Publications

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.

Membrane transporters and channels are generally assumed to be based on distinct structural and functional principles. SLC26A11, a solute carrier with high expression levels in the brain, has been proposed to function as either an anion transporter or a channel. Here, we resolve this apparent discrepancy by demonstrating that SLC26A11 is a dual-function protein capable of operating as both a sulfate transporter and a chloride channel. By resolving its structure and combining biochemical studies and molecular dynamics simulations, we show that SLC26A11 exhibits all the hallmarks of a secondary transporter. The mechanistic basis for its selective ion transport identifies the protein as the elusive lysosomal sulfate exporter. Additionally, we demonstrate that SLC26A11 exhibits an uncoupled, channel-like chloride conductance gated by proton:sulfate symport. Our finding that the chloride-conducting state arises from the transport cycle may contribute to the development of therapeutic strategies for treating brain edema, and the identification of its role in lysosome sulfate efflux may provide new approaches to study and treat lysosomal storage diseases.

The Lotka-Volterra system is the simplest model of the ecological interactions of n species. The sign pattern of its parameter space Rn & times;Rn & times;n defines the network structure of the competitive, mutualistic, and predator-prey interactions between these species. Here, we study the feasible and stable equilibria of the Lotka-Volterra system from the perspective of computational algebraic geometry. The feasibility and stability conditions stratify Rn & times;Rn & times;n into feasible-stable semialgebraic sets. We encode them on the real Grassmannian GrR(n,2n) via a parameter matrix representation, and use oriented matroid theory to develop an algorithm, combining Grassmann-Pl & uuml;cker relations with branching under feasibility and stability constraints. This symbolic approach determines whether a given sign pattern in Rn & times;Rn & times;n admits a consistent extension to Pl & uuml;cker coordinates. As an application, we establish the impossibility of certain interaction networks, showing that the corresponding patterns admit no such extension satisfying feasibility and stability conditions, through an effective implementation. We complement these results using numerical nonlinear algebra with HypersurfaceRegions.jl to decompose the parameter space and detect rare feasible-stable sign patterns.

In this paper, we construct solutions of the open WDVV equations starting from any Hurwitz Dubrovin–Frobenius manifold. The WDVV equations play a crucial role in the structure of Frobenius manifolds, quantum cohomology, and integrable systems. Extending these ideas, the open WDVV equations provide a framework to incorporate boundary conditions, making them fundamental in open Gromov–Witten theory. Using Dubrovin's construction of Landau–Ginzburg superpotentials associated with Hurwitz spaces, we demonstrate that their primitives satisfy the open WDVV equations. Our approach provides an efficient method for computing open WDVV solutions associated with any Hurwitz Dubrovin–Frobenius manifold.

We provide an equivariant extension of Carlsson's BGG correspondence in characteristic two. As an application we classify perfect cochain complexes of (Z/2 & times;Z/2)& rtimes;Q -representations with four-dimensional total homology for finite groups Q of odd order. We deduce that cochain complexes of finite, free A4 -CW complexes with four-dimensional total homology are rigid: They are determined by the degrees of the nonzero homology groups.

Systemic inflammatory response syndrome (SIRS) is a frequent critical condition in clinical patients marked by dysregulated immune activation and high mortality. Early initiation of appropriate interventions are important for patient outcome, but molecular markers for diagnosis are not SIRS-specific.

Developing organs grow to reproducible sizes and shapes, yet the growth of their constituent cells can be highly heterogeneous and fluctuating. During wild-type Arabidopsis thaliana sepal development, fluctuations in cell growth average because the fluctuations are not strongly correlated spatially or temporally, and so the sepals grow to uniform sizes and shapes. In contrast, the sepals of the ftsh4-5 mutant develop to variable sizes and shapes. F ts H4 encodes a mitochondrial i-AAA protease. Reactive oxygen species (ROS) accumulate in ftsh4-5 mutants, and lowering ROS levels rescues the sepal size and shape variability. Here, we find that elevated ROS promotes correlated growth fluctuations and causes cortical microtubules to become more "crisscrossed" and stable. The growth rates of the cells with crisscrossed microtubules are lower and more correlated in time, which impairs spatiotemporal averaging of growth. This suggests that ROS affects microtubule dynamics and cell growth fluctuations, which are necessary for robust morphogenesis.

Shape analysis and classification are popular methods for biologists, biophysicists, and mathematicians investigating relationships between function and form. Classic shape descriptors, such as sphericity, can be powerful but may be insufficient for more complex shapes. Here, we present "napari-toska" a topological skeleton-based method to analyze complex shapes by representing their asymmetries as networks. Using global neighborhood principles, classic network science metrics, and spatial feature embedding, we create instance segmentation object profiles for immediate or downstream classification. napari-toska also follows temporal dynamics and identifies network features that differentiate experimental phenotypes. We incorporated absolute spatial feature measurements of objects to retain aspects of scale. Furthermore, napari-toska identifies certain segmentation errors through the emergence or loss of network cycles. Combined, napari-toska functions allow for flexible and in-depth shape profiling of intricate shapes often observed in biological and physical settings where robust, yet precise, system configuration is essential to functionality.

We give an exact solution of the ferromagnetic Ising model on a random regular graph ensemble via analytic combinatorics. Expressing the partition function as the generating function of labeled edge-bicolored graphs, we obtain the free energy in the thermodynamic limit from the asymptotic enumeration of these graphs. A simple analysis of the resulting formula reveals a second-order phase transition with critical exponents of the mean-field universality class.