Morfologische, ecologische en governance principes voor ecodynamisch ontwerpen: toegespitst op de 'Bouwen met Natuur' pilots Friese IJsselmeerkust : building with nature, case Markermeer IJsselmeer, MIJ 4.2, Deliverable 1.6

Het concept ‘Bouwen met Natuur’ richt zich op gebiedsgerichte ontwerpprocessen langs kusten met het doel om de interactie tussen menselijke ingrepen en ecosysteem processen te vergroten. Het concept maakt maximaal gebruik van dynamiek van natuurlijke processen en van de inzet van bio@engineers bij de ontwikkeling van nieuwe kustlandschappen. De uitdaging bij ‘Bouwen met Natuur’ projecten is om een menselijke ambitie m.b.t. waterbouw te realiseren op een wijze die maximaal gebruik maakt van het ecosysteem en tevens dit ecosysteem versterkt. Het zoeken naar een win@win situatie voor zowel de menselijke waterbouwambitie als voor de natuurwaarden is dus iets anders dan natuur behouden die er is of nieuwe natuur ontwikkelen. Ook is het concept fundamenteel anders dan het compenseren van natuur die elders verloren gaat

Localized vs delocalized description of photoelectron spectra

A model calculation is presented to investigate the conditions under which an excitation of a molecule or solid should be treated in a symmetry restricted or localized manner. The three important quantities in the model, the hole delocalization energy, the response time of the polarizable medium, and the interaction between the hole and the polarizable medium are included as variables. The exact solution is compared to approximations, and ranges of the three above‐mentioned quantities are found for which the symmetry restricted or localized solutions yield the best results. It is found that the localized solutions with symmetrization afterwards yield the best results for a surprisingly large range of the three interactions and seems to be the better solution even for describing valence orbital photoelectron spectra

A covalent antagonist for the human adenosine A(2A) receptor

The structure of the human A(2A) adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA(2A) receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A(2A)-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A(2A) receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine

A covalent antagonist for the human adenosine A2A receptor

The structure of the human A2A adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA2A receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A2A-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A2A receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine.KEYWORDS: A2A adenosine receptor; Adenosine; Covalent antagonist; G protein-coupled receptors; Radioligand bindin

Een dubbele dijk met driedubbele doelen

De huidige zeedijk in de Eemsdelta voldoet niet meer aan de veiligheidsnormen. Omdat de dijk in een aardbevingsgevoelig gebied ligt is dijkversterking urgent. Daarnaast heeft Noordoost-Groningen behoefte aan nieuwe economische impulsen, en is voor de natuur in het Eems-estuarium kwaliteitsverbetering dringend gewenst. Dit was aanleiding voor de provincie Groningen om te onderzoeken of een innovatieve, multifunctionele dubbele dijk haalbaar is. Daarmee kunnen drie doelen worden bereikt: meer veiligheid, nieuwe economische dragers en meer biodiversiteit

A covalent antagonist for the human adenosine A_2A receptor

The structure of the human A(2A) adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA(2A) receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A(2A)-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A(2A) receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine.Medicinal Chemistr

Natuurlijk IJsselmeer: ecodynamisch visie IJsselmeer 2100

Deze ecodynamische visie laat een palet van potentiële ontwikkelingen voor het IJsselmeer zien: ecodynamische ontwikkelingen, die bijdragen aan meerdere functies en ambities waaronder natuur, waterveiligheid, visserij, recreatie en infrastructuur, en waarbij optimaal gebruik wordt gemaakt van de in het gebied aanwezige natuurlijke factoren als wind, water, sediment en vegetatie. Deze visie laat zien dat er kansen liggen voor nieuwe vormen van waterbouw, die de veiligheid van de Houtribdijk en de Afsluitdijk vergroten. Ook worden de kansen in kaart gebracht om met moerassen zowel de waterveiligheid als de biodiversiteit langs dijken bij de Noordoostpolder te verbeteren

Economische en ecologische perspectieven van een dubbele dijk langs de Eems-Dollard : waarderen en verzilveren van ecosysteemdiensten en versterken van biodiversiteit bij een Multifunctionele Dubbele Keringzone voor de dijkversterking Eemshaven – Delfzijl

Dit rapport gaat in op het waarderen en verzilveren van ecosysteemdiensten en biodiversiteit in de verkenning van de haalbaarheid van een Multifunctionele Dubbele Keringzone als alternatief bij de Dijkversterking Eemshaven – Delfzijl. Het project richt zich op het waarderen van ecosysteemdiensten die worden geleverd door de voorgestelde een ‘natuurinclusieve’ dijk en de meerwaarde hiervan in termen van biodiversiteit

Sexual Behaviour and HPV Infections in 18 to 29 Year Old Women in the Pre-Vaccine Era in the Netherlands

Contains fulltext : 71058.pdf ( ) (Open Access)BACKGROUND: Infection with Human Papillomavirus (HPV) is a necessary event in the multi-step process of cervical carcinogenesis. Little is known about the natural history of HPV infection among unscreened young adults. As prophylactic vaccines are being developed to prevent specifically HPV 16 and 18 infections, shifts in prevalence in the post vaccine era may be expected. This study provides a unique opportunity to gather baseline data before changes by nationwide vaccination occur. METHODS AND PRINCIPAL FINDINGS: This cross-sectional study is part of a large prospective epidemiologic study performed among 2065 unscreened women aged 18 to 29 years. Women returned a self-collected cervico-vaginal specimen and filled out a questionnaire. All HPV DNA-positive samples (by SPF(10) DEIA) were genotyped using the INNO-LiPA HPV genotyping assay. HPV point prevalence in this sample was 19%. Low and high risk HPV prevalence was 9.1% and 11.8%, respectively. A single HPV-type was detected in 14.9% of all women, while multiple types were found in 4.1%. HPV-types 16 (2.8%) and 18 (1.4%) were found concomitantly in only 3 women (0.1%). There was an increase in HPV prevalence till 22 years. Multivariate analysis showed that number of lifetime sexual partners was the most powerful predictor of HPV positivity, followed by type of relationship, frequency of sexual contact, age, and number of sexual partners over the past 6 months. CONCLUSIONS AND SIGNIFICANCE: This study shows that factors independently associated with HPV prevalence are mainly related to sexual behaviour. Combination of these results with the relative low prevalence of HPV 16 and/or 18 may be promising for expanding the future target group for catch up vaccination. Furthermore, these results provide a basis for research on possible future shifts in HPV genotype prevalence, and enable a better estimate of the effect of HPV 16-18 vaccination on cervical cancer incidence

Improving virtual screening of G protein-coupled receptors via ligand-directed modeling

G protein-coupled receptors (GPCRs) play crucial roles in cell physiology and pathophysiology. There is increasing interest in using structural information for virtual screening (VS) of libraries and for structure-based drug design to identify novel agonist or antagonist leads. However, the sparse availability of experimentally determined GPCR/ligand complex structures with diverse ligands impedes the application of structure-based drug design (SBDD) programs directed to identifying new molecules with a select pharmacology. In this study, we apply ligand-directed modeling (LDM) to available GPCR X-ray structures to improve VS performance and selectivity towards molecules of specific pharmacological profile. The described method refines a GPCR binding pocket conformation using a single known ligand for that GPCR. The LDM method is a computationally efficient, iterative workflow consisting of protein sampling and ligand docking. We developed an extensive benchmark comparing LDM-refined binding pockets to GPCR X-ray crystal structures across seven different GPCRs bound to a range of ligands of different chemotypes and pharmacological profiles. LDM-refined models showed improvement in VS performance over origin X-ray crystal structures in 21 out of 24 cases. In all cases, the LDM-refined models had superior performance in enriching for the chemotype of the refinement ligand. This likely contributes to the LDM success in all cases of inhibitor-bound to agonist-bound binding pocket refinement, a key task for GPCR SBDD programs. Indeed, agonist ligands are required for a plethora of GPCRs for therapeutic intervention, however GPCR X-ray structures are mostly restricted to their inactive inhibitor-bound state