Cyclic Peptoid-Peptide Hybrids as Versatile Molecular Transporters

Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters

The Staudinger Ligation

While the Staudinger reaction has first been described a hundred years ago in 1919, the ligation reaction became one of the most important and efficient bioconjugation techniques in the 1990s and this century. It holds the crucial characteristics for bioorthogonal chemistry: biocompatibility, selectivity, and a rapid and high-yielding turnover for a wide variety of applications. In the past years, it has been used especially in chemical biology for peptide/protein synthesis, posttranslational modifications, and DNA labeling. Furthermore, it can be used for cell-surface engineering, development of microarrays, and drug delivery systems. However, it is also possible to use the reaction in synthetic chemistry for general formation of amide bonds. In this review, the three major types, traceless and nontraceless Staudinger Ligation as well as the Staudinger phosphite reaction, are described in detail. We will further illustrate each reaction mechanism and describe characteristic substrates, intermediates, and products. In addition, not only its advantages but also stereochemical aspects, scope, and limitations, in particular side reactions, are discussed. Finally, the method is compared to other bioorthogonal labeling methods

Final results from the EU project AVATAR: aerodynamic modelling of 10 MW wind turbines

This paper presents final results from the EU project AVATAR in which aerodynamic models are improved and validated for wind turbines on a scale of 10 MW and more. Special attention is paid to the improvement of low fidelity engineering (BEM based) models with higher fidelity (CFD) models but also with intermediate fidelity free vortex wake (FVW) models. The latter methods were found to be a good basis for improvement of induction modelling in engineering methods amongst others for the prediction of yawed cases, which in AVATAR was found to be one of the most challenging subjects to model. FVW methods also helped to improve the prediction of tip losses. Aero-elastic calculations with BEM based and FVW based models showed that fatigue loads for normal production cases were over predicted with approximately 15% or even more. It should then be realised that the outcome of BEM based models does not only depend on the choice of engineering add-ons (as is often assumed) but it is also heavily dependent on the way the induced velocities are solved. To this end an annulus and element approach are discussed which are assessed with the aid of FVW methods. For the prediction of fatigue loads the so-called element approach is recommended but the derived yaw models rely on an annulus approach which pleads for a generalised solution method for the induced velocities

Epidemiology and integrated control of Potato Late Blight in Europe

Phytophthora infestans, the causal agent of late blight, is a major threat to potato production in northwestern Europe. Before 1980, the worldwide population of P. infestans outside Mexico appeared to be asexual and to consist of a single clonal lineage of A1 mating type characterized by a single genotype. It is widely believed that new strains migrated into Europe in 1976 and that this led to subsequent population changes including the introduction of the A2 mating type. The population characteristics of recently collected isolates in NW Europe show a diverse population including both mating types, sexual reproduction and oospores, although differences are observed between regions. Although it is difficult to find direct evidence that new strains are more aggressive, there are several indications from experiments and field epidemics that the aggressiveness of P. infestans has increased in the past 20 years. The relative importance of the different primary inoculum sources and specific measures for reducing their role, such as covering dumps with plastic and preventing seed tubers from becoming infected, is described for the different regions. In NW Europe, varieties with greater resistance tend not to be grown on a large scale. From the grower’s perspective, the savings in fungicide input that can be achieved with these varieties are not compensated by the higher (perceived) risk of blight. Fungicides play a crucial role in the integrated control of late blight. The spray strategies in NW Europe and a table of the specific attributes of the most important fungicides in Europe are presented. The development and use of decision support systems (DSSs) in NW Europe are described. In The Netherlands, it is estimated that almost 40% of potato growers use recommendations based on commercially available DSS. In the Nordic countries, a new DSS concept with a fixed 7-day spray interval and a variable dose rate is being tested. In the UK, commercially available DSSs are used for c. 8% of the area. The validity of Smith Periods for the new population of P. infestans in the UK is currently being evaluated

Modelling Cyclic Walking in Femurs With Metastatic Lesions:Femur-Specific Accumulation of Plasticity

Introduction Clinical fracture risk assessment in metastatic bone disease is extremely difficult, but subject-specific finite element (FE) modelling may improve these assessments in the future [Derikx, 2015]. By coupling to musculoskeletal modelling, realistic loading conditions can be implemented in FE analysis. However, it is unknown whether such analyses require complex elastic-plastic material models, or whether a linear elastic calculation already provides a reasonable prediction of fracture. Moreover, plastic deformation may accumulate over time, which is ignored by linear elastic calculations. In this study we compared linear and non-linear fracture predictions under realistic loading conditions in two patients with metastatic bone disease. Methods Two patients (P1, P2) with lytic lesions were included. Patient-specific femoral geometry and bone density were retrieved from quantitative CT-scans; the latter was used for implementing element-specific material behaviour [Keyak, 2005]. Muscle forces and hip contact forces acting on the femur during walking were calculated using musculoskeletal modelling (one typical case, adapted from [Wesseling, 2014]), and subsequently normalized to the patient’s body weight. Muscle forces were applied to attachment points that were morphed onto the patient femurs. Hip contact forces were applied to a cup mimicking the acetabulum, via a control node in the hip joint centre. Two simulations were run for each patient: a linear elastic analysis simulating a single walk cycle and a non-linear elastic-plastic analysis simulating 10 subsequent walk cycles. The safety factor (SF; yield stress/Von Mises stress) and plasticity were studied as measures of femoral failure in the linear and non-linear simulations, respectively, and compared between patients. Results The volume of elements with SF<1 (Figure 1A) as well as the volume of elements that underwent plastic deformation (Figure 1B) was highest in the femur of P1. In P1 the volume of plastic deformation increased over the loading cycles and eventually exceeded the peak volume of elements with SF<1 in the linear analysis. In P2, the volume of plasticity more or less stabilized after two loading cycles, and eventually resembled the volume of elements with SF<1 in the linear analysis. Discussion These preliminary results suggest that accumulation of plasticity under cyclic loading is femur-specific. Due to the variable and local weakening of the bone strength by metastatic lesions, relatively small changes in magnitude or direction of loading may initiate local failure and catalyze progressive failure in subsequent loading cycles. Hence, in some cases a linear analysis is sufficient, while in others it is not. Non-linear material behaviour and cyclic loading conditions are therefore required to capture these phenomena

Latest results from the EU project AVATAR: aerodynamic modelling of 10 MW wind turbines

This paper presents the most recent results from the EU project AVATAR in which aerodynamic models are improved and validated for wind turbines on a scale of 10 MW and more. Measurements on a DU 00-W-212 airfoil are presented which have been taken in the pressurized DNW-HDG wind tunnel up to a Reynolds number of 15 Million. These measurements are compared with measurements in the LM wind tunnel for Reynolds numbers of 3 and 6 Million and with calculational results. In the analysis of results special attention is paid to high Reynolds numbers effects. CFD calculations on airfoil performance showed an unexpected large scatter which eventually was reduced by paying even more attention to grid independency and domain size in relation to grid topology. Moreover calculations are presented on flow devices (leading and trailing edge flaps and vortex generators). Finally results are shown between results from 3D rotor models where a comparison is made between results from vortex wake methods and BEM methods at yawed conditions

Analysis of factors relating to pet rabbits relinquished to two UK re-homing centres

Rabbits are a common companion animal in the UK and some reports suggest that large numbers are relinquished to re-homing centres each year. This study aimed to investigate the characteristics of rabbits relinquished to two UK re-homing centres and explore reasons given for relinquishment. The centres contributed data for all rabbits that entered their centre during 2013 (n=205). Most rabbits (59.5%) were relinquished by an owner. A similar number of males to females were relinquished and a larger number of rabbits were not neutered (72.4%) and adults (56%). Most rabbits were healthy on arrival (61.5%). The most common reasons for relinquishment were: too many rabbits / unplanned litters (30.3%) and housing problems (23.8%). Rabbit related reasons accounted for 12.2% of rabbits relinquished. Reasons for relinquishment were associated with one of the recorded rabbit characteristics. Further detailed studies are needed to explore the dynamics of pet rabbit ownership and factors that affect the breakdown of rabbit-owner relationships in the UK