Merck Serono (Switzerland)

Mass spectrometry (MS)-based top–down proteomics (TDP) has emerged as a powerful tool for characterizing proteoforms to advance both fundamental and translational research. TDP requires high-efficiency liquid-phase separation, high-resolution MS, and tandem MS. Capillary zone electrophoresis (CZE)-MS has been proposed as a promising analytical technique for protein analysis decades ago because of its unique and valuable features, including high separation efficiency and high detection sensitivity. However, CZE-MS has not been widely adopted by the proteomics community, mainly due to concerns with its robustness and reproducibility. Here, we hypothesized that CZE-MS is sufficiently robust and reproducible for broad adoption due to the continued efforts of the community over the last three decades. In this work, for the first time, research teams from around the world validated the robustness, repeatability, and reproducibility of CZE-MS for TDP in both simple and complex model proteoform mixtures employing a full spectrum of commercially available capillary electrophoresis (CE)-MS interfaces, instrumentation, and compared CZE-MS performance with state-of-the-art liquid chromatography (LC)-MS methods. This study offers the research community an informative resource of ready-to-use experimental CE-MS techniques and a better understanding of the CZE-MS approach and its potential in TDP, accelerating the broad adoption of CZE-MS in proteoform research.

Abstract This chapter summarizes the clinical development of praziquantel (PZQ) and its active enantiomer (R)-PZQ focusing on the clinical studies that were performed to support their registration for the treatment and/or prophylaxis of infections due to different Schistosoma species. It begins with a general description of the three different clinical trial phases (I, II, and III) is given. Thereafter, the phase I and the phase II/III trials done for registering PZQ for patients suffering from infections with Schistosoma mansoni, S. haematobium, and S. japonicum in the 1980s are summarized. This is followed by a summary of the more recent trials performed for registering the child-friendly (R)-PZQ dispersible tablet formulation consisting of a phase I trial in healthy volunteers followed by a phase II and a phase III trials in infected children from 3 months to 6 years of age.

<title>Abstract</title> Schistosomiasis remains a major global health burden, with praziquantel as the only available treatment despite limitations such as reduced efficacy against juvenile stages. Aryl hydantoins such as Ro 13-3978 (AR02) and its derivative AR102, exhibit potent in vivo activity against all major human schistosome species, yet lack direct in vitro efficacy, suggesting a host-directed mechanism. Here, we identify neutrophils as critical mediators of aryl hydantoin activity. In a murine model of Schistosoma mansoni infection, neutrophil depletion or enzymatic degradation of extracellular DNA significantly impaired drug efficacy. Using human neutrophil co-cultures, we show that schistosomes suppress extracellular trap formation (NETosis), but aryl hydantoins restore this response without directly inducing NETs. Proteomics revealed compound-dependent modulation of neutrophil activation pathways, including chromatin remodeling and degranulation, specifically in the presence of parasite-derived products. Compound effects were limited to PMA-induced NETosis, implicating a pathway downstream of ROS production. While the precise molecular target remains elusive, our findings provide key mechanistic insight into a unique host-directed anthelmintic strategy, highlighting a neutrophil-dependent mode of action that restores NETosis suppressed by schistosomes -offering a promising pathway for immunomodulatory anti-parasitic therapies.

A natural hazard event that highly impacted a society might trigger a wave of post-disaster research analysis, which looks into the cause of the disaster, the types of impact, or any lessons learned to prevent similar events in the future. In short, post-disaster research contains valuable knowledge that should be utilized in disaster risk management. However, in the past 70 years, the scientific community published around 600,000 articles on hydro-hazards, such as floods, droughts, and landslides. Finding articles that describe specific disaster events and synthesizing their knowledge is not humanly possible anymore due to near exponentially increasing numbers of publications. However, recent advancements in large language models allow the analysis and extraction of described disaster events in the scientific literature.Here we make use of the Wealth over Woe scientific abstract dataset (Stein et al. 2024), with abstracts that were automatically annotated for hydro-hazards and geolocation.&amp;#160; It allows us to track publication trends and to identify disaster events that triggered a wave of new research. We additionally make use of the large language model Llama 70B to extract specific hazard events mentioned in each abstract (e.g. 2003 summer drought in Europe, Pakistan flood in 2010, 2002 Elbe flood, etc.) as well as other described details surrounding the event.While we know that hydro-hazard research is biased against low-income countries, exceptional disaster events can shift research priorities for several years. The additional funding can support valuable local post-disaster research. The named event recognition can therefore help us answer questions such as: What kind of hydro-hazards are studied in detail and where? What are the key research foci for post-disaster analysis? And are there regional differences to these answers?

To recover normal functions, remyelination in multiple sclerosis is crucial. Although endogenous remyelination occurs, it is often insufficient, and finding molecules promoting repair of demyelinated lesions is needed. To compare the remyelination potential of evobrutinib, an inhibitor of Bruton's tyrosine kinase and clemastine, an antagonist of M1 muscarinic acetylcholine receptor. Remyelination was investigated in lysolecithin demyelinated organotypic mouse cerebellar slices and a transgenic Xenopus model of inducible-demyelination. Evobrutinib (100 nM) and clemastine (200 nM) potentiated remyelination of mouse cerebellar slices by a factor of 2.9 and 1.76, respectively. In conditionally demyelinated Xenopus, evobrutinib and clemastine increased remyelination by a factor of 1.61 and 1.92, respectively. Evobrutinib targets Bruton's tyrosine kinase expressed by microglia, and we showed that the increase in number of myeloid cells following demyelination is due to an extravasation from nearby vessels of macrophages migrating toward the optic nerve. In contrast, clemastine is expected to antagonize muscarinic receptor 1 expressing cells of the oligodendroglial lineage. We investigated a possible synergistic effect on remyelination by adding simultaneously both molecules. In both experimental models tested no significative improvement on remyelination of co-treatment with evobrutinib plus clemastine was observed. While evobrutinib increased 1.59 fold the number of microglia/macrophages, in the presence of clemastine the number of innate immune cells was decreased by 0.39 fold, therefore counteracting the beneficial effect of microglia/macrophages on remyelination.