The impact of roughness elements on sediment fluxes in coastal dunes and dune valleys: solving the puzzle for Spanjaards Duin

In 2009 a new dune area called Spanjaards Duin was constructed in front of the Delfland Coast. Spanjaards Duin was created as a compensation measure for the expected increase in nitrogen deposition from the expansion of the Rotterdam harbour (Maasvlakte 2). The predefined compensation goal is to reach 6 ha of moist dune slack vegetation and 10 ha of dry grey dune in 2033. This is pursued by creating favourable abiotic conditions for natural vegetation establishment (van der Meulen et al., 2014). Sediment fluxes affect establishment and growth of vegetation and shape the dune landscape. Therefore, there is need to know how sediment fluxes behave in Spanjaards Duin

MyChEMBL: A Virtual Platform for Distributing Cheminformatics Tools and Open Data

MyChEMBL is an open virtual platform which provides a free, secure, standardised and easy to use chemoinformatics environment for bioactivity data mining, machine learning, application development, learning and teaching. The main technical features of myChEMBL along with its applications and future plans are discussed here.FWN – Publicaties zonder aanstelling Universiteit Leide

Data-driven methods to estimate the committor function in conceptual ocean models

In recent years, several climate subsystems have been identified that may undergo a relatively rapid transition compared to the changes in their forcing. Such transitions are rare events in general, and simulating long-enough trajectories in order to gather sufficient data to determine transition statistics would be too expensive. Conversely, rare events algorithms like TAMS (trajectory-adaptive multilevel sampling) encourage the transition while keeping track of the model statistics. However, this algorithm relies on a score function whose choice is crucial to ensure its efficiency. The optimal score function, called the committor function, is in practice very difficult to compute. In this paper, we compare different data-based methods (analog Markov chains, neural networks, reservoir computing, dynamical Galerkin approximation) to estimate the committor from trajectory data. We apply these methods on two models of the Atlantic Ocean circulation featuring very different dynamical behavior. We compare these methods in terms of two measures, evaluating how close the estimate is from the true committor and in terms of the computational time. We find that all methods are able to extract information from the data in order to provide a good estimate of the committor. Analog Markov Chains provide a very reliable estimate of the true committor in simple models but prove not so robust when applied to systems with a more complex phase space. Neural network methods clearly stand out by their relatively low testing time, and their training time scales more favorably with the complexity of the model than the other methods. In particular, feedforward neural networks consistently achieve the best performance when trained with enough data, making this method promising for committor estimation in sophisticated climate models.</p

Structure–Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family

The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified alpha-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the alpha-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs

Somatotopic map and inter- and intra-digit distance in Brodmann area 2 by pressure stimulation

The somatotopic representation of the tactile stimulation on the finger in the brain is an essential part of understanding the human somatosensory system as well as rehabilitation and other clinical therapies. Many studies have used vibrotactile stimulations and reported finger somatotopic representations in the Brodmann area 3 (BA 3). On the contrary, few studies investigated finger somatotopic representation using pressure stimulations. Therefore, the present study aimed to find a comprehensive somatotopic representation (somatotopic map and inter- and intra-digit distance) within BA 2 of humans that could describe tactile stimulations on different joints across the fingers by applying pressure stimulation to three joints-the first (p1), second (p2), and third (p3) joints-of four fingers (index, middle, ring, and little finger). Significant differences were observed in the inter-digit distance between the first joints (p1) of the index and little fingers, and between the third joints (p3) of the index and little fingers. In addition, a significant difference was observed in the intra-digit distance between p1 and p3 of the little finger. This study suggests that a somatotopic map and inter- and intra-digit distance could be found in BA 2 in response to pressure stimulation on finger joints.ope

Preclinical evaluation of EpCAM-binding designed ankyrin repeat proteins (DARPins) as targeting moieties for bimodal near-infrared fluorescence and photoacoustic imaging of cancer

PURPOSE Fluorescence-guided surgery (FGS) can play a key role in improving radical resection rates by assisting surgeons to gain adequate visualization of malignant tissue intraoperatively. Designed ankyrin repeat proteins (DARPins) possess optimal pharmacokinetic and other properties for in vivo imaging. This study aims to evaluate the preclinical potential of epithelial cell adhesion molecule (EpCAM)-binding DARPins as targeting moieties for near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging of cancer. METHODS EpCAM-binding DARPins Ac2, Ec4.1, and non-binding control DARPin Off7 were conjugated to IRDye 800CW and their binding efficacy was evaluated on EpCAM-positive HT-29 and EpCAM-negative COLO-320 human colon cancer cell lines. Thereafter, NIRF and PA imaging of all three conjugates were performed in HT-29_luc2 tumor-bearing mice. At 24 h post-injection, tumors and organs were resected and tracer biodistributions were analyzed. RESULTS Ac2-800CW and Ec4.1-800CW specifically bound to HT-29 cells, but not to COLO-320 cells. Next, 6 nmol and 24 h were established as the optimal in vivo dose and imaging time point for both DARPin tracers. At 24 h post-injection, mean tumor-to-background ratios of 2.60 ± 0.3 and 3.1 ± 0.3 were observed for Ac2-800CW and Ec4.1-800CW, respectively, allowing clear tumor delineation using the clinical Artemis NIRF imager. Biodistribution analyses in non-neoplastic tissue solely showed high fluorescence signal in the liver and kidney, which reflects the clearance of the DARPin tracers. CONCLUSION Our encouraging results show that EpCAM-binding DARPins are a promising class of targeting moieties for pan-carcinoma targeting, providing clear tumor delineation at 24 h post-injection. The work described provides the preclinical foundation for DARPin-based bimodal NIRF/PA imaging of cancer