@article{14362, abstract = {Motivated by recent applications to entropy theory in dynamical systems, we generalise notions introduced by Matthews and define weakly weighted and componentwise weakly weighted (generalised) quasi-metrics. We then systematise and extend to full generality the correspondences between these objects and other structures arising in theoretical computer science and dynamics. In particular, we study the correspondences with weak partial metrics and, if the underlying space is a semilattice, with invariant (generalised) quasi-metrics satisfying the descending path condition, and with strictly monotone semi(-co-)valuations. We conclude discussing, for endomorphisms of generalised quasi-metric semilattices, a generalisation of both the known intrinsic semilattice entropy and the semigroup entropy.}, author = {Castellano, Ilaria and Giordano Bruno, Anna and Zava, Nicolò}, issn = {0304-3975}, journal = {Theoretical Computer Science}, publisher = {Elsevier}, title = {{Weakly weighted generalised quasi-metric spaces and semilattices}}, doi = {10.1016/j.tcs.2023.114129}, volume = {977}, year = {2023}, } @article{14363, abstract = {Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.}, author = {Maes, Margaret E and Colombo, Gloria and Schoot Uiterkamp, Florianne E and Sternberg, Felix and Venturino, Alessandro and Pohl, Elena E. and Siegert, Sandra}, issn = {2589-0042}, journal = {iScience}, number = {10}, publisher = {Elsevier}, title = {{Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout}}, doi = {10.1016/j.isci.2023.107780}, volume = {26}, year = {2023}, } @article{14364, abstract = {We introduce extension-based proofs, a class of impossibility proofs that includes valency arguments. They are modelled as an interaction between a prover and a protocol. Using proofs based on combinatorial topology, it has been shown that it is impossible to deterministically solve -set agreement among processes or approximate agreement on a cycle of length 4 among processes in a wait-free manner in asynchronous models where processes communicate using objects that can be constructed from shared registers. However, it was unknown whether proofs based on simpler techniques were possible. We show that these impossibility results cannot be obtained by extension-based proofs in the iterated snapshot model and, hence, extension-based proofs are limited in power.}, author = {Alistarh, Dan-Adrian and Aspnes, James and Ellen, Faith and Gelashvili, Rati and Zhu, Leqi}, issn = {1095-7111}, journal = {SIAM Journal on Computing}, number = {4}, pages = {913--944}, publisher = {Society for Industrial and Applied Mathematics}, title = {{Why extension-based proofs fail}}, doi = {10.1137/20M1375851}, volume = {52}, year = {2023}, } @article{14368, abstract = {Purpose: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. Methods: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. Results: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. Conclusion: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.}, author = {Accogli, Andrea and Lin, Sheng-Jia and Severino, Mariasavina and Kim, Sung-Hoon and Huang, Kevin and Rocca, Clarissa and Landsverk, Megan and Zaki, Maha S. and Al-Maawali, Almundher and Srinivasan, Varunvenkat M. and Al-Thihli, Khalid and Schaefer, G. Bradly and Davis, Monica and Tonduti, Davide and Doneda, Chiara and Marten, Lara M. and Mühlhausen, Chris and Gomez, Maria and Lamantea, Eleonora and Mena, Rafael and Nizon, Mathilde and Procaccio, Vincent and Begtrup, Amber and Telegrafi, Aida and Cui, Hong and Schulz, Heidi L. and Mohr, Julia and Biskup, Saskia and Loos, Mariana Amina and Aráoz, Hilda Verónica and Salpietro, Vincenzo and Keppen, Laura Davis and Chitre, Manali and Petree, Cassidy and Raymond, Lucy and Vogt, Julie and Sawyer, Lindsey B. and Basinger, Alice A. and Pedersen, Signe Vandal and Pearson, Toni S. and Grange, Dorothy K. and Lingappa, Lokesh and McDunnah, Paige and Horvath, Rita and Cognè, Benjamin and Isidor, Bertrand and Hahn, Andreas and Gripp, Karen W. and Jafarnejad, Seyed Mehdi and Østergaard, Elsebet and Prada, Carlos E. and Ghezzi, Daniele and Gowda, Vykuntaraju K. and Taylor, Robert W. and Sonenberg, Nahum and Houlden, Henry and Sissler, Marie and Varshney, Gaurav K. and Maroofian, Reza}, issn = {1098-3600}, journal = {Genetics in Medicine}, keywords = {Genetics (clinical)}, number = {11}, publisher = {Elsevier}, title = {{Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder}}, doi = {10.1016/j.gim.2023.100938}, volume = {25}, year = {2023}, } @phdthesis{14374, abstract = {Superconductivity has many important applications ranging from levitating trains over qubits to MRI scanners. The phenomenon is successfully modeled by Bardeen-Cooper-Schrieffer (BCS) theory. From a mathematical perspective, BCS theory has been studied extensively for systems without boundary. However, little is known in the presence of boundaries. With the help of numerical methods physicists observed that the critical temperature may increase in the presence of a boundary. The goal of this thesis is to understand the influence of boundaries on the critical temperature in BCS theory and to give a first rigorous justification of these observations. On the way, we also study two-body Schrödinger operators on domains with boundaries and prove additional results for superconductors without boundary. BCS theory is based on a non-linear functional, where the minimizer indicates whether the system is superconducting or in the normal, non-superconducting state. By considering the Hessian of the BCS functional at the normal state, one can analyze whether the normal state is possibly a minimum of the BCS functional and estimate the critical temperature. The Hessian turns out to be a linear operator resembling a Schrödinger operator for two interacting particles, but with more complicated kinetic energy. As a first step, we study the two-body Schrödinger operator in the presence of boundaries. For Neumann boundary conditions, we prove that the addition of a boundary can create new eigenvalues, which correspond to the two particles forming a bound state close to the boundary. Second, we need to understand superconductivity in the translation invariant setting. While in three dimensions this has been extensively studied, there is no mathematical literature for the one and two dimensional cases. In dimensions one and two, we compute the weak coupling asymptotics of the critical temperature and the energy gap in the translation invariant setting. We also prove that their ratio is independent of the microscopic details of the model in the weak coupling limit; this property is referred to as universality. In the third part, we study the critical temperature of superconductors in the presence of boundaries. We start by considering the one-dimensional case of a half-line with contact interaction. Then, we generalize the results to generic interactions and half-spaces in one, two and three dimensions. Finally, we compare the critical temperature of a quarter space in two dimensions to the critical temperatures of a half-space and of the full space.}, author = {Roos, Barbara}, issn = {2663 - 337X}, pages = {206}, publisher = {Institute of Science and Technology Austria}, title = {{Boundary superconductivity in BCS theory}}, doi = {10.15479/at:ista:14374}, year = {2023}, } @article{14377, abstract = {Coherent flows of self-propelled particles are characterized by vortices and jets that sustain chaotic flows, referred to as active turbulence. Here, we reveal a crossover between defect-free active turbulence and active turbulence laden with topological defects. Interestingly, we show that concurrent to the crossover from defect-free to defect-laden active turbulence is the restoration of the previously broken SO(2) symmetry signaled by the fast decay of the two-point correlations. By stability analyses of the topological charge density field, we provide theoretical insights on the criterion for the crossover to the defect-laden active turbulent state. Despite the distinct symmetry features between these two active turbulence regimes, the flow fluctuations exhibit universal statistical scaling behaviors at large scales, while the spectrum of polarity fluctuations decays exponentially at small length scales compared to the active energy injection length. These findings reveal a dynamical crossover between distinct spatiotemporal organization patterns in polar active matter.}, author = {Andersen, Benjamin H. and Renaud, Julian B and Rønning, Jonas and Angheluta, Luiza and Doostmohammadi, Amin}, issn = {2469-990X}, journal = {Physical Review Fluids}, keywords = {Fluid Flow and Transfer Processes, Modeling and Simulation, Computational Mechanics}, number = {6}, publisher = {American Physical Society}, title = {{Symmetry-restoring crossover from defect-free to defect-laden turbulence in polar active matter}}, doi = {10.1103/physrevfluids.8.063101}, volume = {8}, year = {2023}, } @article{14378, abstract = {Branching morphogenesis is a ubiquitous process that gives rise to high exchange surfaces in the vasculature and epithelial organs. Lymphatic capillaries form branched networks, which play a key role in the circulation of tissue fluid and immune cells. Although mouse models and correlative patient data indicate that the lymphatic capillary density directly correlates with functional output, i.e., tissue fluid drainage and trafficking efficiency of dendritic cells, the mechanisms ensuring efficient tissue coverage remain poorly understood. Here, we use the mouse ear pinna lymphatic vessel network as a model system and combine lineage-tracing, genetic perturbations, whole-organ reconstructions and theoretical modeling to show that the dermal lymphatic capillaries tile space in an optimal, space-filling manner. This coverage is achieved by two complementary mechanisms: initial tissue invasion provides a non-optimal global scaffold via self-organized branching morphogenesis, while VEGF-C dependent side-branching from existing capillaries rapidly optimizes local coverage by directionally targeting low-density regions. With these two ingredients, we show that a minimal biophysical model can reproduce quantitatively whole-network reconstructions, across development and perturbations. Our results show that lymphatic capillary networks can exploit local self-organizing mechanisms to achieve tissue-scale optimization.}, author = {Ucar, Mehmet C and Hannezo, Edouard B and Tiilikainen, Emmi and Liaqat, Inam and Jakobsson, Emma and Nurmi, Harri and Vaahtomeri, Kari}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Self-organized and directed branching results in optimal coverage in developing dermal lymphatic networks}}, doi = {10.1038/s41467-023-41456-7}, volume = {14}, year = {2023}, } @article{14400, abstract = {We consider the problem of computing the maximal probability of satisfying an -regular specification for stochastic, continuous-state, nonlinear systems evolving in discrete time. The problem reduces, after automata-theoretic constructions, to finding the maximal probability of satisfying a parity condition on a (possibly hybrid) state space. While characterizing the exact satisfaction probability is open, we show that a lower bound on this probability can be obtained by (I) computing an under-approximation of the qualitative winning region, i.e., states from which the parity condition can be enforced almost surely, and (II) computing the maximal probability of reaching this qualitative winning region. The heart of our approach is a technique to symbolically compute the under-approximation of the qualitative winning region in step (I) via a finite-state abstraction of the original system as a -player parity game. Our abstraction procedure uses only the support of the probabilistic evolution; it does not use precise numerical transition probabilities. We prove that the winning set in the abstract -player game induces an under-approximation of the qualitative winning region in the original synthesis problem, along with a policy to solve it. By combining these contributions with (a) a symbolic fixpoint algorithm to solve -player games and (b) existing techniques for reachability policy synthesis in stochastic nonlinear systems, we get an abstraction-based algorithm for finding a lower bound on the maximal satisfaction probability. We have implemented the abstraction-based algorithm in Mascot-SDS, where we combined the outlined abstraction step with our tool Genie (Majumdar et al., 2023) that solves -player parity games (through a reduction to Rabin games) more efficiently than existing algorithms. We evaluated our implementation on the nonlinear model of a perturbed bistable switch from the literature. We show empirically that the lower bound on the winning region computed by our approach is precise, by comparing against an over-approximation of the qualitative winning region. Moreover, our implementation outperforms a recently proposed tool for solving this problem by a large margin.}, author = {Majumdar, Rupak and Mallik, Kaushik and Schmuck, Anne Kathrin and Soudjani, Sadegh}, issn = {1751-570X}, journal = {Nonlinear Analysis: Hybrid Systems}, publisher = {Elsevier}, title = {{Symbolic control for stochastic systems via finite parity games}}, doi = {10.1016/j.nahs.2023.101430}, volume = {51}, year = {2023}, } @article{14401, abstract = {Background: Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective therapies and an understanding of the kinetics of BAX activation and the mechanisms controlling the two stages of this process in RGCs is potentially valuable in informing the development of a neuroprotective strategy. Methods: The kinetics of BAX translocation were assessed by both static and live-cell imaging of a GFP-BAX fusion protein introduced into RGCs using AAV2-mediated gene transfer in mice. Activation of BAX was achieved using an acute optic nerve crush (ONC) protocol. Live-cell imaging of GFP-BAX was achieved using explants of mouse retina harvested 7 days after ONC. Kinetics of translocation in RGCs were compared to GFP-BAX translocation in 661W tissue culture cells. Permeabilization of GFP-BAX was assessed by staining with the 6A7 monoclonal antibody, which recognizes a conformational change in this protein after MOM insertion. Assessment of individual kinases associated with both stages of activation was made using small molecule inhibitors injected into the vitreous either independently or in concert with ONC surgery. The contribution of the Dual Leucine Zipper-JUN-N-Terminal Kinase cascade was evaluated using mice with a double conditional knock-out of both Mkk4 and Mkk7. Results: ONC induces the translocation of GFP-BAX in RGCs at a slower rate and with less intracellular synchronicity than 661W cells, but exhibits less variability among mitochondrial foci within a single cell. GFP-BAX was also found to translocate in all compartments of an RGC including the dendritic arbor and axon. Approximately 6% of translocating RGCs exhibited retrotranslocation of BAX immediately following translocation. Unlike tissue culture cells, which exhibit simultaneous translocation and permeabilization, RGCs exhibited a significant delay between these two stages, similar to detached cells undergoing anoikis. Translocation, with minimal permeabilization could be induced in a subset of RGCs using an inhibitor of Focal Adhesion Kinase (PF573228). Permeabilization after ONC, in a majority of RGCs, could be inhibited with a broad spectrum kinase inhibitor (sunitinib) or a selective inhibitor for p38/MAPK14 (SB203580). Intervention of DLK-JNK axis signaling abrogated GFP-BAX translocation after ONC. Conclusions: A comparison between BAX activation kinetics in tissue culture cells and in cells of a complex tissue environment shows distinct differences indicating that caution should be used when translating findings from one condition to the other. RGCs exhibit both a delay between translocation and permeabilization and the ability for translocated BAX to be retrotranslocated, suggesting several stages at which intervention of the activation process could be exploited in the design of a therapeutic strategy.}, author = {Maes, Margaret E and Donahue, Ryan J. and Schlamp, Cassandra L. and Marola, Olivia J. and Libby, Richard T. and Nickells, Robert W.}, issn = {1750-1326}, journal = {Molecular Neurodegeneration}, publisher = {Springer Nature}, title = {{BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps}}, doi = {10.1186/s13024-023-00659-8}, volume = {18}, year = {2023}, } @article{14402, abstract = {Alpha oscillations are a distinctive feature of the awake resting state of the human brain. However, their functional role in resting-state neuronal dynamics remains poorly understood. Here we show that, during resting wakefulness, alpha oscillations drive an alternation of attenuation and amplification bouts in neural activity. Our analysis indicates that inhibition is activated in pulses that last for a single alpha cycle and gradually suppress neural activity, while excitation is successively enhanced over a few alpha cycles to amplify neural activity. Furthermore, we show that long-term alpha amplitude fluctuations—the “waxing and waning” phenomenon—are an attenuation-amplification mechanism described by a power-law decay of the activity rate in the “waning” phase. Importantly, we do not observe such dynamics during non-rapid eye movement (NREM) sleep with marginal alpha oscillations. The results suggest that alpha oscillations modulate neural activity not only through pulses of inhibition (pulsed inhibition hypothesis) but also by timely enhancement of excitation (or disinhibition).}, author = {Lombardi, Fabrizio and Herrmann, Hans J. and Parrino, Liborio and Plenz, Dietmar and Scarpetta, Silvia and Vaudano, Anna Elisabetta and De Arcangelis, Lucilla and Shriki, Oren}, issn = {2211-1247}, journal = {Cell Reports}, number = {10}, publisher = {Elsevier}, title = {{Beyond pulsed inhibition: Alpha oscillations modulate attenuation and amplification of neural activity in the awake resting state}}, doi = {10.1016/j.celrep.2023.113162}, volume = {42}, year = {2023}, } @inproceedings{14405, abstract = {We introduce hypernode automata as a new specification formalism for hyperproperties of concurrent systems. They are finite automata with nodes labeled with hypernode logic formulas and transitions labeled with actions. A hypernode logic formula specifies relations between sequences of variable values in different system executions. Unlike HyperLTL, hypernode logic takes an asynchronous view on execution traces by constraining the values and the order of value changes of each variable without correlating the timing of the changes. Different execution traces are synchronized solely through the transitions of hypernode automata. Hypernode automata naturally combine asynchronicity at the node level with synchronicity at the transition level. We show that the model-checking problem for hypernode automata is decidable over action-labeled Kripke structures, whose actions induce transitions of the specification automata. For this reason, hypernode automaton is a suitable formalism for specifying and verifying asynchronous hyperproperties, such as declassifying observational determinism in multi-threaded programs.}, author = {Bartocci, Ezio and Henzinger, Thomas A and Nickovic, Dejan and Oliveira da Costa, Ana}, booktitle = {34th International Conference on Concurrency Theory}, isbn = {9783959772990}, issn = {18688969}, location = {Antwerp, Belgium}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Hypernode automata}}, doi = {10.4230/LIPIcs.CONCUR.2023.21}, volume = {279}, year = {2023}, } @article{14406, abstract = {Recently, a concept of generalized multifractality, which characterizes fluctuations and correlations of critical eigenstates, was introduced and explored for all 10 symmetry classes of disordered systems. Here, by using the nonlinear sigma-model ( NL σ M ) field theory, we extend the theory of generalized multifractality to boundaries of systems at criticality. Our numerical simulations on two-dimensional systems of symmetry classes A, C, and AII fully confirm the analytical predictions of pure-scaling observables and Weyl symmetry relations between critical exponents of surface generalized multifractality. This demonstrates the validity of the NL σ M for the description of Anderson-localization critical phenomena, not only in the bulk but also on the boundary. The critical exponents strongly violate generalized parabolicity, in analogy with earlier results for the bulk, corroborating the conclusion that the considered Anderson-localization critical points are not described by conformal field theories. We further derive relations between generalized surface multifractal spectra and linear combinations of Lyapunov exponents of a strip in quasi-one-dimensional geometry, which hold under the assumption of invariance with respect to a logarithmic conformal map. Our numerics demonstrate that these relations hold with an excellent accuracy. Taken together, our results indicate an intriguing situation: the conformal invariance is broken but holds partially at critical points of Anderson localization.}, author = {Babkin, Serafim and Karcher, Jonas F. and Burmistrov, Igor S. and Mirlin, Alexander D.}, issn = {2469-9969}, journal = {Physical Review B}, number = {10}, publisher = {American Physical Society}, title = {{Generalized surface multifractality in two-dimensional disordered systems}}, doi = {10.1103/PhysRevB.108.104205}, volume = {108}, year = {2023}, } @article{14408, abstract = {We prove that the mesoscopic linear statistics ∑if(na(σi−z0)) of the eigenvalues {σi}i of large n×n non-Hermitian random matrices with complex centred i.i.d. entries are asymptotically Gaussian for any H20-functions f around any point z0 in the bulk of the spectrum on any mesoscopic scale 0