Biology subjects

Rueger, M. A.

Publications and source records attributed to Rueger, M. A..

3 recordsLinked to original sources

bioRxiv2026

Raw-count embeddings improve single-cell foundation models

Single-cell transformer foundation models have grown to hundreds of millions of parameters, yet the preprocessing choices that underlie them, including gene ranking and library-size normalisation, have not been systematically benchmarked. Testing seven strategies, we find these elaborations are largely unnecessary: non-normalised, log-transformed counts give the best performance, and gene order barely matters, with even random ordering outperforming sophisticated rank-based schemes. The resulting model, Gene Intelligence, projects log1p-transformed raw counts directly onto each token embedding and jointly predicts masked tokens and counts, using no normalisation, positional encoding, or read-depth tokens. Despite this simplicity, it achieves state-of-the-art performance in the tested gene-level tasks and in doublet detection, and matches large current foundation models on cell-classification tasks while using 10-to 200-fold fewer parameters.

bioinformatics↗

bioRxiv2022

Selectively expressed RNA molecules: a new dimension infunctionalized cell targeting

Exact targeting of specific mammalian cell types or diseased cells is one of the most urgently needed prerequisites for a new generation of potent pharmaceuticals. Different approaches have been pursued, failing mainly due to a lack of specific surface markers in most cases. Developing a completely novel RNA-based methodology, we can now ensure exact cell targeting and simultaneously combine this with selective expression of effector proteins, thereby functionalization of the target cell for therapy, diagnostics or cell steering. The specific combination of the molecular properties of antisense technology and mRNA therapy with functional RNA secondary structures allowed us to develop selectively expressed RNA molecules for medical applications. These so-called seRNAs remain inactive in non-target cells and are only activated by partial degradation to induce translation in preselected cell types of interest. Cell type specificity and type of functionalization are easily adaptable based on a simple modular system. In proof of concept in vitro and in vivo studies we used seRNAs as a highly selective platform technology for powerful glioblastoma cancer cell targeting and significantly reduce brain tumors of mice without detectable side effects with just a single treatment within days. Our data open up new potential avenues for the efficient treatment of various cancers and other human diseases.

cell biology↗

bioRxiv2021

Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice

The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN)-channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN-channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN-channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a novel role for HCN-channel subunits as a part of a general mechanism influencing cortical development in mammals. Significance StatementImpaired cell cycle regulation of neural stem and progenitor cells can affect cortical development and cause microcephaly. During cell cycle progression, the cellular membrane potential changes through the activity of ion channels and tends to be more depolarized in proliferating cells. HCN channels, which mediate a depolarizing current in neurons and cardiac cells, are linked to neurodevelopmental diseases, also contribute to the control of cell-cycle progression and proliferation of neuronal precursor cells. In this study, HCN-channel deficiency during embryonic and fetal brain development resulted in marked microcephaly of mice designed to be deficient in HCN-channel function in dorsal forebrain progenitors. The findings suggest that HCN-channel subunits are part of a general mechanism influencing cortical development in mammals.

neuroscience↗