Evaluatie Tijdelijke wet Groningen

Het rapport evalueert de Tijdelijke wet Groningen (TwG). Het geeft belangrijke conclusies over de doelen van de TwG en de uitwerking van de wet in de praktijk

A new convective model of the Weddell Polyny: Deep convection in the Southern Ocean

The Weddell Polynya, a large hole in the Antarctic sea ice, reappeared in 2017. The polynya forms due to deep convection, which is caused by static instability of the water column. Observations and model studies show periodic heat accumulation in the subsurface layer prior to a polynya. This heat accumulation could be caused by internal ocean dynamics: the Southern Ocean Mode. Periodic subsurface heat and salt accumulation could be the major driver in causing periodic deep convection, which is in contrast with earlier studies. These studies focus on surface processes, and see the polynya as an irregular event. In this study a simple convective model is used to look into this contrast. Model simulations excluding and including periodic subsurface heat and salt fluxes have been performed. Multiple polynya events were only simulated in the model set up including subsurface fluxes. The dominant frequency for polynya events in these simulations equals the frequency of the subsurface heat and salt accumulation. This frequency is still visible in runs with white noise added to the freshwater flux, showing the importance and dominance of the subsurface forcing. In combination with earlier studies, this study suggests that periodic subsurface processes are most dominant and govern the initial formation and periodicity of the Weddell Polynya

Multidecadal polynya formation in a conceptual (box) model

Maud Rise polynyas (MRPs) form due to deep convection, which is caused by static instabilities of the water column. Recent studies with the Community Earth System Model (CESM) have indicated that a multidecadal varying heat accumulation in the subsurface layer occurs prior to MRP formation due to the heat transport over the Weddell Gyre. In this study, a conceptual MRP box model, forced with CESM data, is used to investigate the role of this subsurface heat accumulation in MRP formation. Cases excluding and including multidecadal varying subsurface heat and salt fluxes are considered, and multiple polynya events are only simulated in the cases where subsurface fluxes are included. The dominant frequency for MRP events in these results, approximately the frequency of the subsurface heat and salt accumulation, is still visible in cases where white noise is added to the freshwater flux. This indicates the importance and dominance of the subsurface heat accumulation in MRP formation

Yttrium Alkyl Complexes with Triamino-Amide Ligands

Two new monoanionic tetradentate triamino-amide ligands, [(Me2NCH2CH2)2N-B-N(t-Bu)]- (B = (CH2)2, L1; SiMe2, L2) were prepared. Reaction of L1H with Y(CH2SiMe3)3(THF)2 yielded L1Y(CH2SiMe3)2 (1), which was structurally characterized. Compound 1 decomposes at ambient temperature via metalation of one of the NMe2 methyl groups to give {[(CH2)MeN(CH2)2][Me2N(CH2)2]N(CH2)2N(t-Bu)}Y(CH2SiMe3) (2). Attempts to prepare L2Y(CH2SiMe3)2 resulted in very rapid ligand metalation. Both 1 and 2 react with [PhNMe2H][B(C6F5)4] to generate the cation [(L1)YCH2SiMe3]+. The combination of 1 and [Ph3C][B(C6F5)4] is active in catalytic ethene polymerization, but with a short catalyst lifetime. The metalated complex 2 reacts with ethene and with pyridine by stoichiometric insertion into the Y-CH2N bond, and the latter product was structurally characterized. In L1Y(X)(CH2SiMe3) complexes, the Y-amine distance trans to X is very sensitive to the nature of X, suggesting the presence of a trans influence.

Multidecadal polynya formation in a conceptual (box) model

Maud Rise polynyas (MRPs) form due to deep convection, which is caused by static instabilities of the water column. Recent studies with the Community Earth System Model (CESM) have indicated that a multidecadal varying heat accumulation in the subsurface layer occurs prior to MRP formation due to the heat transport over the Weddell Gyre. In this study, a conceptual MRP box model, forced with CESM data, is used to investigate the role of this subsurface heat accumulation in MRP formation. Cases excluding and including multidecadal varying subsurface heat and salt fluxes are considered, and multiple polynya events are only simulated in the cases where subsurface fluxes are included. The dominant frequency for MRP events in these results, approximately the frequency of the subsurface heat and salt accumulation, is still visible in cases where white noise is added to the freshwater flux. This indicates the importance and dominance of the subsurface heat accumulation in MRP formation

Crystal structures of allosamidin derivatives in complex with human macrophage chitinase

The pseudotrisaccharide allosamidin is a potent family 18 chitinase inhibitor with demonstrated biological activity against insects, fungi, and the Plasmodium falciparum life cycle. The synthesis and biological properties of several derivatives have been reported. The structural interactions of allosamidin with several family 18 chitinases have been determined by x-ray crystallography previously. Here, a high resolution structure of chitotriosidase, the human macrophage chitinase, in complex with allosamidin is presented. In addition, complexes of the allosamidin derivatives demethylallosamidin, methylallosamidin, and glucoallosamidin B are described, together with their inhibitory properties. Similar to other chitinases, inhibition of the human chitinase by allosamidin derivatives lacking a methyl group is 10-fold stronger, and smaller effects are observed for the methyl and C3 epimer derivatives. The structures explain the effects on inhibition in terms of altered hydrogen bonding and hydrophobic interactions, together with displaced water molecules. The data reported here represent a first step toward structure-based design of specific allosamidin derivative

Structure of Human Chitotriosidase. Implications for Specific Inhibitor Design and Function of Mammalian Chitinase-like Lectins

Chitin hydrolases have been identified in a variety of organisms ranging from bacteria to eukaryotes. They have been proposed to be possible targets for the design of novel chemotherapeutics against human pathogens such as fungi and protozoan parasites as mammals were not thought to possess chitin-processing enzymes. Recently, a human chitotriosidase was described as a marker for Gaucher disease with plasma levels of the enzyme elevated up to 2 orders of magnitude. The chitotriosidase was shown to be active against colloidal chitin and is inhibited by the family 18 chitinase inhibitor allosamidin. Here, the crystal structure of the human chitotriosidase and complexes with a chitooligosaccharide and allosamidin are described. The structures reveal an elongated active site cleft, compatible with the binding of long chitin polymers, and explain the inactivation of the enzyme through an inherited genetic deficiency. Comparison with YM1 and HCgp-39 shows how the chitinase has evolved into these mammalian lectins by the mutation of key residues in the active site, tuning the substrate binding specificity. The soaking experiments with allosamidin and chitooligosaccharides give insight into ligand binding properties and allow the evaluation of differential binding and design of species-selective chitinase inhibitors.

Evaluatie Tijdelijke wet Groningen

Het rapport evalueert de Tijdelijke wet Groningen (TwG). Het geeft belangrijke conclusies over de doelen van de TwG en de uitwerking van de wet in de praktijk

Specificity and affinity of natural product cyclopentapeptide inhibitors against A. fumigatus, human, and bacterial chitinases

Family 18 chitinases play key roles in organisms ranging from bacteria to man. There is a need for specific, potent inhibitors to probe the function of these chitinases in different organisms. Such molecules could also provide leads for the development of chemotherapeuticals with fungicidal, insecticidal, or anti-inflammatory potential. Recently, two natural product peptides, argifin and argadin, have been characterized, which structurally mimic chitinase-chitooligosaccharide interactions and inhibit a bacterial chitinase in the nM-mM range. Here, we show that these inhibitors also act on human and Aspergillus fumigatus chitinases. The structures of these enzymes in complex with argifin and argadin, together with mutagenesis, fluorescence, and enzymology, reveal that subtle changes in the binding site dramatically affect affinity and selectivity. The data show that it may be possible to develop specific chitinase inhibitors based on the argifin/argadin scaffold