Publikationen

We discover that biomolecular condensates, formed by intrinsically disordered proteins without inherent chemical activity, can spontaneously drive nonenzymatic reductive amination. These condensates facilitate reactions between amines and aldehydes or ketones, yielding imines, which are subsequently hydrogenated to form alkylated amines leading to C-N bond formation. Our experiments show that condensates modulate the reductive amination of diverse types of metabolite containing carbonyl groups. Using combinatorial metabolomics, we found that condensates generate previously unknown metabolites through the dimerization of natural amines with ketones and aldehydes. Metabolomics in living cells confirms that the ability of condensates in mediating C-N bond formation enables the synthesis of new metabolites and regulates cellular pathways. These findings uncover a previously unrecognized inherent function of biomolecular condensates, redefining their roles in metabolism. This further highlights the broader influence of condensates on chemical homeostasis and biochemical regulation in biological and prebiotic chemistry.

Most cells polarize and migrate in response to electrical fields. In this issue of Cell, Belliveau et al. identify TMEM154/Galvanin, a receptor that serves as a cellular antenna to sense electrical gradients and guide migration toward the cathode.

Environmental exposures play a pivotal role in carcinogenesis, yet their molecular imprints in human tissues remain incompletely understood. Here, we present an extensive catalog of mutational signatures induced by a panel of environmental carcinogens using human tissue-derived organoids coupled with high-fidelity duplex sequencing (NanoSeq). This unique combination enables direct detection of mutations without clonal expansion and reveals consistent carcinogen-specific signatures across multiple organ types (i.e., colon, stomach, liver, kidney, and pancreas). We identify mutational signatures for agents such as benzo[a]pyrene, aflatoxin B1, aristolochic acid I, and alkylating agents, some of which show strong concordance with known tumor signatures (e.g., SBS4, SBS11, SBS22, and SBS24) and previous experimentally-derived signatures. Our findings validate organoid models as physiologically relevant platforms for chemical mutagenesis and provide a foundational resource for decoding the environmental origins of human cancer.

Neuronal networks are characterized by complex and functionally relevant connectivity motifs. We developed an intuitive explanation for its emergence. While a class of neurons on average innervates its entire surroundings, each individual neuron can only cover a small part of the space. That region is different for each neuron but not completely random, as it is physically constrained by the spatial continuity of the axon. This hypothesis was successfully tested against a morphologically detailed model and an electron-microscopic reconstruction of cortical connectivity. We distilled it into a stochastic algorithm that generates networks, which accurately match the reference data. Our work bridges previous efforts to capture network complexity with top-down or bottom-up methods, that is, by adding complexity constraints to simple stochastic models or by predicting synapses from neuron appositions. It may improve the understanding of the impact of neuron malformations and the functional role of non-random network structure in simplified models.

Cells employ cytoskeletal polymers to move, divide, and pass information inside and outside of the cell. Previous work on eukaryotic cytoskeletal elements such as actin, microtubules, and intermediate filaments investigating the mechanisms of polymerization have been critical to understand how cells control the assembly of the cytoskeleton. Most biophysical analyses have considered cooperative versus isodesmic modes of polymerization; this framework is useful for specifying functions of regulatory proteins that control nucleation and understanding how cells regulate elongation in time and space. The septins are considered a fourth component of the eukaryotic cytoskeleton, but they are poorly understood in many ways despite their conserved roles in membrane dynamics, cytokinesis, and cell shape, and in their links to a myriad of human diseases. Because septin function is intimately linked to their assembled state, we set out to investigate the mechanisms by which septin polymers elongate under different conditions. We used simulations, in vitro reconstitution of purified septin complexes, and quantitative microscopy to directly interrogate septin polymerization behaviors in solution and on synthetic lipid bilayers of different geometries. We first used reactive Brownian dynamics simulations to determine if the presence of a membrane induces cooperativity to septin polymerization. We then used fluorescence correlation spectroscopy to assess septins' ability to form filaments in solution at different salt conditions. Finally, we investigated septin membrane adsorption and polymerization on planar and curved supported lipid bilayers. Septins clearly show signs of salt-dependent cooperative assembly in solution, but cooperativity is limited by binding a membrane. Thus, septin assembly is dramatically influenced by extrinsic conditions and substrate properties and can show properties of both isodesmic and cooperative polymers. This versatility in assembly modes may explain the extensive array of assembly types, functions, and subcellular locations in which septins act.

The sequestration of the malaria parasite in the microvasculature is a major driver of severe malaria, but the human specificity of Plasmodium falciparum has challenged our understanding of this key pathogenic process. Advances in induced pluripotent stem cell (iPSC) technologies offer unique opportunities to study parasite-host interactions in a well-defined environment. However, endothelial iPSC differentiation methods often result in cells with mixed epithelial identity. Here, we have generated an iPSC line with inducible and simultaneous expression of ETS transcription factors (ETV2, FLI1, ERG), resulting in cells with improved endothelial identity and strong barrier function (ETS-iBMEC). Parasite-infected red blood cells and neutrophils display high binding to ETS-iBMEC. Exposure to parasite products caused transcriptional changes in metabolic and splicing genes, and key endothelial barrier and angiogenic pathways. Our study confirms the role of the angiopoietin-Tie2 axis in parasite-mediated barrier disruption and highlights the importance of new pathways, including VEGF-Notch signalling. Our novel iPSC-based approach represents a new in vitro platform to study the pathogenesis of human vascular infections.

Epithelial neuroendocrine neoplasms (NENs) are a rare and heterogeneous group of malignancies with limited treatment options. Comprehensive molecular characterization may reveal novel therapeutic opportunities for these clinically challenging tumors.

N-acetyltransferase 1 (NAT1) is an enzyme that acetylates certain drugs and carcinogens and is involved in folate metabolism. Some NAT1 variants are associated with susceptibility to cancer and birth defects. We show that while nearly all present-day humans carry a valine residue at position 149 and a serine residue at position 214, some carry the ancestral amino acids isoleucine and alanine at these positions because of gene flow from Neanderthals. Neither substitution affects enzymatic activity. However, replacing the serine residue, a known phosphorylation site, with a phosphomimetic aspartate reduces NAT1 activity by ~60%. Phosphorylation at this site may allow NAT1 to be down-regulated during pregnancy to reduce birth defect risk, while maintaining high activity in adults for xenobiotic clearance. This regulatory site is a molecular feature that differs between modern humans and Neanderthals.

Epigenetic alterations play an increasingly recognized role in carcinogenesis and in the development of resistance to anticancer therapies. Epigenetic enzymes (writers and erasers) and effectors (readers) are largely influenced by the availability of metabolites generated through one-carbon metabolism (OCM), the tricarboxylic acid (TCA) cycle, and acetyl-CoA synthesis (ACS). In this study we examined the expression of epigenetic and metabolic genes to investigate their interplay in cholangiocarcinoma (CCA).

We propose a method for variable selection in the intensity function of spatial point processes that combines sparsity-promoting estimation with noise-robust model selection. As high-resolution spatial data becomes increasingly available through remote sensing and automated image analysis, identifying spatial covariates that influence the localization of events is crucial to understand the underlying mechanism. However, results from automated acquisition techniques are often noisy, for example due to measurement uncertainties and detection errors. We study the impact of such noise on sparse point-process estimation across different models. To improve noise robustness without requiring additional knowledge about the true process, we propose to use stability selection based on point-process subsampling and to incorporate a non-convex best-subset penalty to enhance sparsity. In extensive simulations, we demonstrate that this approach reliably recovers true covariates under diverse noise scenarios and improves both selection accuracy and stability. We then apply the proposed method to a forestry data set, analyzing the distribution of trees in a tropical rain forest. This shows the practical utility of the method for robust variable selection in spatial point-process models under noise, without requiring additional knowledge of the process.