Chemical Biology Tools To Investigate Malaria Parasites

Parasitic diseases like malaria tropica have been shaping human evolution and history since the beginning of mankind. After infection, the response of the human host ranges from asymptomatic to severe and may culminate in death. Therefore, proper examination of the parasite's biology is pivotal to deciphering unique molecular, biochemical and cell biological processes, which in turn ensure the identification of treatment strategies, such as potent drug targets and vaccine candidates. However, implementing molecular biology methods for genetic manipulation proves to be difficult for many parasite model organisms. The development of fast and straightforward applicable alternatives, for instance small-molecule probes from the field of chemical biology, is essential. In this review, we will recapitulate the highlights of previous molecular and chemical biology approaches that have already created insight and understanding of the malaria parasite Plasmodium falciparum. We discuss current developments from the field of chemical biology and explore how their application could advance research into this parasite in the future. We anticipate that the described approaches will help to close knowledge gaps in the biology of P. falciparum and we hope that researchers will be inspired to use these methods to gain knowledge – with the aim of ending this devastating disease.     

Twenty-Five Years of Homogeneous Catalysis for the Production of Bulk and Fine Chemicals: A Personal Account

A personal account is given of a selection of the research projects the author has been involved in over the past 25 years, aimed at developing production processes for fine chemicals and bulk chemicals using homogeneous catalysis. The focus in fine chemicals has been on asymmetric hydrogenation using monodentate phosphoramidites (MonoPhos), palladium-catalysed C–C bond formation (“homeopathic palladium”), copper-catalysed amination, nanocatalysis and combinations of enzymes and homogeneous catalysis. Rhodium-catalysed isomerising hydroformylation was developed for a new process for caprolactam based on butadiene and palladium-catalysed methoxycarbonylation was used in a new adipic acid process based on levulinic acid. The use of high throughput experimentation has been crucial in a large part of this research. Collaborations with universities, in particular with the University of Groningen has also played a major role.

     

Future publication success in science is better predicted by traditional measures than by the <Emphasis Type="Italic">h</Emphasis> index

Although the use of bibliometric indicators for evaluations in science is becoming more and more ubiquitous, little is known about how future publication success can be predicted from past publication success. Here, we investigated how the post-2000 publication success of 85 researchers in oncology could be predicted from their previous publication record. Our main findings are: (i) Rates of past achievement were better predictors than measures of cumulative achievement. (ii) A combination of authors’ past productivity and the past citation rate of their average paper was most successful in predicting future publication success (R ² ≈ 0.60). (iii) This combination of traditional bibliographic indicators clearly outperformed predictions based on the rate of the h index (R ² between 0.37 and 0.52). We discuss implications of our findings for views on creativity and for science evaluation.     

Effect of Lowering Asymmetric Dimethylarginine (ADMA) on Vascular Pathology in Atherosclerotic ApoE-Deficient Mice with Reduced Renal Mass

The purpose of the work was to study the impact of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1), on atherosclerosis in subtotally nephrectomized (SNX) ApoE-deficient mice. Male DDAH1 transgenic mice (TG, n = 39) and C57Bl/6J wild-type littermates (WT, n = 27) with or without the deletion of the ApoE gene underwent SNX at the age of eight weeks. Animals were sacrificed at 12 months of age, and blood chemistry, as well as the extent of atherosclerosis within the entire aorta were analyzed. Sham treated (no renal mass reduction) ApoE-competent DDAH1 transgenic and wild-type littermates (n = 11) served as a control group. Overexpression of DDAH1 was associated with significantly lower ADMA levels in all treatment groups. Surprisingly, SNX mice did not exhibit higher ADMA levels compared to sham treated control mice. Furthermore, the degree of atherosclerosis in ApoE-deficient mice with SNX was similar in mice with or without overexpression of DDAH1. Overexpression of the ADMA degrading enzyme, DDAH1, did not ameliorate atherosclerosis in ApoE-deficient SNX mice. Furthermore, SNX in mice had no impact on ADMA levels, suggesting a minor role of this molecule in chronic kidney disease (CKD) in this mouse model.     

The Flexible Rare Event Sampling Harness System (FRESHS)

We present the software package FRESHS (http://www.freshs.org) for parallel simulation of rare events using sampling techniques from the ‘splitting’ family of methods. Initially, Forward Flux Sampling (FFS) and Stochastic Process Rare Event Sampling (SPRES) have been implemented. These two methods together make rare event sampling available for both quasi-static and full non-equilibrium regimes. Our framework provides a plugin system for software implementing the underlying physics of the system of interest. At present, example plugins exist for our framework to steer the popular MD packages GROMACS, LAMMPS and ESPResSo, but due to the simple interface of our plugin system, it is also easy to attach other simulation software or self-written code. Use of our framework does not require recompilation of the simulation program. The modular structure allows the flexible implementation of further sampling methods or physics engines and creates a basis for objective comparison of different sampling algorithms.     

Surface ageing at drop scale

Surface ageing of a micro-drop populated by surfactants below the critical micellar concentration and subject to evaporation is considered, motivated by our interest in the transport of biomolecules in digital microfluidics. The classical approach based on diffusion–sorption processes is reviewed in order to address a finite-sized system of digital microfluidics. Short-time and long-time asymptotic approximations for a diffusion-limited regime, as well as full analytical expressions for adsorption- and evaporation-limited regimes, are constructed, which help to validate numerical calculations of full coupling between all these kinetics. The impact of the small drop size and the continuous lack of equilibrium induced by evaporation are described by introducing specific dimensionless numbers. By taking into account evaporative mass transfer in the mass balance, the boundary condition for surfactant transport to and from the interface is modified. Furthermore, the small size of the geometry suggests allowing a novel non-dimensionalisation for surface concentration, following from the mass balance of surfactant molecules in thermo-dynamic equilibrium. This order of magnitude quantifies the equilibrium surface concentration for small-sized geometries.