsive biomimetic networks from polyisocyanopeptide hydrogels. Nature, 493: 651‐655, 2013

The influence of strain stiffening properties on hMSC

morphology inside 3D PIC‐fibrinogen hydrogels

Suzanne Timmermans

Supervisor: Prof. dr. W.T.S. Huck, Department of Physical Organic

Chemistry, Radboud University Nijmegen


54 R H A ‐ F NW I

Abstract: This bachelor internship deals with operational aspects of FLARE, a terahertz free‐electron laser. It

reports on calculations on the propagation of light in the cavity of FLARE in a search for the origin of so‐called

gaps in the scanning range of the laser. This internship also investigates a method of transforming the output of

FLARE, which is prescribed by the operational mechanism, into pulses of a certain length and shape. This

process uses laser driven switchable mirrors to select light pulses of tuneable length.

Samenvatting: Deze bachelorstage heeft zich beziggehouden met twee onderwerpen. Allereerst is de vrije

elektronenlaser FLARE onderzocht. Deze vijftien meter lange laser produceert niet al het licht dat het zou

moeten en het is onduidelijk wat de reden voor dit defect is. Daarnaast is de mogelijk van pulsknippen

onderzocht. Dit gebeurt met spiegels die heel snel aan‐ en uitschakelen met behulp van een sterke laser.

FLARE is a free‐electron laser designed by the Radboud university [1]. It is a special kind of laser in that its

output wavelength can be scanned continuously, an attribute that aids spectroscopy considerably. However,

upon the completion of the machine it became clear that the laser could only produce light effectively at a few

wavelengths.

Multiple experiments were carried out over the course of the project to collect data on the most basic

operations of FLARE. Taking one of the laser cavity mirrors out, the spontaneous emission of the laser could be

investigated spectrally and temporally to see whether the problem lies at the very root of the lasing

mechanism. In the end, sadly, no clear correlation between spontaneous emission and lasing could be found. In

addition to practical experiments, both the propagation of light in FLARE’s waveguide and the effects of

irregular electron bunches were mapped as a function of laser parameters. These investigations have brought

new insights to light concerning possible disruptions in FLARE’s

lasing process, such as a disadvantageous electron bunch

shapes.

As a more personal project, the feasibility of THz pulse

slicing using silicon‐on‐insulator plasma switches was

investigated. FLARE’s light pulses are 2‐15 μs long [1], making

them inconvenient to use on physical processes that work on

much shorter timescales. In order to produce shorter pulses of

light, a strong laser can be fired at a thin layer of silicon to

produce a short‐lived plasma and make it reflective for THz light

for a brief period of time [2]. In this project, the reflectivity of

several mirrors with varying thicknesses was measured with

nanosecond resolution. THz pulses on the order of tens of

nanoseconds could be created with these switchable mirrors.

References

[1] Jongma, R.T., van der Zande, W.J., van der Meer, A.F.G., Lehnert, U., Michel, P., Wünsch, R., van der Geer, C.A.J., Dunkel,

K., Piel, C., van der Slot, P.J.M. Design of the Nijmegen High‐Resolution THz‐FEL. Proceedings of FEL08, 2008

[2] Doty, M.F., Cole, B.E., King, B.T., Sherwin, M.S. Wavelength‐specific laser‐activated switches for improved contrast ratio

in generation of short THz pulses.Review of Scientific Instruments, 75(9), 2921‐2925, September 2004

The Scanning Problem of FLARE and THz Pulse Slicing

Milo Vermeulen

Supervisor: Prof. dr. W. J. van der Zande, Molecular Biophysics within

FELIX Facility within the Institute for Molecules and Materials

Figure 1: The reflectivity of the plasma switches asa function of time. A swift rise time is followed byslow decay.


Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 55

Abstract: In this project we looked at the output morphology of heterozygous knockout mice for EHMT1, and

found that the axonal properties are altered in the knockout mice. They show fewer long‐range connections and

more connectivity in their home column.

Samenvatting: Wij hebben in dit project naar de morfologie van cellen in de hersenen van muizen met het

Kleefstra Syndroom gekeken en hebben uitgevonden, dat er verschillend zijn in de cellen tussen deze en gewone

muzien.

The Kleefstra Syndrome (KS) is an intellectual development disorder, which is also

classified under the umbrella of autism‐spectrum disorders. Besides severe

intellectual disability (ID) with an IQ below 50, patients with KS show a wide variety

of different symptoms. Most prominent are the characteristic facial features (fig.1).

These facial characteristics are a tool for the diagnosis of KS, even though they make

the distinction between KS and other ID syndromes, such as Down‐Syndrome, more

difficult. A definite diagnosis can only be made by using genetic tools. Also

associated with KS are childhood hypotonia, developmental delay, speech

impairment and an autism‐like phenotype. Causes for KS lie in mutations or

deletions of a part of the 9th chromosome, where the gene for the epigenetic factor

Euchromatin Histone‐lysine N‐Methyltransferase 1 (EHMT1) is located.

Previous research on autism models showed that the basic neuronal

morphology in the part of the brain that processes somatosensory input

– the somatosensory cortex – is altered. We therefore did 3D neuronal

reconstructions of layer II/III pyramidal neurons of the somatosensory

cortex in wild type mice and also in heterozygous knock out mice

(Ehmt1+/‐).

We found that the basic axonal morphology of the Ehmt1+/‐ neurons is

altered in a way that there are fewer long‐range connections, that

means connections outside of the home column, as compared to wild

type cells.

Since we were only able to reconstruct 4 cells per genotype, more research needs to be done, but the results

are promising, and, combined with the results of other projects concerning Kleefstra Syndrome, may lead to

the understanding of the underlying causes.

References

[1] Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A., Bokhoven, H. Van. (2006). Loss‐of‐

Function Mutations in Euchromatin Histone Methyl Transferase 1 ( EHMT1 ) Cause the 9q34 Subtelomeric Deletion

Syndrome, 79(August), 370–377

Structural and functional connectivity in the

somatosensory system of a mouse‐model for

Kleefstra Syndrome

Rebecca Wallrafen

Supervisor: Dr Dirk Schubert, department of cognitive neuroscience, Donders

Center for Brain, Cognition and Behavior

Figure 1: 5 patients with

Kleefstra Syndrome. Picture

from Kleefstra et al.(2006)[1]

Figure 2: Overlay of the reconstructed cells.

The axon is always depicted in red, the

receptive surface is always blue. Barrels are

depicted in grey. Left: overlay of

reconstructed wild type cells. Right: Overlay

of reconstructed Ehmt1+/‐ cells.

56 R H A ‐ F NW I

R H A – F NW I S c i e n t i f i c O u t p u t

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 57

Scientific Output

The scientific output listed here is work that has appeared in the peer‐reviewed scientific

literature in 2013‐2014. All contributions contain (part of) the work that the RHA Science

students have done as part of their research project. Because writing and publishing does

take time, some of the papers are from previous year’s RHA Science students that have

appeared in the literature 2013‐2014 and some of the output from the 2013‐2014 RHA

Science students, who figure in this yearbook, will appear later and will be included in next

year’s yearbook.

J o u r n a l p a p e r s †

Smits, F. C. M., Casteleijns, W. W. A. and van Hest, J. C. M.; “Crosslinked ELP‐based

nanoparticles, using the strains promoted azide‐alkyne cycloaddition.” European

Polymer Journal, in press, DOI: 10.1016/j.eurpolymj.2014.07.004

Teun Dings, Erik Koelink; “On the Mathieu conjecture for SU(2)” Indagationes

Mathematicae, accepted for publication

C o n f e r e n c e C o n t r i b u t i o n s a n d P r o c e e d i n g s †

Paul H.J. Kouwer, Matthieu Koepf, Alan E. Rowan, Roeland J.M. Nolte, Maarten Jaspers,

Zaskia H. Eksteen‐Akeroyd, Mathijs Mabesoone, Vincent A.A. Le Sage. "Responsive

biomimetic Hydrogels", 5‐5‐2014, St. Petersburg State University.

† the names of the RHA science students presenting/concerned have been underlined

58 R H A ‐ F NW I

R H A – F NW I P r o g r amm e C o u n c i l

Y e a r b o o k 2 0 1 3 ‐ 2 0 1 4 59

Leden RHA Programma Raad 2013‐2014

Prof dr John van Opstal (voorzitter, natuurkunde, DCC)

Drs Hay Geurts (secretaris, onderwijscentrum)

Drs Jan van den Broek (vaardigheden training, onderwijscentrum)

Wilke Castelijns (studentlid moleculaire levenswetenschappen)

Teun Dings (studentlid wiskunde)

Dr. Ernst van Eck (scheikunde, IMM)

Dr. Leonie Kamminga (Biologie, NCMLS)

Prof. dr. Klaas Landsman (wiskunde, IMAPP)

Dr. Elena Marchiori (informatica, ICIS)

Nicolette Poelen (ondersteuning, onderwijscentrum)

Drs Muriel van Teeseling (PhD studentlid biologie)

From left to right: Ernst van Eck, Jan van den Broek, Nicolette Poelen, Teun Dings, Hay Geurts, Elena Marchiori, Muriel vanTeeseling, Klaas Landsman, Leonie Kamminga and John van Opstal

60 R H A ‐ F NW I

Colofon

Productie, Design & Layout Ernst R.H. van Eck

Photography cover: Dick van Aalst

Print: Rikken print bv

Postal address:

RHA FNWI

Faculty of Science


PO Box 9010

6500 GL Nijmegen

Visiting address:

Heyendaalseweg 135

6525 AJ Nijmegen

www.ru.nl/rha/fnwi/

radboud honours academy fnwi yearbook 2013 2014 · 2017-02-01 · preface 4 rha ‐ fnwi preface...

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