Publications

Developing automated platforms is essential for accelerating the preparation of bioactive compound libraries. After a decade of biopolymer synthesis, it is clear that automating these processes was pivotal to the development of biochemistry and chemical biology for advancing medicinal chemistry and for providing new diagnoses and therapeutic tools. Synthesis of glycans and glycoconjugates is far more complicated than the other biopolymer families. Automating glycan synthesis has been a long and hard journey which is still ongoing. This chapter focuses on the development of a commercial platform, Glyconeer™, aimed to automate the synthesis of glycans. The design and process leading to the establishment of the current setup are described. The unique considerations required from a system that is suitable for glycan synthesis are the focus of the chapter. We explain how the selected setup architecture and its unique features comply with the unusual demands of automated solid phase synthesis of glycans. We will present the common modules, building blocks, and chemistries used by the synthesizer. Preparation, handling, and running of both software and hardware are presented from the user point of view. A critical view of the limitations and advantages of the system is aimed to provide a roadmap for future improvement.

Abstract Multi phosphorylated peptides are key tools in understanding the biological roles of protein phosphorylation patterns. In this work, we focused on multi phosphorylated peptides with over four, clustered, phosphorylation sites that are termed herein heavily phosphorylated peptides (HPPs). The synthesis of heavily phosphorylated peptides is extremely difficult and requires the use of a wide temperature range. Standard peptide synthesizers are incapable of both cooling and heating, which impedes the automated synthesis of those peptides. Herein, we used the oligosaccharide synthesizer Glyconeer 2.1 to develop a protocol for the automated synthesis of heavily phosphorylated peptides. The Glyconeer 2.1 is able to both cool and heat, which enabled the development of highly controlled coupling and deprotection conditions that were used for the automated synthesis of four different heavily phosphorylated peptides with five or more, clustered, phosphorylation sites. Our approach paves the way for an easy automated synthesis of a variety of heavily phosphorylated peptides.

The chapter provides an overview of the field of biosecurity mostly as it developed in the US. It begins by providing essential insights about historical and political developments in the biosecurity arena. It shows that biosecurity has origins as early as World War II, when the fighting parties were developing both biological weapons and countermeasures. Since then and to this day, the biosecurity apparatus has evolved to face various kinds of threats including accidental, intentional and unintentional release of pathogens – each deserving appropriate action. The chapter then directs its attention to the most recent development, namely the risk that well-intended life sciences research might be abused to cause harm – i.e. dual-use research of concern. To illustrate the biosecurity risks of dual-use research, the chapter uses the H5N1 controversy as a case study. Through describing the H5N1 case, the chapter delineates the biosecurity risks it generated and the various ways in which US policy has evolved to address them. It demonstrates that the US government as well as international bodies have been moving away from the notion that scientists should police themselves with regard to dual-use research towards an understanding that specific regulations are needed in order to protect national security and public health.

Despite widespread concern over the alleged rise of conspiracy theories, scholars continue to disagree whether it is possible to distinguish specific kinds of conspiracist accounts that can justifiably be denounced as objectionable. In this article, we review scholarship from multiple disciplines to develop a composite definition of “conspiracy theories proper” (CTP) that violate fundamental norms of democratic discourse. Besides referring to grand conspiracies to account for social phenomena, we argue, such conspiracy theories: (a) assume conspirators’ pervasive control over events and information, (b) construct dissent as a Manichean binary, and (c) employ an elusive, dogmatic epistemology. We discuss the operational potential and limitations of our definition using news user talkbacks on the U.S., British and German online editions of Russia Today (RT), a popular platform among proponents of out-of-mainstream political views. Identifying key operational challenges in the classification of natural discourse, we sketch avenues toward a more rigorous study of contentious political talk.

Specialisation and plasticity are important for many forms of collective behaviour, but the interplay between these factors is little understood. In insect societies, workers are often developmentally primed to specialise in different tasks, sometimes with morphological or physiological adaptations, facilitating a division of labour. Workers may also plastically switch between tasks or vary their effort. The degree to which developmentally primed specialisation limits plasticity is not clear and has not been systematically tested in ecologically relevant contexts. We addressed this question in 20 free-foraging bumble bee (Bombus terrestris) colonies by continually manipulating colonies to contain either a typically diverse, or a reduced (“homogeneous”), worker body size distribution while keeping the same mean body size, over two trials. Pooling both trials, diverse colonies produced a larger comb mass, an index of colony performance. The link between body size and task was further corroborated by the finding that foragers were larger than nurses even in homogeneous colonies with a very narrow body size range. However, the overall effect of size diversity stemmed mostly from one trial. In the other trial, homogeneous and diverse colonies showed comparable performance. By comparing behavioural profiles based on several thousand observations of individuals, we found evidence that workers in homogeneous colonies in this trial rescued colony performance by plastically increasing behavioural specialisation and/or individual effort, compared to same-sized individuals in diverse colonies. Our results are consistent with a benefit to colonies of large and small specialists under certain conditions, but also suggest that plasticity or effort can compensate for reduced (size-related) specialisation. Thus, we suggest that an intricate interplay between specialisation and plasticity is functionally adaptive in bumble bee colonies.

Ultraconfined block copolymer films present non-bulk structures that are highly sensitive to film thickness and are strongly influenced by the wetting properties of the substrate. Here we describe the self-assembly of bottlebrush block copolymers with varying side-chain lengths on different types of substrates. Our results show a pronounced influence of the nature of the substrate on the self-assembled morphology and the surface patterns that evolve during solvent-vapor annealing. In particular, we observe by experiments and simulations a transient, substrate-driven morphology of cylinder-like structures obtained in films of doubly symmetric (i.e., backbone and side-chains) bottlebrush block copolymer despite the general tendency of these polymers to form lamellar structures. The insights gained from this study highlight the ability to use the substrate chemistry for inducing the formation of unique morphologies in bottlebrush block copolymer films.

Vesicles enriched in certain negatively charged lipids, such as phosphatidylserine and PIP2, are known to undergo fusion in the presence of calcium ions without assistance from protein assemblies. Other lipids do not exhibit this propensity, even if they are negatively charged. Using our recently developed methodology, we extract elastic properties of a representative set of lipids. This allows us to trace the origin of lipid-calcium selectivity in membrane fusion to the formation of lipid clusters with long-range correlations that induce negative curvature on the membrane surface. Furthermore, the clusters generate lateral tension in the headgroup region at the membrane surface, concomitantly also stabilizing negative Gaussian curvature. Finally, calcium binding also reduces the orientational polarization of water around the membrane head groups, potentially reducing the hydration force acting between membranes. Binding calcium only weakly increases membrane bending rigidity and tilt moduli, in agreement with experiments. We show how the combined effects of calcium binding to membranes lower the barriers along the fusion pathway that lead to the formation of the fusion stalk as well as the fusion pore.

A formal write-up of the simple proof (1995) of the existence of calibrated forecasts by the minimax theorem, which moreover shows that N^3 periods suffice to guarantee a 1/N calibration error.