Biology subjects

de Vries, N.

Publications and source records attributed to de Vries, N..

3 recordsLinked to original sources

bioRxiv2026

AbSolution: interactive exploration of sequence-derived features in AIRR-seq repertoires

High-throughput sequencing of B-cell and T-cell immune receptor repertoires provides unprecedented insight into adaptive immune responses. The data produced are structured by clonal relationships and somatic mutation signatures, and yield extremely rich information in sequence-derived features, including physicochemical properties and compositional patterns. However, integrated analysis across datasets, conditions, and time points remains challenging. Current analytical tools typically focus only on certain features within individual repertoires, without enabling integrated, multivariable comparisons across datasets, conditions, and time points to address their diversity and variability. Here we present AbSolution, a user-friendly and flexible interactive application for comprehensive exploration of immune repertoires and their sequence-based properties. AbSolution enables multiscale analysis of thousands of sequence-derived features across receptor regions, while accounting for V(D)J usage, clonal composition and experimental groupings. We demonstrate its utility by identifying distinct sequence-based profiles associated with dominant (highly abundant) and non-dominant B-cell clones in peripheral blood BCR repertoires from patients with idiopathic inflammatory myopathies, and with antigen-responsive T-cell populations over time in a longitudinal in vitro antigen-stimulation dataset. Through interactive, interlinked visualizations, statistical feature selection and multi-sample comparisons, AbSolution facilitates integrated feature profiling that supports the interpretation of immune selection processes and enables systematic analysis of complex repertoire datasets.

bioinformatics↗

bioRxiv2026

Rational scaffold design mitigates mitochondrial complex I off-target inhibition in bifunctional degraders

Chemical inducers of proximity have transformed small-molecule pharmacology, but the large, bifunctional architectures they often employ introduce new and poorly understood off-target risks. During a targeted protein degrader synthesis project, we identified a subset of compounds that cause rapid and unexpected ATP depletion in cells. Mechanistic studies traced this effect to inhibition of mitochondrial complex I, a central component of oxidative phosphorylation. This inhibition does not stem from off-target binding by either of the two target ligands, but from the overall long, linear architecture of the bifunctional molecules, which renders them effective ligands of the narrow ubiquinone binding tunnel of complex I. Strikingly, this liability extends to structurally unrelated bifunctional molecules, including six androgen receptor PROTACs including the clinical candidate ARV-110, which inhibits complex I at low nanomolar concentrations. To mitigate complex I inhibition, we established a generalizable design strategy to disrupt linear molecular geometry through the introduction of structural "bumps" or "kinks". In a proof-of-concept study, we successfully apply this strategy to the ARV-110 scaffold, discovering potent AR-degrading ARV-110 analogs that do not inhibit complex I. These findings uncover a previously underappreciated structural determinant of off-target mitochondrial toxicity and establish new design principles for safer proximity-inducing therapeutics.

cancer biology↗

bioRxiv2021

Increased frequency of CD4+ and CD8+ follicular helper T cells in human lymph node biopsies during the earliest stages of rheumatoid arthritis

ObjectivesFollicular helper T cells (Tfh cells) provide key B cell help, and are essential in germinal center (GC) formation and (auto) antibody generation. To gain more insight into their role during the earliest phase of rheumatoid arthritis (RA) we analyzed their frequencies, phenotype and cytokine profile in peripheral blood and lymphoid tissues. MethodsUsing flow cytometry, we studied the frequency of Tfh and B cells in peripheral blood and lymph node (LN) needle biopsies. Three donor groups were included and compared: healthy controls (HCs), autoantibody positive individuals at risk for developing RA (RA-risk individuals), and early RA patients. Ex vivo stimulation of lymphocytes with PMA/ionomycin was performed to assess cytokine secretion by Tfh cells. ResultsIn blood, the frequency of circular Tfh cells (cTfh) did not differ between study groups. In lymphoid tissue, the frequency of Tfh cells correlated strongly with the frequency of CD19+ B cells. Compared to healthy controls, LN samples of RA patients and RA-risk individuals showed more CD19+ B cells and more CD4+CXCR5+ and CD8+CXCR5+ Tfh cells. These Tfh cells from LNs expressed less IL-21 upon ex vivo stimulation. ConclusionLN tissue of early RA patients as well as part of RA-risk individuals exhibit increased frequencies of Tfh cells correlating with increased numbers of B cells. Interestingly, IL-21 production is already aberrant in the very early at risk phase of the disease. This suggests that Tfh cells may present a novel rationale for therapeutic targeting during the preclinical stage of the disease to prevent further disease progression.

immunology↗