Biology subjects

Frosch, M.

Publications and source records attributed to Frosch, M..

4 recordsLinked to original sources

bioRxiv2026

Coding agents author interpretable single-cell embedding models from the literature

The single-cell literature catalogs cell states as validated marker-gene programs -- a sparse, compositional prior. Conventional embedding methods do not leverage this prior and learn cell-state structure de novo from the expression matrix, producing dense dimensions needing post-hoc interpretation and batch correction. Here we show coding agents can author single-cell embedding models directly from the literature. Given a scenario that focuses this literature lens on a chosen biological subdomain, the agent edits a structured Python template, curating named, literature-cited gene programs and composing them into axes, without a gene-set database, training, or sight of the data. Across mouse and human tissues these zero-shot embeddings are competitive in biological quality with conventional, foundation-model, and program-informed baselines, batch-robust by construction and reproducible across runs, complementing data-driven embeddings. Because each dimension is a named, cited gene program, the embedding is interpretable and auditable, and its composable axes can be steered into a developmental tree.

bioinformatics↗

bioRxiv2024

Ubiquitin-specific protease 8 controls B cell proteostasis and cell survival in multiple myeloma

Ubiquitin-specific protease 8 (USP8) is a multifunctional deubiquitinating enzyme that plays a pivotal role in the regulation of endosomal and lysosomal trafficking. Several studies showed that USP8 is critically involved in the pathogenesis of various tumor entities. Recently, USP8 emerged as a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we have comprehensively analyzed mice with deletion of Usp8 at different stages of B-cell development. Furthermore, we evaluated the function of USP8 in proteasome inhibition susceptible and Bortezomib (BTZ) resistant patient derived MM cells using depletion of USP8 and treatment with DUB-IN-2, a widely used inhibitor published to target USP8. Usp8 depletion in Usp8f/fCd19-Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin/NEDD8 chains, indicating proteotoxic stress. Moreover, we identified these modifications as preferred substrates of USP8. In MM cells, efficient USP8 knockdown reduced survival by inducing lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ. Our results highlight the potential of targeting USP8 and the combination of DUB-IN-2 and BTZ in treating BTZ-resistant MM. However, our biochemical and cellular analyses raise fundamental concerns about the function of DUB-IN-2 as a USP8 inhibitor.

molecular biology↗

bioRxiv2022

A cross-disease human microglial framework identifies disease-enriched subsets and tool compounds for microglial polarization.

Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. We use single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and central nervous system regions. We observe a central divide between oxidative and heterocyclic metabolism and identify subsets associated with antigen presentation, motility, and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and leverage our dataset as a classification resource, finding that iPSC model systems recapitulate substantial in vivo heterogeneity. Finally, we identify and validate candidates for chemically inducing subtype-specific states in vitro, showing that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimers.

neuroscience↗

bioRxiv2021

A multimodal imaging and analysis pipeline for creating a cellular census of the human cerebral cortex

Cells are not uniformly distributed in the human cerebral cortex. Rather, they are arranged in a regional and laminar fashion that span a range of scales. Here we demonstrate an innovative imaging and analysis pipeline to construct a reliable cell census across the human cerebral cortex. Magnetic resonance imaging (MRI) is used to establish a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with both traditional immunohistochemistry, to provide a stereological gold-standard, and with a custom-made inverted confocal light-sheet fluorescence microscope (LSFM) for 3D imaging at cellular resolution. Finally, mesoscale optical coherence tomography (OCT) enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system.

neuroscience↗