De omslag tegen het licht gehouden : wegenheffing en de kostentoedeling daarvan vanaf 2009 onder de nieuwe Waterschapswet door Hoogheemraadschap Hollands Noorderkwartier

Het Hoogheemraadschap Hollands Noorderkwartier is één van de zes waterschappen in ons land met een wegbeheerstaak. Waterschappen die belast zijn met wegbeheer zien niet al hun gemaakte kosten vergoed door algemene overheidslichamen. De niet gedekte kosten moeten worden omgeslagen over de belangencategorieën door middel van een kostentoedelingsverordening. Om deze op te kunnen stellen is door Wageningen Universiteit in 1995 een kostentoedelingsmethodiek ontwikkeld, gebaseerd op het profijt dat de verschillende categorieën hebben bij de waterschapswegen. Vanwege een fusie van waterschappen en vanwege nieuwe Waterschapswetgeving heeft thans een bijstelling van de methode plaatsgevonden

Bosjes van Poot : onderzoek bezoekers en honden

De Bosjes van Poot is een duingebied dat sinds 1990 behoort tot Natuurmonument Westduinpark. Daarmee valt het onder de Natuurbeschermingswet en in 2008 wordt de aanwijzing tot Natura 2000 gebied verwacht. In opdracht van Dienst Stadsbeheer van Den Haag is nu een onderzoek opgezet en uitgevoerd om beter zicht te krijgen op een gewenst hondenbeleid. De vraagstelling is hoeveel honden er gebruik maken van het gebied en hoe dat over het gebied verdeeld i

Prevalence of baseline polymorphisms for potential resistance to NS5A inhibitors in drug-naive individuals infected with hepatitis C genotypes 1–4

Background: The non-structural 5A (NS5A) protein of HCV is a multifunctional phosphoprotein involved in regulation of viral replication and virion assembly. NS5A inhibitors targeting domain I of NS5A protein have demonstrated high potency and pan-genotypic antiviral activity, however they possess a low genetic barrier to resistance. At present, only genotype 1, the most prevalent HCV genotype has been studied in detail for resistant variants. Methods: Utilising a panel of genotypic-specific resistance assays, population sequencing was performed on plasma derived viral RNA isolated from 138 patients infected with HCV genotypes 1-4 and not treated with directly acting anti-viral agents (DAAs). Amino acid changes in HCV NS5A domain I at codon positions 28, 30, 31, 32 and 93, reported to confer reduced susceptibility to certain NS5A inhibitors were examined. Additionally, genotypic outcome based on NS5A sequences were compared with LiPA and Abbott® real time. Results: Amino acid substitutions associated with moderate to high level resistance to NS5A inhibitors were detected in 2/42 (4.76%) HCV-1a, 3/23 (13.04%) HCV-1b, 4/26 ( 15.38% ) HCV-2, 1/24 (4.17%) HCV-3 and 1/23 (4.35%) HCV-4 infected patients who had not been treated with NS5A inhibitors. Genotype prediction based on NS5A sequences were concordant with LiPA and/or Abbott® real-time for 97.10% of cases. Conclusion: Primary resistance mutations associated with resistance to first generation NS5A inhibitors such as Daclatasvir (DCV) were observed in all genotypes, albeit at low frequencies. An excellent correlation based on NS5A genotyping and LiPA or Abbott® real-time was achieved

Development and application of a data-driven reaction classification model : comparison of an electronic lab notebook and the medicinal chemistry literature

Reaction classification has often been considered an important task for many different applications, and has traditionally been accomplished using hand-coded rule-based approaches. However, the availability of large collections of reactions enables data-driven approaches to be developed. We present the development and validation of a 336-class machine learning-based classification model integrated within a Conformal Prediction (CP) framework in order to associate reaction class predictions with confidence estimations. We also propose a data-driven approach for 'dynamic' reaction fingerprinting to maximise the effectiveness of reaction encoding, as well as developing a novel reaction classification system that organises labels in four hierarchical levels (SHREC: Sheffield Hierarchical REaction Classification). We show that the performance of the CP augmented model can be improved by defining confidence thresholds to detect predictions that are less likely to be false. For example, the external validation of the model reports 95% of predictions as correct by filtering out less than 15% of the uncertain classifications. The application of the model is demonstrated by classifying two reaction datasets: one extracted from an industrial ELN and the other from the medicinal chemistry literature. We show how confidence estimations and class compositions across different levels of information can be used to gain immediate insights on the nature of reaction collections and hidden relationship between reaction classes

Enhancing reaction-based de novo design using a multi-label reaction class recommender

Reaction-based de novo design refers to the in-silico generation of novel chemical structures by combining reagents using structural transformations derived from known reactions. The driver for using reaction-based transformations is to increase the likelihood of the designed molecules being synthetically accessible. We have previously described a reaction-based de novo design method based on reaction vectors which are transformation rules that are encoded automatically from reaction databases. A limitation of reaction vectors is that they account for structural changes that occur at the core of a reaction only, and they do not consider the presence of competing functionalities that can compromise the reaction outcome. Here, we present the development of a Reaction Class Recommender to enhance the reaction vector framework. The recommender is intended to be used as a filter on the reaction vectors that are applied during de novo design to reduce the combinatorial explosion of in-silico molecules produced while limiting the generated structures to those which are most likely to be synthesisable. The recommender has been validated using an external data set extracted from the recent medicinal chemistry literature and in two simulated de novo design experiments. Results suggest that the use of the recommender drastically reduces the number of solutions explored by the algorithm while preserving the chance of finding relevant solutions and increasing the global synthetic accessibility of the designed molecules

Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients

Major depressive disorder (MDD) is a leading cause of disability worldwide and results tragically in the loss of almost one million lives in Western societies every year. This is due to poor understanding of the disease pathophysiology and lack of empirical medical tests for accurate diagnosis or for guiding antidepressant treatment strategies. Here, we have used shotgun proteomics in the analysis of post-mortem dorsolateral prefrontal cortex brain tissue from 24 MDD patients and 12 matched controls. Brain proteomes were pre-fractionated by gel electrophoresis and further analyzed by shotgun data-independent label-free liquid chromatography-mass spectrometry. This led to identification of distinct proteome fingerprints between MDD and control subjects. Some of these differences were validated by Western blot or selected reaction monitoring mass spectrometry. This included proteins associated with energy metabolism and synaptic function and we also found changes in the histidine triad nucleotide-binding protein 1 (HINT1), which has been implicated recently in regulation of mood and behavior. We also found differential proteome profiles in MDD with (n=11) and without (n=12) psychosis. Interestingly, the psychosis fingerprint showed a marked overlap to changes seen in the brain proteome of schizophrenia patients. These findings suggest that it may be possible to contribute to the disease understanding by distinguishing different subtypes of MDD based on distinct brain proteomic profiles

Antimicrobial mouthwashes (gargling) and nasal sprays administered to patients with suspected or confirmed COVID‐19 infection to improve patient outcomes and to protect healthcare workers treating them (Review)

A C K N O W L E D G E M E N T S: We would like to thank the peer reviewers, Professor Jeremy Bagg, Dr Karolin Hijazi, Professor Carl Philpott and Professor Claire Hopkins, fortheirinsightful comments, which helped us to improve these reviews. Thanks also to Professor Peter Tugwell, Senior Editor Cochrane MOSS Network, for acting as sign-oF editor for these projects. We are also grateful to Doug Salzwedel from the Cochrane Hypertension Group for providing search peer review comments for the draK search strategy. Professor Schilder's time for this project was supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre, London, UK. This project was supported by the National Institute for Health Research, via Cochrane Infrastructure, Cochrane Programme Grant or Cochrane Incentive funding to Cochrane ENT and Cochrane Oral Health. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Interactive effects between paylean™ (Ractopamine HCl) and dietary lysine on finishing pig growth performance, carcass characteristics and tissue accretion

A total of 432 pigs were used to evaluate the effects of Paylean and dietary lysine on finishing pig growth performance, carcass characteristics and tissue accretion. The 12 dietary treatments included Paylean (0, 4.5, and 9.0 g/ton) and 4 levels of lysine. For pigs fed no Paylean, lysine levels were 0.60, 0.80, 1.00, and 1.20%. For pigs fed 4.5 or 9.0 g/ton of Paylean, lysine levels were 0.80, 1.00, 1.20, and 1.40%. The results indicate that pigs fed Paylean need at least 1.0% dietary lysine to optimize growth, carcass parameters, and tissue accretion

RENATE : a pseudo-retrosynthetic tool for synthetically accessible de novo design

Reaction-based de novo design refers to the generation of synthetically accessible molecules using transformation rules extracted from known reactions in the literature. In this context, we have previously described the extraction of reaction vectors from a reactions database and their coupling with a structure generation algorithm for the generation of novel molecules from a starting material. An issue when designing molecules from a starting material is the combinatorial explosion of possible product molecules that can be generated, especially for multistep syntheses. Here, we present the development of RENATE, a reaction-based de novo design tool, which is based on a pseudo-retrosynthetic fragmentation of a reference ligand and an inside-out approach to de novo design. The reference ligand is fragmented; each fragment is used to search for similar fragments as building blocks; the building blocks are combined into products using reaction vectors; and a synthetic route is suggested for each product molecule. The RENATE methodology is presented followed by a retrospective validation to recreate a set of approved drugs. Results show that RENATE can generate very similar or even identical structures to the corresponding input drugs, hence validating the fragmentation, search, and design heuristics implemented in the tool

Evidence for a subtractive component in motion adaptation

Adaptation to a moving stimulus changes the perception of a stationary grating and also reduces contrast sensitivity to the adaptor. We determined whether the first effect could be predicted from the second. The contrast discrimination (T vs C) function for a drifting 7.5 Hz grating test stimulus was determined when observers were adapted to a low contrast (0.075) grating of the same spatial and temporal frequency, moving in either the same or the opposite direction as the test. The effect of an adaptor moving in the same direction was to move the T vs C function upwards and to the right, in a manner consistent with an increase in divisive inhibition. We also measured the effect of adaptation on the motion-null point for a counterphasing grating containing two components, one moving in the same direction as the adaptor and the other in the opposite direction. Adaptation increased the amount of contrast of the adapted component required to achieve the motion-null point. However, this shift could not be predicted from the effects of adaptation on contrast sensitivity. In particular, the balance point was shifted in gratings of high contrast where there was no effect of adaptation on contrast discrimination. We suggest that adaptation has a subtractive (recalibration) effect in addition to its effects on the contrast transduction function, and that this subtractive effect may explain the movement after-effect seen with stationary tests