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Use of 11C-MPDX and PET to Study Adenosine A1 Receptor Occupancy by Nonradioactive Agonists and Antagonists
No full textAdenosine A1 receptors (A1Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11C-methyl-3-propylxanthine (11C-MPDX) and PET. Here we investigated whether A1R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n = 7); pretreated with a centrally active A1R agonist, N6-cyclopentyladenosine (CPA; 0.25 mg/kg intraperitoneally; dissociation constant, 0.48 nM; n = 7); pretreated with a moderate dose of caffeine (antagonist for A1Rs and adenosine A2A receptors; 4 mg/kg intraperitoneally; dissociation constant, 11 µM; n = 6); and pretreated with a high dose of caffeine (40 mg/kg intraperitoneally; n = 6). Results: The administration of CPA resulted in a strong reduction (>50%) in the heart rate, and caffeine administration resulted in a small increase (10%–15%). A caffeine dose of 4 mg/kg (n = 6) resulted in 65.9% A1R occupancy, and a dose of 40 mg/kg (n = 6) resulted in 98.5% occupancy (calculated from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11C-MPDX binding in the brain. Conclusion: Small-animal PET with 11C-MPDX can be used to assess antagonist but not agonist binding at A1Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A1R protein having allosteric interactions.
Total synthesis of sulfolipid-1
No full textSulfolipid-1, a tetra-acylated sulfotrehalose from Mycobacterium tuberculosis, was isolated over 40 years ago. Being a main component of the mycomembrane of M. tuberculosis, its biosynthesis and function have been studied in depth, but the chemical synthesis of sulfolipid-1 has not been reported. The synthesis presented here is based on iterative catalytic asymmetric conjugate additions of methylmagnesium bromide for the preparation of the phthioceranic and hydroxyphthioceranic acid side chains, a double regioselective reductive ring-opening and a five-fold deprotection in the final step.
Adaptive resolution simulation of an atomistic protein in MARTINI water
No full textWe present an adaptive resolution simulation of protein G in multiscale water. We couple atomistic water around the protein with mesoscopic water, where four water molecules are represented with one coarse-grained bead, farther away. We circumvent the difficulties that arise from coupling to the coarse-grained model via a 4-to-1 molecule coarse-grain mapping by using bundled water models, i.e., we restrict the relative movement of water molecules that are mapped to the same coarse-grained bead employing harmonic springs. The water molecules change their resolution from four molecules to one coarse-grained particle and vice versa adaptively on-the-fly. Having performed 15 ns long molecular dynamics simulations, we observe within our error bars no differences between structural (e.g., root-mean-squared deviation and fluctuations of backbone atoms, radius of gyration, the stability of native contacts and secondary structure, and the solvent accessible surface area) and dynamical properties of the protein in the adaptive resolution approach compared to the fully atomistically solvated model. Our multiscale model is compatible with the widely used MARTINI force field and will therefore significantly enhance the scope of biomolecular simulations.
Explicit simplicial discretization of distributed-parameter port-Hamiltonian systems
No full textSimplicial Dirac structures as finite analogues of the canonical Stokes–Dirac structure, capturing the topological laws of the system, are defined on simplicial manifolds in terms of primal and dual cochains related by the coboundary operators. These finite-dimensional Dirac structures offer a framework for the formulation of standard input–output finite-dimensional port-Hamiltonian systems that emulate the behavior of distributed-parameter port-Hamiltonian systems. This paper elaborates on the matrix representations of simplicial Dirac structures and the resulting port-Hamiltonian systems on simplicial manifolds. Employing these representations, we consider the existence of structural invariants and demonstrate how they pertain to the energy shaping of port-Hamiltonian systems on simplicial manifolds.
Essay: The biological role and uptake of niacin and folate
No full textDe begeleider en/of auteur heeft geen toestemming gegeven tot het openbaar maken van de scriptie.
The supervisor and/or the author did not authorize public publication of the thesis.
Control of Surface Wettability Using Tripodal Light-Activated Molecular Motors
No full textMonolayers of fluorinated light-driven molecular motors were synthesized and immobilized on gold films in an altitudinal orientation via tripodal stators. In this design the functionalized molecular motors are not interfering and preserve their rotary function on gold. The wettability of the self-assembled monolayers can be modulated by UV irradiation.
From Photosystem I to Photosystem II
No full textIk heb gericht op de studie van de fotosynthetische complexen in Chlamydomonas reinhardtii. Het doel was om uitgebreide structurele en functionele informatie over Fotosysteem I en Fotosysteem II te krijgen en om hun flexibiliteit in verschillende omgevingsomstandigheden te testen. Al de resultaten zien dat de light-harvesting capaciteit van beide Fotosysteem I en Fotosysteem II in C. reinhardtii groter is dan die van de fotosystemen van planten. Om aan de veranderende lichtomstandigheden aan te passen, is de light-harvesting capaciteit van PSI en PSII gemoduleerd om fotosynthese te maximaliseren en fotobeschadiging te minimaliseren. We zien dat PSI in toestand 2 de mogelijkheid heeft om twee LHCII trimeren en een monomeer, te binden als aanvulling op zijn negen Lhca’s. Dat is het grootste PSI complex dat ooit is geobserveerd, veel groter dan dat van vaatplanten waar slechts één LHCII trimeer een verband met PSI bleek te houden in toestand 2. De verkregen informatie vormt de basis voor een volledig begrip van light-harvesting en de regulatie daarvan in deze alge.
The purpose of this thesis is to provide a comprehensive picture of the structural and functional properties of Photosystem I (PSI) and Photosystem II (PSII) supercomplexes of the green alga Chlamydomonas reinhardtii (C.r.) and to test their flexibility in different environmental conditions. Novel PSI and PSII complexes have been purified and characterized, allowing relating the protein composition and organization to the functional behavior of the supercomplexes. PSI complex contains a core complex and a light harvesting antenna system composed of nine Lhcas organized on one side of the core in a double half-ring arrangement. The novel PSII-LHCII supercomplex contains six LHCII trimers per dimeric core. The results show that capacity of both Photosystem I and Photosystem II in C. reinhardtii is larger than that of the photosystems of plants. To adapt to changing light conditions, the light harvesting capacity of PSI and PSII is modulated, to maximize photosynthesis and minimize photodamage. PSI in state 2, is able to bind two LHCII trimers and one monomer, in addition to its nine Lhcas. This is the largest PSI complex ever observed, far larger than that of higher plants where only one LHCII trimer was found to be associated with PSI in state 2. The information obtained represents the basis for a full understanding of light-harvesting and its regulation in this alga.
On the geometry of coating layers formed by overlap
No full textA recursive model is presented for the prediction of the profile of a coating layer formed by single track overlap. A known shape of single track is assumed and on the base of simple physical assumptions the recursive sequence is deduced to construct an entire profile of such coatings. Calculations of these profiles for different basic shapes and overlaps of tracks show the dependence of coating thickness, waviness and cladding angle on these parameters. A generalized formulation of the model based on purely geometric considerations allows for an application towards different types of cladding processes, including multilayer cladding and 3D depositions. The model is tested experimentally for the laser cladding process in two different set-ups. The cladding track is formed by a continuous deposition of metallic particles into the melt-pool formed by a high power laser beam that continuously moves over a substrate. Good agreement with the parabolic shape of a single track and experimental observations of height and waviness was concluded for a wide range of overlap ratios.
A Dithienylethene-Based Rewritable Hydrogelator
No full textDithienylethene photochromic switching units have been incorporated into a hydrogelating system based on a tripeptide motif. The resulting hybrid system provided both a photochromic response and the ability to gelate water under acidic and neutral conditions. Fluorescence spectroscopy shows that the dithienylethene units are in sufficient proximity to each other to stack in gel fibers, with the tripeptide unit determining solubility. TEM measurements provided insight into the microscopic structure of the fibers formed.
'It wie in histoarysk momint doe't de Amerikaanske astronaut Armstrong as earste minsk op de moanne stie': De uitspraak van de woord-finale /sk/-cluster in het Fries
No full textHet Fries kent een woord-finale /sk/-cluster, die zowel aan het eind van een woord als in inflectie voor kan komen. Eerdere onderzoekers beweerden dat de /k/ uit deze cluster in de uitspraak aan het verdwijnen is. In deze scriptie wordt onderzocht of dit inderdaad het geval is, en welke factoren (zowel sociaal als linguïstisch) hier op van invloed zijn. Dit is onderzocht door 31 mensen te testen d.m.v. een vertaaltaak en een map-task. Uit de resultaten hiervan blijkt dat de /k/ nog steeds aanwezig is in de uitspraak, maar inderdaad in veel gevallen ook niet meer uitgesproken wordt. Onder andere schrijfvaardigheid Fries en taalachtergrond van het woord zorgen ervoor dat de /k/ nog een sterke positie heeft. Naast dit onderzoek, is er onder dezelfde 31 deelnemers een kwalitatieve analyse uitgevoerd, zowel naar onbewuste of bewuste houding tegenover de /k/. Hieruit kwam naar voren dat de /k/ wordt gezien als ‘correct Fries’. De meeste deelnemers staan positief tegenover het gebruik van deze klank, al geven ze zelf ook aan deze klank niet vaak te gebruiken in hun taal.