TY - JOUR AB - Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube. AU - Guerrero, Pilar AU - Perez-Carrasco, Ruben AU - Zagórski, Marcin P AU - Page, David AU - Kicheva, Anna AU - Briscoe, James AU - Page, Karen M. ID - 7165 IS - 23 JF - Development SN - 0950-1991 TI - Neuronal differentiation influences progenitor arrangement in the vertebrate neuroepithelium VL - 146 ER - TY - CONF AB - Cyber-physical systems (CPS) and the Internet-of-Things (IoT) result in a tremendous amount of generated, measured and recorded time-series data. Extracting temporal segments that encode patterns with useful information out of these huge amounts of data is an extremely difficult problem. We propose shape expressions as a declarative formalism for specifying, querying and extracting sophisticated temporal patterns from possibly noisy data. Shape expressions are regular expressions with arbitrary (linear, exponential, sinusoidal, etc.) shapes with parameters as atomic predicates and additional constraints on these parameters. We equip shape expressions with a novel noisy semantics that combines regular expression matching semantics with statistical regression. We characterize essential properties of the formalism and propose an efficient approximate shape expression matching procedure. We demonstrate the wide applicability of this technique on two case studies. AU - Ničković, Dejan AU - Qin, Xin AU - Ferrere, Thomas AU - Mateis, Cristinel AU - Deshmukh, Jyotirmoy ID - 7159 SN - 0302-9743 T2 - 19th International Conference on Runtime Verification TI - Shape expressions for specifying and extracting signal features VL - 11757 ER - TY - CONF AB - A probabilistic vector addition system with states (pVASS) is a finite state Markov process augmented with non-negative integer counters that can be incremented or decremented during each state transition, blocking any behaviour that would cause a counter to decrease below zero. The pVASS can be used as abstractions of probabilistic programs with many decidable properties. The use of pVASS as abstractions requires the presence of nondeterminism in the model. In this paper, we develop techniques for checking fast termination of pVASS with nondeterminism. That is, for every initial configuration of size n, we consider the worst expected number of transitions needed to reach a configuration with some counter negative (the expected termination time). We show that the problem whether the asymptotic expected termination time is linear is decidable in polynomial time for a certain natural class of pVASS with nondeterminism. Furthermore, we show the following dichotomy: if the asymptotic expected termination time is not linear, then it is at least quadratic, i.e., in Ω(n2). AU - Brázdil, Tomás AU - Chatterjee, Krishnendu AU - Kucera, Antonín AU - Novotný, Petr AU - Velan, Dominik ID - 7183 SN - 03029743 T2 - International Symposium on Automated Technology for Verification and Analysis TI - Deciding fast termination for probabilistic VASS with nondeterminism VL - 11781 ER - TY - JOUR AB - During infection pathogens secrete small molecules, termed effectors, to manipulate and control the interaction with their specific hosts. Both the pathogen and the plant are under high selective pressure to rapidly adapt and co-evolve in what is usually referred to as molecular arms race. Components of the host’s immune system form a network that processes information about molecules with a foreign origin and damage-associated signals, integrating them with developmental and abiotic cues to adapt the plant’s responses. Both in the case of nucleotide-binding leucine-rich repeat receptors and leucine-rich repeat receptor kinases interaction networks have been extensively characterized. However, little is known on whether pathogenic effectors form complexes to overcome plant immunity and promote disease. Ustilago maydis, a biotrophic fungal pathogen that infects maize plants, produces effectors that target hubs in the immune network of the host cell. Here we assess the capability of U. maydis effector candidates to interact with each other, which may play a crucial role during the infection process. Using a systematic yeast-two-hybrid approach and based on a preliminary pooled screen, we selected 63 putative effectors for one-on-one matings with a library of nearly 300 effector candidates. We found that 126 of these effector candidates interacted either with themselves or other predicted effectors. Although the functional relevance of the observed interactions remains elusive, we propose that the observed abundance in complex formation between effectors adds an additional level of complexity to effector research and should be taken into consideration when studying effector evolution and function. Based on this fundamental finding, we suggest various scenarios which could evolutionarily drive the formation and stabilization of an effector interactome. AU - Alcântara, André AU - Bosch, Jason AU - Nazari, Fahimeh AU - Hoffmann, Gesa AU - Gallei, Michelle C AU - Uhse, Simon AU - Darino, Martin A. AU - Olukayode, Toluwase AU - Reumann, Daniel AU - Baggaley, Laura AU - Djamei, Armin ID - 7182 IS - 11 JF - Frontiers in Plant Science TI - Systematic Y2H screening reveals extensive effector-complex formation VL - 10 ER - TY - JOUR AB - Arabidopsis PIN2 protein directs transport of the phytohormone auxin from the root tip into the root elongation zone. Variation in hormone transport, which depends on a delicate interplay between PIN2 sorting to and from polar plasma membrane domains, determines root growth. By employing a constitutively degraded version of PIN2, we identify brassinolides as antagonists of PIN2 endocytosis. This response does not require de novo protein synthesis, but involves early events in canonical brassinolide signaling. Brassinolide-controlled adjustments in PIN2 sorting and intracellular distribution governs formation of a lateral PIN2 gradient in gravistimulated roots, coinciding with adjustments in auxin signaling and directional root growth. Strikingly, simulations indicate that PIN2 gradient formation is no prerequisite for root bending but rather dampens asymmetric auxin flow and signaling. Crosstalk between brassinolide signaling and endocytic PIN2 sorting, thus, appears essential for determining the rate of gravity-induced root curvature via attenuation of differential cell elongation. AU - Retzer, Katarzyna AU - Akhmanova, Maria AU - Konstantinova, Nataliia AU - Malínská, Kateřina AU - Leitner, Johannes AU - Petrášek, Jan AU - Luschnig, Christian ID - 7180 JF - Nature Communications TI - Brassinosteroid signaling delimits root gravitropism via sorting of the Arabidopsis PIN2 auxin transporter VL - 10 ER - TY - JOUR AB - Multiple sequence alignments (MSAs) are used for structural1,2 and evolutionary predictions1,2, but the complexity of aligning large datasets requires the use of approximate solutions3, including the progressive algorithm4. Progressive MSA methods start by aligning the most similar sequences and subsequently incorporate the remaining sequences, from leaf-to-root, based on a guide-tree. Their accuracy declines substantially as the number of sequences is scaled up5. We introduce a regressive algorithm that enables MSA of up to 1.4 million sequences on a standard workstation and substantially improves accuracy on datasets larger than 10,000 sequences. Our regressive algorithm works the other way around to the progressive algorithm and begins by aligning the most dissimilar sequences. It uses an efficient divide-and-conquer strategy to run third-party alignment methods in linear time, regardless of their original complexity. Our approach will enable analyses of extremely large genomic datasets such as the recently announced Earth BioGenome Project, which comprises 1.5 million eukaryotic genomes6. AU - Garriga, Edgar AU - Di Tommaso, Paolo AU - Magis, Cedrik AU - Erb, Ionas AU - Mansouri, Leila AU - Baltzis, Athanasios AU - Laayouni, Hafid AU - Kondrashov, Fyodor AU - Floden, Evan AU - Notredame, Cedric ID - 7181 IS - 12 JF - Nature Biotechnology SN - 10870156 TI - Large multiple sequence alignments with a root-to-leaf regressive method VL - 37 ER - TY - JOUR AB - The cerebral cortex contains multiple areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modelling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas. AU - Llorca, Alfredo AU - Ciceri, Gabriele AU - Beattie, Robert J AU - Wong, Fong Kuan AU - Diana, Giovanni AU - Serafeimidou-Pouliou, Eleni AU - Fernández-Otero, Marian AU - Streicher, Carmen AU - Arnold, Sebastian J. AU - Meyer, Martin AU - Hippenmeyer, Simon AU - Maravall, Miguel AU - Marín, Oscar ID - 7202 JF - eLife TI - A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture VL - 8 ER - TY - JOUR AB - Glutamate is the major excitatory neurotransmitter in the CNS binding to a variety of glutamate receptors. Metabotropic glutamate receptors (mGluR1 to mGluR8) can act excitatory or inhibitory, depending on associated signal cascades. Expression and localization of inhibitory acting mGluRs at inner hair cells (IHCs) in the cochlea are largely unknown. Here, we analyzed expression of mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, and mGluR8 and investigated their localization with respect to the presynaptic ribbon of IHC synapses. We detected transcripts for mGluR2, mGluR3, and mGluR4 as well as for mGluR7a, mGluR7b, mGluR8a, and mGluR8b splice variants. Using receptor-specific antibodies in cochlear wholemounts, we found expression of mGluR2, mGluR4, and mGluR8b close to presynaptic ribbons. Super resolution and confocal microscopy in combination with 3-dimensional reconstructions indicated a postsynaptic localization of mGluR2 that overlaps with postsynaptic density protein 95 on dendrites of afferent type I spiral ganglion neurons. In contrast, mGluR4 and mGluR8b were expressed at the presynapse close to IHC ribbons. In summary, we localized in detail 3 mGluR types at IHC ribbon synapses, providing a fundament for new therapeutical strategies that could protect the cochlea against noxious stimuli and excitotoxicity. AU - Klotz, Lisa AU - Wendler, Olaf AU - Frischknecht, Renato AU - Shigemoto, Ryuichi AU - Schulze, Holger AU - Enz, Ralf ID - 7179 IS - 12 JF - FASEB Journal TI - Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses VL - 33 ER - TY - CONF AB - Applying machine learning techniques to the quickly growing data in science and industry requires highly-scalable algorithms. Large datasets are most commonly processed "data parallel" distributed across many nodes. Each node's contribution to the overall gradient is summed using a global allreduce. This allreduce is the single communication and thus scalability bottleneck for most machine learning workloads. We observe that frequently, many gradient values are (close to) zero, leading to sparse of sparsifyable communications. To exploit this insight, we analyze, design, and implement a set of communication-efficient protocols for sparse input data, in conjunction with efficient machine learning algorithms which can leverage these primitives. Our communication protocols generalize standard collective operations, by allowing processes to contribute arbitrary sparse input data vectors. Our generic communication library, SparCML1, extends MPI to support additional features, such as non-blocking (asynchronous) operations and low-precision data representations. As such, SparCML and its techniques will form the basis of future highly-scalable machine learning frameworks. AU - Renggli, Cedric AU - Ashkboos, Saleh AU - Aghagolzadeh, Mehdi AU - Alistarh, Dan-Adrian AU - Hoefler, Torsten ID - 7201 SN - 21674329 T2 - International Conference for High Performance Computing, Networking, Storage and Analysis, SC TI - SparCML: High-performance sparse communication for machine learning ER - TY - GEN AB - Genetic incompatibilities contribute to reproductive isolation between many diverging populations, but it is still unclear to what extent they play a role if divergence happens with gene flow. In contact zones between the "Crab" and "Wave" ecotypes of the snail Littorina saxatilis divergent selection forms strong barriers to gene flow, while the role of postzygotic barriers due to selection against hybrids remains unclear. High embryo abortion rates in this species could indicate the presence of such barriers. Postzygotic barriers might include genetic incompatibilities (e.g. Dobzhansky-Muller incompatibilities) but also maladaptation, both expected to be most pronounced in contact zones. In addition, embryo abortion might reflect physiological stress on females and embryos independent of any genetic stress. We examined all embryos of >500 females sampled outside and inside contact zones of three populations in Sweden. Females' clutch size ranged from 0 to 1011 embryos (mean 130±123) and abortion rates varied between 0 and100% (mean 12%). We described female genotypes by using a hybrid index based on hundreds of SNPs differentiated between ecotypes with which we characterised female genotypes. We also calculated female SNP heterozygosity and inversion karyotype. Clutch size did not vary with female hybrid index and abortion rates were only weakly related to hybrid index in two sites but not at all in a third site. No additional variation in abortion rate was explained by female SNP heterozygosity, but increased female inversion heterozygosity added slightly to increased abortion. Our results show only weak and probably biologically insignificant postzygotic barriers contributing to ecotype divergence and the high and variable abortion rates were marginally, if at all, explained by hybrid index of females. AU - Johannesson, Kerstin AU - Zagrodzka, Zuzanna AU - Faria, Rui AU - Westram, Anja M AU - Butlin, Roger ID - 13067 TI - Data from: Is embryo abortion a postzygotic barrier to gene flow between Littorina ecotypes? ER - TY - JOUR AB - Background: Many cancer genomes are extensively rearranged with highly aberrant chromosomal karyotypes. Structural and copy number variations in cancer genomes can be determined via abnormal mapping of sequenced reads to the reference genome. Recently it became possible to reconcile both of these types of large-scale variations into a karyotype graph representation of the rearranged cancer genomes. Such a representation, however, does not directly describe the linear and/or circular structure of the underlying rearranged cancer chromosomes, thus limiting possible analysis of cancer genomes somatic evolutionary process as well as functional genomic changes brought by the large-scale genome rearrangements. Results: Here we address the aforementioned limitation by introducing a novel methodological framework for recovering rearranged cancer chromosomes from karyotype graphs. For a cancer karyotype graph we formulate an Eulerian Decomposition Problem (EDP) of finding a collection of linear and/or circular rearranged cancer chromosomes that are determined by the graph. We derive and prove computational complexities for several variations of the EDP. We then demonstrate that Eulerian decomposition of the cancer karyotype graphs is not always unique and present the Consistent Contig Covering Problem (CCCP) of recovering unambiguous cancer contigs from the cancer karyotype graph, and describe a novel algorithm CCR capable of solving CCCP in polynomial time. We apply CCR on a prostate cancer dataset and demonstrate that it is capable of consistently recovering large cancer contigs even when underlying cancer genomes are highly rearranged. Conclusions: CCR can recover rearranged cancer contigs from karyotype graphs thereby addressing existing limitation in inferring chromosomal structures of rearranged cancer genomes and advancing our understanding of both patient/cancer-specific as well as the overall genetic instability in cancer. AU - Aganezov, Sergey AU - Zban, Ilya AU - Aksenov, Vitalii AU - Alexeev, Nikita AU - Schatz, Michael C. ID - 7214 JF - BMC Bioinformatics TI - Recovering rearranged cancer chromosomes from karyotype graphs VL - 20 ER - TY - JOUR AB - This is a literature teaching resource review for biologically inspired microfluidics courses or exploring the diverse applications of microfluidics. The structure is around key papers and model organisms. While courses gradually change over time, a focus remains on understanding how microfluidics has developed as well as what it can and cannot do for researchers. As a primary starting point, we cover micro-fluid mechanics principles and microfabrication of devices. A variety of applications are discussed using model prokaryotic and eukaryotic organisms from the set of bacteria (Escherichia coli), trypanosomes (Trypanosoma brucei), yeast (Saccharomyces cerevisiae), slime molds (Physarum polycephalum), worms (Caenorhabditis elegans), flies (Drosophila melangoster), plants (Arabidopsis thaliana), and mouse immune cells (Mus musculus). Other engineering and biochemical methods discussed include biomimetics, organ on a chip, inkjet, droplet microfluidics, biotic games, and diagnostics. While we have not yet reached the end-all lab on a chip, microfluidics can still be used effectively for specific applications. AU - Merrin, Jack ID - 7225 IS - 4 JF - Bioengineering TI - Frontiers in microfluidics, a teaching resource review VL - 6 ER - TY - CONF AB - Traditional concurrent programming involves manipulating shared mutable state. Alternatives to this programming style are communicating sequential processes (CSP) and actor models, which share data via explicit communication. These models have been known for almost half a century, and have recently had started to gain significant traction among modern programming languages. The common abstraction for communication between several processes is the channel. Although channels are similar to producer-consumer data structures, they have different semantics and support additional operations, such as the select expression. Despite their growing popularity, most known implementations of channels use lock-based data structures and can be rather inefficient. In this paper, we present the first efficient lock-free algorithm for implementing a communication channel for CSP programming. We provide implementations and experimental results in the Kotlin and Go programming languages. Our new algorithm outperforms existing implementations on many workloads, while providing non-blocking progress guarantee. Our design can serve as an example of how to construct general communication data structures for CSP and actor models. AU - Koval, Nikita AU - Alistarh, Dan-Adrian AU - Elizarov, Roman ID - 7228 SN - 0302-9743 T2 - 25th Anniversary of Euro-Par TI - Scalable FIFO channels for programming via communicating sequential processes VL - 11725 ER - TY - CONF AB - We present LiveTraVeL (Live Transit Vehicle Labeling), a real-time system to label a stream of noisy observations of transit vehicle trajectories with the transit routes they are serving (e.g., northbound bus #5). In order to scale efficiently to large transit networks, our system first retrieves a small set of candidate routes from a geometrically indexed data structure, then applies a fine-grained scoring step to choose the best match. Given that real-time data remains unavailable for the majority of the world’s transit agencies, these inferences can help feed a real-time map of a transit system’s trips, infer transit trip delays in real time, or measure and correct noisy transit tracking data. This system can run on vehicle observations from a variety of sources that don’t attach route information to vehicle observations, such as public imagery streams or user-contributed transit vehicle sightings.We abstract away the specifics of the sensing system and demonstrate the effectiveness of our system on a "semisynthetic" dataset of all New York City buses, where we simulate sensed trajectories by starting with fully labeled vehicle trajectories reported via the GTFS-Realtime protocol, removing the transit route IDs, and perturbing locations with synthetic noise. Using just the geometric shapes of the trajectories, we demonstrate that our system converges on the correct route ID within a few minutes, even after a vehicle switches from serving one trip to the next. AU - Osang, Georg F AU - Cook, James AU - Fabrikant, Alex AU - Gruteser, Marco ID - 7216 SN - 9781538670248 T2 - 2019 IEEE Intelligent Transportation Systems Conference TI - LiveTraVeL: Real-time matching of transit vehicle trajectories to transit routes at scale ER - TY - CONF AB - Piecewise Barrier Tubes (PBT) is a new technique for flowpipe overapproximation for nonlinear systems with polynomial dynamics, which leverages a combination of barrier certificates. PBT has advantages over traditional time-step based methods in dealing with those nonlinear dynamical systems in which there is a large difference in speed between trajectories, producing an overapproximation that is time independent. However, the existing approach for PBT is not efficient due to the application of interval methods for enclosure-box computation, and it can only deal with continuous dynamical systems without uncertainty. In this paper, we extend the approach with the ability to handle both continuous and hybrid dynamical systems with uncertainty that can reside in parameters and/or noise. We also improve the efficiency of the method significantly, by avoiding the use of interval-based methods for the enclosure-box computation without loosing soundness. We have developed a C++ prototype implementing the proposed approach and we evaluate it on several benchmarks. The experiments show that our approach is more efficient and precise than other methods in the literature. AU - Kong, Hui AU - Bartocci, Ezio AU - Jiang, Yu AU - Henzinger, Thomas A ID - 7231 SN - 0302-9743 T2 - 17th International Conference on Formal Modeling and Analysis of Timed Systems TI - Piecewise robust barrier tubes for nonlinear hybrid systems with uncertainty VL - 11750 ER - TY - JOUR AB - Coupling of endoplasmic reticulum stress to dimerisation‑dependent activation of the UPR transducer IRE1 is incompletely understood. Whilst the luminal co-chaperone ERdj4 promotes a complex between the Hsp70 BiP and IRE1's stress-sensing luminal domain (IRE1LD) that favours the latter's monomeric inactive state and loss of ERdj4 de-represses IRE1, evidence linking these cellular and in vitro observations is presently lacking. We report that enforced loading of endogenous BiP onto endogenous IRE1α repressed UPR signalling in CHO cells and deletions in the IRE1α locus that de-repressed the UPR in cells, encode flexible regions of IRE1LD that mediated BiP‑induced monomerisation in vitro. Changes in the hydrogen exchange mass spectrometry profile of IRE1LD induced by ERdj4 and BiP confirmed monomerisation and were consistent with active destabilisation of the IRE1LD dimer. Together, these observations support a competition model whereby waning ER stress passively partitions ERdj4 and BiP to IRE1LD to initiate active repression of UPR signalling. AU - Amin-Wetzel, Niko Paresh AU - Neidhardt, Lisa AU - Yan, Yahui AU - Mayer, Matthias P. AU - Ron, David ID - 7340 JF - eLife TI - Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR VL - 8 ER - TY - JOUR AB - Biochemical reactions often occur at low copy numbers but at once in crowded and diverse environments. Space and stochasticity therefore play an essential role in biochemical networks. Spatial-stochastic simulations have become a prominent tool for understanding how stochasticity at the microscopic level influences the macroscopic behavior of such systems. While particle-based models guarantee the level of detail necessary to accurately describe the microscopic dynamics at very low copy numbers, the algorithms used to simulate them typically imply trade-offs between computational efficiency and biochemical accuracy. eGFRD (enhanced Green’s Function Reaction Dynamics) is an exact algorithm that evades such trade-offs by partitioning the N-particle system into M ≤ N analytically tractable one- and two-particle systems; the analytical solutions (Green’s functions) then are used to implement an event-driven particle-based scheme that allows particles to make large jumps in time and space while retaining access to their state variables at arbitrary simulation times. Here we present “eGFRD2,” a new eGFRD version that implements the principle of eGFRD in all dimensions, thus enabling efficient particle-based simulation of biochemical reaction-diffusion processes in the 3D cytoplasm, on 2D planes representing membranes, and on 1D elongated cylinders representative of, e.g., cytoskeletal tracks or DNA; in 1D, it also incorporates convective motion used to model active transport. We find that, for low particle densities, eGFRD2 is up to 6 orders of magnitude faster than conventional Brownian dynamics. We exemplify the capabilities of eGFRD2 by simulating an idealized model of Pom1 gradient formation, which involves 3D diffusion, active transport on microtubules, and autophosphorylation on the membrane, confirming recent experimental and theoretical results on this system to hold under genuinely stochastic conditions. AU - Sokolowski, Thomas R AU - Paijmans, Joris AU - Bossen, Laurens AU - Miedema, Thomas AU - Wehrens, Martijn AU - Becker, Nils B. AU - Kaizu, Kazunari AU - Takahashi, Koichi AU - Dogterom, Marileen AU - ten Wolde, Pieter Rein ID - 7422 IS - 5 JF - The Journal of Chemical Physics SN - 0021-9606 TI - eGFRD in all dimensions VL - 150 ER - TY - CONF AB - Simple drawings of graphs are those in which each pair of edges share at most one point, either a common endpoint or a proper crossing. In this paper we study the problem of extending a simple drawing D(G) of a graph G by inserting a set of edges from the complement of G into D(G) such that the result is a simple drawing. In the context of rectilinear drawings, the problem is trivial. For pseudolinear drawings, the existence of such an extension follows from Levi’s enlargement lemma. In contrast, we prove that deciding if a given set of edges can be inserted into a simple drawing is NP-complete. Moreover, we show that the maximization version of the problem is APX-hard. We also present a polynomial-time algorithm for deciding whether one edge uv can be inserted into D(G) when {u,v} is a dominating set for the graph G. AU - Arroyo Guevara, Alan M AU - Derka, Martin AU - Parada, Irene ID - 7230 SN - 0302-9743 T2 - 27th International Symposium on Graph Drawing and Network Visualization TI - Extending simple drawings VL - 11904 ER - TY - CONF AB - We present Mixed-time Signal Temporal Logic (STL−MX), a specification formalism which extends STL by capturing the discrete/ continuous time duality found in many cyber-physical systems (CPS), as well as mixed-signal electronic designs. In STL−MX, properties of components with continuous dynamics are expressed in STL, while specifications of components with discrete dynamics are written in LTL. To combine the two layers, we evaluate formulas on two traces, discrete- and continuous-time, and introduce two interface operators that map signals, properties and their satisfaction signals across the two time domains. We show that STL-mx has the expressive power of STL supplemented with an implicit T-periodic clock signal. We develop and implement an algorithm for monitoring STL-mx formulas and illustrate the approach using a mixed-signal example. AU - Ferrere, Thomas AU - Maler, Oded AU - Nickovic, Dejan ID - 7232 SN - 0302-9743 T2 - 17th International Conference on Formal Modeling and Analysis of Timed Systems TI - Mixed-time signal temporal logic VL - 11750 ER - TY - JOUR AB - β1-integrins mediate cell–matrix interactions and their trafficking is important in the dynamic regulation of cell adhesion, migration and malignant processes, including cancer cell invasion. Here, we employ an RNAi screen to characterize regulators of integrin traffic and identify the association of Golgi-localized gamma ear-containing Arf-binding protein 2 (GGA2) with β1-integrin, and its role in recycling of active but not inactive β1-integrin receptors. Silencing of GGA2 limits active β1-integrin levels in focal adhesions and decreases cancer cell migration and invasion, which is in agreement with its ability to regulate the dynamics of active integrins. By using the proximity-dependent biotin identification (BioID) method, we identified two RAB family small GTPases, i.e. RAB13 and RAB10, as novel interactors of GGA2. Functionally, RAB13 silencing triggers the intracellular accumulation of active β1-integrin, and reduces integrin activity in focal adhesions and cell migration similarly to GGA2 depletion, indicating that both facilitate active β1-integrin recycling to the plasma membrane. Thus, GGA2 and RAB13 are important specificity determinants for integrin activity-dependent traffic. AU - Sahgal, Pranshu AU - Alanko, Jonna H AU - Icha, Jaroslav AU - Paatero, Ilkka AU - Hamidi, Hellyeh AU - Arjonen, Antti AU - Pietilä, Mika AU - Rokka, Anne AU - Ivaska, Johanna ID - 7420 IS - 11 JF - Journal of Cell Science SN - 0021-9533 TI - GGA2 and RAB13 promote activity-dependent β1-integrin recycling VL - 132 ER - TY - JOUR AB - We compare finite rank perturbations of the following three ensembles of complex rectangular random matrices: First, a generalised Wishart ensemble with one random and two fixed correlation matrices introduced by Borodin and Péché, second, the product of two independent random matrices where one has correlated entries, and third, the case when the two random matrices become also coupled through a fixed matrix. The singular value statistics of all three ensembles is shown to be determinantal and we derive double contour integral representations for their respective kernels. Three different kernels are found in the limit of infinite matrix dimension at the origin of the spectrum. They depend on finite rank perturbations of the correlation and coupling matrices and are shown to be integrable. The first kernel (I) is found for two independent matrices from the second, and two weakly coupled matrices from the third ensemble. It generalises the Meijer G-kernel for two independent and uncorrelated matrices. The third kernel (III) is obtained for the generalised Wishart ensemble and for two strongly coupled matrices. It further generalises the perturbed Bessel kernel of Desrosiers and Forrester. Finally, kernel (II), found for the ensemble of two coupled matrices, provides an interpolation between the kernels (I) and (III), generalising previous findings of part of the authors. AU - Akemann, Gernot AU - Checinski, Tomasz AU - Liu, Dangzheng AU - Strahov, Eugene ID - 7423 IS - 1 JF - Annales de l'Institut Henri Poincaré, Probabilités et Statistiques SN - 0246-0203 TI - Finite rank perturbations in products of coupled random matrices: From one correlated to two Wishart ensembles VL - 55 ER - TY - JOUR AB - X and Y chromosomes can diverge when rearrangements block recombination between them. Here we present the first genomic view of a reciprocal translocation that causes two physically unconnected pairs of chromosomes to be coinherited as sex chromosomes. In a population of the common frog (Rana temporaria), both pairs of X and Y chromosomes show extensive sequence differentiation, but not degeneration of the Y chromosomes. A new method based on gene trees shows both chromosomes are sex‐linked. Furthermore, the gene trees from the two Y chromosomes have identical topologies, showing they have been coinherited since the reciprocal translocation occurred. Reciprocal translocations can thus reshape sex linkage on a much greater scale compared with inversions, the type of rearrangement that is much better known in sex chromosome evolution, and they can greatly amplify the power of sexually antagonistic selection to drive genomic rearrangement. Two more populations show evidence of other rearrangements, suggesting that this species has unprecedented structural polymorphism in its sex chromosomes. AU - Toups, Melissa A AU - Rodrigues, Nicolas AU - Perrin, Nicolas AU - Kirkpatrick, Mark ID - 7421 IS - 8 JF - Molecular Ecology SN - 0962-1083 TI - A reciprocal translocation radically reshapes sex‐linked inheritance in the common frog VL - 28 ER - TY - CONF AB - Proofs of sequential work (PoSW) are proof systems where a prover, upon receiving a statement χ and a time parameter T computes a proof ϕ(χ,T) which is efficiently and publicly verifiable. The proof can be computed in T sequential steps, but not much less, even by a malicious party having large parallelism. A PoSW thus serves as a proof that T units of time have passed since χ was received. PoSW were introduced by Mahmoody, Moran and Vadhan [MMV11], a simple and practical construction was only recently proposed by Cohen and Pietrzak [CP18]. In this work we construct a new simple PoSW in the random permutation model which is almost as simple and efficient as [CP18] but conceptually very different. Whereas the structure underlying [CP18] is a hash tree, our construction is based on skip lists and has the interesting property that computing the PoSW is a reversible computation. The fact that the construction is reversible can potentially be used for new applications like constructing proofs of replication. We also show how to “embed” the sloth function of Lenstra and Weselowski [LW17] into our PoSW to get a PoSW where one additionally can verify correctness of the output much more efficiently than recomputing it (though recent constructions of “verifiable delay functions” subsume most of the applications this construction was aiming at). AU - Abusalah, Hamza M AU - Kamath Hosdurg, Chethan AU - Klein, Karen AU - Pietrzak, Krzysztof Z AU - Walter, Michael ID - 7411 SN - 0302-9743 T2 - Advances in Cryptology – EUROCRYPT 2019 TI - Reversible proofs of sequential work VL - 11477 ER - TY - JOUR AB - Background Synaptic vesicles (SVs) are an integral part of the neurotransmission machinery, and isolation of SVs from their host neuron is necessary to reveal their most fundamental biochemical and functional properties in in vitro assays. Isolated SVs from neurons that have been genetically engineered, e.g. to introduce genetically encoded indicators, are not readily available but would permit new insights into SV structure and function. Furthermore, it is unclear if cultured neurons can provide sufficient starting material for SV isolation procedures. New method Here, we demonstrate an efficient ex vivo procedure to obtain functional SVs from cultured rat cortical neurons after genetic engineering with a lentivirus. Results We show that ∼108 plated cortical neurons allow isolation of suitable SV amounts for functional analysis and imaging. We found that SVs isolated from cultured neurons have neurotransmitter uptake comparable to that of SVs isolated from intact cortex. Using total internal reflection fluorescence (TIRF) microscopy, we visualized an exogenous SV-targeted marker protein and demonstrated the high efficiency of SV modification. Comparison with existing methods Obtaining SVs from genetically engineered neurons currently generally requires the availability of transgenic animals, which is constrained by technical (e.g. cost and time) and biological (e.g. developmental defects and lethality) limitations. Conclusions These results demonstrate the modification and isolation of functional SVs using cultured neurons and viral transduction. The ability to readily obtain SVs from genetically engineered neurons will permit linking in situ studies to in vitro experiments in a variety of genetic contexts. AU - Mckenzie, Catherine AU - Spanova, Miroslava AU - Johnson, Alexander J AU - Kainrath, Stephanie AU - Zheden, Vanessa AU - Sitte, Harald H. AU - Janovjak, Harald L ID - 7406 JF - Journal of Neuroscience Methods SN - 0165-0270 TI - Isolation of synaptic vesicles from genetically engineered cultured neurons VL - 312 ER - TY - CONF AB - Most of today's distributed machine learning systems assume reliable networks: whenever two machines exchange information (e.g., gradients or models), the network should guarantee the delivery of the message. At the same time, recent work exhibits the impressive tolerance of machine learning algorithms to errors or noise arising from relaxed communication or synchronization. In this paper, we connect these two trends, and consider the following question: Can we design machine learning systems that are tolerant to network unreliability during training? With this motivation, we focus on a theoretical problem of independent interest-given a standard distributed parameter server architecture, if every communication between the worker and the server has a non-zero probability p of being dropped, does there exist an algorithm that still converges, and at what speed? The technical contribution of this paper is a novel theoretical analysis proving that distributed learning over unreliable network can achieve comparable convergence rate to centralized or distributed learning over reliable networks. Further, we prove that the influence of the packet drop rate diminishes with the growth of the number of parameter servers. We map this theoretical result onto a real-world scenario, training deep neural networks over an unreliable network layer, and conduct network simulation to validate the system improvement by allowing the networks to be unreliable. AU - Yu, Chen AU - Tang, Hanlin AU - Renggli, Cedric AU - Kassing, Simon AU - Singla, Ankit AU - Alistarh, Dan-Adrian AU - Zhang, Ce AU - Liu, Ji ID - 7437 SN - 9781510886988 T2 - 36th International Conference on Machine Learning, ICML 2019 TI - Distributed learning over unreliable networks VL - 2019-June ER - TY - JOUR AB - We develop a framework for the rigorous analysis of focused stochastic local search algorithms. These algorithms search a state space by repeatedly selecting some constraint that is violated in the current state and moving to a random nearby state that addresses the violation, while (we hope) not introducing many new violations. An important class of focused local search algorithms with provable performance guarantees has recently arisen from algorithmizations of the Lovász local lemma (LLL), a nonconstructive tool for proving the existence of satisfying states by introducing a background measure on the state space. While powerful, the state transitions of algorithms in this class must be, in a precise sense, perfectly compatible with the background measure. In many applications this is a very restrictive requirement, and one needs to step outside the class. Here we introduce the notion of measure distortion and develop a framework for analyzing arbitrary focused stochastic local search algorithms, recovering LLL algorithmizations as the special case of no distortion. Our framework takes as input an arbitrary algorithm of such type and an arbitrary probability measure and shows how to use the measure as a yardstick of algorithmic progress, even for algorithms designed independently of the measure. AU - Achlioptas, Dimitris AU - Iliopoulos, Fotis AU - Kolmogorov, Vladimir ID - 7412 IS - 5 JF - SIAM Journal on Computing SN - 0097-5397 TI - A local lemma for focused stochastical algorithms VL - 48 ER - TY - JOUR AB - Multiple importance sampling (MIS) has become an indispensable tool in Monte Carlo rendering, widely accepted as a near-optimal solution for combining different sampling techniques. But an MIS combination, using the common balance or power heuristics, often results in an overly defensive estimator, leading to high variance. We show that by generalizing the MIS framework, variance can be substantially reduced. Specifically, we optimize one of the combined sampling techniques so as to decrease the overall variance of the resulting MIS estimator. We apply the approach to the computation of direct illumination due to an HDR environment map and to the computation of global illumination using a path guiding algorithm. The implementation can be as simple as subtracting a constant value from the tabulated sampling density done entirely in a preprocessing step. This produces a consistent noise reduction in all our tests with no negative influence on run time, no artifacts or bias, and no failure cases. AU - Karlík, Ondřej AU - Šik, Martin AU - Vévoda, Petr AU - Skrivan, Tomas AU - Křivánek, Jaroslav ID - 7418 IS - 6 JF - ACM Transactions on Graphics SN - 0730-0301 TI - MIS compensation: Optimizing sampling techniques in multiple importance sampling VL - 38 ER - TY - JOUR AB - We consider Bose gases consisting of N particles trapped in a box with volume one and interacting through a repulsive potential with scattering length of order N−1 (Gross–Pitaevskii regime). We determine the ground state energy and the low-energy excitation spectrum, up to errors vanishing as N→∞. Our results confirm Bogoliubov’s predictions. AU - Boccato, Chiara AU - Brennecke, Christian AU - Cenatiempo, Serena AU - Schlein, Benjamin ID - 7413 IS - 2 JF - Acta Mathematica SN - 0001-5962 TI - Bogoliubov theory in the Gross–Pitaevskii limit VL - 222 ER - TY - JOUR AB - The study of parallel ecological divergence provides important clues to the operation of natural selection. Parallel divergence often occurs in heterogeneous environments with different kinds of environmental gradients in different locations, but the genomic basis underlying this process is unknown. We investigated the genomics of rapid parallel adaptation in the marine snail Littorina saxatilis in response to two independent environmental axes (crab-predation versus wave-action and low-shore versus high-shore). Using pooled whole-genome resequencing, we show that sharing of genomic regions of high differentiation between environments is generally low but increases at smaller spatial scales. We identify different shared genomic regions of divergence for each environmental axis and show that most of these regions overlap with candidate chromosomal inversions. Several inversion regions are divergent and polymorphic across many localities. We argue that chromosomal inversions could store shared variation that fuels rapid parallel adaptation to heterogeneous environments, possibly as balanced polymorphism shared by adaptive gene flow. AU - Morales, Hernán E. AU - Faria, Rui AU - Johannesson, Kerstin AU - Larsson, Tomas AU - Panova, Marina AU - Westram, Anja M AU - Butlin, Roger K. ID - 7393 IS - 12 JF - Science Advances SN - 2375-2548 TI - Genomic architecture of parallel ecological divergence: Beyond a single environmental contrast VL - 5 ER - TY - JOUR AB - Polymer additives can substantially reduce the drag of turbulent flows and the upperlimit, the so called “maximum drag reduction” (MDR) asymptote is universal, i.e. inde-pendent of the type of polymer and solvent used. Until recently, the consensus was that,in this limit, flows are in a marginal state where only a minimal level of turbulence activ-ity persists. Observations in direct numerical simulations using minimal sized channelsappeared to support this view and reported long “hibernation” periods where turbu-lence is marginalized. In simulations of pipe flow we find that, indeed, with increasingWeissenberg number (Wi), turbulence expresses long periods of hibernation if the domainsize is small. However, with increasing pipe length, the temporal hibernation continuouslyalters to spatio-temporal intermittency and here the flow consists of turbulent puffs sur-rounded by laminar flow. Moreover, upon an increase in Wi, the flow fully relaminarises,in agreement with recent experiments. At even larger Wi, a different instability is en-countered causing a drag increase towards MDR. Our findings hence link earlier minimalflow unit simulations with recent experiments and confirm that the addition of polymersinitially suppresses Newtonian turbulence and leads to a reverse transition. The MDRstate on the other hand results from a separate instability and the underlying dynamicscorresponds to the recently proposed state of elasto-inertial-turbulence (EIT). AU - Lopez Alonso, Jose M AU - Choueiri, George H AU - Hof, Björn ID - 7397 JF - Journal of Fluid Mechanics SN - 0022-1120 TI - Dynamics of viscoelastic pipe flow at low Reynolds numbers in the maximum drag reduction limit VL - 874 ER - TY - JOUR AB - The order-k Voronoi tessellation of a locally finite set 𝑋⊆ℝ𝑛 decomposes ℝ𝑛 into convex domains whose points have the same k nearest neighbors in X. Assuming X is a stationary Poisson point process, we give explicit formulas for the expected number and total area of faces of a given dimension per unit volume of space. We also develop a relaxed version of discrete Morse theory and generalize by counting only faces, for which the k nearest points in X are within a given distance threshold. AU - Edelsbrunner, Herbert AU - Nikitenko, Anton ID - 5678 IS - 4 JF - Discrete and Computational Geometry SN - 01795376 TI - Poisson–Delaunay Mosaics of Order k VL - 62 ER - TY - JOUR AB - Hippocampus is needed for both spatial working and reference memories. Here, using a radial eight-arm maze, we examined how the combined demand on these memories influenced CA1 place cell assemblies while reference memories were partially updated. This was contrasted with control tasks requiring only working memory or the update of reference memory. Reference memory update led to the reward-directed place field shifts at newly rewarded arms and to the gradual strengthening of firing in passes between newly rewarded arms but not between those passes that included a familiar-rewarded arm. At the maze center, transient network synchronization periods preferentially replayed trajectories of the next chosen arm in reference memory tasks but the previously visited arm in the working memory task. Hence, reference memory demand was uniquely associated with a gradual, goal novelty-related reorganization of place cell assemblies and with trajectory replay that reflected the animal's decision of which arm to visit next. AU - Xu, Haibing AU - Baracskay, Peter AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 5828 IS - 1 JF - Neuron SN - 10974199 TI - Assembly responses of hippocampal CA1 place cells predict learned behavior in goal-directed spatial tasks on the radial eight-arm maze VL - 101 ER - TY - JOUR AB - We give a bound on the ground-state energy of a system of N non-interacting fermions in a three-dimensional cubic box interacting with an impurity particle via point interactions. We show that the change in energy compared to the system in the absence of the impurity is bounded in terms of the gas density and the scattering length of the interaction, independently of N. Our bound holds as long as the ratio of the mass of the impurity to the one of the gas particles is larger than a critical value m∗ ∗≈ 0.36 , which is the same regime for which we recently showed stability of the system. AU - Moser, Thomas AU - Seiringer, Robert ID - 5856 IS - 4 JF - Annales Henri Poincare SN - 14240637 TI - Energy contribution of a point-interacting impurity in a Fermi gas VL - 20 ER - TY - THES AB - In many shear flows like pipe flow, plane Couette flow, plane Poiseuille flow, etc. turbulence emerges subcritically. Here, when subjected to strong enough perturbations, the flow becomes turbulent in spite of the laminar base flow being linearly stable. The nature of this instability has puzzled the scientific community for decades. At onset, turbulence appears in localized patches and flows are spatio-temporally intermittent. In pipe flow the localized turbulent structures are referred to as puffs and in planar flows like plane Couette and channel flow, patches arise in the form of localized oblique bands. In this thesis, we study the onset of turbulence in channel flow in direct numerical simulations from a dynamical system theory perspective, as well as by performing experiments in a large aspect ratio channel. The aim of the experimental work is to determine the critical Reynolds number where turbulence first becomes sustained. Recently, the onset of turbulence has been described in analogy to absorbing state phase transition (i.e. directed percolation). In particular, it has been shown that the critical point can be estimated from the competition between spreading and decay processes. Here, by performing experiments, we identify the mechanisms underlying turbulence proliferation in channel flow and find the critical Reynolds number, above which turbulence becomes sustained. Above the critical point, the continuous growth at the tip of the stripes outweighs the stochastic shedding of turbulent patches at the tail and the stripes expand. For growing stripes, the probability to decay decreases while the probability of stripe splitting increases. Consequently, and unlike for the puffs in pipe flow, neither of these two processes is time-independent i.e. memoryless. Coupling between stripe expansion and creation of new stripes via splitting leads to a significantly lower critical point ($Re_c=670+/-10$) than most earlier studies suggest. While the above approach sheds light on how turbulence first becomes sustained, it provides no insight into the origin of the stripes themselves. In the numerical part of the thesis we investigate how turbulent stripes form from invariant solutions of the Navier-Stokes equations. The origin of these turbulent stripes can be identified by applying concepts from the dynamical system theory. In doing so, we identify the exact coherent structures underlying stripes and their bifurcations and how they give rise to the turbulent attractor in phase space. We first report a family of localized nonlinear traveling wave solutions of the Navier-Stokes equations in channel flow. These solutions show structural similarities with turbulent stripes in experiments like obliqueness, quasi-streamwise streaks and vortices, etc. A parametric study of these traveling wave solution is performed, with parameters like Reynolds number, stripe tilt angle and domain size, including the stability of the solutions. These solutions emerge through saddle-node bifurcations and form a phase space skeleton for the turbulent stripes observed in the experiments. The lower branches of these TW solutions at different tilt angles undergo Hopf bifurcation and new solutions branches of relative periodic orbits emerge. These RPO solutions do not belong to the same family and therefore the routes to chaos for different angles are different. In shear flows, turbulence at onset is transient in nature. Consequently,turbulence can not be tracked to lower Reynolds numbers, where the dynamics may simplify. Before this happens, turbulence becomes short-lived and laminarizes. In the last part of the thesis, we show that using numerical simulations we can continue turbulent stripes in channel flow past the 'relaminarization barrier' all the way to their origin. Here, turbulent stripe dynamics simplifies and the fluctuations are no longer stochastic and the stripe settles down to a relative periodic orbit. This relative periodic orbit originates from the aforementioned traveling wave solutions. Starting from the relative periodic orbit, a small increase in speed i.e. Reynolds number gives rise to chaos and the attractor dimension sharply increases in contrast to the classical transition scenario where the instabilities affect the flow globally and give rise to much more gradual route to turbulence. AU - Paranjape, Chaitanya S ID - 6957 KW - Instabilities KW - Turbulence KW - Nonlinear dynamics TI - Onset of turbulence in plane Poiseuille flow ER - TY - JOUR AB - We consider large random matrices with a general slowly decaying correlation among its entries. We prove universality of the local eigenvalue statistics and optimal local laws for the resolvent away from the spectral edges, generalizing the recent result of Ajanki et al. [‘Stability of the matrix Dyson equation and random matrices with correlations’, Probab. Theory Related Fields 173(1–2) (2019), 293–373] to allow slow correlation decay and arbitrary expectation. The main novel tool is a systematic diagrammatic control of a multivariate cumulant expansion. AU - Erdös, László AU - Krüger, Torben H AU - Schröder, Dominik J ID - 6182 JF - Forum of Mathematics, Sigma TI - Random matrices with slow correlation decay VL - 7 ER - TY - JOUR AB - We prove that the local eigenvalue statistics of real symmetric Wigner-type matrices near the cusp points of the eigenvalue density are universal. Together with the companion paper [arXiv:1809.03971], which proves the same result for the complex Hermitian symmetry class, this completes the last remaining case of the Wigner-Dyson-Mehta universality conjecture after bulk and edge universalities have been established in the last years. We extend the recent Dyson Brownian motion analysis at the edge [arXiv:1712.03881] to the cusp regime using the optimal local law from [arXiv:1809.03971] and the accurate local shape analysis of the density from [arXiv:1506.05095, arXiv:1804.07752]. We also present a PDE-based method to improve the estimate on eigenvalue rigidity via the maximum principle of the heat flow related to the Dyson Brownian motion. AU - Cipolloni, Giorgio AU - Erdös, László AU - Krüger, Torben H AU - Schröder, Dominik J ID - 6186 IS - 4 JF - Pure and Applied Analysis SN - 2578-5893 TI - Cusp universality for random matrices, II: The real symmetric case VL - 1 ER - TY - JOUR AB - Across diverse biological systems—ranging from neural networks to intracellular signaling and genetic regulatory networks—the information about changes in the environment is frequently encoded in the full temporal dynamics of the network nodes. A pressing data-analysis challenge has thus been to efficiently estimate the amount of information that these dynamics convey from experimental data. Here we develop and evaluate decoding-based estimation methods to lower bound the mutual information about a finite set of inputs, encoded in single-cell high-dimensional time series data. For biological reaction networks governed by the chemical Master equation, we derive model-based information approximations and analytical upper bounds, against which we benchmark our proposed model-free decoding estimators. In contrast to the frequently-used k-nearest-neighbor estimator, decoding-based estimators robustly extract a large fraction of the available information from high-dimensional trajectories with a realistic number of data samples. We apply these estimators to previously published data on Erk and Ca2+ signaling in mammalian cells and to yeast stress-response, and find that substantial amount of information about environmental state can be encoded by non-trivial response statistics even in stationary signals. We argue that these single-cell, decoding-based information estimates, rather than the commonly-used tests for significant differences between selected population response statistics, provide a proper and unbiased measure for the performance of biological signaling networks. AU - Cepeda Humerez, Sarah A AU - Ruess, Jakob AU - Tkačik, Gašper ID - 6900 IS - 9 JF - PLoS computational biology TI - Estimating information in time-varying signals VL - 15 ER - TY - JOUR AB - Clathrin-mediated endocytosis (CME) is a highly conserved and essential cellular process in eukaryotic cells, but its dynamic and vital nature makes it challenging to study using classical genetics tools. In contrast, although small molecules can acutely and reversibly perturb CME, the few chemical CME inhibitors that have been applied to plants are either ineffective or show undesirable side effects. Here, we identify the previously described endosidin9 (ES9) as an inhibitor of clathrin heavy chain (CHC) function in both Arabidopsis and human cells through affinity-based target isolation, in vitro binding studies and X-ray crystallography. Moreover, we present a chemically improved ES9 analog, ES9-17, which lacks the undesirable side effects of ES9 while retaining the ability to target CHC. ES9 and ES9-17 have expanded the chemical toolbox used to probe CHC function, and present chemical scaffolds for further design of more specific and potent CHC inhibitors across different systems. AU - Dejonghe, Wim AU - Sharma, Isha AU - Denoo, Bram AU - De Munck, Steven AU - Lu, Qing AU - Mishev, Kiril AU - Bulut, Haydar AU - Mylle, Evelien AU - De Rycke, Riet AU - Vasileva, Mina K AU - Savatin, Daniel V. AU - Nerinckx, Wim AU - Staes, An AU - Drozdzecki, Andrzej AU - Audenaert, Dominique AU - Yperman, Klaas AU - Madder, Annemieke AU - Friml, Jiří AU - Van Damme, Daniël AU - Gevaert, Kris AU - Haucke, Volker AU - Savvides, Savvas N. AU - Winne, Johan AU - Russinova, Eugenia ID - 6377 IS - 6 JF - Nature Chemical Biology SN - 15524450 TI - Disruption of endocytosis through chemical inhibition of clathrin heavy chain function VL - 15 ER - TY - THES AB - Tissue morphogenesis in developmental or physiological processes is regulated by molecular and mechanical signals. While the molecular signaling cascades are increasingly well described, the mechanical signals affecting tissue shape changes have only recently been studied in greater detail. To gain more insight into the mechanochemical and biophysical basis of an epithelial spreading process (epiboly) in early zebrafish development, we studied cell-cell junction formation and actomyosin network dynamics at the boundary between surface layer epithelial cells (EVL) and the yolk syncytial layer (YSL). During zebrafish epiboly, the cell mass sitting on top of the yolk cell spreads to engulf the yolk cell by the end of gastrulation. It has been previously shown that an actomyosin ring residing within the YSL pulls on the EVL tissue through a cable-constriction and a flow-friction motor, thereby dragging the tissue vegetal wards. Pulling forces are likely transmitted from the YSL actomyosin ring to EVL cells; however, the nature and formation of the junctional structure mediating this process has not been well described so far. Therefore, our main aim was to determine the nature, dynamics and potential function of the EVL-YSL junction during this epithelial tissue spreading. Specifically, we show that the EVL-YSL junction is a mechanosensitive structure, predominantly made of tight junction (TJ) proteins. The process of TJ mechanosensation depends on the retrograde flow of non-junctional, phase-separated Zonula Occludens-1 (ZO-1) protein clusters towards the EVL-YSL boundary. Interestingly, we could demonstrate that ZO-1 is present in a non-junctional pool on the surface of the yolk cell, and ZO-1 undergoes a phase separation process that likely renders the protein responsive to flows. These flows are directed towards the junction and mediate proper tension-dependent recruitment of ZO-1. Upon reaching the EVL-YSL junction ZO-1 gets incorporated into the junctional pool mediated through its direct actin-binding domain. When the non-junctional pool and/or ZO-1 direct actin binding is absent, TJs fail in their proper mechanosensitive responses resulting in slower tissue spreading. We could further demonstrate that depletion of ZO proteins within the YSL results in diminished actomyosin ring formation. This suggests that a mechanochemical feedback loop is at work during zebrafish epiboly: ZO proteins help in proper actomyosin ring formation and actomyosin contractility and flows positively influence ZO-1 junctional recruitment. Finally, such a mesoscale polarization process mediated through the flow of phase-separated protein clusters might have implications for other processes such as immunological synapse formation, C. elegans zygote polarization and wound healing. AU - Schwayer, Cornelia ID - 7186 SN - 2663-337X TI - Mechanosensation of tight junctions depends on ZO-1 phase separation and flow ER - TY - THES AB - The first part of the thesis considers the computational aspects of the homotopy groups πd(X) of a topological space X. It is well known that there is no algorithm to decide whether the fundamental group π1(X) of a given finite simplicial complex X is trivial. On the other hand, there are several algorithms that, given a finite simplicial complex X that is simply connected (i.e., with π1(X) trivial), compute the higher homotopy group πd(X) for any given d ≥ 2. However, these algorithms come with a caveat: They compute the isomorphism type of πd(X), d ≥ 2 as an abstract finitely generated abelian group given by generators and relations, but they work with very implicit representations of the elements of πd(X). We present an algorithm that, given a simply connected space X, computes πd(X) and represents its elements as simplicial maps from suitable triangulations of the d-sphere Sd to X. For fixed d, the algorithm runs in time exponential in size(X), the number of simplices of X. Moreover, we prove that this is optimal: For every fixed d ≥ 2, we construct a family of simply connected spaces X such that for any simplicial map representing a generator of πd(X), the size of the triangulation of S d on which the map is defined, is exponential in size(X). In the second part of the thesis, we prove that the following question is algorithmically undecidable for d < ⌊3(k+1)/2⌋, k ≥ 5 and (k, d) ̸= (5, 7), which covers essentially everything outside the meta-stable range: Given a finite simplicial complex K of dimension k, decide whether there exists a piecewise-linear (i.e., linear on an arbitrarily fine subdivision of K) embedding f : K ↪→ Rd of K into a d-dimensional Euclidean space. AU - Zhechev, Stephan Y ID - 6681 SN - 2663-337X TI - Algorithmic aspects of homotopy theory and embeddability ER - TY - GEN AB - Suppose that $n\neq p^k$ and $n\neq 2p^k$ for all $k$ and all primes $p$. We prove that for any Hausdorff compactum $X$ with a free action of the symmetric group $\mathfrak S_n$ there exists an $\mathfrak S_n$-equivariant map $X \to {\mathbb R}^n$ whose image avoids the diagonal $\{(x,x\dots,x)\in {\mathbb R}^n|x\in {\mathbb R}\}$. Previously, the special cases of this statement for certain $X$ were usually proved using the equivartiant obstruction theory. Such calculations are difficult and may become infeasible past the first (primary) obstruction. We take a different approach which allows us to prove the vanishing of all obstructions simultaneously. The essential step in the proof is classifying the possible degrees of $\mathfrak S_n$-equivariant maps from the boundary $\partial\Delta^{n-1}$ of $(n-1)$-simplex to itself. Existence of equivariant maps between spaces is important for many questions arising from discrete mathematics and geometry, such as Kneser's conjecture, the Square Peg conjecture, the Splitting Necklace problem, and the Topological Tverberg conjecture, etc. We demonstrate the utility of our result applying it to one such question, a specific instance of envy-free division problem. AU - Avvakumov, Sergey AU - Kudrya, Sergey ID - 8182 T2 - arXiv TI - Vanishing of all equivariant obstructions and the mapping degree ER - TY - GEN AB - In this paper we study envy-free division problems. The classical approach to some of such problems, used by David Gale, reduces to considering continuous maps of a simplex to itself and finding sufficient conditions when this map hits the center of the simplex. The mere continuity is not sufficient for such a conclusion, the usual assumption (for example, in the Knaster--Kuratowski--Mazurkiewicz and the Gale theorem) is a certain boundary condition. We follow Erel Segal-Halevi, Fr\'ed\'eric Meunier, and Shira Zerbib, and replace the boundary condition by another assumption, which has the economic meaning of possibility for a player to prefer an empty part in the segment partition problem. We solve the problem positively when $n$, the number of players that divide the segment, is a prime power, and we provide counterexamples for every $n$ which is not a prime power. We also provide counterexamples relevant to a wider class of fair or envy-free partition problems when $n$ is odd and not a prime power. AU - Avvakumov, Sergey AU - Karasev, Roman ID - 8185 T2 - arXiv TI - Envy-free division using mapping degree ER - TY - GEN AB - We prove a lower bound for the free energy (per unit volume) of the two-dimensional Bose gas in the thermodynamic limit. We show that the free energy at density $\rho$ and inverse temperature $\beta$ differs from the one of the non-interacting system by the correction term $4 \pi \rho^2 |\ln a^2 \rho|^{-1} (2 - [1 - \beta_{\mathrm{c}}/\beta]_+^2)$. Here $a$ is the scattering length of the interaction potential, $[\cdot]_+ = \max\{ 0, \cdot \}$ and $\beta_{\mathrm{c}}$ is the inverse Berezinskii--Kosterlitz--Thouless critical temperature for superfluidity. The result is valid in the dilute limit $a^2\rho \ll 1$ and if $\beta \rho \gtrsim 1$. AU - Deuchert, Andreas AU - Mayer, Simon AU - Seiringer, Robert ID - 7524 T2 - arXiv:1910.03372 TI - The free energy of the two-dimensional dilute Bose gas. I. Lower bound ER - TY - JOUR AB - We use the canonical bases produced by the tri-partition algorithm in (Edelsbrunner and Ölsböck, 2018) to open and close holes in a polyhedral complex, K. In a concrete application, we consider the Delaunay mosaic of a finite set, we let K be an Alpha complex, and we use the persistence diagram of the distance function to guide the hole opening and closing operations. The dependences between the holes define a partial order on the cells in K that characterizes what can and what cannot be constructed using the operations. The relations in this partial order reveal structural information about the underlying filtration of complexes beyond what is expressed by the persistence diagram. AU - Edelsbrunner, Herbert AU - Ölsböck, Katharina ID - 6608 JF - Computer Aided Geometric Design TI - Holes and dependences in an ordered complex VL - 73 ER - TY - CONF AB - The Fiat-Shamir heuristic transforms a public-coin interactive proof into a non-interactive argument, by replacing the verifier with a cryptographic hash function that is applied to the protocol’s transcript. Constructing hash functions for which this transformation is sound is a central and long-standing open question in cryptography. We show that solving the END−OF−METERED−LINE problem is no easier than breaking the soundness of the Fiat-Shamir transformation when applied to the sumcheck protocol. In particular, if the transformed protocol is sound, then any hard problem in #P gives rise to a hard distribution in the class CLS, which is contained in PPAD. Our result opens up the possibility of sampling moderately-sized games for which it is hard to find a Nash equilibrium, by reducing the inversion of appropriately chosen one-way functions to #SAT. Our main technical contribution is a stateful incrementally verifiable procedure that, given a SAT instance over n variables, counts the number of satisfying assignments. This is accomplished via an exponential sequence of small steps, each computable in time poly(n). Incremental verifiability means that each intermediate state includes a sumcheck-based proof of its correctness, and the proof can be updated and verified in time poly(n). AU - Choudhuri, Arka Rai AU - Hubáček, Pavel AU - Kamath Hosdurg, Chethan AU - Pietrzak, Krzysztof Z AU - Rosen, Alon AU - Rothblum, Guy N. ID - 6677 SN - 9781450367059 T2 - Proceedings of the 51st Annual ACM SIGACT Symposium on Theory of Computing - STOC 2019 TI - Finding a Nash equilibrium is no easier than breaking Fiat-Shamir ER - TY - JOUR AB - Given a triangulation of a point set in the plane, a flip deletes an edge e whose removal leaves a convex quadrilateral, and replaces e by the opposite diagonal of the quadrilateral. It is well known that any triangulation of a point set can be reconfigured to any other triangulation by some sequence of flips. We explore this question in the setting where each edge of a triangulation has a label, and a flip transfers the label of the removed edge to the new edge. It is not true that every labelled triangulation of a point set can be reconfigured to every other labelled triangulation via a sequence of flips, but we characterize when this is possible. There is an obvious necessary condition: for each label l, if edge e has label l in the first triangulation and edge f has label l in the second triangulation, then there must be some sequence of flips that moves label l from e to f, ignoring all other labels. Bose, Lubiw, Pathak and Verdonschot formulated the Orbit Conjecture, which states that this necessary condition is also sufficient, i.e. that all labels can be simultaneously mapped to their destination if and only if each label individually can be mapped to its destination. We prove this conjecture. Furthermore, we give a polynomial-time algorithm (with 𝑂(𝑛8) being a crude bound on the run-time) to find a sequence of flips to reconfigure one labelled triangulation to another, if such a sequence exists, and we prove an upper bound of 𝑂(𝑛7) on the length of the flip sequence. Our proof uses the topological result that the sets of pairwise non-crossing edges on a planar point set form a simplicial complex that is homeomorphic to a high-dimensional ball (this follows from a result of Orden and Santos; we give a different proof based on a shelling argument). The dual cell complex of this simplicial ball, called the flip complex, has the usual flip graph as its 1-skeleton. We use properties of the 2-skeleton of the flip complex to prove the Orbit Conjecture. AU - Lubiw, Anna AU - Masárová, Zuzana AU - Wagner, Uli ID - 5986 IS - 4 JF - Discrete & Computational Geometry SN - 0179-5376 TI - A proof of the orbit conjecture for flipping edge-labelled triangulations VL - 61 ER - TY - JOUR AB - Problems involving quantum impurities, in which one or a few particles are interacting with a macroscopic environment, represent a pervasive paradigm, spanning across atomic, molecular, and condensed-matter physics. In this paper we introduce new variational approaches to quantum impurities and apply them to the Fröhlich polaron–a quasiparticle formed out of an electron (or other point-like impurity) in a polar medium, and to the angulon–a quasiparticle formed out of a rotating molecule in a bosonic bath. We benchmark these approaches against established theories, evaluating their accuracy as a function of the impurity-bath coupling. AU - Li, Xiang AU - Bighin, Giacomo AU - Yakaboylu, Enderalp AU - Lemeshko, Mikhail ID - 5886 JF - Molecular Physics SN - 00268976 TI - Variational approaches to quantum impurities: from the Fröhlich polaron to the angulon ER - TY - CONF AB - Motivated by fixed-parameter tractable (FPT) problems in computational topology, we consider the treewidth tw(M) of a compact, connected 3-manifold M, defined to be the minimum treewidth of the face pairing graph of any triangulation T of M. In this setting the relationship between the topology of a 3-manifold and its treewidth is of particular interest. First, as a corollary of work of Jaco and Rubinstein, we prove that for any closed, orientable 3-manifold M the treewidth tw(M) is at most 4g(M)-2, where g(M) denotes Heegaard genus of M. In combination with our earlier work with Wagner, this yields that for non-Haken manifolds the Heegaard genus and the treewidth are within a constant factor. Second, we characterize all 3-manifolds of treewidth one: These are precisely the lens spaces and a single other Seifert fibered space. Furthermore, we show that all remaining orientable Seifert fibered spaces over the 2-sphere or a non-orientable surface have treewidth two. In particular, for every spherical 3-manifold we exhibit a triangulation of treewidth at most two. Our results further validate the parameter of treewidth (and other related parameters such as cutwidth or congestion) to be useful for topological computing, and also shed more light on the scope of existing FPT-algorithms in the field. AU - Huszár, Kristóf AU - Spreer, Jonathan ID - 6556 KW - computational 3-manifold topology KW - fixed-parameter tractability KW - layered triangulations KW - structural graph theory KW - treewidth KW - cutwidth KW - Heegaard genus SN - 1868-8969 T2 - 35th International Symposium on Computational Geometry TI - 3-manifold triangulations with small treewidth VL - 129 ER - TY - JOUR AB - In graph theory, as well as in 3-manifold topology, there exist several width-type parameters to describe how "simple" or "thin" a given graph or 3-manifold is. These parameters, such as pathwidth or treewidth for graphs, or the concept of thin position for 3-manifolds, play an important role when studying algorithmic problems; in particular, there is a variety of problems in computational 3-manifold topology - some of them known to be computationally hard in general - that become solvable in polynomial time as soon as the dual graph of the input triangulation has bounded treewidth. In view of these algorithmic results, it is natural to ask whether every 3-manifold admits a triangulation of bounded treewidth. We show that this is not the case, i.e., that there exists an infinite family of closed 3-manifolds not admitting triangulations of bounded pathwidth or treewidth (the latter implies the former, but we present two separate proofs). We derive these results from work of Agol, of Scharlemann and Thompson, and of Scharlemann, Schultens and Saito by exhibiting explicit connections between the topology of a 3-manifold M on the one hand and width-type parameters of the dual graphs of triangulations of M on the other hand, answering a question that had been raised repeatedly by researchers in computational 3-manifold topology. In particular, we show that if a closed, orientable, irreducible, non-Haken 3-manifold M has a triangulation of treewidth (resp. pathwidth) k then the Heegaard genus of M is at most 18(k+1) (resp. 4(3k+1)). AU - Huszár, Kristóf AU - Spreer, Jonathan AU - Wagner, Uli ID - 7093 IS - 2 JF - Journal of Computational Geometry SN - 1920-180X TI - On the treewidth of triangulated 3-manifolds VL - 10 ER - TY - JOUR AB - During bacterial cell division, the tubulin-homolog FtsZ forms a ring-like structure at the center of the cell. This Z-ring not only organizes the division machinery, but treadmilling of FtsZ filaments was also found to play a key role in distributing proteins at the division site. What regulates the architecture, dynamics and stability of the Z-ring is currently unknown, but FtsZ-associated proteins are known to play an important role. Here, using an in vitro reconstitution approach, we studied how the well-conserved protein ZapA affects FtsZ treadmilling and filament organization into large-scale patterns. Using high-resolution fluorescence microscopy and quantitative image analysis, we found that ZapA cooperatively increases the spatial order of the filament network, but binds only transiently to FtsZ filaments and has no effect on filament length and treadmilling velocity. Together, our data provides a model for how FtsZ-associated proteins can increase the precision and stability of the bacterial cell division machinery in a switch-like manner. AU - Dos Santos Caldas, Paulo R AU - Lopez Pelegrin, Maria D AU - Pearce, Daniel J. G. AU - Budanur, Nazmi B AU - Brugués, Jan AU - Loose, Martin ID - 7197 JF - Nature Communications SN - 2041-1723 TI - Cooperative ordering of treadmilling filaments in cytoskeletal networks of FtsZ and its crosslinker ZapA VL - 10 ER -