968 research outputs found
Naschrift: Nederlandse ziekenhuizen toch echt te groot
No full textPomp en Heida plaatsen een aantal vraagtekens bij ons artikel 'Nederlandse ziekenhuizen te groot voor verdere schaalvoordelen'. In deze reactie laten wij zien dat de kritiek een aantal onjuistheden, denkfouten en drogredenen bevat.Economics of Technology and Innovatio
Stuytinghe van een Tastelijcke Loghen : al heymelyck gesonden uyt Vranckrijck tot nadeel van den E. Hooch-gheleerden ende Voortreffelijcken Mr. Hvgo De Groot. Door een simpel verhael vande naeckte vvaerheydt, by syne E. ghestelt, ende in't Latijn en Fransch uytghegheven. Nu verduytscht Ten dienste ende gherijf der Nederlanders
No full textKnuttel, W.P.C. Catalogus van de pamfletten-verzameling berustende in de Koninklijke Bibliotheek, 3255Tiele: "... De Heer van Langerack, ambassadeur in Frankrijk, had namelijk aan de Staten valsche berichten van de Groot doen toekomen, die hij later vergeefs moeite gedaan had te supprimeren. Vergelijk K. Brandt. leven van de Groot, 271 v.".BL: "Consisting of the letter by de Groot to the States General of 30 Mar. 1621 and editorial matter naming Baron Gideon van den Boetzelaer, Heer van Langerak, as author of the calumnies".Vorlageform des Erscheinungsvermerks: Ghedruckt in't Iaer ons Heeren 1621.In FrakturKnuttel 3255Tiele, P. A. Bibliotheek van Nederlandsche pamfletten 1,1,1882STCN 861566769Ter Meulen-Diermanse 87
Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations
No full textBoeckmann RA, de Groot BL, Kakorin S, Neumann E, Grubmueller H. Kinetics, statistics, and energetics of lipid membrane electroporation studied by molecular dynamics simulations. BIOPHYSICAL JOURNAL. 2008;95(4):1837-1850.Membrane electroporation is the method to directly transfer bioactive substances such as drugs and genes into living cells, as well as preceding electrofusion. Although much information on the microscopic mechanism has been obtained both from experiment and simulation, the existence and nature of possible intermediates is still unclear. To elucidate intermediates of electropore formation by direct comparison with measured prepore formation kinetics, we have carried out 49 atomistic electroporation simulations on a palmitoyl-oleoyl-phosphatidylcholine bilayer for electric field strengths between 0.04 and 0.7 V/nm. A statistical theory is developed to facilitate direct comparison of experimental (macroscopic) prepore formation kinetics with the (single event) preporation times derived from the simulations, which also allows us to extract an effective number of lipids involved in each pore formation event. A linear dependency of the activation energy for prepore formation on the applied field is seen, with quantitative agreement between experiment and simulation. The distribution of preporation times suggests a four-state pore formation model. The model involves a first intermediate characterized by a differential tilt of the polar lipid headgroups on both leaflets, and a second intermediate (prepore), where a polar chain across the bilayer is formed by 3-4 lipid headgroups and several water molecules, thereby providing a microscopic explanation for the polarizable volume derived previously from the measured kinetics. An average pore radius of 0.47 +/- 0.15 nm is seen, in favorable agreement with conductance measurements and electrooptical experiments of lipid vesicles
Mean or green? Values, morality and environmental significant behavior.
No full textIn most cases, pro-environmental behavior does not maximize individual interests, but mainly benefits other people or the environment. We propose that although acting on the basis of egoistic considerations may result in pro-environmental behavior, altruistic and biospheric considerations provide the most stable basis for pro-environmental behavior. We present two strategies to promote stable pro-environmental behavior. The first way is increasing the saliency of altruistic and biospheric values in specific situations, thereby reducing the relative strength of egoistic values. The second way is making the often “anti-environmental” egoistic values compatible with “pro-environmental” altruistic and biospheric values. We explain these options and translate it to possible interventions, policy implications, and follow-up research to promote “green” behavior
Effect of two activators on the gating of a K2P channel
No full texthttp://dx.doi.org/10.13039/501100004189 Max Planck Societ
Dynamic Modelling Reveals ‘Hotspots’ on the Pathway to Enzyme-Substrate Complex Formation
No full textDihydrodipicolinate synthase (DHDPS) catalyzes the first committed step in the diaminopimelate pathway of bacteria, yielding amino acids required for cell wall and protein biosyntheses. The essentiality of the enzyme to bacteria, coupled with its absence in humans, validates DHDPS as an antibacterial drug target. Conventional drug design efforts have thus far been unsuccessful in identifying potent DHDPS inhibitors. Here, we make use of contemporary molecular dynamics simulation and Markov state models to explore the interactions between DHDPS from the human pathogen Staphylococcus aureus and its cognate substrate, pyruvate. Our simulations recover the crystallographic DHDPS-pyruvate complex without a priori knowledge of the final bound structure. The highly conserved residue Arg140 was found to have a pivotal role in coordinating the entry of pyruvate into the active site from bulk solvent, consistent with previous kinetic reports, indicating an indirect role for the residue in DHDPS catalysis. A metastable binding intermediate characterized by multiple points of intermolecular interaction between pyruvate and key DHDPS residue Arg140 was found to be a highly conserved feature of the binding trajectory when comparing alternative binding pathways. By means of umbrella sampling we show that these binding intermediates are thermodynamically metastable, consistent with both the available experimental data and the substrate binding model presented in this study. Our results provide insight into an important enzyme-substrate interaction in atomistic detail that offers the potential to be exploited for the discovery of more effective DHDPS inhibitors and, in a broader sense, dynamic protein-drug interactions
Lipid bilayer composition influences the activity of the antimicrobial peptide dermcidin channel.
No full textAntimicrobial peptides (AMPs) carry great potential as new antibiotics against "superbugs." Dermcidin (DCD), a broad-spectrum AMP in human sweat, has been recently crystallized in its oligomeric state and showed channel-like properties. In this work, we performed multiscale molecular dynamics simulations to study how the membrane composition influences the behavior of a transmembrane pore formed by the DCD oligomer in the hope of revealing the origin of the membrane selectivity of this AMP toward bacteria. Our results indicate that bilayers composed of various lipids (DMPC, DPPC, and DSPC) with different thicknesses result in different orientations of the DCD oligomer when embedded in lipid bilayers. The thicker the bilayer, the less tilted the channel. Cholesterol makes the bilayers more rigid and thicker, which also affects the orientation of the channel. Furthermore, we observed that the predicted conductance of the channel from computational electrophysiology simulations is related to its orientation in the lipid bilayer: the larger the tilt, the larger the conductance. Our results indicate that the membrane composition has a significant influence on the activity of the DCD channel, with thicker, cholesterol-rich membranes showing lower conductance than that of thinner membranes
Biomolecular simulations at the exascale: From drug design to organelles and beyond.
No full textThe rapid advancement in computational power available for research offers to bring not only quantitative improvements, but also qualitative changes in the field of biomolecular simulation. Here, we review the state of biomolecular dynamics simulations at the threshold to exascale resources becoming available. Both developments in parallel and distributed computing will be discussed, providing a perspective on the state of the art of both. A main focus will be on obtaining binding and conformational free energies, with an outlook to macromolecular complexes and (sub)cellular assemblies
Nederlandse ziekenhuizen te groot voor verdere schaalvoordelen
No full textDoor fusies zijn Nederlandse ziekenhuizen in de laatste decennia steeds groter geworden. Uit een meta-analyse van internationale studies blijkt dat de zorgkosten juist het laagst zijn in ziekenhuizen die kleiner zijn dan de meeste Nederlandse ziekenhuizen. Het is daarom onwaarschijnlijk dat verdere schaalvergroting de zorgkosten zal drukken
Het groot Mvnster
No full textKnuttel, W.P.C. Catalogus van de pamfletten-verzameling berustende in de Koninklijke Bibliotheek, 5327Knuttel: "Against France and other 'monstruous' (catholic) states". - BL: "On the peace negociations at Munster".Tiele: "Het Munstersche? wapen op de titel".Vorlageform des Erscheinungsvermerk: Gedruct in't Iaer ons Heeren, Anno 1646.Knuttel 5327Tiele, P. A. Bibliotheek van Nederlandsche pamfletten 1,1,3074STCN 86175350
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