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 - 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 - TY - JOUR AB - The rate of biological evolution depends on the fixation probability and on the fixation time of new mutants. Intensive research has focused on identifying population structures that augment the fixation probability of advantageous mutants. But these amplifiers of natural selection typically increase fixation time. Here we study population structures that achieve a tradeoff between fixation probability and time. First, we show that no amplifiers can have an asymptotically lower absorption time than the well-mixed population. Then we design population structures that substantially augment the fixation probability with just a minor increase in fixation time. Finally, we show that those structures enable higher effective rate of evolution than the well-mixed population provided that the rate of generating advantageous mutants is relatively low. Our work sheds light on how population structure affects the rate of evolution. Moreover, our structures could be useful for lab-based, medical, or industrial applications of evolutionary optimization. AU - Tkadlec, Josef AU - Pavlogiannis, Andreas AU - Chatterjee, Krishnendu AU - Nowak, Martin A. ID - 7210 JF - Communications Biology SN - 2399-3642 TI - Population structure determines the tradeoff between fixation probability and fixation time VL - 2 ER - TY - CONF AB - The verification of concurrent programs remains an open challenge, as thread interaction has to be accounted for, which leads to state-space explosion. Stateless model checking battles this problem by exploring traces rather than states of the program. As there are exponentially many traces, dynamic partial-order reduction (DPOR) techniques are used to partition the trace space into equivalence classes, and explore a few representatives from each class. The standard equivalence that underlies most DPOR techniques is the happens-before equivalence, however recent works have spawned a vivid interest towards coarser equivalences. The efficiency of such approaches is a product of two parameters: (i) the size of the partitioning induced by the equivalence, and (ii) the time spent by the exploration algorithm in each class of the partitioning. In this work, we present a new equivalence, called value-happens-before and show that it has two appealing features. First, value-happens-before is always at least as coarse as the happens-before equivalence, and can be even exponentially coarser. Second, the value-happens-before partitioning is efficiently explorable when the number of threads is bounded. We present an algorithm called value-centric DPOR (VCDPOR), which explores the underlying partitioning using polynomial time per class. Finally, we perform an experimental evaluation of VCDPOR on various benchmarks, and compare it against other state-of-the-art approaches. Our results show that value-happens-before typically induces a significant reduction in the size of the underlying partitioning, which leads to a considerable reduction in the running time for exploring the whole partitioning. AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Toman, Viktor ID - 10190 KW - safety KW - risk KW - reliability and quality KW - software T2 - Proceedings of the 34th ACM International Conference on Object-Oriented Programming, Systems, Languages, and Applications TI - Value-centric dynamic partial order reduction VL - 3 ER - TY - CONF AB - Several classic problems in graph processing and computational geometry are solved via incremental algorithms, which split computation into a series of small tasks acting on shared state, which gets updated progressively. While the sequential variant of such algorithms usually specifies a fixed (but sometimes random) order in which the tasks should be performed, a standard approach to parallelizing such algorithms is to relax this constraint to allow for out-of-order parallel execution. This is the case for parallel implementations of Dijkstra's single-source shortest-paths (SSSP) algorithm, and for parallel Delaunay mesh triangulation. While many software frameworks parallelize incremental computation in this way, it is still not well understood whether this relaxed ordering approach can still provide any complexity guarantees. In this paper, we address this problem, and analyze the efficiency guarantees provided by a range of incremental algorithms when parallelized via relaxed schedulers. We show that, for algorithms such as Delaunay mesh triangulation and sorting by insertion, schedulers with a maximum relaxation factor of k in terms of the maximum priority inversion allowed will introduce a maximum amount of wasted work of O(łog n poly(k)), where n is the number of tasks to be executed. For SSSP, we show that the additional work is O(poly(k), dmax / wmin), where dmax is the maximum distance between two nodes, and wmin is the minimum such distance. In practical settings where n >> k, this suggests that the overheads of relaxation will be outweighed by the improved scalability of the relaxed scheduler. On the negative side, we provide lower bounds showing that certain algorithms will inherently incur a non-trivial amount of wasted work due to scheduler relaxation, even for relatively benign relaxed schedulers. AU - Alistarh, Dan-Adrian AU - Nadiradze, Giorgi AU - Koval, Nikita ID - 6673 SN - 9781450361842 T2 - 31st ACM Symposium on Parallelism in Algorithms and Architectures TI - Efficiency guarantees for parallel incremental algorithms under relaxed schedulers ER - TY - JOUR AB - Transporters of the solute carrier 6 (SLC6) family translocate their cognate substrate together with Na+ and Cl−. Detailed kinetic models exist for the transporters of GABA (GAT1/SLC6A1) and the monoamines dopamine (DAT/SLC6A3) and serotonin (SERT/SLC6A4). Here, we posited that the transport cycle of individual SLC6 transporters reflects the physiological requirements they operate under. We tested this hypothesis by analyzing the transport cycle of glycine transporter 1 (GlyT1/SLC6A9) and glycine transporter 2 (GlyT2/SLC6A5). GlyT2 is the only SLC6 family member known to translocate glycine, Na+, and Cl− in a 1:3:1 stoichiometry. We analyzed partial reactions in real time by electrophysiological recordings. Contrary to monoamine transporters, both GlyTs were found to have a high transport capacity driven by rapid return of the empty transporter after release of Cl− on the intracellular side. Rapid cycling of both GlyTs was further supported by highly cooperative binding of cosubstrate ions and substrate such that their forward transport mode was maintained even under conditions of elevated intracellular Na+ or Cl−. The most important differences in the transport cycle of GlyT1 and GlyT2 arose from the kinetics of charge movement and the resulting voltage-dependent rate-limiting reactions: the kinetics of GlyT1 were governed by transition of the substrate-bound transporter from outward- to inward-facing conformations, whereas the kinetics of GlyT2 were governed by Na+ binding (or a related conformational change). Kinetic modeling showed that the kinetics of GlyT1 are ideally suited for supplying the extracellular glycine levels required for NMDA receptor activation. AU - Erdem, Fatma Asli AU - Ilic, Marija AU - Koppensteiner, Peter AU - Gołacki, Jakub AU - Lubec, Gert AU - Freissmuth, Michael AU - Sandtner, Walter ID - 7398 IS - 8 JF - The Journal of General Physiology SN - 0022-1295 TI - A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2 VL - 151 ER - TY - JOUR AB - The mitochondrial electron transport chain complexes are organized into supercomplexes (SCs) of defined stoichiometry, which have been proposed to regulate electron flux via substrate channeling. We demonstrate that CoQ trapping in the isolated SC I+III2 limits complex (C)I turnover, arguing against channeling. The SC structure, resolved at up to 3.8 Å in four distinct states, suggests that CoQ oxidation may be rate limiting because of unequal access of CoQ to the active sites of CIII2. CI shows a transition between “closed” and “open” conformations, accompanied by the striking rotation of a key transmembrane helix. Furthermore, the state of CI affects the conformational flexibility within CIII2, demonstrating crosstalk between the enzymes. CoQ was identified at only three of the four binding sites in CIII2, suggesting that interaction with CI disrupts CIII2 symmetry in a functionally relevant manner. Together, these observations indicate a more nuanced functional role for the SCs. AU - Letts, James A AU - Fiedorczuk, Karol AU - Degliesposti, Gianluca AU - Skehel, Mark AU - Sazanov, Leonid A ID - 7395 IS - 6 JF - Molecular Cell SN - 1097-2765 TI - Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk VL - 75 ER - TY - JOUR AB - Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool (www.netpyne.org) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, for example connectivity rules, to create millions of cell-to-cell connections. NetPyNE then enables users to generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis – connectivity matrices, voltage traces, spike raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing standardized formats (NeuroML and SONATA). NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate brain regions and phenomena. AU - Dura-Bernal, Salvador AU - Suter, Benjamin AU - Gleeson, Padraig AU - Cantarelli, Matteo AU - Quintana, Adrian AU - Rodriguez, Facundo AU - Kedziora, David J AU - Chadderdon, George L AU - Kerr, Cliff C AU - Neymotin, Samuel A AU - McDougal, Robert A AU - Hines, Michael AU - Shepherd, Gordon MG AU - Lytton, William W ID - 7405 JF - eLife SN - 2050-084X TI - NetPyNE, a tool for data-driven multiscale modeling of brain circuits VL - 8 ER - TY - JOUR AB - Suppressed recombination allows divergence between homologous sex chromosomes and the functionality of their genes. Here, we reveal patterns of the earliest stages of sex-chromosome evolution in the diploid dioecious herb Mercurialis annua on the basis of cytological analysis, de novo genome assembly and annotation, genetic mapping, exome resequencing of natural populations, and transcriptome analysis. The genome assembly contained 34,105 expressed genes, of which 10,076 were assigned to linkage groups. Genetic mapping and exome resequencing of individuals across the species range both identified the largest linkage group, LG1, as the sex chromosome. Although the sex chromosomes of M. annua are karyotypically homomorphic, we estimate that about one-third of the Y chromosome, containing 568 transcripts and spanning 22.3 cM in the corresponding female map, has ceased recombining. Nevertheless, we found limited evidence for Y-chromosome degeneration in terms of gene loss and pseudogenization, and most X- and Y-linked genes appear to have diverged in the period subsequent to speciation between M. annua and its sister species M. huetii, which shares the same sex-determining region. Taken together, our results suggest that the M. annua Y chromosome has at least two evolutionary strata: a small old stratum shared with M. huetii, and a more recent larger stratum that is probably unique to M. annua and that stopped recombining ∼1 MYA. Patterns of gene expression within the nonrecombining region are consistent with the idea that sexually antagonistic selection may have played a role in favoring suppressed recombination. AU - Veltsos, Paris AU - Ridout, Kate E. AU - Toups, Melissa A AU - González-Martínez, Santiago C. AU - Muyle, Aline AU - Emery, Olivier AU - Rastas, Pasi AU - Hudzieczek, Vojtech AU - Hobza, Roman AU - Vyskot, Boris AU - Marais, Gabriel A. B. AU - Filatov, Dmitry A. AU - Pannell, John R. ID - 7400 IS - 3 JF - Genetics SN - 0016-6731 TI - Early sex-chromosome evolution in the diploid dioecious plant Mercurialis annua VL - 212 ER - TY - JOUR AB - The formation of neuronal dendrite branches is fundamental for the wiring and function of the nervous system. Indeed, dendrite branching enhances the coverage of the neuron's receptive field and modulates the initial processing of incoming stimuli. Complex dendrite patterns are achieved in vivo through a dynamic process of de novo branch formation, branch extension and retraction. The first step towards branch formation is the generation of a dynamic filopodium-like branchlet. The mechanisms underlying the initiation of dendrite branchlets are therefore crucial to the shaping of dendrites. Through in vivo time-lapse imaging of the subcellular localization of actin during the process of branching of Drosophila larva sensory neurons, combined with genetic analysis and electron tomography, we have identified the Actin-related protein (Arp) 2/3 complex as the major actin nucleator involved in the initiation of dendrite branchlet formation, under the control of the activator WAVE and of the small GTPase Rac1. Transient recruitment of an Arp2/3 component marks the site of branchlet initiation in vivo. These data position the activation of Arp2/3 as an early hub for the initiation of branchlet formation. AU - Stürner, Tomke AU - Tatarnikova, Anastasia AU - Müller, Jan AU - Schaffran, Barbara AU - Cuntz, Hermann AU - Zhang, Yun AU - Nemethova, Maria AU - Bogdan, Sven AU - Small, Vic AU - Tavosanis, Gaia ID - 7404 IS - 7 JF - Development SN - 0950-1991 TI - Transient localization of the Arp2/3 complex initiates neuronal dendrite branching in vivo VL - 146 ER - TY - CONF AB - Graph planning gives rise to fundamental algorithmic questions such as shortest path, traveling salesman problem, etc. A classical problem in discrete planning is to consider a weighted graph and construct a path that maximizes the sum of weights for a given time horizon T. However, in many scenarios, the time horizon is not fixed, but the stopping time is chosen according to some distribution such that the expected stopping time is T. If the stopping time distribution is not known, then to ensure robustness, the distribution is chosen by an adversary, to represent the worst-case scenario. A stationary plan for every vertex always chooses the same outgoing edge. For fixed horizon or fixed stopping-time distribution, stationary plans are not sufficient for optimality. Quite surprisingly we show that when an adversary chooses the stopping-time distribution with expected stopping time T, then stationary plans are sufficient. While computing optimal stationary plans for fixed horizon is NP-complete, we show that computing optimal stationary plans under adversarial stopping-time distribution can be achieved in polynomial time. Consequently, our polynomial-time algorithm for adversarial stopping time also computes an optimal plan among all possible plans. AU - Chatterjee, Krishnendu AU - Doyen, Laurent ID - 7402 SN - 9781728136080 T2 - 34th Annual ACM/IEEE Symposium on Logic in Computer Science TI - Graph planning with expected finite horizon ER - TY - JOUR AB - We prove that the observable telegraph signal accompanying the bistability in the photon-blockade-breakdown regime of the driven and lossy Jaynes–Cummings model is the finite-size precursor of what in the thermodynamic limit is a genuine first-order phase transition. We construct a finite-size scaling of the system parameters to a well-defined thermodynamic limit, in which the system remains the same microscopic system, but the telegraph signal becomes macroscopic both in its timescale and intensity. The existence of such a finite-size scaling completes and justifies the classification of the photon-blockade-breakdown effect as a first-order dissipative quantum phase transition. AU - Vukics, A. AU - Dombi, A. AU - Fink, Johannes M AU - Domokos, P. ID - 7451 JF - Quantum SN - 2521-327X TI - Finite-size scaling of the photon-blockade breakdown dissipative quantum phase transition VL - 3 ER - TY - CONF AB - We present a new proximal bundle method for Maximum-A-Posteriori (MAP) inference in structured energy minimization problems. The method optimizes a Lagrangean relaxation of the original energy minimization problem using a multi plane block-coordinate Frank-Wolfe method that takes advantage of the specific structure of the Lagrangean decomposition. We show empirically that our method outperforms state-of-the-art Lagrangean decomposition based algorithms on some challenging Markov Random Field, multi-label discrete tomography and graph matching problems. AU - Swoboda, Paul AU - Kolmogorov, Vladimir ID - 7468 SN - 10636919 T2 - Proceedings of the IEEE Computer Society Conference on Computer Vision and Pattern Recognition TI - Map inference via block-coordinate Frank-Wolfe algorithm VL - 2019-June ER - TY - JOUR AU - Morandell, Jasmin AU - Nicolas, Armel AU - Schwarz, Lena A AU - Novarino, Gaia ID - 7415 IS - Supplement 6 JF - European Neuropsychopharmacology SN - 0924-977X TI - S.16.05 Illuminating the role of the e3 ubiquitin ligase cullin3 in brain development and autism VL - 29 ER - TY - JOUR AU - Knaus, Lisa AU - Tarlungeanu, Dora-Clara AU - Novarino, Gaia ID - 7414 IS - Supplement 6 JF - European Neuropsychopharmacology SN - 0924-977X TI - S.16.03 A homozygous missense mutation in SLC7A5 leads to autism spectrum disorder and microcephaly VL - 29 ER - TY - JOUR AU - Benková, Eva AU - Dagdas, Yasin ID - 7394 IS - 12 JF - Current Opinion in Plant Biology SN - 1369-5266 TI - Editorial overview: Cell biology in the era of omics? VL - 52 ER - TY - CONF AB - Multi-exit architectures, in which a stack of processing layers is interleaved with early output layers, allow the processing of a test example to stop early and thus save computation time and/or energy. In this work, we propose a new training procedure for multi-exit architectures based on the principle of knowledge distillation. The method encourage searly exits to mimic later, more accurate exits, by matching their output probabilities. Experiments on CIFAR100 and ImageNet show that distillation-based training significantly improves the accuracy of early exits while maintaining state-of-the-art accuracy for late ones. The method is particularly beneficial when training data is limited and it allows a straightforward extension to semi-supervised learning,i.e. making use of unlabeled data at training time. Moreover, it takes only afew lines to implement and incurs almost no computational overhead at training time, and none at all at test time. AU - Bui Thi Mai, Phuong AU - Lampert, Christoph ID - 7479 SN - 15505499 T2 - IEEE International Conference on Computer Vision TI - Distillation-based training for multi-exit architectures VL - 2019-October ER - TY - CONF AB - We present a novel class of convolutional neural networks (CNNs) for set functions,i.e., data indexed with the powerset of a finite set. The convolutions are derivedas linear, shift-equivariant functions for various notions of shifts on set functions.The framework is fundamentally different from graph convolutions based on theLaplacian, as it provides not one but several basic shifts, one for each element inthe ground set. Prototypical experiments with several set function classificationtasks on synthetic datasets and on datasets derived from real-world hypergraphsdemonstrate the potential of our new powerset CNNs. AU - Wendler, Chris AU - Alistarh, Dan-Adrian AU - Püschel, Markus ID - 7542 SN - 1049-5258 TI - Powerset convolutional neural networks VL - 32 ER - TY - CHAP AB - Social insects (i.e., ants, termites and the social bees and wasps) protect their colonies from disease using a combination of individual immunity and collectively performed defenses, termed social immunity. The first line of social immune defense is sanitary care, which is performed by colony members to protect their pathogen-exposed nestmates from developing an infection. If sanitary care fails and an infection becomes established, a second line of social immune defense is deployed to stop disease transmission within the colony and to protect the valuable queens, which together with the males are the reproductive individuals of the colony. Insect colonies are separated into these reproductive individuals and the sterile worker force, forming a superorganismal reproductive unit reminiscent of the differentiated germline and soma in a multicellular organism. Ultimately, the social immune response preserves the germline of the superorganism insect colony and increases overall fitness of the colony in case of disease. AU - Cremer, Sylvia AU - Kutzer, Megan ED - Choe, Jae ID - 7513 SN - 9780128132517 T2 - Encyclopedia of Animal Behavior TI - Social immunity ER - TY - CONF AB - Bending-active structures are able to efficiently produce complex curved shapes starting from flat panels. The desired deformation of the panels derives from the proper selection of their elastic properties. Optimized panels, called FlexMaps, are designed such that, once they are bent and assembled, the resulting static equilibrium configuration matches a desired input 3D shape. The FlexMaps elastic properties are controlled by locally varying spiraling geometric mesostructures, which are optimized in size and shape to match the global curvature (i.e., bending requests) of the target shape. The design pipeline starts from a quad mesh representing the input 3D shape, which defines the edge size and the total amount of spirals: every quad will embed one spiral. Then, an optimization algorithm tunes the geometry of the spirals by using a simplified pre-computed rod model. This rod model is derived from a non-linear regression algorithm which approximates the non-linear behavior of solid FEM spiral models subject to hundreds of load combinations. This innovative pipeline has been applied to the project of a lightweight plywood pavilion named FlexMaps Pavilion, which is a single-layer piecewise twisted arc that fits a bounding box of 3.90x3.96x3.25 meters. AU - Laccone, Francesco AU - Malomo, Luigi AU - Perez Rodriguez, Jesus AU - Pietroni, Nico AU - Ponchio, Federico AU - Bickel, Bernd AU - Cignoni, Paolo ID - 9261 SN - 2518-6582 T2 - IASS Symposium 2019 - 60th Anniversary Symposium of the International Association for Shell and Spatial Structures; Structural Membranes 2019 - 9th International Conference on Textile Composites and Inflatable Structures, FORM and FORCE TI - FlexMaps Pavilion: A twisted arc made of mesostructured flat flexible panels ER - TY - CONF AB - We propose a new model for detecting visual relationships, such as "person riding motorcycle" or "bottle on table". This task is an important step towards comprehensive structured mage understanding, going beyond detecting individual objects. Our main novelty is a Box Attention mechanism that allows to model pairwise interactions between objects using standard object detection pipelines. The resulting model is conceptually clean, expressive and relies on well-justified training and prediction procedures. Moreover, unlike previously proposed approaches, our model does not introduce any additional complex components or hyperparameters on top of those already required by the underlying detection model. We conduct an experimental evaluation on two datasets, V-COCO and Open Images, demonstrating strong quantitative and qualitative results. AU - Kolesnikov, Alexander AU - Kuznetsova, Alina AU - Lampert, Christoph AU - Ferrari, Vittorio ID - 7640 SN - 9781728150239 T2 - Proceedings of the 2019 International Conference on Computer Vision Workshop TI - Detecting visual relationships using box attention ER - TY - CONF AB - Deep neural networks (DNNs) have become increasingly important due to their excellent empirical performance on a wide range of problems. However, regularization is generally achieved by indirect means, largely due to the complex set of functions defined by a network and the difficulty in measuring function complexity. There exists no method in the literature for additive regularization based on a norm of the function, as is classically considered in statistical learning theory. In this work, we study the tractability of function norms for deep neural networks with ReLU activations. We provide, to the best of our knowledge, the first proof in the literature of the NP-hardness of computing function norms of DNNs of 3 or more layers. We also highlight a fundamental difference between shallow and deep networks. In the light on these results, we propose a new regularization strategy based on approximate function norms, and show its efficiency on a segmentation task with a DNN. AU - Rannen-Triki, Amal AU - Berman, Maxim AU - Kolmogorov, Vladimir AU - Blaschko, Matthew B. ID - 7639 SN - 9781728150239 T2 - Proceedings of the 2019 International Conference on Computer Vision Workshop TI - Function norms for neural networks ER - TY - CHAP AB - We review the history of population genetics, starting with its origins a century ago from the synthesis between Mendel and Darwin's ideas, through to the recent development of sophisticated schemes of inference from sequence data, based on the coalescent. We explain the close relation between the coalescent and a diffusion process, which we illustrate by their application to understand spatial structure. We summarise the powerful methods available for analysis of multiple loci, when linkage equilibrium can be assumed, and then discuss approaches to the more challenging case, where associations between alleles require that we follow genotype, rather than allele, frequencies. Though we can hardly cover the whole of population genetics, we give an overview of the current state of the subject, and future challenges to it. AU - Barton, Nicholas H AU - Etheridge, Alison ED - Balding, David ED - Moltke, Ida ED - Marioni, John ID - 8281 SN - 9781119429142 T2 - Handbook of statistical genomics TI - Mathematical models in population genetics ER - TY - GEN AB - Denote by ∆N the N-dimensional simplex. A map f : ∆N → Rd is an almost r-embedding if fσ1∩. . .∩fσr = ∅ whenever σ1, . . . , σr are pairwise disjoint faces. A counterexample to the topological Tverberg conjecture asserts that if r is not a prime power and d ≥ 2r + 1, then there is an almost r-embedding ∆(d+1)(r−1) → Rd. This was improved by Blagojevi´c–Frick–Ziegler using a simple construction of higher-dimensional counterexamples by taking k-fold join power of lower-dimensional ones. We improve this further (for d large compared to r): If r is not a prime power and N := (d+ 1)r−r l d + 2 r + 1 m−2, then there is an almost r-embedding ∆N → Rd. For the r-fold van Kampen–Flores conjecture we also produce counterexamples which are stronger than previously known. Our proof is based on generalizations of the Mabillard–Wagner theorem on construction of almost r-embeddings from equivariant maps, and of the Ozaydin theorem on existence of equivariant maps. AU - Avvakumov, Sergey AU - Karasev, R. AU - Skopenkov, A. ID - 8184 T2 - arXiv TI - Stronger counterexamples to the topological Tverberg conjecture ER - TY - CONF AB - A proxy re-encryption (PRE) scheme is a public-key encryption scheme that allows the holder of a key pk to derive a re-encryption key for any other key 𝑝𝑘′. This re-encryption key lets anyone transform ciphertexts under pk into ciphertexts under 𝑝𝑘′ without having to know the underlying message, while transformations from 𝑝𝑘′ to pk should not be possible (unidirectional). Security is defined in a multi-user setting against an adversary that gets the users’ public keys and can ask for re-encryption keys and can corrupt users by requesting their secret keys. Any ciphertext that the adversary cannot trivially decrypt given the obtained secret and re-encryption keys should be secure. All existing security proofs for PRE only show selective security, where the adversary must first declare the users it wants to corrupt. This can be lifted to more meaningful adaptive security by guessing the set of corrupted users among the n users, which loses a factor exponential in Open image in new window , rendering the result meaningless already for moderate Open image in new window . Jafargholi et al. (CRYPTO’17) proposed a framework that in some cases allows to give adaptive security proofs for schemes which were previously only known to be selectively secure, while avoiding the exponential loss that results from guessing the adaptive choices made by an adversary. We apply their framework to PREs that satisfy some natural additional properties. Concretely, we give a more fine-grained reduction for several unidirectional PREs, proving adaptive security at a much smaller loss. The loss depends on the graph of users whose edges represent the re-encryption keys queried by the adversary. For trees and chains the loss is quasi-polynomial in the size and for general graphs it is exponential in their depth and indegree (instead of their size as for previous reductions). Fortunately, trees and low-depth graphs cover many, if not most, interesting applications. Our results apply e.g. to the bilinear-map based PRE schemes by Ateniese et al. (NDSS’05 and CT-RSA’09), Gentry’s FHE-based scheme (STOC’09) and the LWE-based scheme by Chandran et al. (PKC’14). AU - Fuchsbauer, Georg AU - Kamath Hosdurg, Chethan AU - Klein, Karen AU - Pietrzak, Krzysztof Z ID - 6430 SN - 03029743 TI - Adaptively secure proxy re-encryption VL - 11443 ER - TY - JOUR AB - Electron transport in two-dimensional conducting materials such as graphene, with dominant electron–electron interaction, exhibits unusual vortex flow that leads to a nonlocal current-field relation (negative resistance), distinct from the classical Ohm’s law. The transport behavior of these materials is best described by low Reynolds number hydrodynamics, where the constitutive pressure–speed relation is Stoke’s law. Here we report evidence of such vortices observed in a viscous flow of Newtonian fluid in a microfluidic device consisting of a rectangular cavity—analogous to the electronic system. We extend our experimental observations to elliptic cavities of different eccentricities, and validate them by numerically solving bi-harmonic equation obtained for the viscous flow with no-slip boundary conditions. We verify the existence of a predicted threshold at which vortices appear. Strikingly, we find that a two-dimensional theoretical model captures the essential features of three-dimensional Stokes flow in experiments. AU - Mayzel, Jonathan AU - Steinberg, Victor AU - Varshney, Atul ID - 6069 JF - Nature Communications SN - 2041-1723 TI - Stokes flow analogous to viscous electron current in graphene VL - 10 ER - TY - JOUR AB - Speed of sound waves in gases and liquids are governed by the compressibility of the medium. There exists another type of non-dispersive wave where the wave speed depends on stress instead of elasticity of the medium. A well-known example is the Alfven wave, which propagates through plasma permeated by a magnetic field with the speed determined by magnetic tension. An elastic analogue of Alfven waves has been predicted in a flow of dilute polymer solution where the elastic stress of the stretching polymers determines the elastic wave speed. Here we present quantitative evidence of elastic Alfven waves in elastic turbulence of a viscoelastic creeping flow between two obstacles in channel flow. The key finding in the experimental proof is a nonlinear dependence of the elastic wave speed cel on the Weissenberg number Wi, which deviates from predictions based on a model of linear polymer elasticity. AU - Varshney, Atul AU - Steinberg, Victor ID - 6014 JF - Nature Communications SN - 2041-1723 TI - Elastic alfven waves in elastic turbulence VL - 10 ER - TY - JOUR AB - Epidermal growth factor receptor (EGFR) signaling controls skin development and homeostasis inmice and humans, and its deficiency causes severe skin inflammation, which might affect epidermalstem cell behavior. Here, we describe the inflammation-independent effects of EGFR deficiency dur-ing skin morphogenesis and in adult hair follicle stem cells. Expression and alternative splicing analysisof RNA sequencing data from interfollicular epidermis and outer root sheath indicate that EGFR con-trols genes involved in epidermal differentiation and also in centrosome function, DNA damage, cellcycle, and apoptosis. Genetic experiments employingp53deletion in EGFR-deficient epidermis revealthat EGFR signaling exhibitsp53-dependent functions in proliferative epidermal compartments, aswell asp53-independent functions in differentiated hair shaft keratinocytes. Loss of EGFR leads toabsence of LEF1 protein specifically in the innermost epithelial hair layers, resulting in disorganizationof medulla cells. Thus, our results uncover important spatial and temporal features of cell-autonomousEGFR functions in the epidermis. AU - Amberg, Nicole AU - Sotiropoulou, Panagiota A. AU - Heller, Gerwin AU - Lichtenberger, Beate M. AU - Holcmann, Martin AU - Camurdanoglu, Bahar AU - Baykuscheva-Gentscheva, Temenuschka AU - Blanpain, Cedric AU - Sibilia, Maria ID - 6451 JF - iScience SN - 2589-0042 TI - EGFR controls hair shaft differentiation in a p53-independent manner VL - 15 ER - TY - JOUR AB - We study effects of a bounded and compactly supported perturbation on multidimensional continuum random Schrödinger operators in the region of complete localisation. Our main emphasis is on Anderson orthogonality for random Schrödinger operators. Among others, we prove that Anderson orthogonality does occur for Fermi energies in the region of complete localisation with a non-zero probability. This partially confirms recent non-rigorous findings [V. Khemani et al., Nature Phys. 11 (2015), 560–565]. The spectral shift function plays an important role in our analysis of Anderson orthogonality. We identify it with the index of the corresponding pair of spectral projections and explore the consequences thereof. All our results rely on the main technical estimate of this paper which guarantees separate exponential decay of the disorder-averaged Schatten p-norm of χa(f(H)−f(Hτ))χb in a and b. Here, Hτ is a perturbation of the random Schrödinger operator H, χa is the multiplication operator corresponding to the indicator function of a unit cube centred about a∈Rd, and f is in a suitable class of functions of bounded variation with distributional derivative supported in the region of complete localisation for H. AU - Dietlein, Adrian M AU - Gebert, Martin AU - Müller, Peter ID - 10879 IS - 3 JF - Journal of Spectral Theory KW - Random Schrödinger operators KW - spectral shift function KW - Anderson orthogonality SN - 1664-039X TI - Perturbations of continuum random Schrödinger operators with applications to Anderson orthogonality and the spectral shift function VL - 9 ER - TY - JOUR AB - Starting from a microscopic model for a system of neurons evolving in time which individually follow a stochastic integrate-and-fire type model, we study a mean-field limit of the system. Our model is described by a system of SDEs with discontinuous coefficients for the action potential of each neuron and takes into account the (random) spatial configuration of neurons allowing the interaction to depend on it. In the limit as the number of particles tends to infinity, we obtain a nonlinear Fokker-Planck type PDE in two variables, with derivatives only with respect to one variable and discontinuous coefficients. We also study strong well-posedness of the system of SDEs and prove the existence and uniqueness of a weak measure-valued solution to the PDE, obtained as the limit of the laws of the empirical measures for the system of particles. AU - Flandoli, Franco AU - Priola, Enrico AU - Zanco, Giovanni A ID - 10878 IS - 6 JF - Discrete and Continuous Dynamical Systems KW - Applied Mathematics KW - Discrete Mathematics and Combinatorics KW - Analysis SN - 1553-5231 TI - A mean-field model with discontinuous coefficients for neurons with spatial interaction VL - 39 ER - TY - CONF AB - This paper investigates the power of preprocessing in the CONGEST model. Schmid and Suomela (ACM HotSDN 2013) introduced the SUPPORTED CONGEST model to study the application of distributed algorithms in Software-Defined Networks (SDNs). In this paper, we show that a large class of lower bounds in the CONGEST model still hold in the SUPPORTED model, highlighting the robustness of these bounds. This also raises the question how much does preprocessing help in the CONGEST model. AU - Foerster, Klaus-Tycho AU - Korhonen, Janne AU - Rybicki, Joel AU - Schmid, Stefan ID - 6935 SN - 9781450362177 T2 - Proceedings of the 2019 ACM Symposium on Principles of Distributed Computing TI - Does preprocessing help under congestion? ER - TY - JOUR AB - Autoregulation is the direct modulation of gene expression by the product of the corresponding gene. Autoregulation of bacterial gene expression has been mostly studied at the transcriptional level, when a protein acts as the cognate transcriptional repressor. A recent study investigating dynamics of the bacterial toxin–antitoxin MazEF system has shown how autoregulation at both the transcriptional and post-transcriptional levels affects the heterogeneity of Escherichia coli populations. Toxin–antitoxin systems hold a crucial but still elusive part in bacterial response to stress. This perspective highlights how these modules can also serve as a great model system for investigating basic concepts in gene regulation. However, as the genomic background and environmental conditions substantially influence toxin activation, it is important to study (auto)regulation of toxin–antitoxin systems in well-defined setups as well as in conditions that resemble the environmental niche. AU - Nikolic, Nela ID - 138 IS - 1 JF - Current Genetics TI - Autoregulation of bacterial gene expression: lessons from the MazEF toxin–antitoxin system VL - 65 ER - TY - JOUR AB - We construct planar bi-Sobolev mappings whose local volume distortion is bounded from below by a given function f∈Lp with p>1. More precisely, for any 1<q<(p+1)/2 we construct W1,q-bi-Sobolev maps with identity boundary conditions; for f∈L∞, we provide bi-Lipschitz maps. The basic building block of our construction are bi-Lipschitz maps which stretch a given compact subset of the unit square by a given factor while preserving the boundary. The construction of these stretching maps relies on a slight strengthening of the celebrated covering result of Alberti, Csörnyei, and Preiss for measurable planar sets in the case of compact sets. We apply our result to a model functional in nonlinear elasticity, the integrand of which features fast blowup as the Jacobian determinant of the deformation becomes small. For such functionals, the derivation of the equilibrium equations for minimizers requires an additional regularization of test functions, which our maps provide. AU - Fischer, Julian L AU - Kneuss, Olivier ID - 151 IS - 1 JF - Journal of Differential Equations TI - Bi-Sobolev solutions to the prescribed Jacobian inequality in the plane with L p data and applications to nonlinear elasticity VL - 266 ER - TY - JOUR AB - The cerebral cortex is composed of a large variety of distinct cell-types including projection neurons, interneurons and glial cells which emerge from distinct neural stem cell (NSC) lineages. The vast majority of cortical projection neurons and certain classes of glial cells are generated by radial glial progenitor cells (RGPs) in a highly orchestrated manner. Recent studies employing single cell analysis and clonal lineage tracing suggest that NSC and RGP lineage progression are regulated in a profound deterministic manner. In this review we focus on recent advances based mainly on correlative phenotypic data emerging from functional genetic studies in mice. We establish hypotheses to test in future research and outline a conceptual framework how epigenetic cues modulate the generation of cell-type diversity during cortical development. This article is protected by copyright. All rights reserved. AU - Amberg, Nicole AU - Laukoter, Susanne AU - Hippenmeyer, Simon ID - 27 IS - 1 JF - Journal of Neurochemistry TI - Epigenetic cues modulating the generation of cell type diversity in the cerebral cortex VL - 149 ER - TY - JOUR AB - Tissue morphogenesis is driven by mechanical forces that elicit changes in cell size, shape and motion. The extent by which forces deform tissues critically depends on the rheological properties of the recipient tissue. Yet, whether and how dynamic changes in tissue rheology affect tissue morphogenesis and how they are regulated within the developing organism remain unclear. Here, we show that blastoderm spreading at the onset of zebrafish morphogenesis relies on a rapid, pronounced and spatially patterned tissue fluidization. Blastoderm fluidization is temporally controlled by mitotic cell rounding-dependent cell–cell contact disassembly during the last rounds of cell cleavages. Moreover, fluidization is spatially restricted to the central blastoderm by local activation of non-canonical Wnt signalling within the blastoderm margin, increasing cell cohesion and thereby counteracting the effect of mitotic rounding on contact disassembly. Overall, our results identify a fluidity transition mediated by loss of cell cohesion as a critical regulator of embryo morphogenesis. AU - Petridou, Nicoletta AU - Grigolon, Silvia AU - Salbreux, Guillaume AU - Hannezo, Edouard B AU - Heisenberg, Carl-Philipp J ID - 5789 JF - Nature Cell Biology SN - 14657392 TI - Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling VL - 21 ER - TY - JOUR AB - The abelian sandpile serves as a model to study self-organized criticality, a phenomenon occurring in biological, physical and social processes. The identity of the abelian group is a fractal composed of self-similar patches, and its limit is subject of extensive collaborative research. Here, we analyze the evolution of the sandpile identity under harmonic fields of different orders. We show that this evolution corresponds to periodic cycles through the abelian group characterized by the smooth transformation and apparent conservation of the patches constituting the identity. The dynamics induced by second and third order harmonics resemble smooth stretchings, respectively translations, of the identity, while the ones induced by fourth order harmonics resemble magnifications and rotations. Starting with order three, the dynamics pass through extended regions of seemingly random configurations which spontaneously reassemble into accentuated patterns. We show that the space of harmonic functions projects to the extended analogue of the sandpile group, thus providing a set of universal coordinates identifying configurations between different domains. Since the original sandpile group is a subgroup of the extended one, this directly implies that it admits a natural renormalization. Furthermore, we show that the harmonic fields can be induced by simple Markov processes, and that the corresponding stochastic dynamics show remarkable robustness over hundreds of periods. Finally, we encode information into seemingly random configurations, and decode this information with an algorithm requiring minimal prior knowledge. Our results suggest that harmonic fields might split the sandpile group into sub-sets showing different critical coefficients, and that it might be possible to extend the fractal structure of the identity beyond the boundaries of its domain. AU - Lang, Moritz AU - Shkolnikov, Mikhail ID - 196 IS - 8 JF - Proceedings of the National Academy of Sciences TI - Harmonic dynamics of the Abelian sandpile VL - 116 ER - TY - CONF AB - Learning disentangled representations is considered a cornerstone problem in representation learning. Recently, Locatello et al. (2019) demonstrated that unsupervised disentanglement learning without inductive biases is theoretically impossible and that existing inductive biases and unsupervised methods do not allow to consistently learn disentangled representations. However, in many practical settings, one might have access to a limited amount of supervision, for example through manual labeling of (some) factors of variation in a few training examples. In this paper, we investigate the impact of such supervision on state-of-the-art disentanglement methods and perform a large scale study, training over 52000 models under well-defined and reproducible experimental conditions. We observe that a small number of labeled examples (0.01--0.5\% of the data set), with potentially imprecise and incomplete labels, is sufficient to perform model selection on state-of-the-art unsupervised models. Further, we investigate the benefit of incorporating supervision into the training process. Overall, we empirically validate that with little and imprecise supervision it is possible to reliably learn disentangled representations. AU - Locatello, Francesco AU - Tschannen, Michael AU - Bauer, Stefan AU - Rätsch, Gunnar AU - Schölkopf, Bernhard AU - Bachem, Olivier ID - 14184 T2 - 8th International Conference on Learning Representations TI - Disentangling factors of variation using few labels ER - TY - CONF AB - We consider the problem of recovering a common latent source with independent components from multiple views. This applies to settings in which a variable is measured with multiple experimental modalities, and where the goal is to synthesize the disparate measurements into a single unified representation. We consider the case that the observed views are a nonlinear mixing of component-wise corruptions of the sources. When the views are considered separately, this reduces to nonlinear Independent Component Analysis (ICA) for which it is provably impossible to undo the mixing. We present novel identifiability proofs that this is possible when the multiple views are considered jointly, showing that the mixing can theoretically be undone using function approximators such as deep neural networks. In contrast to known identifiability results for nonlinear ICA, we prove that independent latent sources with arbitrary mixing can be recovered as long as multiple, sufficiently different noisy views are available. AU - Gresele, Luigi AU - Rubenstein, Paul K. AU - Mehrjou, Arash AU - Locatello, Francesco AU - Schölkopf, Bernhard ID - 14189 T2 - Proceedings of the 35th Conference on Uncertainty in Artificial Intelligence TI - The incomplete Rosetta Stone problem: Identifiability results for multi-view nonlinear ICA VL - 115 ER - TY - CONF AB - Recently there has been a significant interest in learning disentangled representations, as they promise increased interpretability, generalization to unseen scenarios and faster learning on downstream tasks. In this paper, we investigate the usefulness of different notions of disentanglement for improving the fairness of downstream prediction tasks based on representations. We consider the setting where the goal is to predict a target variable based on the learned representation of high-dimensional observations (such as images) that depend on both the target variable and an \emph{unobserved} sensitive variable. We show that in this setting both the optimal and empirical predictions can be unfair, even if the target variable and the sensitive variable are independent. Analyzing the representations of more than \num{12600} trained state-of-the-art disentangled models, we observe that several disentanglement scores are consistently correlated with increased fairness, suggesting that disentanglement may be a useful property to encourage fairness when sensitive variables are not observed. AU - Locatello, Francesco AU - Abbati, Gabriele AU - Rainforth, Tom AU - Bauer, Stefan AU - Schölkopf, Bernhard AU - Bachem, Olivier ID - 14197 SN - 9781713807933 T2 - Advances in Neural Information Processing Systems TI - On the fairness of disentangled representations VL - 32 ER - TY - CONF AB - A broad class of convex optimization problems can be formulated as a semidefinite program (SDP), minimization of a convex function over the positive-semidefinite cone subject to some affine constraints. The majority of classical SDP solvers are designed for the deterministic setting where problem data is readily available. In this setting, generalized conditional gradient methods (aka Frank-Wolfe-type methods) provide scalable solutions by leveraging the so-called linear minimization oracle instead of the projection onto the semidefinite cone. Most problems in machine learning and modern engineering applications, however, contain some degree of stochasticity. In this work, we propose the first conditional-gradient-type method for solving stochastic optimization problems under affine constraints. Our method guarantees O(k−1/3) convergence rate in expectation on the objective residual and O(k−5/12) on the feasibility gap. AU - Locatello, Francesco AU - Yurtsever, Alp AU - Fercoq, Olivier AU - Cevher, Volkan ID - 14191 SN - 9781713807933 T2 - Advances in Neural Information Processing Systems TI - Stochastic Frank-Wolfe for composite convex minimization VL - 32 ER - TY - CONF AB - A disentangled representation encodes information about the salient factors of variation in the data independently. Although it is often argued that this representational format is useful in learning to solve many real-world down-stream tasks, there is little empirical evidence that supports this claim. In this paper, we conduct a large-scale study that investigates whether disentangled representations are more suitable for abstract reasoning tasks. Using two new tasks similar to Raven's Progressive Matrices, we evaluate the usefulness of the representations learned by 360 state-of-the-art unsupervised disentanglement models. Based on these representations, we train 3600 abstract reasoning models and observe that disentangled representations do in fact lead to better down-stream performance. In particular, they enable quicker learning using fewer samples. AU - Steenkiste, Sjoerd van AU - Locatello, Francesco AU - Schmidhuber, Jürgen AU - Bachem, Olivier ID - 14193 SN - 9781713807933 T2 - Advances in Neural Information Processing Systems TI - Are disentangled representations helpful for abstract visual reasoning? VL - 32 ER - TY - CONF AB - The key idea behind the unsupervised learning of disentangled representations is that real-world data is generated by a few explanatory factors of variation which can be recovered by unsupervised learning algorithms. In this paper, we provide a sober look at recent progress in the field and challenge some common assumptions. We first theoretically show that the unsupervised learning of disentangled representations is fundamentally impossible without inductive biases on both the models and the data. Then, we train more than 12000 models covering most prominent methods and evaluation metrics in a reproducible large-scale experimental study on seven different data sets. We observe that while the different methods successfully enforce properties ``encouraged'' by the corresponding losses, well-disentangled models seemingly cannot be identified without supervision. Furthermore, increased disentanglement does not seem to lead to a decreased sample complexity of learning for downstream tasks. Our results suggest that future work on disentanglement learning should be explicit about the role of inductive biases and (implicit) supervision, investigate concrete benefits of enforcing disentanglement of the learned representations, and consider a reproducible experimental setup covering several data sets. AU - Locatello, Francesco AU - Bauer, Stefan AU - Lucic, Mario AU - Rätsch, Gunnar AU - Gelly, Sylvain AU - Schölkopf, Bernhard AU - Bachem, Olivier ID - 14200 T2 - Proceedings of the 36th International Conference on Machine Learning TI - Challenging common assumptions in the unsupervised learning of disentangled representations VL - 97 ER - TY - JOUR AB - We theoretically study the shapes of lipid vesicles confined to a spherical cavity, elaborating a framework based on the so-called limiting shapes constructed from geometrically simple structural elements such as double-membrane walls and edges. Partly inspired by numerical results, the proposed non-compartmentalized and compartmentalized limiting shapes are arranged in the bilayer-couple phase diagram which is then compared to its free-vesicle counterpart. We also compute the area-difference-elasticity phase diagram of the limiting shapes and we use it to interpret shape transitions experimentally observed in vesicles confined within another vesicle. The limiting-shape framework may be generalized to theoretically investigate the structure of certain cell organelles such as the mitochondrion. AU - Kavcic, Bor AU - Sakashita, A. AU - Noguchi, H. AU - Ziherl, P. ID - 5817 IS - 4 JF - Soft Matter SN - 1744-683X TI - Limiting shapes of confined lipid vesicles VL - 15 ER - TY - JOUR AB - We consider the space of probability measures on a discrete set X, endowed with a dynamical optimal transport metric. Given two probability measures supported in a subset Y⊆X, it is natural to ask whether they can be connected by a constant speed geodesic with support in Y at all times. Our main result answers this question affirmatively, under a suitable geometric condition on Y introduced in this paper. The proof relies on an extension result for subsolutions to discrete Hamilton-Jacobi equations, which is of independent interest. AU - Erbar, Matthias AU - Maas, Jan AU - Wirth, Melchior ID - 73 IS - 1 JF - Calculus of Variations and Partial Differential Equations SN - 09442669 TI - On the geometry of geodesics in discrete optimal transport VL - 58 ER - TY - CONF AB - Learning meaningful and compact representations with disentangled semantic aspects is considered to be of key importance in representation learning. Since real-world data is notoriously costly to collect, many recent state-of-the-art disentanglement models have heavily relied on synthetic toy data-sets. In this paper, we propose a novel data-set which consists of over one million images of physical 3D objects with seven factors of variation, such as object color, shape, size and position. In order to be able to control all the factors of variation precisely, we built an experimental platform where the objects are being moved by a robotic arm. In addition, we provide two more datasets which consist of simulations of the experimental setup. These datasets provide for the first time the possibility to systematically investigate how well different disentanglement methods perform on real data in comparison to simulation, and how simulated data can be leveraged to build better representations of the real world. We provide a first experimental study of these questions and our results indicate that learned models transfer poorly, but that model and hyperparameter selection is an effective means of transferring information to the real world. AU - Gondal, Muhammad Waleed AU - Wüthrich, Manuel AU - Miladinović, Đorđe AU - Locatello, Francesco AU - Breidt, Martin AU - Volchkov, Valentin AU - Akpo, Joel AU - Bachem, Olivier AU - Schölkopf, Bernhard AU - Bauer, Stefan ID - 14190 SN - 9781713807933 T2 - Advances in Neural Information Processing Systems TI - On the transfer of inductive bias from simulation to the real world: a new disentanglement dataset VL - 32 ER - TY - JOUR AB - We present an efficient algorithm for a problem in the interface between clustering and graph embeddings. An embedding ϕ : G → M of a graph G into a 2-manifold M maps the vertices in V(G) to distinct points and the edges in E(G) to interior-disjoint Jordan arcs between the corresponding vertices. In applications in clustering, cartography, and visualization, nearby vertices and edges are often bundled to the same point or overlapping arcs due to data compression or low resolution. This raises the computational problem of deciding whether a given map ϕ : G → M comes from an embedding. A map ϕ : G → M is a weak embedding if it can be perturbed into an embedding ψ ϵ : G → M with ‖ ϕ − ψ ϵ ‖ < ϵ for every ϵ > 0, where ‖.‖ is the unform norm. A polynomial-time algorithm for recognizing weak embeddings has recently been found by Fulek and Kynčl. It reduces the problem to solving a system of linear equations over Z2. It runs in O(n2ω)≤ O(n4.75) time, where ω ∈ [2,2.373) is the matrix multiplication exponent and n is the number of vertices and edges of G. We improve the running time to O(n log n). Our algorithm is also conceptually simpler: We perform a sequence of local operations that gradually “untangles” the image ϕ(G) into an embedding ψ(G) or reports that ϕ is not a weak embedding. It combines local constraints on the orientation of subgraphs directly, thereby eliminating the need for solving large systems of linear equations. AU - Akitaya, Hugo AU - Fulek, Radoslav AU - Tóth, Csaba ID - 6982 IS - 4 JF - ACM Transactions on Algorithms TI - Recognizing weak embeddings of graphs VL - 15 ER - TY - THES AB - Hybrid automata combine finite automata and dynamical systems, and model the interaction of digital with physical systems. Formal analysis that can guarantee the safety of all behaviors or rigorously witness failures, while unsolvable in general, has been tackled algorithmically using, e.g., abstraction, bounded model-checking, assisted theorem proving. Nevertheless, very few methods have addressed the time-unbounded reachability analysis of hybrid automata and, for current sound and automatic tools, scalability remains critical. We develop methods for the polyhedral abstraction of hybrid automata, which construct coarse overapproximations and tightens them incrementally, in a CEGAR fashion. We use template polyhedra, i.e., polyhedra whose facets are normal to a given set of directions. While, previously, directions were given by the user, we introduce (1) the first method for computing template directions from spurious counterexamples, so as to generalize and eliminate them. The method applies naturally to convex hybrid automata, i.e., hybrid automata with (possibly non-linear) convex constraints on derivatives only, while for linear ODE requires further abstraction. Specifically, we introduce (2) the conic abstractions, which, partitioning the state space into appropriate (possibly non-uniform) cones, divide curvy trajectories into relatively straight sections, suitable for polyhedral abstractions. Finally, we introduce (3) space-time interpolation, which, combining interval arithmetic and template refinement, computes appropriate (possibly non-uniform) time partitioning and template directions along spurious trajectories, so as to eliminate them. We obtain sound and automatic methods for the reachability analysis over dense and unbounded time of convex hybrid automata and hybrid automata with linear ODE. We build prototype tools and compare—favorably—our methods against the respective state-of-the-art tools, on several benchmarks. AU - Giacobbe, Mirco ID - 6894 TI - Automatic time-unbounded reachability analysis of hybrid systems ER - TY - GEN AB - The spread of adaptive alleles is fundamental to evolution, and in theory, this process is well‐understood. However, only rarely can we follow this process—whether it originates from the spread of a new mutation, or by introgression from another population. In this issue of Molecular Ecology, Hanemaaijer et al. (2018) report on a 25‐year long study of the mosquitoes Anopheles gambiae (Figure 1) and Anopheles coluzzi in Mali, based on genotypes at 15 single‐nucleotide polymorphism (SNP). The species are usually reproductively isolated from each other, but in 2002 and 2006, bursts of hybridization were observed, when F1 hybrids became abundant. Alleles backcrossed from A. gambiae into A. coluzzi, but after the first event, these declined over the following years. In contrast, after 2006, an insecticide resistance allele that had established in A. gambiae spread into A. coluzzi, and rose to high frequency there, over 6 years (~75 generations). Whole genome sequences of 74 individuals showed that A. gambiae SNP from across the genome had become common in the A. coluzzi population, but that most of these were clustered in 34 genes around the resistance locus. A new set of SNP from 25 of these genes were assayed over time; over the 4 years since near‐fixation of the resistance allele; some remained common, whereas others declined. What do these patterns tell us about this introgression event? AU - Barton, Nicholas H ID - 9805 TI - Data from: The consequences of an introgression event ER - TY - JOUR AB - Despite their different origins, Drosophila glia and hemocytes are related cell populations that provide an immune function. Drosophila hemocytes patrol the body cavity and act as macrophages outside the nervous system whereas glia originate from the neuroepithelium and provide the scavenger population of the nervous system. Drosophila glia are hence the functional orthologs of vertebrate microglia, even though the latter are cells of immune origin that subsequently move into the brain during development. Interestingly, the Drosophila immune cells within (glia) and outside the nervous system (hemocytes) require the same transcription factor Glide/Gcm for their development. This raises the issue of how do glia specifically differentiate in the nervous system and hemocytes in the procephalic mesoderm. The Repo homeodomain transcription factor and pan-glial direct target of Glide/Gcm is known to ensure glial terminal differentiation. Here we show that Repo also takes center stage in the process that discriminates between glia and hemocytes. First, Repo expression is repressed in the hemocyte anlagen by mesoderm-specific factors. Second, Repo ectopic activation in the procephalic mesoderm is sufficient to repress the expression of hemocyte-specific genes. Third, the lack of Repo triggers the expression of hemocyte markers in glia. Thus, a complex network of tissue-specific cues biases the potential of Glide/Gcm. These data allow us to revise the concept of fate determinants and help us understand the bases of cell specification. Both sexes were analyzed.SIGNIFICANCE STATEMENTDistinct cell types often require the same pioneer transcription factor, raising the issue of how does one factor trigger different fates. In Drosophila, glia and hemocytes provide a scavenger activity within and outside the nervous system, respectively. While they both require the Glide/Gcm transcription factor, glia originate from the ectoderm, hemocytes from the mesoderm. Here we show that tissue-specific factors inhibit the gliogenic potential of Glide/Gcm in the mesoderm by repressing the expression of the homeodomain protein Repo, a major glial-specific target of Glide/Gcm. Repo expression in turn inhibits the expression of hemocyte-specific genes in the nervous system. These cell-specific networks secure the establishment of the glial fate only in the nervous system and allow cell diversification. AU - Trébuchet, Guillaume AU - Cattenoz, Pierre B AU - Zsámboki, János AU - Mazaud, David AU - Siekhaus, Daria E AU - Fanto, Manolis AU - Giangrande, Angela ID - 8 IS - 2 JF - Journal of Neuroscience TI - The Repo homeodomain transcription factor suppresses hematopoiesis in Drosophila and preserves the glial fate VL - 39 ER - TY - JOUR AB - In this paper, we introduce a quantum version of the wonderful compactification of a group as a certain noncommutative projective scheme. Our approach stems from the fact that the wonderful compactification encodes the asymptotics of matrix coefficients, and from its realization as a GIT quotient of the Vinberg semigroup. In order to define the wonderful compactification for a quantum group, we adopt a generalized formalism of Proj categories in the spirit of Artin and Zhang. Key to our construction is a quantum version of the Vinberg semigroup, which we define as a q-deformation of a certain Rees algebra, compatible with a standard Poisson structure. Furthermore, we discuss quantum analogues of the stratification of the wonderful compactification by orbits for a certain group action, and provide explicit computations in the case of SL2. AU - Ganev, Iordan V ID - 5 IS - 3 JF - Journal of the London Mathematical Society TI - The wonderful compactification for quantum groups VL - 99 ER - TY - THES AB - The development and growth of Arabidopsis thaliana is regulated by a combination of genetic programing and also by the environmental influences. An important role in these processes play the phytohormones and among them, auxin is crucial as it controls many important functions. It is transported through the whole plant body by creating local and temporal concentration maxima and minima, which have an impact on the cell status, tissue and organ identity. Auxin has the property to undergo a directional and finely regulated cell-to-cell transport, which is enabled by the transport proteins, localized on the plasma membrane. An important role in this process have the PIN auxin efflux proteins, which have an asymmetric/polar subcellular localization and determine the directionality of the auxin transport. During the last years, there were significant advances in understanding how the trafficking molecular machineries function, including studies on molecular interactions, function, subcellular localization and intracellular distribution. However, there is still a lack of detailed characterization on the steps of endocytosis, exocytosis, endocytic recycling and degradation. Due to this fact, I focused on the identification of novel trafficking factors and better characterization of the intracellular trafficking pathways. My PhD thesis consists of an introductory chapter, three experimental chapters, a chapter containing general discussion, conclusions and perspectives and also an appendix chapter with published collaborative papers. The first chapter is separated in two different parts: I start by a general introduction to auxin biology and then I introduce the trafficking pathways in the model plant Arabidopsis thaliana. Then, I explain also the phosphorylation-signals for polar targeting and also the roles of the phytohormone strigolactone. The second chapter includes the characterization of bar1/sacsin mutant, which was identified in a forward genetic screen for novel trafficking components in Arabidopsis thaliana, where by the implementation of an EMS-treated pPIN1::PIN1-GFP marker line and by using the established inhibitor of ARF-GEFs, Brefeldin A (BFA) as a tool to study trafficking processes, we identified a novel factor, which is mediating the adaptation of the plant cell to ARF-GEF inhibition. The mutation is in a previously uncharacterized gene, encoding a very big protein that we, based on its homologies, called SACSIN with domains suggesting roles as a molecular chaperon or as a component of the ubiquitin-proteasome system. Our physiology and imaging studies revealed that SACSIN is a crucial plant cell component of the adaptation to the ARF-GEF inhibition. The third chapter includes six subchapters, where I focus on the role of the phytohormone strigolactone, which interferes with auxin feedback on PIN internalization. Strigolactone moderates the polar auxin transport by increasing the internalization of the PIN auxin efflux carriers, which reduces the canalization related growth responses. In addition, I also studied the role of phosphorylation in the strigolactone regulation of auxin feedback on PIN internalization. In this chapter I also present my results on the MAX2-dependence of strigolactone-mediated root growth inhibition and I also share my results on the auxin metabolomics profiling after application of GR24. In the fourth chapter I studied the effect of two small molecules ES-9 and ES9-17, which were identified from a collection of small molecules with the property to impair the clathrin-mediated endocytosis. In the fifth chapter, I discuss all my observations and experimental findings and suggest alternative hypothesis to interpret my results. In the appendix there are three collaborative published projects. In the first, I participated in the characterization of the role of ES9 as a small molecule, which is inhibitor of clathrin- mediated endocytosis in different model organisms. In the second paper, I contributed to the characterization of another small molecule ES9-17, which is a non-protonophoric analog of ES9 and also impairs the clathrin-mediated endocytosis not only in plant cells, but also in mammalian HeLa cells. Last but not least, I also attach another paper, where I tried to establish the grafting method as a technique in our lab to study canalization related processes. AU - Vasileva, Mina K ID - 7172 TI - Molecular mechanisms of endomembrane trafficking in Arabidopsis thaliana ER - TY - THES AB - Single cells are constantly interacting with their environment and each other, more importantly, the accurate perception of environmental cues is crucial for growth, survival, and reproduction. This communication between cells and their environment can be formalized in mathematical terms and be quantified as the information flow between them, as prescribed by information theory. The recent availability of real–time dynamical patterns of signaling molecules in single cells has allowed us to identify encoding about the identity of the environment in the time–series. However, efficient estimation of the information transmitted by these signals has been a data–analysis challenge due to the high dimensionality of the trajectories and the limited number of samples. In the first part of this thesis, we develop and evaluate decoding–based estimation methods to lower bound the mutual information and derive model–based precise information estimates for biological reaction networks governed by the chemical master equation. This is followed by applying the decoding-based methods to study the intracellular representation of extracellular changes in budding yeast, by observing the transient dynamics of nuclear translocation of 10 transcription factors in response to 3 stress conditions. Additionally, we apply these estimators to previously published data on ERK and Ca2+ signaling and yeast stress response. We argue that this single cell decoding-based measure of information provides an unbiased, quantitative and interpretable measure for the fidelity of biological signaling processes. Finally, in the last section, we deal with gene regulation which is primarily controlled by transcription factors (TFs) that bind to the DNA to activate gene expression. The possibility that non-cognate TFs activate transcription diminishes the accuracy of regulation with potentially disastrous effects for the cell. This ’crosstalk’ acts as a previously unexplored source of noise in biochemical networks and puts a strong constraint on their performance. To mitigate erroneous initiation we propose an out of equilibrium scheme that implements kinetic proofreading. We show that such architectures are favored over their equilibrium counterparts for complex organisms despite introducing noise in gene expression. AU - Cepeda Humerez, Sarah A ID - 6473 KW - Information estimation KW - Time-series KW - data analysis SN - 2663-337X TI - Estimating information flow in single cells ER - TY - THES AB - Transcription factors, by binding to specific sequences on the DNA, control the precise spatio-temporal expression of genes inside a cell. However, this specificity is limited, leading to frequent incorrect binding of transcription factors that might have deleterious consequences on the cell. By constructing a biophysical model of TF-DNA binding in the context of gene regulation, I will first explore how regulatory constraints can strongly shape the distribution of a population in sequence space. Then, by directly linking this to a picture of multiple types of transcription factors performing their functions simultaneously inside the cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions between transcription factors and binding sites that lead to erroneous regulatory states -- and understand the constraints this places on the design of regulatory systems. I will then develop a generic theoretical framework to investigate the coevolution of multiple transcription factors and multiple binding sites, in the context of a gene regulatory network that performs a certain function. As a particular tractable version of this problem, I will consider the evolution of two transcription factors when they transmit upstream signals to downstream target genes. Specifically, I will describe the evolutionary steady states and the evolutionary pathways involved, along with their timescales, of a system that initially undergoes a transcription factor duplication event. To connect this important theoretical model to the prominent biological event of transcription factor duplication giving rise to paralogous families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription factors, a major family in humans, and focus on the patterns of evolution that paralogs have undergone in their various protein domains in the recent past. AU - Prizak, Roshan ID - 6071 SN - 2663-337X TI - Coevolution of transcription factors and their binding sites in sequence space ER -