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Structural Mass Spectrometry Resolves the Conformational Dynamics of Semaglutide Oligomerization
Item type: Journal Article
Huang S.; Zhou Y.; Lui T.y.; et al. (2026)
Recent studies showed that several widely used glucagon-like peptide-1 receptor agonists (GLP-1RAs) can self-assemble into dynamic oligomeric species and ultimately less-regular, non-amyloid aggregates. While mature aggregates can be characterized by high-resolution microscopy methods, probing the conformational dynamics of early-stage oligomeric species remains challenging, which limits our understanding of how the misfolding and aggregation propensity of GLP-1RAs is modulated by physiologically relevant conditions such as protein concentration or the presence of metal ions. In this work, multiple structural mass spectrometry (MS) methods were used in combination to resolve the earliest molecular changes that lead to semaglutide oligomerization. These structural MS methods together reveal important information such as the heterogeneity and stoichiometry of oligomers, their structural/thermal stability, protein conformational changes, the molecular interface for self-assembly, relative monomer orientation in oligomers, and aggregation pathway of the resulting oligomeric species, both with and without metal ions present. We found that semaglutide forms oligomers up to 10-mers within 24 h; among seven essential metals for humans, low micromolar concentrations of Cu2+ and Zn2+ ions drive the formation of higher-order and more abundant oligomeric species, an effect attributed to metal binding-mediated stabilization of small oligomers. Oligomeric species are associated via hydrophobic C-termini in a parallel orientation. N-termini and the lipid chain are, instead, loosely engaged and available for high-affinity binding to human serum albumin (HSA), an interaction that facilitates the dissociation of oligomeric species and is further enhanced when HSA is glycated. Our findings underscore the power of structural MS to track early-stage oligomerization.
Molecular and Surface W-Sites through 31P-Detected and Dynamic Nuclear Polarization Surface-Enhanced 183W NMR Spectroscopy across Olefin Metathesis Catalysts
Item type: Journal Article
Seidel M.Z.; de Zwart F.J.; Ciuoli M.; et al. (2026)
Supported tungsten catalysts are widely employed in industrial olefin metathesis reactions. However, further optimization of their performance requires detailed insight into the local structure of the active sites. Accessing this information remains challenging because of the limited site resolution and surface sensitivity of conventional spectroscopic techniques. While 183W solid-state NMR spectroscopy could in principle offer direct information on the tungsten coordination environment, its practical application is severely limited because of intrinsically low sensitivity. Herein, we demonstrate that the 183W NMR signatures of molecular and supported alkylidene complexes are readily accessible through indirect 31P detection. Through this strategy, we are able to identify two distinct Lewis acidic tungsten surface sites on WOx/SiO2 catalysts and resolve their structural characteristics through their NMR fingerprints. A fraction of the total number of sites (ca. 30%), which correspond to isolated dioxo sites, are able to coordinate PMe3, a requirement for NMR detection; these sites can likely also coordinate other small molecules, to possibly generate active sites. These findings provide a structural basis for understanding the catalytic activity and the rational design of supported metathesis catalysts.
Distinct Environmental DNA States Reveal Biodiversity and Transport Patterns Across Alpine Watersheds
Item type: Journal Article
Kirtane A.; van der Loo E.; Doppmann Z.; et al. (2026)
Environmental DNA (eDNA) exists in three states: membrane-bound, adsorbed and dissolved. These states differ in persistence and degradation, strongly influencing the interpretation of eDNA data. Despite this, they have rarely been separated and analyzed independently from environmental samples. We developed a state-sorting workflow to isolate and analyze them, applying it to samples from 221 sites from 58 streams across eight lake watersheds with COI and ITS metabarcoding, targeting metazoans and plants, respectively, to reveal differences in biodiversity content and transport dynamics. Our results show that all three states contain both shared and unique taxonomic diversity of metazoan eDNA. However, the plant eDNA was only detected in the membrane-bound state. For metazoans, membrane-bound eDNA contained 87.8% of observed ASVs, far exceeding the adsorbed (37.2%) and dissolved (20.5%) states. Only membrane-bound eDNA showed evidence of downstream transport, but its extent varied among watersheds due to local hydrology. While upstream eDNA was transported to stream–lake confluences, lake surface samples showed a turnover in community composition. Clarifying the fate of membrane-bound eDNA within lakes will enhance catchment-level detection from lake samples and understanding of lake hydrodynamics. Of the environmental parameters assessed, water temperature was most strongly aligned with changes in community composition between sites. Most previous studies have likely captured the majority of the eDNA diversity within their samples by inadvertently targeting the membrane-bound state. This study demonstrates the utility of eDNA state-sorting, but the methods require further refinement. Analyzing states independently improves the interpretation of eDNA data and elucidates the processes governing eDNA fate and transport.
Hybrid untargeted short-read and targeted long-read RNA sequencing facilitates genotype-phenotype associations at single-cell resolution
Item type: Journal Article
Wang J.; Maldifassi M.; Bratus-Neuenschwander A.; et al. (2026)
Long-read single-cell RNA sequencing enables simultaneous and unbiased detection of transcriptomic variants and gene expression, but its application is limited by low read coverage, restricting genotype-phenotype analyses at single-cell resolution. We systematically evaluate short-read whole-transcriptome amplification (SR-WTA), long-read whole-transcriptome amplification (LR-WTA), and long-read targeted sequencing (LR-Twist). Based on these comparisons, we develop a hybrid strategy combining SR-WTA and LR-Twist within a Snakemake pipeline to leverage the strengths of both approaches. SR-WTA provides broad transcriptome coverage, while LR-Twist enriches a 50-gene panel for deeper variant detection. This approach improves the power to link mutational profiles with transcriptional programs at single-cell resolution.
Item type: Person