Discovery and Characterization of a 5-Hydroxymethylfurfural Oxidase from Methylovorus sp. Strain MP688

In the search for useful and renewable chemical building blocks, 5-hydroxymethylfurfural (HMF) has emerged as a very promising candidate, as it can be prepared from sugars. HMF can be oxidized to 2,5-furandicarboxylic acid (FDCA), which is used as a substitute for petroleum-based terephthalate in polymer production. On the basis of a recently identified bacterial degradation pathway for HMF, candidate genes responsible for selective HMF oxidation have been identified. Heterologous expression of a protein from Methylovorus sp. strain MP688 in Escherichia coli and subsequent enzyme characterization showed that the respective gene indeed encodes an efficient HMF oxidase (HMFO). HMFO is a flavin adenine dinucleotide-containing oxidase and belongs to the glucose-methanol-choline-type flavoprotein oxidase family. Intriguingly, the activity of HMFO is not restricted to HMF, as it is active with a wide range of aromatic primary alcohols and aldehydes. The enzyme was shown to be relatively thermostable and active over a broad pH range. This makes HMFO a promising oxidative biocatalyst that can be used for the production of FDCA from HMF, a reaction involving both alcohol and aldehyde oxidations.

Factors that Determine the Extent of Business Process Standardization and the Subsequent Effect on Business Performance

Business process standardization is the activity of unifying different variants of a family of business processes. While the positive effects of business process standardization are well-described, it is often undesirable to fully unify different variants due to cultural, legal, or operational reasons. Consequently, a decision has to be made about the extent to which a family of business processes should be standardized. However, little is known about the factors that drive that decision. This paper fills that gap, by presenting factors that drive the extent to which business processes can be standardized, performance properties that are influenced by business process standardization, and relations between these concepts

A rule driven approach for developing adaptive service oriented business collaboration

Current composite web service development and management solutions, e.g. BPEL, do not cater for flexible and adaptive business collaborations due to their pre-defined and inflexible nature that precludes them accommodating business dynamics. In this paper we propose a rule driven approach for adaptive business collaboration development in which rules drive and govern the development process. We introduce the Business Collaboration Development Framework (BCDF), which provides enterprizes with the context to define their capabilities and business collaboration agreements. Subsequently, we explain how rules can drive and control the business collaboration development process to develop complete, correct and consistent business collaboration agreements that are conform the conditions under which parties wish to cooperate.12 page(s

Evidence of a sudden increase in α-chloralose poisoning in dogs and cats in the Netherlands between 2018 and 2021

BACKGROUND: After changes in European Union biocide legislation, the Dutch Poisons Information Center observed a strong increase in information requests concerning dogs and cats exposed to α-chloralose. To investigate whether α-chloralose-based rodenticides are safe for non-professional use, additional information regarding poisoning scenarios and clinical course was collected. METHODS: Veterinarians reporting α-chloralose exposure over a 2.5-year period were contacted by mail for follow-up information concerning exposure scenario, product formulation, clinical course and treatment, and outcome. In total, information was collected for 96 dogs and 41 cats. RESULTS: Fifty-three of 96 dogs and 17 of 19 cats known to have been exposed to α-chloralose-based rodenticides developed signs of central nervous system (CNS) depression or sensory-induced CNS excitation. Mortality in dogs and cats following exposure was 1% and 18%, respectively. An additional 22 cats presented with clinical signs suggestive of α-chloralose poisoning, with a mortality of 5%. LIMITATIONS: Exposure to α-chloralose was not confirmed by biochemical analyses. CONCLUSION: Dogs and especially cats were at risk of poisoning from α-chloralose. If criteria such as acute toxicity and risk of (secondary) poisoning are applied during the approval of α-chloralose-based rodenticides, similar to anticoagulant-based rodenticides, it can be concluded that α-chloralose is also not safe for non-professional use

Cardiac sodium channel inhibition by lamotrigine: in vitro characterization and clinical implications

Lamotrigine, approved for use as an antiseizure medication (ASM) as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors including mexiletine do not slow cardiac conduction as measured by the electrocardiogram (ECG), at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNaV 1.5 channel and voltage clamp electrophysiology to quantify the potency (IC50 ) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine) and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the Class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder

Natuurverkenning 2010-2040 : visies op de ontwikkeling van natuur en landschap

De Natuurverkenning verschijnt in een turbulente tijd waarin natuur en landschap sterk gepolitiseerd zijn. Met de verkenning wil het PBL een bijdrage leveren aan het structureren van het debat over de vernieuwing van het langetermijnbeleid en een impuls geven aan de politieke afwegingen. Nieuw is het gebruik van normatieve toekomstscenario’s als hulpmiddel om de achterliggende drijfveren voor natuurbeleid te verhelderen

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

Abstract Purpose There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a firstin-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

PURPOSE:There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. METHODS: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. RESULTS: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. CONCLUSIONS: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population