Oliva, F. | bioRxiv Science

bioRxiv2026

An integrated biomaterials-centred approach of the ageing thymic microenvironment reveals design principles for regenerative biomaterials

Thymic involution is commonly addressed as a loss of epithelial and lymphoid tissue, yet the accompanying remodelling of the microenvironment remains poorly defined. This work applied a biomaterials-centered approach to compare young and aged bovine thymus by integrating histology, oscillatory rheology, untargeted lipidomics, ICP-MS and AP-MALDI mass spectrometry imaging. This holistic approach connects the mechanical, compositional, and spatial features of the native thymus with the development of thymus-inspired biomaterials. Ageing increased both storage and loss moduli by more than one order of magnitude and reduced the linear viscoelastic region approximately fivefold, defining a markedly stiffer and more strain-sensitive material state. This mechanical transition was accompanied by lipid remodelling, with double realtive contribution of triacylglycerols to the lipid pool doubled and loss of membrane-associated phospholipids. The elemental profile also contracted, with total metal content decreasing by one-third and zinc showing a reduction of 70%. At the architectural level, the corticomedullary ratio was more than halved, while AP-MALDI imaging revealed an approximately 40% reduction in the annotated molecular repertoire and a shift from homogeneous to fragmented distributions of choline and representative phosphatidylcholine species. These results show that thymic ageing emerges from the concomitant variations of viscoelastic behaviour, chemical composition, and molecular organization. By defining these interconnected alterations, this study establishes a materials-based foundation for the design of bioinspired systems aimed at reproducing features of the young thymic niche and supporting future thymic repair. HighlightsO_LIAgeing increased viscoelastic moduli and reduced deformation tolerance. C_LIO_LIThe lipid profile shifted from membrane lipids towards triacylglycerols. C_LIO_LIThe elemental pool contracted, with zinc showing the strongest depletion. C_LIO_LIHistology and AP-MALDI-MSI revealed loss of spatial organization. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/740917v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1baa8cdorg.highwire.dtl.DTLVardef@1a04649org.highwire.dtl.DTLVardef@1669ce6org.highwire.dtl.DTLVardef@1c6e9ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2022

Modelling eNvironment for Isoforms (MoNvIso): A general platform to predict structural determinants of protein isoforms in genetic diseases

The seamless integration of human disease-related mutation data into protein structures is an essential component of any attempt to correctly assess the impact of the mutation. The key step preliminary to any structural modelling is the identification of the correct isoform onto which mutations should be mapped because there are several functionally different protein isoforms from the same gene. To handle large sets of data coming from omics techniques, this challenging task should be automatized. Here we present our code MoNvIso (Modelling eNvironment for Isoforms), which pinpoints the correct isoform associated with the mutation of interest and builds a structural model of both the wild type isoform and the related variants starting from the name of the gene and the list of mutations of interest.

bioinformatics↗

bioRxiv2020

Substrate Recognition by γ-Glutamyltransferase: A Molecular Dynamics Simulations Study

{gamma}-glutamyltransferase (GGT) is an enzyme that uses {gamma}-glutamyl compounds as substrate and catalyzes their transfer into a water molecule or an acceptor substrate with varied physiological-function in bacteria, plants and animals. Crystal structures of GGT are known for different species and in different states of the chemical reaction; however, structural dynamics of the substrate binding to the catalytic site of GGT is unknown. Here, we modeled Escherichia Coli GGTs glutamine binding by using a swarm of accelerated molecular dynamics (aMD) simulations. Characterization of multiple binding events identified three structural binding motifs composed of polar residues in the binding pocket that govern glutamine binding into the active site. Simulated open and closed conformations of a lid-loop protecting the binding cavity suggests its role as a gating element by allowing or blocking substrates entry into the binding pocket. Partially open states of the lid-loop are accessible within thermal fluctuations, while the estimated free energy cost of a complete open state is 2.4 kcal/mol. Our results suggest that both specific electrostatic interactions and GGT conformational dynamics dictate the molecular recognition of substrate-GGT complexes.

biophysics↗