Publikationen

In this work, we develop a spectral theory for hypergraph limits. We prove the convergence of the spectra of adjacency and Laplacian matrices for hypergraph sequences converging in the 1-cut metric. On the other hand, we give examples of matrix operators associated with hypergraphs whose spectra are not continuous with respect to the 1-cut metric. Furthermore, we show that these operators are continuous with respect to other cut norms

We show that coupling enzymatic activity to condensation under limited resource conditions drives emergent self-regulation via droplet formation and dissolution. Our kinetic models show that in situ phase separation of in-vitro-transcribed mRNA with an intrinsically disordered protein (mutant G3BP1) modulates transcription and degradation kinetics. When resources for mRNA production are limited, condensates spontaneously dissolve, driven by the feedback from compartmentalization on reaction rate constants-with slower degradation within condensates than in the mRNA-protein-poor phase. Consequently, the lifetime of mRNA is prolonged upon condensation compared to the case without condensates. Extending the model to sustained and oscillatory resource supply reveals that condensates elevate mean mRNA levels and buffer deviations from the mean compared to the non-condensate scenario. These findings provide a general mechanism of cross-regulation and feedback between phase separation and enzymatic reactions, highlighting condensates as active regulators of biochemical flux rather than as passive organizers.

MALT1 (mucosa-associated lymphoid tissue lymphoma/leukemia protein 1)-TRAF6 [tumor necrosis factor receptor (TNFR)-associated factor 6] interaction drives lymphocyte activation and adaptive immunity, but it also contributes to maintaining immune homeostasis. MALT1 exists in two isoforms that differ only by either encoding two (MALT1A) or one (MALT1B) TRAF6 binding motif (T6BM). The human mutation MALT1 E806D in T6BM2, expressed in both MALT1A and MALT1B, has been associated with an immune disorder combining symptoms of immune deficiency and autoimmunity. Here, we report that the orthologous germline mutation MALT1 E814D is sufficient to induce a fatal autoimmune syndrome in mice. We demonstrate that species-specific differences in the effects of T6BM2 disruptions can be attributed to alterations in MALT1 splicing and that immune homeostasis is restored by genetically enforcing expression of MALT1A in MALT1 E814D mice. Thus, alternative MALT1 splicing allows tuning of TRAF6 association, thereby functioning as a molecular rheostat to balance between optimal immune activation and maintenance of peripheral tolerance.

Human embryonic development proceeds more slowly than in mice. The segmentation clock offers a tractable model for studying species-specific developmental tempo, as its oscillation period in human induced presomitic mesoderm (iPSM) cells is approximately twice that of mouse. While the core clock gene HES7 exhibits slower protein degradation in human cells, it remains unclear whether such cross-species differences in protein stability reflect a general principle. Here, we perform a dynamic stable isotope labeling of amino acids in cell culture (SILAC)-based proteomic analysis of ∼5,000 proteins in human and mouse iPSM, and we uncover a broad trend of slower protein degradation in human cells, regardless of subcellular localization or degradation pathways. Moreover, inhibition of glycolysis in mouse iPSM partially phenocopies the human protein stability profile, and modulation of protein stability alters the tempo of both the segmentation clock and cellular differentiation. Our findings establish protein stability, with systematic differences across species, as a key mediator linking metabolism to developmental tempo.

Topological defects are a conspicuous feature of active liquid crystals that have been associated with important morphogenetic transitions in organismal development. Robust development thus requires a tight control of the motion and placement of topological defects. In this article, we study a mechanism to control +1 topological defects in an active polar fluid confined to a disk. If activity is localized in an annulus within the disk, the defect moves on a circular trajectory around the center of the disk. Using an ansatz for the polar field, we determine the dependence of the angular speed and the circle radius on the boundary orientation of the polar field and the active annulus. Using a proportional-integral controller, we guide the defect along complex trajectories by changing the active annulus size and the boundary orientation.

Biomolecular condensates formed through phase separation have emerged as a central principle of cellular organization, enabling the dynamic regulation of gene expression, signaling, metabolism, and stress responses. While early conceptual advances in condensate biology have largely originated from animal and in vitro systems, plant cells present a unique set of biological and technical challenges, including rigid cell walls, turgor pressure, plastid autofluorescence, complex endomembrane organization, and acute environmental responsiveness. These distinctive features impede the direct transfer of existing methodologies and drive the development of heterogeneous experimental practices. In this community comment, we present a comprehensive methodological framework for studying biomolecular condensates in plants, spanning in silico prediction, in vitro reconstitution, molecular dynamics simulations, live-cell and super-resolution imaging, material property measurements, membrane-associated condensates, and synthetic condensate engineering. We highlight best practices, common pitfalls, and plant-specific considerations, emphasizing the need for orthogonal validation, quantitative interpretation, and physiological relevance. By consolidating current methodologies and articulating shared principles, this review aims to establish a foundation for rigorous, reproducible, and conceptually coherent research in condensate biology of plants and beyond, with emerging implications for crop genetic improvement and synthetic biology applications.

Dysregulations within the epidermal proteolytic network can cause hyperproliferative and inflammatory disorders. Although the metalloprotease meprin α is localized in the stratum basale in healthy skin, increased levels are found in the upper epidermal layers in wound healing and psoriatic lesions. To investigate a link between meprin α expression and keratinocyte proliferation, we developed a mouse model for inducible expression of pathological meprin α levels (ie, K5Mα mice). K5Mα mice developed a skin phenotype characterized by hyperkeratosis, acanthosis, parakeratosis, and barrier defect. Keratinocyte hyperproliferation and local inflammation were induced upon induction of meprin α expression. By N-terminomics, we identified dermokine, a regulator of keratinocyte proliferation and epidermal immune response, as a putative substrate of meprin α. We validated the proteolysis and identified the cleavage site, which is highly conserved in mammals, suggesting that dermokine degradation by meprin α represents a central mechanism in wound healing and hyperproliferative skin diseases.

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.

Mitotic centrosome maturation requires Polo/PLK1-dependent expansion of the pericentriolar material (PCM). In Drosophila, Centrosomin (Cnn) assembles a scaffold around mitotic centrioles through interactions between its PReM and CM2 domains. Here, we show that PReM adopts an autoinhibited helical hairpin conformation that prevents CM2 binding. Polo/PLK1 phosphorylation relieves this autoinhibition, enabling scaffold assembly, whereas phospho-blocking mutations disrupt PReM-CM2 binding in vitro and Cnn scaffold assembly in vivo. Potential functionally analogous domains have been identified in the human and C. elegans Cnn homologues CDK5RAP2 and SPD-5. We find that the human protein appears to share a structurally similar mechanism for scaffold assembly, but the worm protein does not. Consistent with this, deletion of these domains alters the dynamics of Cnn condensates in vitro, but has little effect on SPD-5 condensate dynamics. We conclude that Polo/PLK1 promotes mitotic centrosome assembly, at least in part, by relieving autoinhibitory intramolecular interactions.

Cell-to-cell signaling between niche and stem cells regulates tissue renewal. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. ISCs orient their Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks. Stem cells with multiple lateral Golgi transport stem cell receptors with a higher efficiency than cells with one single Golgi. The lateral Golgi orientation and enhanced receptor transport requires A-kinase anchor protein 9 (Akap9), and is necessary for normal renewal capacity. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal a stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue renewal, which is compromised in the aged epithelium.