Leiden University Scholary Publications
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New introductions to the same conclusions: a textual analysis of health inequalities in Dutch policy
No full textThe politics and administration of institutional chang
Synthesis of a set of staphylococcus aureus capsular polysaccharide type 1 oligosaccharides carrying taurine esters
No full textStaphylococcus aureus is a Gram-positive bacterium that is responsible for severe nosocomial infections. The protective capsular polysaccharides (CPs), which are key elements of the cell wall, have been proposed as promising candidate antigens. Several CP types have been identified including CP1, CP5, and CP8, and serotype 1 has been associated with increased resistance to phagocytosis and virulence. Here, the synthesis of a set of S. aureus CP 1 (strain M and D) trisaccharides, composed of an alpha-N-acetyl d-fucosamine and two alpha-N-acetyl d-galactosaminuronic acid residues, carrying taurine esters together with a nontaurinated hexasaccharide, is reported. To be able to tune the taurine substitution pattern, an orthogonal C-6-OH protecting group strategy for the galactosamine building blocks was developed, in conjunction with a postglycosylation oxidation protocol to site selectively introduce the taurine amide substitutions. The stereoselectivity in the glycosylations was secured using a silylene-protected 2-azido galactose synthon.Bio-organic Synthesi
Biomimetic total synthesis and paired omics identify an intermolecular Diels-Alder reaction as the key step in lugdunomycin biosynthesis
No full textMicrobial natural products are the basis of the majority of clinical drugs, where the discovery of truly novel structural scaffolds to fill the discovery pipelines is a prerequisite. Lugdunomycin is a highly rearranged angucycline polyketide produced by Streptomyces sp. QL37, with an enigmatic biosynthetic pathway. Here we show that lugdunomycin is formed by a rare intermolecular Diels-Alder reaction, with elmonin as a masked diene and iso-maleimycin as a dienophile. Genomics, mutational analysis, and heterologous expression revealed that the biosynthesis of the substrates is encoded by distinct biosynthetic gene clusters (BGCs), whereby elmonin is specified by an angucycline BGC, while the biosynthesis of iso-maleimycin is encoded by a BGC for a β-lactone-like compound. Biomimetic total synthesis of lugdunomycin showed that the Diels-Alder reaction leads to the production of a diastereomer of lugdunomycin as the main product in vitro. The diastereomeric ratio of the in vitro Diels-Alder reaction shifted toward lugdunomycin in the presence of proteinaceous material, suggesting that the in vivo Diels-Alder reaction is templated. Alphafold modeling and experimental data suggest that GarL could potentially function as a Diels-Alder template in lugdunomycin biosynthesis. The requirement of distinct biosynthetic pathways and complex chemical reactions indicates the challenges we face in discovering new chemical space.Microbial Biotechnolog
Developing a multivariable prediction model to support personalized selection among five major empirically-supported treatments for adult depression: study protocol of a systematic review and individual participant data network meta-analysis
No full textMultivariate analysis of psychological dat
What matters to people when we sanction states?: A conjoint experiment
No full textSecurity and Global Affair
Measuring prison climate across contexts: lessons from administering the Prison Climate Questionnaire in the USA
No full textCriminal Justice: Maatschappelijk effectieve strafrechtspleging 2023-202
Euclid preparation: LXII. Simulations and non-linearities beyond Lambda cold dark matter. 1. Numerical methods and validation
No full textTheoretical Physic
Semantic role extraction in law texts: a comparative analysis of language models for legal information extraction
No full textNorms are essential in our society: they dictate how individuals should behave and interact within a community. They can be written down in laws or other written sources. Interpretations often differ; this is where formalisations offer a solution. They express an interpretation of a source of norms in a transparent manner. However, creating these interpretations is labour intensive. Natural language processing techniques can support this process. Previous work showed the potential of transformer-based models for Dutch law texts. In this paper, we (1) introduce a dataset of 2335 English sentences annotated with legal semantic roles conform the Flint framework; (2) fine-tune a collection of language models on this dataset, and (3) query two non-fine-tuned generative large language models (LLMs). This allows us to compare performance of fine-tuned domain-specific, task-specific, and general language models with non-fine-tuned generative LLMs. The results show that models fine-tuned on our dataset have the best performance (accuracy around 0.88). Furthermore, domain-specific models perform better than general models, indicating that domain knowledge is of added value for this task. Finally, different methods of querying LLMs perform unsatisfactorily, with maximum accuracy scores around 0.6. This indicates that for specific tasks, such as this adaptation of semantic role labelling, the process of annotating data and fine-tuning a smaller language model is preferred over querying a generative LLM, especially when domain-specific models are available.Descriptive and Comparative Linguistic
A historical perspective on the development of antisense oligonucleotide treatments for Duchenne muscular dystrophy and spinal muscular atrophy
No full textSplice modulating antisense oligonucleotides (ASOs) have been approved for the treatment of spinal muscular atrophy (nusinersen) and Duchenne muscular dystrophy (eteplirsen) since 2016. Nusinersen obtained full approval based on convincing functional evidence in treated patients. The treatment is currently approved in over 40 countries. By contrast, eteplirsen received accelerated approval and functional evidence from clinical trials that treatment slows down disease progression is still lacking. Approval and access is restricted to the USA and several countries in the Middle-East. In this historical perspective we look back to the development paths of these two ASOs focusing on the differences between the approaches, the target tissues and the diseases. Based on this we propose learnings for future development of ASOs for progressive neuromuscular diseases.Functional Genomics of Muscle, Nerve and Brain Disorder