Biology subjects

Deutsch, N.

Publications and source records attributed to Deutsch, N..

4 recordsLinked to original sources

bioRxiv2026

Stability of Antibody Repertoires in Astronauts During Long-Term Spaceflight

Long-duration spaceflight is known to disrupt several aspects of immune function yet its impact on the antiviral antibody repertoire remains unclear. We analyzed longitudinal plasma samples from 11 astronauts participating in a 6-month long spaceflight, including preflight, inflight, and postflight timepoints. Using a high-throughput serological method based on phage display of linear peptides from thousands of viruses we assessed the stability of antiviral antibodies over time. Across two phage libraries expressing different pathogen panels, we detected antibodies against Alphainfluenzavirus, Betainfluenzavirus, Enterovirus, and Orthopneumovirus consistently with the highest abundancy in all astronauts over all timepoints. Antibody levels against these infectious agents remained remarkably stable within individuals during and after spaceflight. In contrast, substantial heterogeneity was observed among astronauts, reflecting individualized immune histories and baseline antibody profiles. These results were confirmed by a different immunoassay using whole protein from the most targeted viruses. Together, these findings demonstrate that the antiviral antibody repertoire is largely resilient during prolonged spaceflight, highlighting preserved humoral memory despite potential dysregulation in cellular immune compartments.

immunology↗

bioRxiv2025

Pathogenic Missense Mutations in Intrinsically Disordered Regions Reveal Functional and Clinical Signals

Intrinsically disordered regions (IDRs) play key roles in cellular signaling and regulation, yet their contribution to human disease remains poorly understood. Here we analyzed nearly one million ClinVar missense variants, focusing on those located within IDRs defined by curated and predicted annotations. We found that pathogenic variants were significantly enriched in short linear motifs (SLiMs) and disordered binding regions, consistent with their central functional importance. To extend these insights beyond existing annotations, we applied AlphaMissense, a deep-learning pathogenicity predictor, and uncovered localized "island-like" patterns of elevated pathogenicity within IDRs. Leveraging these signals, we developed a classifier to prioritize predicted ELM motifs (PEMs), revealing thousands of candidate functional sites linked to major disease classes, including neurological, cardiovascular, and cancer-associated genes. Case studies in POLK, FOXP2, and LMOD3 illustrate how this framework connects genetic variation to molecular mechanisms, providing a scalable route to interpret variants of uncertain significance and advancing our understanding of pathogenicity in the disordered proteome. SummaryThis study reveals how deep-learning pathogenicity predictions can uncover functional motifs within intrinsically disordered regions, providing a new framework for interpreting genetic variation in the disordered proteome.

bioinformatics↗

bioRxiv2025

The non-catalytic ϵ DNA polymerase subunit is an NPF motif recognition protein

Short linear motifs (SLiMs) in disordered protein regions direct numerous protein-protein interactions, yet most remain uncharacterized. The Asn-Pro-Phe (NPF) motif is a well-known EH-domain ligand implicated in endocytosis, but here we reveal that the non-catalytic subunit of human DNA polymerase {varepsilon} (POLE2) also serves as a general NPF-motif receptor. Using a quantitative "native holdup" assay, we find that POLE2 selectively binds diverse NPF-containing peptides, including canonical EH-domain ligands (e.g., SYNJ1) and previously uncharacterized motifs. Biochemical measurements and mutational analysis show that NPF motifs interact with a shallow pocket near the POLE2 C-terminus, and AlphaFold predictions confirm key roles for Y513, E520, and S522 in motif coordination. Proteome-scale affinity screens identify NPF-containing nuclear proteins (e.g., WDHD1, DONSON, TTF2) that bind POLE2 with micromolar affinities, and their motif mutations abolish binding in cell extracts. Although POLE2 primarily tethers the catalytic POLE subunit to replication forks, these results indicate that it can also recruit various NPF-bearing partners involved in replication, DNA repair, and transcription regulation. Notably, NPF motifs optimized for EH-domain binding can still associate with POLE2, highlighting the inherent degeneracy of SLiM-mediated networks. Overall, these findings establish POLE2 as a central hub linking replication with other processes via broad NPF-motif recognition.

biochemistry↗

bioRxiv2022

Global landscape of the host response to SARS-CoV-2 variants reveals viral evolutionary trajectories

A series of SARS-CoV-2 variants of concern (VOCs) have evolved in humans during the COVID-19 pandemic--Alpha, Beta, Gamma, Delta, and Omicron. Here, we used global proteomic and genomic analyses during infection to understand the molecular responses driving VOC evolution. We discovered VOC-specific differences in viral RNA and protein expression levels, including for N, Orf6, and Orf9b, and pinpointed several viral mutations responsible. An analysis of the host response to VOC infection and comprehensive interrogation of altered virus-host protein-protein interactions revealed conserved and divergent regulation of biological pathways. For example, regulation of host translation was highly conserved, consistent with suppression of VOC replication in mice using the translation inhibitor plitidepsin. Conversely, modulation of the host inflammatory response was most divergent, where we found Alpha and Beta, but not Omicron BA.1, antagonized interferon stimulated genes (ISGs), a phenotype that correlated with differing levels of Orf6. Additionally, Delta more strongly upregulated proinflammatory genes compared to other VOCs. Systematic comparison of Omicron subvariants revealed BA.5 to have evolved enhanced ISG and proinflammatory gene suppression that similarly correlated with Orf6 expression, effects not seen in BA.4 due to a mutation that disrupts the Orf6-nuclear pore interaction. Our findings describe how VOCs have evolved to fine-tune viral protein expression and protein-protein interactions to evade both innate and adaptive immune responses, offering a likely explanation for increased transmission in humans. One sentence summarySystematic proteomic and genomic analyses of SARS-CoV-2 variants of concern reveal how variant-specific mutations alter viral gene expression, virus-host protein complexes, and the host response to infection with applications to therapy and future pandemic preparedness.

systems biology↗