Copenhagen University Neutron and X-ray Techniques (CoNeXT)

The CoNeXT project was initiated by the new neutron and X-ray synchrotron research infrastructures that were operational or under construction in Lund, Sweden and Hamburg, Germany: ESS, MAX IV, Petra III and European XFEL. The aim of the project was to ensure that UCPH would be ready to use the full potential of the new neutron and X-ray sources and could act as a portal for Danish and North European Industries with potential for use of the unique research infrastructures.

The University of Copenhagen published a whitepaper on the University's use of neutron and X-ray sources (PDF format).

CoNeXT united scientists that were experienced users of the large facilities with others that could see the great potential in the facilities. CoNeXT involved 31 researchers from 5 faculties (HEALTH, HUM, LAW, SOC and SCIENCE) that all were engaged in interfaculty collaborative projects directed towards the large facilities. It was one of the aims of the project that everybody at UCPH should know about the large neutron and X-ray sources and their scientific potential, and the group of the researchers involved expected to grow over the years.

The interfaculty collaborative projects covered a very wide range of research. There were several collaborations of medical importance ranging from fundamental studies related to diseases and to drug development and in particular to the uptake of drugs. These investigations make use of the large research infrastructure that need to be complemented with necessary method development both on the experimental and the data analysis side. Another important component is the use of X-rays in research related to humanities. The first step of these investigations is the study of ancient papyrus. Finally the project possesses new dimensions by including research on the societal and legal aspects of the research that is carried out at large facilities.

Fibroblast Growth Factor Receptor Interactions

Fibroblast Growth Factor Receptor Interactions (FGFR) interactions with protein modulators are implicated in a number of neural disease states. The focus of this project is on investigating at the structural level of interactions of FGFRE, the extracellular ligand biding domain of FGFR, with a selection of these proteins. The project starts "from scratch" with recombinant protein expression and structural characterization will exploit both diffraction and solution scattering techniques and is realized through collaboration between researchers from Department of Chemistry, SCIENCE and Department of Neuroscience and Pharmacology, HEALTH.

Participants:
Associate professor Leila Lo Leggio, Department of Chemistry
Associate professor Peter S. Walmod, Department of Neuroscience & Pharmacology
Post doc Kim Krighaar Rasmussen, funded by CoNeXT
PhD student Maria Hansen
MS in medicinal chemistry Lila Yang, recipient of Novo Scholarship 2014

Interaction of lipidated therapeutic peptides with solid surfaces and membranes: a mechanistic study using neutron reflectivity

Several therapeutic peptides are currently being modified using lipid chains to improve their therapeutic potential. However, this lipidation also causes challenges in terms of altered surface adsorption and interaction with membranes. This project aims to obtain a mechanistic insight into the (altered) interaction of these lipidated peptides with solid surfaces and membranes using amongst others neutron reflectivity. The latter method is expected to give important detailed information on the stucture of the adsorbed layer(s) and the effect of adsorption on membrane structure. This insight can, in turn, be used to improve the formulation of these lipid-modified peptides into better, safer and more stable products.

Participants:
Associate professor Marco van de Weert, Department of Pharmacy
Associate professor Marité Cardenas, Department of Chemistry
Associate professor, Lene Jørgensen, Department of Pharmacy
PhD student Sofie Fogh Hedegaard, Department of Pharmacy

Funding:
The project is funded by CoNeXT (2/3) and by the Department of Pharmacy (1/3)

Pharmaceutical materials research

Large-scale facilities opens the possibilities to study hanges as they happen, in situ and to charaterize the inhomogeneity of crystalline materials at the nano-scale. We study the mechanical and thermodynamic stability of polymorphic pharmaceutical materials using a range of techniques.

1. Combined in-situ micro-indentation and X-ray microscopy
2. In-situ pressure studies using synchrotron powder diffraction
3. In-situ solubility studies using PXRD and SAXS / WAXS
4. Thermodynamic stability studied by multi-temperature X-ray and neutron experiments

This project is realized through a collaboration between researchers from the Department of Chemistry, the Faculty of Science and the Department of Pharmaceutics at the Faculty of Health.

Participants
Associate Professor Anders Østergaard Madsen, Department of Chemistry, the Faculty of Science
Professor Jukka Rantanen, Pharmaceutical department, the Faculty of Health
Post-doc Anna Hoser, Department of Chemistry, the Faculty of Science
Master student Philip Miguel Kofoed, the Department of Chemistry, the Faculty of Science
PhD student NN (currently being employed)

An Ethnography of regional potentialities

The detection of sociocultural factors significantly influencing and potentially facilitating collaborative innovation related to the new large research facilities of the Oresund region

A comparative, transnational and multi-sited business-antrhopological research project connected to the initiary phases of the large synchrotron research facilities in the Oresund region. A team of anthropologists follow and ethnographically document selected socio-cultural aspects of the development of scientific-commercial collaborations and governance policies (with specific regard to social agencies and network) and their effects on synchrotron based commercial innovation in the context of regional development. The project situates itself in the field of organisational and business anthropology, but also draws on the anthropology of innovation, anthropology of governance and management and anthropological science and technology studies.

Collaborating institutes: The research is situated at the Department of Anthropology, Faculty of Social Sciences, University of Copenhagen

Participants:
PhD, Associate professor Karen Lisa Salamon, Department of Anthropology, Faculty of Social Sciences, Copenhagen University. kls@anthro.ku.dk
Post doc, Torbjörn Friberg, Department of Anthropology
Post doc, Simon Westergaard Lex, Department of Anthropology

Masterstudents with affiliation to the project:
MS in anthropology, Sophie Therese Burisch, Department of Anthropology
MS in anthropology, Maia Ebsen, Department of Anthropology
MS in anthropology, Sandra Thomas, Department of Anthropology

Conformational stages of full-length membrane-bound receptors and transporters

The overall aim is to determine low resolution structures of membrane-bound receptors and trasnporters as well as ligand-induced structural rearrangements by using combined synchrotron small angle x-ray scattering (SAXS) and small angle neutron scattering (SANS). This will lead to increased knowledge of theses systems as drug targets, specifically laeding to the identification and understanding of new sites for interactions with ligands for modulation of function. This research will be at the forefront of structural biology and will require method developements and extensive use of international synchrotron X-ray and neutron scattering facilities.

This project is realized throuch a collaboration between researchers from Department of Drug Design and Pharmacology, Faculty of Healt and Medical Sciences and the Niels Bohr Institute, Faculty of Science.

Participants:
Associate professor Osman Mirza, Department of Drug Design and Pharmacology
Associate professor Jette Sandholm Kastrup, Department of Drug Design and Pharmacology
Associate professor Lise Arleth, Niels Bohr Institute

Post doc Nis Pedersen, funded by CoNeXT (November 2013 - April 2014)
NN Post doc (September 2014 - August 2016)
NN PhD student (August 2014 - August 2017)

Post doc Heidi Asschenfeldt Ernst
Post doc Søren Roi Midtgaard
PhD student Bala Krishna
Technician Sussi Rosenørn Dohn

Legal challenges to large-scale international research infrastructures: The case of ESS and MAX IV

The legal sub-project of CoNeXT will focus on the challenges related to the managing and administraion of transnational consortia during the establishment and operation of large-scale research infrastructures. As part of the project i.a. the following questions occur: What legal frameworks can act as basis for such consortia? Who decides, and on what basis? To what extent is national participation subject to EU public procurement rules? And how do such procurement rules limit solutions whereby a consortium grants participants free access to suse the infrastructure as compensation for their co-funding. What role do intellectual property rights play in that regards? May competition laws of state subsidies within the EU affect such decision making?

Recognizing that this list of these potential questions is far from exhaustive, we have become engaged in collaborative article projects and seminar series. This is realized through collaboration with Professor Sine Larsen (Department of Chemistry, SCIENCE) and Karen Lisa Salamon (SAMF).

Participants:
Associate professor Timo Minssen, Faculty of Law, Centre of Information & Innovation Law (CIIR)
Professor Mads Bryde-Andersen, Copenhagen Centre for Commercial Law (CCCL)
Research assistant & post doc in spe: Torsten Bjørn Larsen

Structural studies of chromatin regulating complexes formed by histone demethylases from the KDM5B family and their interaction partners

The aims of the project are to characterize multi-protein complexes of putative cancer target KDM5B with its interaction partners, particularly components of Z3 co-regulator complex (namely ZMYND8, ZNF592 and ZNF687). This will contribute to the understanding of the role of these protein complexes in transcriptional regulation and will test the broader hypothesis that the chromatin methylation machinery drives chromatin looping in eukaryotic cells.

Participants:
Associate professor Bente Vestergaard (ILF, SUND)
Professor Kell Mortensen, Niels Bohr Institute, SCIENCE
Associate professor Kasper Dyrberg Rand, IF, SUND
Professor Michael Gajede, IFL, SUND

Structural studies of Plasmodium falciparum proteins implicated in severe malaria pathogenesis and immunity

Studies on the protozoan parasite Plasmodium falciparum that causes the most severe forms of malaria in humans is the focus of this collaborative project. the virulence of Plasmodium falciparum is related to the expression of high-molecular weight adhesive proteins called PfEMP1 on the surface of intected erythrocytes (IEs). The PfEMP1 proteins can bind to host vascular receptors, thereby mediating sequestraion of IEs in various tissues, which leads to inflammation and organ dysfunction. Through the UCPH 2016 project, we aim to obtain low- and high-resolution topological information of ligand-receptor interaction through small-angle X-ray and neutron scattering (SAXS and SANS) and crystallographic analysis of the PfEMP1 adhesive domains and/or co-crystals of these domains in comples either with receptors or ligand-specific monoclonal antibodies or with peptide mimics of these.

This project is realized through collaboration between researchers from the Faculty of SCIENCE (Department of Chemistry) and the Faculty of HEALTH and Medical Sciences (Department of International Health, Immunology and Microbiology).

Participants:
Professor Sine Larsen#
Professor Lars Hviid*
Professor Anja T.R. Jensen*
Postdoc, PhD Vladislav Soroka*#
Postdoc Anja Bengtsson*

Affiliations:
*Centre for Medical Parasitology at Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and at Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet).
# Department of Chemistry, SCIENCE, University of Copenhagen

Neutron and X-ray scattering to study the structural dynamics of nano particles in microfluidics system for drug delivery applications

Microfluidics are used as a template to perform an in-flow formation of nanoparticles such as cubosomes and hexasomes, which are being heavily studied at the pharmacology department at the University of Copenhagen. Moreoever, the microfluidic template is designed in a way that allows us as researchers to perform SANS/SAXS (small angle neutron and x-ray scattering) in real time under different conditions (temperatures, flow rates, shear stresses, etc...).

This project is realized throudh collaboration between researchers from Pharma at the University of Copenhagen and the Niels Bohr Institute.

Participants:
Professor Kell Mortensen, main supervisor and Head of Neutron and X-ray scattering department at the Niels Bohr Institute
PhD Aghiad Ghazal, Niels Bohr Institute and Pharma
Associate professor Anan Yaghmur, co-supervisor at Pharma, Univ. of Copenhagen
PhD Diana Intan Azmil, Pharma
Associate professor Camilla Foged, co-supervisor at Pharma, University of Copenhagen
Assistant professor Susan Weng, co-supervisor at Pharma, University of Copenhagen

Collborations:
Professor Jorg P. Kutter, Pharma, University of Copenhagen
Assistant professor Josiane Lafleur, Pharma, University of Copenhagen
Associate professor Jakob Kirkensgaard, Niels Bohr Institute
Professor Lisa Arleth and her group members (Søren Midtgaard, Grethe Jensen, Søren Kynde, Martin Pedersen, Pie Huda and others), Niels Bohr Institute
PhD Tomas Stankevic, Niels Bohr Institute

Synchrotron μ-CT Imaging of stemcell- or substitute mediated bone, blood vessels and implant integration

A) Synchrotron μ-CT imaging of substitute mediated bone formation in dental implant integration

The part aims at visualizing and describing bone microarchitecture in close proximity to a dental titanium implant surface, and evaluate bone density in a radial distance from an implant surface, after immediate implant installation and bone substitute augmentation.

B) Synchrotron μ-CT imaging of stem cell mediated bone and blood vessels

Development of an in vivo model comprised of fat-derived stroma cells isolated from mice, differentiated into mature osteoblasts ex vivo and subsequently transplantd back into the live mice with and without titanium granules (oxidized and non-oxidized) as osteogenic stimulus. Specimens will be examined with non-decalcified histology/histomorphometry, X-ray microscopy and SRμCT. Furthermore, a collagen culture/scaffold model in which bone cells can be cultured and differentiated from fat-deried stroma cells into mature osteoblasts will be developed. This is complemented with examinations of the in vivo bone regenerating ability of inserting 3D cell-containing collagen matrices into critical size defects in a rat model of bone regneration.

The fundings from the CoNeXT program are dedicated to 2 part-time PhD salaries at ICM and for salary for evaluations at the Niels Bohr Institute of the scans of the different specimens from the projects A) and B)

Participants
Associate Professor, MD, dr.med. Niklas Rye Jørgensen, Institute of Clinical Medicine and head, Department of Diagnostis, Glostrup University Hospital
Professor Else M. Pinholt, DDS, dr.odont, former at the Institute of Odontology, University of Copenhagen
Professor Robert Feidenhansl', the Niels Bohr Institute, University of Copenhagen
PhD student Camilla Neldam, DDS, Institute of Clinical Medicine, University of Copenhagen
PhD student Morten Dahl, DDS, Institute of Clinical Medicine, University of Copenhagen

Collaborators
Associate Professor, MD, dr.med. Ellen Hauge, Department of Rheumatology, Aarhus University Hospital

Human Sciences: Ancient Ink as a Technology

X-ray synchrotron sources have the potential to provide exciting new perspectives of fundamental importance within the Human Sciences. The project focusses on ancient manuscripts where one of the many challenges facing the historian is the fact that the majority lack a recorded archaeological context. This is not least true for the many thousands of texts from the earliest civilizations, sc. Egypt and Mesopotamia, of which a large proportion derive from the extensive antiquities trade and poorly documented excavations. For the historian it is important whether a diplomatic correspondence, administrative documents, or familly archives come from one place or another. Moreoever, many manuscripts are divided between different collections and considerable effort is spent trying to discover what material originally belonged together. It is our expectations that use of X-ray analysis will be able to deliver a chemical and structural "fingerprint", which reflects the physical properties of manuscripts and will enable a mapping of local traits in terms of both the nature of the inks, which can be shown to different properties, and the physical qualities of the papyri. The focal point of the analysis is the extensive Papyrus Carlsberg Collection which includes about 1400 manuscripts from a variety of geographical and social contexts that span some four millennia. If our expectations are fulfilled and it proves possible to map various physical properties onto the archaeological maps, the same procedure can be applied to various other forms of manuscripts across different periods and cultures and the scientific impact will be far-reaching.

Participants:
Professor Kim Ryholt, Professor Sine Larsen, Professor emeritus Poul Erik Lindelof, Professor Kell Mortensen, MA Thomas Christiansen (PhD fellow)

Read on "Ancient Ink" from an article in Jyllandsposten, March 18th 2016 (in danish)

See our Poster on "Ancient Ink as Technology"

Paragraph method development

A variety of projects within CoNeXT concerns the development of new basic instrumentation for X-ray and neutron scattering, new auxiliary equipment and new advanced methods for data treatment that ensure an optimal outcome of these techniques.

The use of advanced neutron optics has evolved over the last decade with the advent of well-defined mirrors, innovative ideas and stronger simulation tools. The CoNeXT project was inspired by the SELENE-guide concept to use McStas-simulations to evaluate the appliation of "Montel geometry" to define the neutron beam spot on the sample, with BIFROST used as the test case. The project resulted in an improved description of mirror waviness in McStas and show that an 8 meter Montel optics section will work very well for neutron wavelengths above 2 and sample sizes in the range 0.1 mm to 3 mm. It is possible to tailor the beam to size and shape by inserting a sample-shaped diaphragm before the Montel optics section.

For X-ray imaging, a CoNeXT project has developed new algorithm showing that 3D-virtual histology Synchrotron radiation μCT tomography evaluations has an inherent statistical uncertainty that is only half of that observed in 2D virtual histology. Thereby the porject has added important new knowledge by describing the geometry and distribution of bone in osseo-integration of titanium implants. The results have emphasixed that the SRμCT method in bone and implant evaluation is todays golden standard for obtaining high resolution, artifact-free, very exact, vast amounts of tomographic images in 3 dimensions. The interdisciplinary collaboration lines bone-biology and physics.

The CoNeXT development on new axillary instrumentation includes micro-fluids systems. Our aim has been to make in-situ time-resolved X-ray studies possible. We have developed a relative simple system based on a thiolene-polymer system with polystyrene X-ray windows. The microfluidic system acts as a diffusive mixer based on hydrodynamic focusing. This thiolene-based chip is easy and fast to manufacture and efficient on the synchrotron beamline.

A CoNeXT project aimed for pharmaceutical materials research combine techniques that are known in physics and chemical crystallography, but that are unknown in the study of pharmaceutical materials. Such new tools aim for more realistic systems that are close to the pharmaceutical production line. The methods include inelastic X-ray and neutron scattering techniques that combined with theoretical calculations have proven their ability to provide important information on the dynamics of molecular crystalline sytems of pharmaceutical relevance.

Participants
Kim Lefmann
Anders Østergaard Madsen
Brian Vinter
Kell Mortensen
Robert Feidenhans'l

CoNeXT played a very significant role in the education of young researchers in the use of large facilities. The majority (90 %) of the funding was used for Ph.D. stipends or salaries to post.docs. The research was collaborative across the faculties which gave the education a valuable additional component.

• Imaging
• Spectroscopy and Microscopy
• Diffraction

CoNeXT Appointments partly or fully financed from the CoNeXT grant

X-ray Analysis and the human sciences
PhD student Thomas Christiansen

Protein Fibril Structure
Postdoc Carlotta Marasini

Membrane proteins
Postdoc Nis Pedersen, November 15 2013 - April 30 2014

Fibroplast Growth Factor Receptor interactions
Postdoc Kim Krighaar Rasmussen 

Plasmodium falciparum Proteins implicated in severe malaria pathogenesis and immunity
Postdoc Vladyslav Soroka

Large Complexes
Postdoc Jerzy Dorosz

Stem cell osseous reconstruction
PhD student Camilla Neidam 
PhD student Morten Dahl

Therapeutic Proteins at interfaces
PhD student, Sofie Fogh Hedegaard

Formulation and Structural Characterization of Soft Self-assembled nanopharmaceuticals
PhD student Aghiad Ghazal

Detection of socio-cultural factors facilitating collaborative innovation related to the new large research facilities in the Øresund region
Two positions (postdoc/PhD) 

The Legal Dimension
1 postdoc position 

Pharmaceutical Materials Research
1 PhD stipend 

Publications within the CoNeXT project             

Friberg GT, Fransson O. Constructive alignment: From professional teaching technique to governance of profession. European Journal of Higher Education. 2015;5(2):141-56.

Friberg GT. A holistic, self-reflective perspective on victimization within higher education in Sweden. Critical Studies in Education. 2014:56(3):384-94

Friberg GT. A Note on Maurice Godelier's 'Re-ism': Towards an Ethnography of Moral Existence in Higher Education. Anthropological Theory. 2014. Submitted

Jeppesen A, Ditlev SB, Soroka V, Stevenson L, Turner L, Dzikowski R, Hviid L, Barfod L. Multiple Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants per gonome can bind IgM via F_cU. Infect Immun. 2015;10.1128/IAI.00337-15:1-34

Subramani R, Quadt K, Jeppesen AE, Hempel C, Petersen JEV, Hassenkam T, Hviid L, Barfod L. Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed. mBio. 2015:1-31

Stevenson L, Huda P, Jeppesen A, Laursen E, Rowe JA, Craig A, Streicher W, Barfod L, Hviid L. Investigating the funtion of F_c-specific binding of IgM to Plasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting. Cell Microbiol. 2015;17(6), 819-31

Martin-Bertelsen B, Korsholm KS, Rose F, Nordly P, Franzyk H, Andersen P, Agger EM, Christensen D, Yaghmur A, Foged C. The supramodular structure is decisive for the immunostimulatory properties of synthetic analogues of a mycobacterial lipid in vitro. RCS Advances. 2013;3:20673-83

Colombo S, Cun D, Remaut K, Bunker M, Zhang J, Martin-Bertelsen B, Yaghumr A, Braeckmans, K, Nielsen HM, Foged C. Mechanistic profiling of the siRNA delivery dynamics of lipid-polymer hybrid nanoparticles. J Conrel. 2014;201:22-31

Ladefoged CN, Andersen FL, Keller SH, Löfgren J, Hansen AE, Holm S, Højgaard L, Beyer T. PET/CT imaging of the pelvis in the presence of endoprosthses: reducing image artifacts and increasing accuracy through inpainting. Eur J Nucl Med Mol Imaging. 2013;40(4):594-601

Andersen FL, Ladefoged CN, Beyer T, Keller SH, Hansen AE, Højgaard L, Kjær A, Law I, Holm S. Combined PET/MR imaging in neurology: MR-based attenuation correction implies a strong spatial bias when ignoring bone. NeuroImage. 2014;84:206-16

Aznar M, Sersar R, Saabye J, Ladefoged CN, Andersen FL, Rasmussen J, Löfgren J, Beyer T. Whole-body PET/MRI: The effect of ignoring bone during MR-based attenuation correction in oncology imaging. Eur Radiol. 2014;83:1177-83

Ladefoged CN, Andersen FL, Keller SH, Beyer T, Højgaard L, Lauze F. Correction of dental artifacts within the anatomical surface in PET/MRI using Active Shape Models and k-Nearest-Neighbors. proc.SPIE 9034, Medical Imaging 2014: Image Processing, 90341M

Ladefoged CN, Hansen AE, Keller SH, Holm S, Law I, Beyer T, Højgaard L, Kjær A, Andersen FL. Impact of incorrect tissue classification in Dixon-based MR-AC: fat-water tissue inversion. EJNMMI Physics, 2014;1:101

Keller SH, Hansen C, Andersen FL, Ladefoged CN, Svarer C, Kjær A, Højgaard L, Law I, Henriksen OM, Hansen AE. Motion correction in simultaneous PET/MR brain imaging using sparsely sampled MR navigators: a clinically feasible tool. EJNMMI Physics, 2015;2(1)

Ladefoged CN, Hansen AE, Keller SH, Fischer BM, Rasmussen JH, Law I, Kjær A, Højgaard L, Lauze F, Beyer T, Andersen FL. Dental artifacts in the head and neck region: implications for Dixon-based attenuation correction in PET/MR. EJNMMI Physics, 2015;2(1)

Schwartz RM, Minssen T. Life after Myriad: The Uncertain Future of Patenting Biomedical Innovation & Personalized Medicine in an International Context. Intellectual Property Quaterly, 2015;3(08):189-241.

Price WN, Minssen T. Will Clinical trial data disclosure reduce incentives to develop new uses of drugs? Nat Biotech 2015;33:685-6

Principal Investigator (PI)
Professor Emerita Sine Larsen
Department of Chemistry
Mail: sine@chem.ku.dk
Phone: +45 35 32 02 82