Biology subjects

van der Meer, F.

Publications and source records attributed to van der Meer, F..

5 recordsLinked to original sources

bioRxiv2026

High-resolution cryo-EM structure of integrin αIIbβ3 bound to disease-causing maternal HPA-1a antibody that blocks integrin activation

Integrins promote immunity, embryonic development, wound healing, and hemostasis, and are activated by bent/closed to extended/open conformational changes. Integrin IIb{beta}3, being crucial for platelet activation and aggregation, is a therapeutic target for bleeding disorders and thrombosis. Human Platelet Antigen-1a (HPA-1a) on {beta}3 is recognized by pregnancy-associated maternal alloantibodies, potentially causing fetal/neonatal alloimmune thrombocytopenia (FNAIT) and even intracranial hemorrhage or perinatal death. However, severe disease determinants are largely unknown. We report the first structure of an anti-HPA-1a antibody fragment (Fab 26.4) in complex with integrin IIb{beta}3 at high resolution by cryo-electron microscopy. Fab 26.4 binding traps IIb{beta}3 in the inactive, bent/closed conformation, is incompatible with integrin extension, and inhibits IIb{beta}3-dependent fibrinogen binding and platelet aggregation. Thus, anti-HPA-1a antibodies directly impair integrin activation by preventing required conformational changes. These insights will improve FNAIT diagnostics and treatment, and spark the development of novel allosteric inhibitors against {beta}3 integrins for future therapeutic applications.

biophysics↗

bioRxiv2025

Early pandemic HIV-1 integration site preferences differ across anatomical reservoirs

Despite effective viral suppression with modern antiretroviral therapy (ART), HIV-1 persists in latent reservoirs across multiple tissues. Integration into the host genome is essential for viral persistence, yet the characteristics of these reservoir sites across anatomical locations remain poorly understood. To address this, we analyzed integration sites from matched esophagus, PBL/PBMC, stomach, duodenum, colon, and unmatched brain tissue samples of individuals infected with HIV-1 subtype B. The virus used in this study was from 1993, an early stage of the HIV pandemic, providing insights into integration patterns before extensive ART use. Our analysis examined genomic feature enrichment, proximity to non-B DNA structures, integration hotspots, and site overlap across tissues and individuals. We identified a distinct integration pattern in brain tissue, characterized by reduced gene targeting and increased enrichment in Short Interspersed Nuclear Elements (SINEs) and DNase I hypersensitivity sites (DHS). Tissue-specific preferences for integration near non-B DNA structures were evident, alongside shared and unique hotspots across tissues and individuals. Notably, genes associated with HIV-related diseases were frequent integration targets. These findings underscore the complex interplay between viral integration, host genetics, and tissue-specific factors, highlighting the potential role of integration sites in disease development.

microbiology↗

bioRxiv2024

Apollo: A comprehensive GPU-powered within-host simulator for viral evolution and infection dynamics across population, tissue, and cell

Modern sequencing instruments bring unprecedented opportunity to study within-host viral evolution in conjunction with viral transmissions between hosts. However, no computational simulators are available to assist the characterization of within-host dynamics. This limits our ability to interpret epidemiological predictions incorporating within-host evolution and to validate computational inference tools. To fill this need we developed Apollo, a GPU-accelerated, out-of-core tool for within-host simulation of viral evolution and infection dynamics across population, tissue, and cellular levels. Apollo is scalable to hundreds of millions of viral genomes and can handle complex demographic and population genetic models. Apollo can replicate real within-host viral evolution; accurately recapturing observed viral sequences from an HIV cohort derived from initial population-genetic configurations. For practical applications, using Apollo-simulated viral genomes and transmission networks, we validated and uncovered the limitations of a widely used viral transmission inference tool.

bioinformatics↗

bioRxiv2022

A Single Intranasal Dose of Bacterial Therapeutics to Calves Confers Longitudinal Modulation of the Nasopharyngeal Microbiota

To address the emergence of antimicrobial-resistant pathogens in livestock, microbiome-based strategies are increasingly being sought to reduce antimicrobial use. Here, we describe the intranasal application of bacterial therapeutics (BTs) for mitigating bovine respiratory disease (BRD) and used structural equation modeling to investigate the causal networks after BT application. Beef cattle received i) an intranasal cocktail of previously characterized BT strains, ii) an injection of metaphylactic antimicrobial (tulathromycin), or iii) intranasal saline. Despite being transient colonizers, inoculated BT strains induced longitudinal modulation of the nasopharyngeal bacterial microbiota while showing no adverse effect on animal health. The BT-mediated changes in bacteria included reduced diversity and richness and strengthened cooperative and competitive interactions. In contrast, tulathromycin increased bacterial diversity and antibiotic resistance, and disrupted bacterial interactions. Overall, a single intranasal dose of BTs can modulate the bovine respiratory microbiota, highlighting that microbiome-based strategies have the potential in being utilized to mitigate BRD in feedlot cattle.

microbiology↗

bioRxiv2019

Pooled CRISPR Inverse PCR sequencing (PCIP-seq): simultaneous sequencing of retroviral insertion points and the associated provirus in thousands of cells with long reads

Retroviral infections create a large population of cells, each defined by a unique proviral insertion site. Methods based on short-read high throughput sequencing can identify thousands of insertion sites, but the proviruses within remain unobserved. We have developed Pooled CRISPR Inverse PCR sequencing (PCIP-seq), a method that leverages long reads on the Oxford Nanopore MinION platform to sequence the insertion site and its associated provirus. We have applied the technique to three exogenous retroviruses, HTLV-1, HIV-1 and BLV, as well as endogenous retroviruses in both cattle and sheep. The long reads of PCIP-seq improved the accuracy of insertion site identification in repetitive regions of the genome. The high efficiency of the method facilitated the identification of tens of thousands of insertion sites in a single sample. We observed thousands of SNPs and dozens of structural variants within proviruses and uncovered evidence of viral hypermutation, recombination and recurrent selection.

genomics↗