TY - JOUR AB - We consider the least singular value of a large random matrix with real or complex i.i.d. Gaussian entries shifted by a constant z∈C. We prove an optimal lower tail estimate on this singular value in the critical regime where z is around the spectral edge, thus improving the classical bound of Sankar, Spielman and Teng (SIAM J. Matrix Anal. Appl. 28:2 (2006), 446–476) for the particular shift-perturbation in the edge regime. Lacking Brézin–Hikami formulas in the real case, we rely on the superbosonization formula (Comm. Math. Phys. 283:2 (2008), 343–395). AU - Cipolloni, Giorgio AU - Erdös, László AU - Schröder, Dominik J ID - 15063 IS - 1 JF - Probability and Mathematical Physics KW - General Medicine SN - 2690-1005 TI - Optimal lower bound on the least singular value of the shifted Ginibre ensemble VL - 1 ER - TY - CONF AB - In this paper we present a room temperature radiometer that can eliminate the need of using cryostats in satellite payload reducing its weight and improving reliability. The proposed radiometer is based on an electro-optic upconverter that boosts up microwave photons energy by upconverting them into an optical domain what makes them immune to thermal noise even if operating at room temperature. The converter uses a high-quality factor whispering gallery mode (WGM) resonator providing naturally narrow bandwidth and therefore might be useful for applications like microwave hyperspectral sensing. The upconversion process is explained by providing essential information about photon conversion efficiency and sensitivity. To prove the concept, we describe an experiment which shows state-of-the-art photon conversion efficiency n=10-5 per mW of pump power at the frequency of 80 GHz. AU - Wasiak, Michal AU - Botello, Gabriel Santamaria AU - Abdalmalak, Kerlos Atia AU - Sedlmeir, Florian AU - Rueda Sanchez, Alfredo R AU - Segovia-Vargas, Daniel AU - Schwefel, Harald G. L. AU - Munoz, Luis Enrique Garcia ID - 15059 T2 - 14th European Conference on Antennas and Propagation TI - Compact millimeter and submillimeter-wave photonic radiometer for cubesats ER - TY - CONF AB - We introduce a new graph problem, the token dropping game, and we show how to solve it efficiently in a distributed setting. We use the token dropping game as a tool to design an efficient distributed algorithm for the stable orientation problem, which is a special case of the more general locally optimal semi-matching problem. The prior work by Czygrinow et al. (DISC 2012) finds a locally optimal semi-matching in O(Δ⁵) rounds in graphs of maximum degree Δ, which directly implies an algorithm with the same runtime for stable orientations. We improve the runtime to O(Δ⁴) for stable orientations and prove a lower bound of Ω(Δ) rounds. AU - Brandt, Sebastian AU - Keller, Barbara AU - Rybicki, Joel AU - Suomela, Jukka AU - Uitto, Jara ID - 15074 T2 - 34th International Symposium on Distributed Computing TI - Brief announcement: Efficient load-balancing through distributed token dropping VL - 179 ER - TY - CONF AB - We consider the following dynamic load-balancing process: given an underlying graph G with n nodes, in each step t≥ 0, one unit of load is created, and placed at a randomly chosen graph node. In the same step, the chosen node picks a random neighbor, and the two nodes balance their loads by averaging them. We are interested in the expected gap between the minimum and maximum loads at nodes as the process progresses, and its dependence on n and on the graph structure. Variants of the above graphical balanced allocation process have been studied previously by Peres, Talwar, and Wieder [Peres et al., 2015], and by Sauerwald and Sun [Sauerwald and Sun, 2015]. These authors left as open the question of characterizing the gap in the case of cycle graphs in the dynamic case, where weights are created during the algorithm’s execution. For this case, the only known upper bound is of 𝒪(n log n), following from a majorization argument due to [Peres et al., 2015], which analyzes a related graphical allocation process. In this paper, we provide an upper bound of 𝒪 (√n log n) on the expected gap of the above process for cycles of length n. We introduce a new potential analysis technique, which enables us to bound the difference in load between k-hop neighbors on the cycle, for any k ≤ n/2. We complement this with a "gap covering" argument, which bounds the maximum value of the gap by bounding its value across all possible subsets of a certain structure, and recursively bounding the gaps within each subset. We provide analytical and experimental evidence that our upper bound on the gap is tight up to a logarithmic factor. AU - Alistarh, Dan-Adrian AU - Nadiradze, Giorgi AU - Sabour, Amirmojtaba ID - 15077 T2 - 47th International Colloquium on Automata, Languages, and Programming TI - Dynamic averaging load balancing on cycles VL - 168 ER - TY - CONF AB - Two plane drawings of geometric graphs on the same set of points are called disjoint compatible if their union is plane and they do not have an edge in common. For a given set S of 2n points two plane drawings of perfect matchings M1 and M2 (which do not need to be disjoint nor compatible) are disjoint tree-compatible if there exists a plane drawing of a spanning tree T on S which is disjoint compatible to both M1 and M2. We show that the graph of all disjoint tree-compatible perfect geometric matchings on 2n points in convex position is connected if and only if 2n ≥ 10. Moreover, in that case the diameter of this graph is either 4 or 5, independent of n. AU - Aichholzer, Oswin AU - Obmann, Julia AU - Patak, Pavel AU - Perz, Daniel AU - Tkadlec, Josef ID - 15082 T2 - 36th European Workshop on Computational Geometry TI - Disjoint tree-compatible plane perfect matchings ER - TY - JOUR AB - Fitting a function by using linear combinations of a large number N of `simple' components is one of the most fruitful ideas in statistical learning. This idea lies at the core of a variety of methods, from two-layer neural networks to kernel regression, to boosting. In general, the resulting risk minimization problem is non-convex and is solved by gradient descent or its variants. Unfortunately, little is known about global convergence properties of these approaches. Here we consider the problem of learning a concave function f on a compact convex domain Ω⊆ℝd, using linear combinations of `bump-like' components (neurons). The parameters to be fitted are the centers of N bumps, and the resulting empirical risk minimization problem is highly non-convex. We prove that, in the limit in which the number of neurons diverges, the evolution of gradient descent converges to a Wasserstein gradient flow in the space of probability distributions over Ω. Further, when the bump width δ tends to 0, this gradient flow has a limit which is a viscous porous medium equation. Remarkably, the cost function optimized by this gradient flow exhibits a special property known as displacement convexity, which implies exponential convergence rates for N→∞, δ→0. Surprisingly, this asymptotic theory appears to capture well the behavior for moderate values of δ,N. Explaining this phenomenon, and understanding the dependence on δ,N in a quantitative manner remains an outstanding challenge. AU - Javanmard, Adel AU - Mondelli, Marco AU - Montanari, Andrea ID - 6748 IS - 6 JF - Annals of Statistics SN - 1932-6157 TI - Analysis of a two-layer neural network via displacement convexity VL - 48 ER - TY - JOUR AB - This workshop focused on interactions between the various perspectives on the moduli space of Higgs bundles over a Riemann surface. This subject draws on algebraic geometry, geometric topology, geometric analysis and mathematical physics, and the goal was to promote interactions between these various branches of the subject. The main current directions of research were well represented by the participants, and the talks included many from both senior and junior participants. AU - Anderson, Lara AU - Hausel, Tamás AU - Mazzeo, Rafe AU - Schaposnik, Laura ID - 15070 IS - 2 JF - Oberwolfach Reports KW - Organic Chemistry KW - Biochemistry SN - 1660-8933 TI - Geometry and physics of Higgs bundles VL - 16 ER - TY - JOUR AB - In ecology, climate and other fields, (sub)systems have been identified that can transition into a qualitatively different state when a critical threshold or tipping point in a driving process is crossed. An understanding of those tipping elements is of great interest given the increasing influence of humans on the biophysical Earth system. Complex interactions exist between tipping elements, e.g. physical mechanisms connect subsystems of the climate system. Based on earlier work on such coupled nonlinear systems, we systematically assessed the qualitative long-term behaviour of interacting tipping elements. We developed an understanding of the consequences of interactions on the tipping behaviour allowing for tipping cascades to emerge under certain conditions. The (narrative) application of these qualitative results to real-world examples of interacting tipping elements indicates that tipping cascades with profound consequences may occur: the interacting Greenland ice sheet and thermohaline ocean circulation might tip before the tipping points of the isolated subsystems are crossed. The eutrophication of the first lake in a lake chain might propagate through the following lakes without a crossing of their individual critical nutrient input levels. The possibility of emerging cascading tipping dynamics calls for the development of a unified theory of interacting tipping elements and the quantitative analysis of interacting real-world tipping elements. AU - Klose, Ann Kristin AU - Karle, Volker AU - Winkelmann, Ricarda AU - Donges, Jonathan F. ID - 8741 IS - 6 JF - Royal Society Open Science TI - Emergence of cascading dynamics in interacting tipping elements of ecology and climate: Cascading dynamics in tipping elements VL - 7 ER - TY - JOUR AB - A working group, which was established within the Network of Repository Managers (RepManNet), has dealt with common certifications for repositories. In addition, current requirements of the research funding agencies FWF and EU were also taken into account. The Core Trust Seal was examined in more detail. For this purpose, a questionnaire was sent to those organizations that are already certified with CTS in Austria. The answers were summarized and evaluated anonymously. It is recommended to go for a repository certification. Moreover, the development of a DINI certificate in Austria is strongly suggested. AU - Ernst, Doris AU - Novotny, Gertraud AU - Schönher, Eva Maria ID - 7687 IS - 1 JF - Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare SN - 1022-2588 TI - (Core Trust) Seal your repository! VL - 73 ER - TY - JOUR AB - Large complex systems tend to develop universal patterns that often represent their essential characteristics. For example, the cumulative effects of independent or weakly dependent random variables often yield the Gaussian universality class via the central limit theorem. For non-commutative random variables, e.g. matrices, the Gaussian behavior is often replaced by another universality class, commonly called random matrix statistics. Nearby eigenvalues are strongly correlated, and, remarkably, their correlation structure is universal, depending only on the symmetry type of the matrix. Even more surprisingly, this feature is not restricted to matrices; in fact Eugene Wigner, the pioneer of the field, discovered in the 1950s that distributions of the gaps between energy levels of complicated quantum systems universally follow the same random matrix statistics. This claim has never been rigorously proved for any realistic physical system but experimental data and extensive numerics leave no doubt as to its correctness. Since then random matrices have proved to be extremely useful phenomenological models in a wide range of applications beyond quantum physics that include number theory, statistics, neuroscience, population dynamics, wireless communication and mathematical finance. The ubiquity of random matrices in natural sciences is still a mystery, but recent years have witnessed a breakthrough in the mathematical description of the statistical structure of their spectrum. Random matrices and closely related areas such as log-gases have become an extremely active research area in probability theory. This workshop brought together outstanding researchers from a variety of mathematical backgrounds whose areas of research are linked to random matrices. While there are strong links between their motivations, the techniques used by these researchers span a large swath of mathematics, ranging from purely algebraic techniques to stochastic analysis, classical probability theory, operator algebra, supersymmetry, orthogonal polynomials, etc. AU - Erdös, László AU - Götze, Friedrich AU - Guionnet, Alice ID - 15079 IS - 4 JF - Oberwolfach Reports SN - 1660-8933 TI - Random matrices VL - 16 ER - TY - JOUR AB - The interaction among fundamental particles in nature leads to many interesting effects in quantum statistical mechanics; examples include superconductivity for charged systems and superfluidity in cold gases. It is a huge challenge for mathematical physics to understand the collective behavior of systems containing a large number of particles, emerging from known microscopic interactions. In this workshop we brought together researchers working on different aspects of many-body quantum mechanics to discuss recent developments, exchange ideas and propose new challenges and research directions. AU - Hainzl, Christian AU - Schlein, Benjamin AU - Seiringer, Robert AU - Warzel, Simone ID - 15072 IS - 3 JF - Oberwolfach Reports SN - 1660-8933 TI - Many-body quantum systems VL - 16 ER - TY - CONF AB - A mesophilic methanogenic culture, designated JL01, was isolated from Holocene permafrost in the Russian Arctic [1]. After long-term extensive cultivation at 15°C it turned out to be a tied binary culture of archaeal (JL01) and bacterial (Sphaerochaeta associata GLS2) strains. Strain JL01 was a strict anaerobe and grew on methanol, acetate and methylamines as energy and carbon sources. Cells were irregular coccoid, non-motile, non-spore-forming, and Gram-stainpositive. Optimum conditions for growth were 24-28 oC, pH 6.8–7.3 and 0.075-0.1 M NaCl. Phylogenetic tree reconstructions based on 16S rRNA and concatenated alignment of broadly conserved protein-coding genes revealed its close relation to Methanosarcina mazei S-6 T (similarity 99.5%). The comparison of whole genomic sequences (ANI) of the isolate and the type strain of M.mazei was 98.5%, which is higher than the values recommended for new species. Thus strain JL01 (=VKM B-2370=JCM 31898) represents the first M. mazei isolated from permanently subzero Arcticsediments. The long-term co-cultivation of JL01 with S. associata GLS2T showed the methane production without any additional carbon and energy sources. Genome analysis of S. associata GLS2T revealed putative genes involved in methanochondroithin catabolism. AU - Oshurkova, Viktoriia AU - Troshina, Olga AU - Trubitsyn, Vladimir AU - Ryzhmanova, Yana AU - Bochkareva, Olga AU - Shcherbakova, Viktoria ID - 15071 T2 - Proceedings of 1st International Electronic Conference on Microbiology TI - Characterization of methanosarcina mazei JL01 isolated from holocene arctic permafrost and study of the archaeon cooperation with bacterium Sphaerochaeta associata GLS2T ER - TY - THES AB - The medial habenula (MHb) is an evolutionary conserved epithalamic structure important for the modulation of emotional memory. It is involved in regulation of anxiety, compulsive behavior, addiction (nicotinic and opioid), sexual and feeding behavior. MHb receives inputs from septal regions and projects exclusively to the interpeduncular nucleus (IPN). Distinct sub-regions of the septum project to different subnuclei of MHb: the bed nucleus of anterior commissure projects to dorsal MHb and the triangular septum projects to ventral MHb. Furthermore, the dorsal and ventral MHb project to the lateral and rostral/central IPN, respectively. Importantly, these projections have unique features of prominent co-release of different neurotransmitters and requirement of a peculiar type of calcium channel for release. In general, synaptic neurotransmission requires an activity-dependent influx of Ca2+ into the presynaptic terminal through voltage-gated calcium channels. The calcium channel family most commonly involved in neurotransmitter release comprises three members, P/Q-, N- and R-type with Cav2.1, Cav2.2 and Cav2.3 subunits, respectively. In contrast to most CNS synapses that mainly express Cav2.1 and/or Cav2.2, MHb terminals in the IPN exclusively express Cav2.3. In other parts of the brain, such as the hippocampus, Cav2.3 is mostly located to postsynaptic elements. This unusual presynaptic location of Cav2.3 in the MHb-IPN pathway implies unique mechanisms of glutamate release in this pathway. One potential example of such uniqueness is the facilitation of release by GABAB receptor (GBR) activation. Presynaptic GBRs usually inhibit the release of neurotransmitters by inhibiting presynaptic calcium channels. MHb shows the highest expression levels of GBR in the brain. GBRs comprise two subunits, GABAB1 (GB1) and GABAB2 (GB2), and are associated with auxiliary subunits, called potassium channel tetramerization domain containing proteins (KCTD) 8, 12, 12b and 16. Among these four subunits, KCTD12b is exclusively expressed in ventral MHb, and KCTD8 shows the strongest expression in the whole MHb among other brain regions, indicating that KCTD8 and KCTD12b may be involved in the unique mechanisms of neurotransmitter release mediated by Cav2.3 and regulated by GBRs in this pathway. In the present study, we first verified that neurotransmission in both dorsal and ventral MHb-IPN pathways is mainly mediated by Cav2.3 using a selective blocker of R-type channels, SNX-482. We next found that baclofen, a GBR agonist, has facilitatory effects on release from ventral MHb terminal in rostral IPN, whereas it has inhibitory effects on release from dorsal MHb terminals in lateral IPN, indicating that KCTD12b expressed exclusively in ventral MHb may have a role in the facilitatory effects of GBR activation. In a heterologous expression system using HEK cells, we found that KCTD8 and KCTD12b but not KCTD12 directly bind with Cav2.3. Pre-embedding immunogold electron microscopy data show that Cav2.3 and KCTD12b are distributed most densely in presynaptic active zone in IPN with KCTD12b being present only in rostral/central but not lateral IPN, whereas GABAB, KCTD8 and KCTD12 are distributed most densely in perisynaptic sites with KCTD12 present more frequently in postsynaptic elements and only in rostral/central IPN. In freeze-fracture replica labelling, Cav2.3, KCTD8 and KCTD12b are co-localized with each other in the same active zone indicating that they may form complexes regulating vesicle release in rostral IPN. On electrophysiological studies of wild type (WT) mice, we found that paired-pulse ratio in rostral IPN of KCTD12b knock-out (KO) mice is lower than those of WT and KCTD8 KO mice. Consistent with this finding, in mean variance analysis, release probability in rostral IPN of KCTD12b KO mice is higher than that of WT and KCTD8 KO mice. Although paired-pulse ratios are not different between WT and KCTD8 KO mice, the mean variance analysis revealed significantly lower release probability in rostral IPN of KCTD8 KO than WT mice. These results demonstrate bidirectional regulation of Cav2.3-mediated release by KCTD8 and KCTD12b without GBR activation in rostral IPN. Finally, we examined the baclofen effects in rostral IPN of KCTD8 and KCTD12b KO mice, and found the facilitation of release remained in both KO mice, indicating that the peculiar effects of the GBR activation in this pathway do not depend on the selective expression of these KCTD subunits in ventral MHb. However, we found that presynaptic potentiation of evoked EPSC amplitude by baclofen falls to baseline after washout faster in KCTD12b KO mice than WT, KCTD8 KO and KCTD8/12b double KO mice. This result indicates that KCTD12b is involved in sustained potentiation of vesicle release by GBR activation, whereas KCTD8 is involved in its termination in the absence of KCTD12b. Consistent with these functional findings, replica labelling revealed an increase in density of KCTD8, but not Cav2.3 or GBR at active zone in rostral IPN of KCTD12b KO mice compared with that of WT mice, suggesting that increased association of KCTD8 with Cav2.3 facilitates the release probability and termination of the GBR effect in the absence of KCTD12b. In summary, our study provided new insights into the physiological roles of presynaptic Cav2.3, GBRs and their auxiliary subunits KCTDs at an evolutionary conserved neuronal circuit. Future studies will be required to identify the exact molecular mechanism underlying the GBR-mediated presynaptic potentiation on ventral MHb terminals. It remains to be determined whether the prominent presence of presynaptic KCTDs at active zone could exert similar neuromodulatory functions in different pathways of the brain. AU - Bhandari, Pradeep ID - 7525 KW - Cav2.3 KW - medial habenula (MHb) KW - interpeduncular nucleus (IPN) SN - 2663-337X TI - Localization and functional role of Cav2.3 in the medial habenula to interpeduncular nucleus pathway ER - TY - JOUR AB - Cryo-electron microscopy (cryo-EM) of cellular specimens provides insights into biological processes and structures within a native context. However, a major challenge still lies in the efficient and reproducible preparation of adherent cells for subsequent cryo-EM analysis. This is due to the sensitivity of many cellular specimens to the varying seeding and culturing conditions required for EM experiments, the often limited amount of cellular material and also the fragility of EM grids and their substrate. Here, we present low-cost and reusable 3D printed grid holders, designed to improve specimen preparation when culturing challenging cellular samples directly on grids. The described grid holders increase cell culture reproducibility and throughput, and reduce the resources required for cell culturing. We show that grid holders can be integrated into various cryo-EM workflows, including micro-patterning approaches to control cell seeding on grids, and for generating samples for cryo-focused ion beam milling and cryo-electron tomography experiments. Their adaptable design allows for the generation of specialized grid holders customized to a large variety of applications. AU - Fäßler, Florian AU - Zens, Bettina AU - Hauschild, Robert AU - Schur, Florian KM ID - 8586 IS - 3 JF - Journal of Structural Biology KW - electron microscopy KW - cryo-EM KW - EM sample preparation KW - 3D printing KW - cell culture SN - 1047-8477 TI - 3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy VL - 212 ER - TY - THES AB - Synthesis of proteins – translation – is a fundamental process of life. Quantitative studies anchor translation into the context of bacterial physiology and reveal several mathematical relationships, called “growth laws,” which capture physiological feedbacks between protein synthesis and cell growth. Growth laws describe the dependency of the ribosome abundance as a function of growth rate, which can change depending on the growth conditions. Perturbations of translation reveal that bacteria employ a compensatory strategy in which the reduced translation capability results in increased expression of the translation machinery. Perturbations of translation are achieved in various ways; clinically interesting is the application of translation-targeting antibiotics – translation inhibitors. The antibiotic effects on bacterial physiology are often poorly understood. Bacterial responses to two or more simultaneously applied antibiotics are even more puzzling. The combined antibiotic effect determines the type of drug interaction, which ranges from synergy (the effect is stronger than expected) to antagonism (the effect is weaker) and suppression (one of the drugs loses its potency). In the first part of this work, we systematically measure the pairwise interaction network for translation inhibitors that interfere with different steps in translation. We find that the interactions are surprisingly diverse and tend to be more antagonistic. To explore the underlying mechanisms, we begin with a minimal biophysical model of combined antibiotic action. We base this model on the kinetics of antibiotic uptake and binding together with the physiological response described by the growth laws. The biophysical model explains some drug interactions, but not all; it specifically fails to predict suppression. In the second part of this work, we hypothesize that elusive suppressive drug interactions result from the interplay between ribosomes halted in different stages of translation. To elucidate this putative mechanism of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using in- ducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks partially causes these interactions. We extend this approach by varying two translation bottlenecks simultaneously. This approach reveals the suppression of translocation inhibition by inhibited translation. We rationalize this effect by modeling dense traffic of ribosomes that move on transcripts in a translation factor-mediated manner. This model predicts a dissolution of traffic jams caused by inhibited translocation when the density of ribosome traffic is reduced by lowered initiation. We base this model on the growth laws and quantitative relationships between different translation and growth parameters. In the final part of this work, we describe a set of tools aimed at quantification of physiological and translation parameters. We further develop a simple model that directly connects the abundance of a translation factor with the growth rate, which allows us to extract physiological parameters describing initiation. We demonstrate the development of tools for measuring translation rate. This thesis showcases how a combination of high-throughput growth rate mea- surements, genetics, and modeling can reveal mechanisms of drug interactions. Furthermore, by a gradual transition from combinations of antibiotics to precise genetic interventions, we demonstrated the equivalency between genetic and chemi- cal perturbations of translation. These findings tile the path for quantitative studies of antibiotic combinations and illustrate future approaches towards the quantitative description of translation. AU - Kavcic, Bor ID - 8657 SN - 2663-337X TI - Perturbations of protein synthesis: from antibiotics to genetics and physiology ER - TY - JOUR AB - How structural and functional properties of synapses relate to each other is a fundamental question in neuroscience. Electrophysiology has elucidated mechanisms of synaptic transmission, and electron microscopy (EM) has provided insight into morphological properties of synapses. Here we describe an enhanced method for functional EM (“flash and freeze”), combining optogenetic stimulation with high-pressure freezing. We demonstrate that the improved method can be applied to intact networks in acute brain slices and organotypic slice cultures from mice. As a proof of concept, we probed vesicle pool changes during synaptic transmission at the hippocampal mossy fiber-CA3 pyramidal neuron synapse. Our findings show overlap of the docked vesicle pool and the functionally defined readily releasable pool and provide evidence of fast endocytosis at this synapse. Functional EM with acute slices and slice cultures has the potential to reveal the structural and functional mechanisms of transmission in intact, genetically perturbed, and disease-affected synapses. AU - Borges Merjane, Carolina AU - Kim, Olena AU - Jonas, Peter M ID - 7473 JF - Neuron SN - 0896-6273 TI - Functional electron microscopy (“Flash and Freeze”) of identified cortical synapses in acute brain slices VL - 105 ER - TY - JOUR AB - Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by “translation bottlenecks”: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of “continuous epistasis” in bacterial physiology. AU - Kavcic, Bor AU - Tkačik, Gašper AU - Bollenbach, Tobias ID - 8250 JF - Nature Communications SN - 2041-1723 TI - Mechanisms of drug interactions between translation-inhibiting antibiotics VL - 11 ER - TY - GEN AB - Combining drugs can improve the efficacy of treatments. However, predicting the effect of drug combinations is still challenging. The combined potency of drugs determines the drug interaction, which is classified as synergistic, additive, antagonistic, or suppressive. While probabilistic, non-mechanistic models exist, there is currently no biophysical model that can predict antibiotic interactions. Here, we present a physiologically relevant model of the combined action of antibiotics that inhibit protein synthesis by targeting the ribosome. This model captures the kinetics of antibiotic binding and transport, and uses bacterial growth laws to predict growth in the presence of antibiotic combinations. We find that this biophysical model can produce all drug interaction types except suppression. We show analytically that antibiotics which cannot bind to the ribosome simultaneously generally act as substitutes for one another, leading to additive drug interactions. Previously proposed null expectations for higher-order drug interactions follow as a limiting case of our model. We further extend the model to include the effects of direct physical or allosteric interactions between individual drugs on the ribosome. Notably, such direct interactions profoundly change the combined drug effect, depending on the kinetic parameters of the drugs used. The model makes additional predictions for the effects of resistance genes on drug interactions and for interactions between ribosome-targeting antibiotics and antibiotics with other targets. These findings enhance our understanding of the interplay between drug action and cell physiology and are a key step toward a general framework for predicting drug interactions. AU - Kavcic, Bor AU - Tkačik, Gašper AU - Bollenbach, Tobias ID - 7673 T2 - bioRxiv TI - A minimal biophysical model of combined antibiotic action ER - TY - JOUR AB - Wound healing in plant tissues, consisting of rigid cell wall-encapsulated cells, represents a considerable challenge and occurs through largely unknown mechanisms distinct from those in animals. Owing to their inability to migrate, plant cells rely on targeted cell division and expansion to regenerate wounds. Strict coordination of these wound-induced responses is essential to ensure efficient, spatially restricted wound healing. Single-cell tracking by live imaging allowed us to gain mechanistic insight into the wound perception and coordination of wound responses after laser-based wounding in Arabidopsis root. We revealed a crucial contribution of the collapse of damaged cells in wound perception and detected an auxin increase specific to cells immediately adjacent to the wound. This localized auxin increase balances wound-induced cell expansion and restorative division rates in a dose-dependent manner, leading to tumorous overproliferation when the canonical TIR1 auxin signaling is disrupted. Auxin and wound-induced turgor pressure changes together also spatially define the activation of key components of regeneration, such as the transcription regulator ERF115. Our observations suggest that the wound signaling involves the sensing of collapse of damaged cells and a local auxin signaling activation to coordinate the downstream transcriptional responses in the immediate wound vicinity. AU - Hörmayer, Lukas AU - Montesinos López, Juan C AU - Marhavá, Petra AU - Benková, Eva AU - Yoshida, Saiko AU - Friml, Jiří ID - 8002 IS - 26 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Wounding-induced changes in cellular pressure and localized auxin signalling spatially coordinate restorative divisions in roots VL - 117 ER - TY - THES AB - Proteins and their complex dynamic interactions regulate cellular mechanisms from sensing and transducing extracellular signals, to mediating genetic responses, and sustaining or changing cell morphology. To manipulate these protein-protein interactions (PPIs) that govern the behavior and fate of cells, synthetically constructed, genetically encoded tools provide the means to precisely target proteins of interest (POIs), and control their subcellular localization and activity in vitro and in vivo. Ideal synthetic tools react to an orthogonal cue, i.e. a trigger that does not activate any other endogenous process, thereby allowing manipulation of the POI alone. In optogenetics, naturally occurring photosensory domain from plants, algae and bacteria are re-purposed and genetically fused to POIs. Illumination with light of a specific wavelength triggers a conformational change that can mediate PPIs, such as dimerization or oligomerization. By using light as a trigger, these tools can be activated with high spatial and temporal precision, on subcellular and millisecond scales. Chemogenetic tools consist of protein domains that recognize and bind small molecules. By genetic fusion to POIs, these domains can mediate PPIs upon addition of their specific ligands, which are often synthetically designed to provide highly specific interactions and exhibit good bioavailability. Most optogenetic tools to mediate PPIs are based on well-studied photoreceptors responding to red, blue or near-UV light, leaving a striking gap in the green band of the visible light spectrum. Among both optogenetic and chemogenetic tools, there is an abundance of methods to induce PPIs, but tools to disrupt them require UV illumination, rely on covalent linkage and subsequent enzymatic cleavage or initially result in protein clustering of unknown stoichiometry. This work describes how the recently structurally and photochemically characterized green-light responsive cobalamin-binding domains (CBDs) from bacterial transcription factors were re-purposed to function as a green-light responsive optogenetic tool. In contrast to previously engineered optogenetic tools, CBDs do not induce PPI, but rather confer a PPI already upon expression, which can be rapidly disrupted by illumination. This was employed to mimic inhibition of constitutive activity of a growth factor receptor, and successfully implement for cell signalling in mammalian cells and in vivo to rescue development in zebrafish. This work further describes the development and application of a chemically induced de-dimerizer (CDD) based on a recently identified and structurally described bacterial oxyreductase. CDD forms a dimer upon expression in absence of its cofactor, the flavin derivative F420. Safety and of domain expression and ligand exposure are demonstrated in vitro and in vivo in zebrafish. The system is further applied to inhibit cell signalling output from a chimeric receptor upon F420 treatment. CBDs and CDD expand the repertoire of synthetic tools by providing novel mechanisms of mediating PPIs, and by recognizing previously not utilized cues. In the future, they can readily be combined with existing synthetic tools to functionally manipulate PPIs in vitro and in vivo. AU - Kainrath, Stephanie ID - 7680 TI - Synthetic tools for optogenetic and chemogenetic inhibition of cellular signals ER - TY - THES AB - The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive. De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency. In conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages. AU - Morandell, Jasmin ID - 8620 SN - 2663-337X TI - Illuminating the role of Cul3 in autism spectrum disorder pathogenesis ER - TY - THES AB - Mitochondria are sites of oxidative phosphorylation in eukaryotic cells. Oxidative phosphorylation operates by a chemiosmotic mechanism made possible by redox-driven proton pumping machines which establish a proton motive force across the inner mitochondrial membrane. This electrochemical proton gradient is used to drive ATP synthesis, which powers the majority of cellular processes such as protein synthesis, locomotion and signalling. In this thesis I investigate the structures and molecular mechanisms of two inner mitochondrial proton pumping enzymes, respiratory complex I and transhydrogenase. I present the first high-resolution structure of the full transhydrogenase from any species, and a significantly improved structure of complex I. Improving the resolution from 3.3 Å available previously to up to 2.3 Å in this thesis allowed us to model bound water molecules, crucial in the proton pumping mechanism. For both enzymes, up to five cryo-EM datasets with different substrates and inhibitors bound were solved to delineate the catalytic cycle and understand the proton pumping mechanism. In transhydrogenase, the proton channel is gated by reversible detachment of the NADP(H)-binding domain which opens the proton channel to the opposite sites of the membrane. In complex I, the proton channels are gated by reversible protonation of key glutamate and lysine residues and breaking of the water wire connecting the proton pumps with the quinone reduction site. The tight coupling between the redox and the proton pumping reactions in transhydrogenase is achieved by controlling the NADP(H) exchange which can only happen when the NADP(H)-binding domain interacts with the membrane domain. In complex I, coupling is achieved by cycling of the whole complex between the closed state, in which quinone can get reduced, and the open state, in which NADH can induce quinol ejection from the binding pocket. On the basis of these results I propose detailed mechanisms for catalytic cycles of transhydrogenase and complex I that are consistent with a large amount of previous work. In both enzymes, conformational and electrostatic mechanisms contribute to the overall catalytic process. Results presented here could be used for better understanding of the human pathologies arising from deficiencies of complex I or transhydrogenase and could be used to develop novel therapies. AU - Kampjut, Domen ID - 8340 SN - 2663-337X TI - Molecular mechanisms of mitochondrial redox-coupled proton pumping enzymes ER - TY - GEN AB - De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages. AU - Morandell, Jasmin AU - Schwarz, Lena A AU - Basilico, Bernadette AU - Tasciyan, Saren AU - Nicolas, Armel AU - Sommer, Christoph M AU - Kreuzinger, Caroline AU - Knaus, Lisa AU - Dobler, Zoe AU - Cacci, Emanuele AU - Danzl, Johann G AU - Novarino, Gaia ID - 7800 T2 - bioRxiv TI - Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development ER - TY - JOUR AB - The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes. AU - Basilico, Bernadette AU - Morandell, Jasmin AU - Novarino, Gaia ID - 8131 IS - 12 JF - Current Opinion in Genetics and Development SN - 0959437X TI - Molecular mechanisms for targeted ASD treatments VL - 65 ER - TY - JOUR AB - Efficient migration on adhesive surfaces involves the protrusion of lamellipodial actin networks and their subsequent stabilization by nascent adhesions. The actin-binding protein lamellipodin (Lpd) is thought to play a critical role in lamellipodium protrusion, by delivering Ena/VASP proteins onto the growing plus ends of actin filaments and by interacting with the WAVE regulatory complex, an activator of the Arp2/3 complex, at the leading edge. Using B16-F1 melanoma cell lines, we demonstrate that genetic ablation of Lpd compromises protrusion efficiency and coincident cell migration without altering essential parameters of lamellipodia, including their maximal rate of forward advancement and actin polymerization. We also confirmed lamellipodia and migration phenotypes with CRISPR/Cas9-mediated Lpd knockout Rat2 fibroblasts, excluding cell type-specific effects. Moreover, computer-aided analysis of cell-edge morphodynamics on B16-F1 cell lamellipodia revealed that loss of Lpd correlates with reduced temporal protrusion maintenance as a prerequisite of nascent adhesion formation. We conclude that Lpd optimizes protrusion and nascent adhesion formation by counteracting frequent, chaotic retraction and membrane ruffling.This article has an associated First Person interview with the first author of the paper. AU - Dimchev, Georgi A AU - Amiri, Behnam AU - Humphries, Ashley C. AU - Schaks, Matthias AU - Dimchev, Vanessa AU - Stradal, Theresia E. B. AU - Faix, Jan AU - Krause, Matthias AU - Way, Michael AU - Falcke, Martin AU - Rottner, Klemens ID - 8434 IS - 7 JF - Journal of Cell Science KW - Cell Biology SN - 0021-9533 TI - Lamellipodin tunes cell migration by stabilizing protrusions and promoting adhesion formation VL - 133 ER - TY - JOUR AB - Autoluminescent plants engineered to express a bacterial bioluminescence gene cluster in plastids have not been widely adopted because of low light output. We engineered tobacco plants with a fungal bioluminescence system that converts caffeic acid (present in all plants) into luciferin and report self-sustained luminescence that is visible to the naked eye. Our findings could underpin development of a suite of imaging tools for plants. AU - Mitiouchkina, Tatiana AU - Mishin, Alexander S. AU - Gonzalez Somermeyer, Louisa AU - Markina, Nadezhda M. AU - Chepurnyh, Tatiana V. AU - Guglya, Elena B. AU - Karataeva, Tatiana A. AU - Palkina, Kseniia A. AU - Shakhova, Ekaterina S. AU - Fakhranurova, Liliia I. AU - Chekova, Sofia V. AU - Tsarkova, Aleksandra S. AU - Golubev, Yaroslav V. AU - Negrebetsky, Vadim V. AU - Dolgushin, Sergey A. AU - Shalaev, Pavel V. AU - Shlykov, Dmitry AU - Melnik, Olesya A. AU - Shipunova, Victoria O. AU - Deyev, Sergey M. AU - Bubyrev, Andrey I. AU - Pushin, Alexander S. AU - Choob, Vladimir V. AU - Dolgov, Sergey V. AU - Kondrashov, Fyodor AU - Yampolsky, Ilia V. AU - Sarkisyan, Karen S. ID - 7889 JF - Nature Biotechnology SN - 1087-0156 TI - Plants with genetically encoded autoluminescence VL - 38 ER - TY - GEN AB - Tension of the actomyosin cell cortex plays a key role in determining cell-cell contact growth and size. The level of cortical tension outside of the cell-cell contact, when pulling at the contact edge, scales with the total size to which a cell-cell contact can grow1,2. Here we show in zebrafish primary germ layer progenitor cells that this monotonic relationship only applies to a narrow range of cortical tension increase, and that above a critical threshold, contact size inversely scales with cortical tension. This switch from cortical tension increasing to decreasing progenitor cell-cell contact size is caused by cortical tension promoting E-cadherin anchoring to the actomyosin cytoskeleton, thereby increasing clustering and stability of E-cadherin at the contact. Once tension-mediated E-cadherin stabilization at the contact exceeds a critical threshold level, the rate by which the contact expands in response to pulling forces from the cortex sharply drops, leading to smaller contacts at physiologically relevant timescales of contact formation. Thus, the activity of cortical tension in expanding cell-cell contact size is limited by tension stabilizing E-cadherin-actin complexes at the contact. AU - Slovakova, Jana AU - Sikora, Mateusz K AU - Caballero Mancebo, Silvia AU - Krens, Gabriel AU - Kaufmann, Walter AU - Huljev, Karla AU - Heisenberg, Carl-Philipp J ID - 9750 T2 - bioRxiv TI - Tension-dependent stabilization of E-cadherin limits cell-cell contact expansion ER - TY - JOUR AB - Eukaryotic cells migrate by coupling the intracellular force of the actin cytoskeleton to the environment. While force coupling is usually mediated by transmembrane adhesion receptors, especially those of the integrin family, amoeboid cells such as leukocytes can migrate extremely fast despite very low adhesive forces1. Here we show that leukocytes cannot only migrate under low adhesion but can also transmit forces in the complete absence of transmembrane force coupling. When confined within three-dimensional environments, they use the topographical features of the substrate to propel themselves. Here the retrograde flow of the actin cytoskeleton follows the texture of the substrate, creating retrograde shear forces that are sufficient to drive the cell body forwards. Notably, adhesion-dependent and adhesion-independent migration are not mutually exclusive, but rather are variants of the same principle of coupling retrograde actin flow to the environment and thus can potentially operate interchangeably and simultaneously. As adhesion-free migration is independent of the chemical composition of the environment, it renders cells completely autonomous in their locomotive behaviour. AU - Reversat, Anne AU - Gärtner, Florian R AU - Merrin, Jack AU - Stopp, Julian A AU - Tasciyan, Saren AU - Aguilera Servin, Juan L AU - De Vries, Ingrid AU - Hauschild, Robert AU - Hons, Miroslav AU - Piel, Matthieu AU - Callan-Jones, Andrew AU - Voituriez, Raphael AU - Sixt, Michael K ID - 7885 JF - Nature SN - 00280836 TI - Cellular locomotion using environmental topography VL - 582 ER - TY - JOUR AB - This paper presents a novel abstraction technique for analyzing Lyapunov and asymptotic stability of polyhedral switched systems. A polyhedral switched system is a hybrid system in which the continuous dynamics is specified by polyhedral differential inclusions, the invariants and guards are specified by polyhedral sets and the switching between the modes do not involve reset of variables. A finite state weighted graph abstracting the polyhedral switched system is constructed from a finite partition of the state–space, such that the satisfaction of certain graph conditions, such as the absence of cycles with product of weights on the edges greater than (or equal) to 1, implies the stability of the system. However, the graph is in general conservative and hence, the violation of the graph conditions does not imply instability. If the analysis fails to establish stability due to the conservativeness in the approximation, a counterexample (cycle with product of edge weights greater than or equal to 1) indicating a potential reason for the failure is returned. Further, a more precise approximation of the switched system can be constructed by considering a finer partition of the state–space in the construction of the finite weighted graph. We present experimental results on analyzing stability of switched systems using the above method. AU - Garcia Soto, Miriam AU - Prabhakar, Pavithra ID - 7426 IS - 5 JF - Nonlinear Analysis: Hybrid Systems SN - 1751-570X TI - Abstraction based verification of stability of polyhedral switched systems VL - 36 ER - TY - THES AB - Metabolic adaptation is a critical feature of migrating cells. It tunes the metabolic programs of migrating cells to allow them to efficiently exert their crucial roles in development, inflammatory responses and tumor metastasis. Cell migration through physically challenging contexts requires energy. However, how the metabolic reprogramming that underlies in vivo cell invasion is controlled is still unanswered. In my PhD project, I identify a novel conserved metabolic shift in Drosophila melanogaster immune cells that by modulating their bioenergetic potential controls developmentally programmed tissue invasion. We show that this regulation requires a novel conserved nuclear protein, named Atossa. Atossa enhances the transcription of a set of proteins, including an RNA helicase Porthos and two metabolic enzymes, each of which increases the tissue invasion of leading Drosophila macrophages and can rescue the atossa mutant phenotype. Porthos selectively regulates the translational efficiency of a subset of mRNAs containing a 5’-UTR cis-regulatory TOP-like sequence. These 5’TOPL mRNA targets encode mitochondrial-related proteins, including subunits of mitochondrial oxidative phosphorylation (OXPHOS) components III and V and other metabolic-related proteins. Porthos powers up mitochondrial OXPHOS to engender a sufficient ATP supply, which is required for tissue invasion of leading macrophages. Atossa’s two vertebrate orthologs rescue the invasion defect. In my PhD project, I elucidate that Atossa displays a conserved developmental metabolic control to modulate metabolic capacities and the cellular energy state, through altered transcription and translation, to aid the tissue infiltration of leading cells into energy demanding barriers. AU - Emtenani, Shamsi ID - 8983 SN - 2663-337X TI - Metabolic regulation of Drosophila macrophage tissue invasion ER - TY - GEN AB - The infiltration of immune cells into tissues underlies the establishment of tissue resident macrophages, and responses to infections and tumors. Yet the mechanisms immune cells utilize to negotiate tissue barriers in living organisms are not well understood, and a role for cortical actin has not been examined. Here we find that the tissue invasion of Drosophila macrophages, also known as plasmatocytes or hemocytes, utilizes enhanced cortical F-actin levels stimulated by the Drosophila member of the fos proto oncogene transcription factor family (Dfos, Kayak). RNA sequencing analysis and live imaging show that Dfos enhances F-actin levels around the entire macrophage surface by increasing mRNA levels of the membrane spanning molecular scaffold tetraspanin TM4SF, and the actin cross-linking filamin Cheerio which are themselves required for invasion. Cortical F-actin levels are critical as expressing a dominant active form of Diaphanous, a actin polymerizing Formin, can rescue the Dfos Dominant Negative macrophage invasion defect. In vivo imaging shows that Dfos is required to enhance the efficiency of the initial phases of macrophage tissue entry. Genetic evidence argues that this Dfos-induced program in macrophages counteracts the constraint produced by the tension of surrounding tissues and buffers the mechanical properties of the macrophage nucleus from affecting tissue entry. We thus identify tuning the cortical actin cytoskeleton through Dfos as a key process allowing efficient forward movement of an immune cell into surrounding tissues. AU - Belyaeva, Vera AU - Wachner, Stephanie AU - Gridchyn, Igor AU - Linder, Markus AU - Emtenani, Shamsi AU - György, Attila AU - Sibilia, Maria AU - Siekhaus, Daria E ID - 8557 T2 - bioRxiv TI - Cortical actin properties controlled by Drosophila Fos aid macrophage infiltration against surrounding tissue resistance ER - TY - GEN AB - Holes in planar Ge have high mobilities, strong spin-orbit interaction and electrically tunable g-factors, and are therefore emerging as a promising candidate for hybrid superconductorsemiconductor devices. This is further motivated by the observation of supercurrent transport in planar Ge Josephson Field effect transistors (JoFETs). A key challenge towards hybrid germanium quantum technology is the design of high quality interfaces and superconducting contacts that are robust against magnetic fields. By combining the assets of Al, which has a long superconducting coherence, and Nb, which has a significant superconducting gap, we form low-disordered JoFETs with large ICRN products that are capable of withstanding high magnetic fields. We furthermore demonstrate the ability of phase-biasing individual JoFETs opening up an avenue to explore topological superconductivity in planar Ge. The persistence of superconductivity in the reported hybrid devices beyond 1.8 T paves the way towards integrating spin qubits and proximity-induced superconductivity on the same chip. AU - Aggarwal, Kushagra AU - Hofmann, Andrea C AU - Jirovec, Daniel AU - Prieto Gonzalez, Ivan AU - Sammak, Amir AU - Botifoll, Marc AU - Marti-Sanchez, Sara AU - Veldhorst, Menno AU - Arbiol, Jordi AU - Scappucci, Giordano AU - Katsaros, Georgios ID - 8831 T2 - arXiv TI - Enhancement of proximity induced superconductivity in planar Germanium ER - TY - JOUR AB - The molecular anatomy of synapses defines their characteristics in transmission and plasticity. Precise measurements of the number and distribution of synaptic proteins are important for our understanding of synapse heterogeneity within and between brain regions. Freeze–fracture replica immunogold electron microscopy enables us to analyze them quantitatively on a two-dimensional membrane surface. Here, we introduce Darea software, which utilizes deep learning for analysis of replica images and demonstrate its usefulness for quick measurements of the pre- and postsynaptic areas, density and distribution of gold particles at synapses in a reproducible manner. We used Darea for comparing glutamate receptor and calcium channel distributions between hippocampal CA3-CA1 spine synapses on apical and basal dendrites, which differ in signaling pathways involved in synaptic plasticity. We found that apical synapses express a higher density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and a stronger increase of AMPA receptors with synaptic size, while basal synapses show a larger increase in N-methyl-D-aspartate (NMDA) receptors with size. Interestingly, AMPA and NMDA receptors are segregated within postsynaptic sites and negatively correlated in density among both apical and basal synapses. In the presynaptic sites, Cav2.1 voltage-gated calcium channels show similar densities in apical and basal synapses with distributions consistent with an exclusion zone model of calcium channel-release site topography. AU - Kleindienst, David AU - Montanaro-Punzengruber, Jacqueline-Claire AU - Bhandari, Pradeep AU - Case, Matthew J AU - Fukazawa, Yugo AU - Shigemoto, Ryuichi ID - 8532 IS - 18 JF - International Journal of Molecular Sciences SN - 16616596 TI - Deep learning-assisted high-throughput analysis of freeze-fracture replica images applied to glutamate receptors and calcium channels at hippocampal synapses VL - 21 ER - TY - CONF AB - Interprocedural data-flow analyses form an expressive and useful paradigm of numerous static analysis applications, such as live variables analysis, alias analysis and null pointers analysis. The most widely-used framework for interprocedural data-flow analysis is IFDS, which encompasses distributive data-flow functions over a finite domain. On-demand data-flow analyses restrict the focus of the analysis on specific program locations and data facts. This setting provides a natural split between (i) an offline (or preprocessing) phase, where the program is partially analyzed and analysis summaries are created, and (ii) an online (or query) phase, where analysis queries arrive on demand and the summaries are used to speed up answering queries. In this work, we consider on-demand IFDS analyses where the queries concern program locations of the same procedure (aka same-context queries). We exploit the fact that flow graphs of programs have low treewidth to develop faster algorithms that are space and time optimal for many common data-flow analyses, in both the preprocessing and the query phase. We also use treewidth to develop query solutions that are embarrassingly parallelizable, i.e. the total work for answering each query is split to a number of threads such that each thread performs only a constant amount of work. Finally, we implement a static analyzer based on our algorithms, and perform a series of on-demand analysis experiments on standard benchmarks. Our experimental results show a drastic speed-up of the queries after only a lightweight preprocessing phase, which significantly outperforms existing techniques. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Ibsen-Jensen, Rasmus AU - Pavlogiannis, Andreas ID - 7810 SN - 03029743 T2 - European Symposium on Programming TI - Optimal and perfectly parallel algorithms for on-demand data-flow analysis VL - 12075 ER - TY - CONF AB - Discrete-time Markov Chains (MCs) and Markov Decision Processes (MDPs) are two standard formalisms in system analysis. Their main associated quantitative objectives are hitting probabilities, discounted sum, and mean payoff. Although there are many techniques for computing these objectives in general MCs/MDPs, they have not been thoroughly studied in terms of parameterized algorithms, particularly when treewidth is used as the parameter. This is in sharp contrast to qualitative objectives for MCs, MDPs and graph games, for which treewidth-based algorithms yield significant complexity improvements. In this work, we show that treewidth can also be used to obtain faster algorithms for the quantitative problems. For an MC with n states and m transitions, we show that each of the classical quantitative objectives can be computed in O((n+m)⋅t2) time, given a tree decomposition of the MC with width t. Our results also imply a bound of O(κ⋅(n+m)⋅t2) for each objective on MDPs, where κ is the number of strategy-iteration refinements required for the given input and objective. Finally, we make an experimental evaluation of our new algorithms on low-treewidth MCs and MDPs obtained from the DaCapo benchmark suite. Our experiments show that on low-treewidth MCs and MDPs, our algorithms outperform existing well-established methods by one or more orders of magnitude. AU - Asadi, Ali AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Mohammadi, Kiarash AU - Pavlogiannis, Andreas ID - 8728 SN - 0302-9743 T2 - Automated Technology for Verification and Analysis TI - Faster algorithms for quantitative analysis of MCs and MDPs with small treewidth VL - 12302 ER - TY - CONF AB - We consider the classical problem of invariant generation for programs with polynomial assignments and focus on synthesizing invariants that are a conjunction of strict polynomial inequalities. We present a sound and semi-complete method based on positivstellensaetze, i.e. theorems in semi-algebraic geometry that characterize positive polynomials over a semi-algebraic set. On the theoretical side, the worst-case complexity of our approach is subexponential, whereas the worst-case complexity of the previous complete method (Kapur, ACA 2004) is doubly-exponential. Even when restricted to linear invariants, the best previous complexity for complete invariant generation is exponential (Colon et al, CAV 2003). On the practical side, we reduce the invariant generation problem to quadratic programming (QCLP), which is a classical optimization problem with many industrial solvers. We demonstrate the applicability of our approach by providing experimental results on several academic benchmarks. To the best of our knowledge, the only previous invariant generation method that provides completeness guarantees for invariants consisting of polynomial inequalities is (Kapur, ACA 2004), which relies on quantifier elimination and cannot even handle toy programs such as our running example. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Goharshady, Amir Kafshdar AU - Goharshady, Ehsan Kafshdar ID - 8089 SN - 9781450376136 T2 - Proceedings of the 41st ACM SIGPLAN Conference on Programming Language Design and Implementation TI - Polynomial invariant generation for non-deterministic recursive programs ER - TY - JOUR AB - We consider the classic problem of Network Reliability. A network is given together with a source vertex, one or more target vertices, and probabilities assigned to each of the edges. Each edge of the network is operable with its associated probability and the problem is to determine the probability of having at least one source-to-target path that is entirely composed of operable edges. This problem is known to be NP-hard. We provide a novel scalable algorithm to solve the Network Reliability problem when the treewidth of the underlying network is small. We also show our algorithm’s applicability for real-world transit networks that have small treewidth, including the metro networks of major cities, such as London and Tokyo. Our algorithm leverages tree decompositions to shrink the original graph into much smaller graphs, for which reliability can be efficiently and exactly computed using a brute force method. To the best of our knowledge, this is the first exact algorithm for Network Reliability that can scale to handle real-world instances of the problem. AU - Goharshady, Amir Kafshdar AU - Mohammadi, Fatemeh ID - 6918 JF - Reliability Engineering and System Safety SN - 09518320 TI - An efficient algorithm for computing network reliability in small treewidth VL - 193 ER - TY - JOUR AB - In this paper, we introduce an inertial projection-type method with different updating strategies for solving quasi-variational inequalities with strongly monotone and Lipschitz continuous operators in real Hilbert spaces. Under standard assumptions, we establish different strong convergence results for the proposed algorithm. Primary numerical experiments demonstrate the potential applicability of our scheme compared with some related methods in the literature. AU - Shehu, Yekini AU - Gibali, Aviv AU - Sagratella, Simone ID - 7161 JF - Journal of Optimization Theory and Applications SN - 0022-3239 TI - Inertial projection-type methods for solving quasi-variational inequalities in real Hilbert spaces VL - 184 ER - TY - JOUR AB - Organisms cope with change by taking advantage of transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. Here, we investigate whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. Using real-time monitoring of gene-copy-number mutations in Escherichia coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy-number and, therefore, expression-level polymorphisms. This amplification-mediated gene expression tuning (AMGET) occurs on timescales that are similar to canonical gene regulation and can respond to rapid environmental changes. Mathematical modelling shows that amplifications also tune gene expression in stochastic environments in which transcription-factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune the expression of any gene, without leaving any genomic signature. AU - Tomanek, Isabella AU - Grah, Rok AU - Lagator, M. AU - Andersson, A. M. C. AU - Bollback, Jonathan P AU - Tkačik, Gašper AU - Guet, Calin C ID - 7652 IS - 4 JF - Nature Ecology & Evolution SN - 2397-334X TI - Gene amplification as a form of population-level gene expression regulation VL - 4 ER - TY - THES AB - Many flows encountered in nature and applications are characterized by a chaotic motion known as turbulence. Turbulent flows generate intense friction with pipe walls and are responsible for considerable amounts of energy losses at world scale. The nature of turbulent friction and techniques aimed at reducing it have been subject of extensive research over the last century, but no definite answer has been found yet. In this thesis we show that in pipes at moderate turbulent Reynolds numbers friction is better described by the power law first introduced by Blasius and not by the Prandtl–von Kármán formula. At higher Reynolds numbers, large scale motions gradually become more important in the flow and can be related to the change in scaling of friction. Next, we present a series of new techniques that can relaminarize turbulence by suppressing a key mechanism that regenerates it at walls, the lift–up effect. In addition, we investigate the process of turbulence decay in several experiments and discuss the drag reduction potential. Finally, we examine the behavior of friction under pulsating conditions inspired by the human heart cycle and we show that under such circumstances turbulent friction can be reduced to produce energy savings. AU - Scarselli, Davide ID - 7258 SN - 2663-337X TI - New approaches to reduce friction in turbulent pipe flow ER - TY - THES AB - Mutations are the raw material of evolution and come in many different flavors. Point mutations change a single letter in the DNA sequence, while copy number mutations like duplications or deletions add or remove many letters of the DNA sequence simultaneously. Each type of mutation exhibits specific properties like its rate of formation and reversal. Gene expression is a fundamental phenotype that can be altered by both, point and copy number mutations. The following thesis is concerned with the dynamics of gene expression evolution and how it is affected by the properties exhibited by point and copy number mutations. Specifically, we are considering i) copy number mutations during adaptation to fluctuating environments and ii) the interaction of copy number and point mutations during adaptation to constant environments.   AU - Tomanek, Isabella ID - 8653 KW - duplication KW - amplification KW - promoter KW - CNV KW - AMGET KW - experimental evolution KW - Escherichia coli SN - 2663-337X TI - The evolution of gene expression by copy number and point mutations ER - TY - JOUR AB - Plants, like other multicellular organisms, survive through a delicate balance between growth and defense against pathogens. Salicylic acid (SA) is a major defense signal in plants, and the perception mechanism as well as downstream signaling activating the immune response are known. Here, we identify a parallel SA signaling that mediates growth attenuation. SA directly binds to A subunits of protein phosphatase 2A (PP2A), inhibiting activity of this complex. Among PP2A targets, the PIN2 auxin transporter is hyperphosphorylated in response to SA, leading to changed activity of this important growth regulator. Accordingly, auxin transport and auxin-mediated root development, including growth, gravitropic response, and lateral root organogenesis, are inhibited. This study reveals how SA, besides activating immunity, concomitantly attenuates growth through crosstalk with the auxin distribution network. Further analysis of this dual role of SA and characterization of additional SA-regulated PP2A targets will provide further insights into mechanisms maintaining a balance between growth and defense. AU - Tan, Shutang AU - Abas, Melinda F AU - Verstraeten, Inge AU - Glanc, Matous AU - Molnar, Gergely AU - Hajny, Jakub AU - Lasák, Pavel AU - Petřík, Ivan AU - Russinova, Eugenia AU - Petrášek, Jan AU - Novák, Ondřej AU - Pospíšil, Jiří AU - Friml, Jiří ID - 7427 IS - 3 JF - Current Biology SN - 09609822 TI - Salicylic acid targets protein phosphatase 2A to attenuate growth in plants VL - 30 ER - TY - JOUR AB - Plant survival depends on vascular tissues, which originate in a self‐organizing manner as strands of cells co‐directionally transporting the plant hormone auxin. The latter phenomenon (also known as auxin canalization) is classically hypothesized to be regulated by auxin itself via the effect of this hormone on the polarity of its own intercellular transport. Correlative observations supported this concept, but molecular insights remain limited. In the current study, we established an experimental system based on the model Arabidopsis thaliana, which exhibits auxin transport channels and formation of vasculature strands in response to local auxin application. Our methodology permits the genetic analysis of auxin canalization under controllable experimental conditions. By utilizing this opportunity, we confirmed the dependence of auxin canalization on a PIN‐dependent auxin transport and nuclear, TIR1/AFB‐mediated auxin signaling. We also show that leaf venation and auxin‐mediated PIN repolarization in the root require TIR1/AFB signaling. Further studies based on this experimental system are likely to yield better understanding of the mechanisms underlying auxin transport polarization in other developmental contexts. AU - Mazur, E AU - Kulik, Ivan AU - Hajny, Jakub AU - Friml, Jiří ID - 7500 IS - 5 JF - New Phytologist SN - 0028-646x TI - Auxin canalization and vascular tissue formation by TIR1/AFB-mediated auxin signaling in arabidopsis VL - 226 ER - TY - THES AB - Self-organization is a hallmark of plant development manifested e.g. by intricate leaf vein patterns, flexible formation of vasculature during organogenesis or its regeneration following wounding. Spontaneously arising channels transporting the phytohormone auxin, created by coordinated polar localizations of PIN-FORMED 1 (PIN1) auxin exporter, provide positional cues for these as well as other plant patterning processes. To find regulators acting downstream of auxin and the TIR1/AFB auxin signaling pathway essential for PIN1 coordinated polarization during auxin canalization, we performed microarray experiments. Besides the known components of general PIN polarity maintenance, such as PID and PIP5K kinases, we identified and characterized a new regulator of auxin canalization, the transcription factor WRKY DNA-BINDING PROTEIN 23 (WRKY23). Next, we designed a subsequent microarray experiment to further uncover other molecular players, downstream of auxin-TIR1/AFB-WRKY23 involved in the regulation of auxin-mediated PIN repolarization. We identified a novel and crucial part of the molecular machinery underlying auxin canalization. The auxin-regulated malectin-type receptor-like kinase CAMEL and the associated leucine-rich repeat receptor-like kinase CANAR target and directly phosphorylate PIN auxin transporters. camel and canar mutants are impaired in PIN1 subcellular trafficking and auxin-mediated repolarization leading to defects in auxin transport, ultimately to leaf venation and vasculature regeneration defects. Our results describe the CAMEL-CANAR receptor complex, which is required for auxin feed-back on its own transport and thus for coordinated tissue polarization during auxin canalization. AU - Hajny, Jakub ID - 8822 SN - 2663-337X TI - Identification and characterization of the molecular machinery of auxin-dependent canalization during vasculature formation and regeneration ER - TY - THES AB - Cytoplasm is a gel-like crowded environment composed of tens of thousands of macromolecules, organelles, cytoskeletal networks and cytosol. The structure of the cytoplasm is thought to be highly organized and heterogeneous due to the crowding of its constituents and their effective compartmentalization. In such an environment, the diffusive dynamics of the molecules is very restricted, an effect that is further amplified by clustering and anchoring of molecules. Despite the jammed nature of the cytoplasm at the microscopic scale, large-scale reorganization of cytoplasm is essential for important cellular functions, such as nuclear positioning and cell division. How such mesoscale reorganization of the cytoplasm is achieved, especially for very large cells such as oocytes or syncytial tissues that can span hundreds of micrometers in size, has only begun to be understood. In this thesis, I focus on the recent advances in elucidating the molecular, cellular and biophysical principles underlying cytoplasmic organization across different scales, structures and species. First, I outline which of these principles have been identified by reductionist approaches, such as in vitro reconstitution assays, where boundary conditions and components can be modulated at ease. I then describe how the theoretical and experimental framework established in these reduced systems have been applied to their more complex in vivo counterparts, in particular oocytes and embryonic syncytial structures, and discuss how such complex biological systems can initiate symmetry breaking and establish patterning. Specifically, I examine an example of large-scale reorganizations taking place in zebrafish embryos, where extensive cytoplasmic streaming leads to the segregation of cytoplasm from yolk granules along the animal-vegetal axis of the embryo. Using biophysical experimentation and theory, I investigate the forces underlying this process, to show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the embryo. This wave functions in segregation by both pulling cytoplasm animally and pushing yolk granules vegetally. Cytoplasm pulling is mediated by bulk actin network flows exerting friction forces on the cytoplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. This study defines a novel role of bulk actin polymerization waves in embryo polarization via cytoplasmic segregation. Lastly, I describe the cytoplasmic reorganizations taking place during zebrafish oocyte maturation, where the initial segregation of the cytoplasm and yolk granules occurs. Here, I demonstrate a previously uncharacterized wave of microtubule aster formation, traveling the oocyte along the animal-vegetal axis. Further research is required to determine the role of such microtubule structures in cytoplasmic reorganizations therein. Collectively, these studies provide further evidence for the coupling between cell cytoskeleton and cell cycle machinery, which can underlie a core self-organizing mechanism for orchestrating large-scale reorganizations in a cell-cycle-tunable manner, where the modulations of the force-generating machinery and cytoplasmic mechanics can be harbored to fulfill cellular functions. AU - Shamipour, Shayan ID - 8350 SN - 2663-337X TI - Bulk actin dynamics drive phase segregation in zebrafish oocytes ER - TY - JOUR AB - Concerted radial migration of newly born cortical projection neurons, from their birthplace to their final target lamina, is a key step in the assembly of the cerebral cortex. The cellular and molecular mechanisms regulating the specific sequential steps of radial neuronal migration in vivo are however still unclear, let alone the effects and interactions with the extracellular environment. In any in vivo context, cells will always be exposed to a complex extracellular environment consisting of (1) secreted factors acting as potential signaling cues, (2) the extracellular matrix, and (3) other cells providing cell–cell interaction through receptors and/or direct physical stimuli. Most studies so far have described and focused mainly on intrinsic cell-autonomous gene functions in neuronal migration but there is accumulating evidence that non-cell-autonomous-, local-, systemic-, and/or whole tissue-wide effects substantially contribute to the regulation of radial neuronal migration. These non-cell-autonomous effects may differentially affect cortical neuron migration in distinct cellular environments. However, the cellular and molecular natures of such non-cell-autonomous mechanisms are mostly unknown. Furthermore, physical forces due to collective migration and/or community effects (i.e., interactions with surrounding cells) may play important roles in neocortical projection neuron migration. In this concise review, we first outline distinct models of non-cell-autonomous interactions of cortical projection neurons along their radial migration trajectory during development. We then summarize experimental assays and platforms that can be utilized to visualize and potentially probe non-cell-autonomous mechanisms. Lastly, we define key questions to address in the future. AU - Hansen, Andi H AU - Hippenmeyer, Simon ID - 8569 IS - 9 JF - Frontiers in Cell and Developmental Biology SN - 2296-634X TI - Non-cell-autonomous mechanisms in radial projection neuron migration in the developing cerebral cortex VL - 8 ER - TY - JOUR AB - Beginning from a limited pool of progenitors, the mammalian cerebral cortex forms highly organized functional neural circuits. However, the underlying cellular and molecular mechanisms regulating lineage transitions of neural stem cells (NSCs) and eventual production of neurons and glia in the developing neuroepithelium remains unclear. Methods to trace NSC division patterns and map the lineage of clonally related cells have advanced dramatically. However, many contemporary lineage tracing techniques suffer from the lack of cellular resolution of progeny cell fate, which is essential for deciphering progenitor cell division patterns. Presented is a protocol using mosaic analysis with double markers (MADM) to perform in vivo clonal analysis. MADM concomitantly manipulates individual progenitor cells and visualizes precise division patterns and lineage progression at unprecedented single cell resolution. MADM-based interchromosomal recombination events during the G2-X phase of mitosis, together with temporally inducible CreERT2, provide exact information on the birth dates of clones and their division patterns. Thus, MADM lineage tracing provides unprecedented qualitative and quantitative optical readouts of the proliferation mode of stem cell progenitors at the single cell level. MADM also allows for examination of the mechanisms and functional requirements of candidate genes in NSC lineage progression. This method is unique in that comparative analysis of control and mutant subclones can be performed in the same tissue environment in vivo. Here, the protocol is described in detail, and experimental paradigms to employ MADM for clonal analysis and lineage tracing in the developing cerebral cortex are demonstrated. Importantly, this protocol can be adapted to perform MADM clonal analysis in any murine stem cell niche, as long as the CreERT2 driver is present. AU - Beattie, Robert J AU - Streicher, Carmen AU - Amberg, Nicole AU - Cheung, Giselle T AU - Contreras, Ximena AU - Hansen, Andi H AU - Hippenmeyer, Simon ID - 7815 IS - 159 JF - Journal of Visual Experiments SN - 1940-087X TI - Lineage tracing and clonal analysis in developing cerebral cortex using mosaic analysis with double markers (MADM) ER - TY - THES AB - Mosaic genetic analysis has been widely used in different model organisms such as the fruit fly to study gene-function in a cell-autonomous or tissue-specific fashion. More recently, and less easily conducted, mosaic genetic analysis in mice has also been enabled with the ambition to shed light on human gene function and disease. These genetic tools are of particular interest, but not restricted to, the study of the brain. Notably, the MADM technology offers a genetic approach in mice to visualize and concomitantly manipulate small subsets of genetically defined cells at a clonal level and single cell resolution. MADM-based analysis has already advanced the study of genetic mechanisms regulating brain development and is expected that further MADM-based analysis of genetic alterations will continue to reveal important insights on the fundamental principles of development and disease to potentially assist in the development of new therapies or treatments. In summary, this work completed and characterized the necessary genome-wide genetic tools to perform MADM-based analysis at single cell level of the vast majority of mouse genes in virtually any cell type and provided a protocol to perform lineage tracing using the novel MADM resource. Importantly, this work also explored and revealed novel aspects of biologically relevant events in an in vivo context, such as the chromosome-specific bias of chromatid sister segregation pattern, the generation of cell-type diversity in the cerebral cortex and in the cerebellum and finally, the relevance of the interplay between the cell-autonomous gene function and cell-non-autonomous (community) effects in radial glial progenitor lineage progression. This work provides a foundation and opens the door to further elucidating the molecular mechanisms underlying neuronal diversity and astrocyte generation. AU - Contreras, Ximena ID - 7902 SN - 2663-337X TI - Genetic dissection of neural development in health and disease at single cell resolution ER - TY - JOUR AU - Sixt, Michael K AU - Huttenlocher, Anna ID - 8190 IS - 8 JF - The Journal of Cell Biology TI - Zena Werb (1945-2020): Cell biology in context VL - 219 ER - TY - JOUR AB - Flowering plants display the highest diversity among plant species and have notably shaped terrestrial landscapes. Nonetheless, the evolutionary origin of their unprecedented morphological complexity remains largely an enigma. Here, we show that the coevolution of cis-regulatory and coding regions of PIN-FORMED (PIN) auxin transporters confined their expression to certain cell types and directed their subcellular localization to particular cell sides, which together enabled dynamic auxin gradients across tissues critical to the complex architecture of flowering plants. Extensive intraspecies and interspecies genetic complementation experiments with PINs from green alga up to flowering plant lineages showed that PIN genes underwent three subsequent, critical evolutionary innovations and thus acquired a triple function to regulate the development of three essential components of the flowering plant Arabidopsis: shoot/root, inflorescence, and floral organ. Our work highlights the critical role of functional innovations within the PIN gene family as essential prerequisites for the origin of flowering plants. AU - Zhang, Yuzhou AU - Rodriguez Solovey, Lesia AU - Li, Lanxin AU - Zhang, Xixi AU - Friml, Jiří ID - 8986 IS - 50 JF - Science Advances TI - Functional innovations of PIN auxin transporters mark crucial evolutionary transitions during rise of flowering plants VL - 6 ER - TY - JOUR AB - Drought and salt stress are the main environmental cues affecting the survival, development, distribution, and yield of crops worldwide. MYB transcription factors play a crucial role in plants’ biological processes, but the function of pineapple MYB genes is still obscure. In this study, one of the pineapple MYB transcription factors, AcoMYB4, was isolated and characterized. The results showed that AcoMYB4 is localized in the cell nucleus, and its expression is induced by low temperature, drought, salt stress, and hormonal stimulation, especially by abscisic acid (ABA). Overexpression of AcoMYB4 in rice and Arabidopsis enhanced plant sensitivity to osmotic stress; it led to an increase in the number stomata on leaf surfaces and lower germination rate under salt and drought stress. Furthermore, in AcoMYB4 OE lines, the membrane oxidation index, free proline, and soluble sugar contents were decreased. In contrast, electrolyte leakage and malondialdehyde (MDA) content increased significantly due to membrane injury, indicating higher sensitivity to drought and salinity stresses. Besides the above, both the expression level and activities of several antioxidant enzymes were decreased, indicating lower antioxidant activity in AcoMYB4 transgenic plants. Moreover, under osmotic stress, overexpression of AcoMYB4 inhibited ABA biosynthesis through a decrease in the transcription of genes responsible for ABA synthesis (ABA1 and ABA2) and ABA signal transduction factor ABI5. These results suggest that AcoMYB4 negatively regulates osmotic stress by attenuating cellular ABA biosynthesis and signal transduction pathways. AU - Chen, Huihuang AU - Lai, Linyi AU - Li, Lanxin AU - Liu, Liping AU - Jakada, Bello Hassan AU - Huang, Youmei AU - He, Qing AU - Chai, Mengnan AU - Niu, Xiaoping AU - Qin, Yuan ID - 8283 IS - 16 JF - International Journal of Molecular Sciences SN - 16616596 TI - AcoMYB4, an Ananas comosus L. MYB transcription factor, functions in osmotic stress through negative regulation of ABA signaling VL - 21 ER - TY - JOUR AB - Clathrin-mediated endocytosis (CME) is a crucial cellular process implicated in many aspects of plant growth, development, intra- and inter-cellular signaling, nutrient uptake and pathogen defense. Despite these significant roles, little is known about the precise molecular details of how it functions in planta. In order to facilitate the direct quantitative study of plant CME, here we review current routinely used methods and present refined, standardized quantitative imaging protocols which allow the detailed characterization of CME at multiple scales in plant tissues. These include: (i) an efficient electron microscopy protocol for the imaging of Arabidopsis CME vesicles in situ, thus providing a method for the detailed characterization of the ultra-structure of clathrin-coated vesicles; (ii) a detailed protocol and analysis for quantitative live-cell fluorescence microscopy to precisely examine the temporal interplay of endocytosis components during single CME events; (iii) a semi-automated analysis to allow the quantitative characterization of global internalization of cargos in whole plant tissues; and (iv) an overview and validation of useful genetic and pharmacological tools to interrogate the molecular mechanisms and function of CME in intact plant samples. AU - Johnson, Alexander J AU - Gnyliukh, Nataliia AU - Kaufmann, Walter AU - Narasimhan, Madhumitha AU - Vert, G AU - Bednarek, SY AU - Friml, Jiří ID - 8139 IS - 15 JF - Journal of Cell Science SN - 0021-9533 TI - Experimental toolbox for quantitative evaluation of clathrin-mediated endocytosis in the plant model Arabidopsis VL - 133 ER - TY - JOUR AB - Auxin is a key hormonal regulator, that governs plant growth and development in concert with other hormonal pathways. The unique feature of auxin is its polar, cell-to-cell transport that leads to the formation of local auxin maxima and gradients, which coordinate initiation and patterning of plant organs. The molecular machinery mediating polar auxin transport is one of the important points of interaction with other hormones. Multiple hormonal pathways converge at the regulation of auxin transport and form a regulatory network that integrates various developmental and environmental inputs to steer plant development. In this review, we discuss recent advances in understanding the mechanisms that underlie regulation of polar auxin transport by multiple hormonal pathways. Specifically, we focus on the post-translational mechanisms that contribute to fine-tuning of the abundance and polarity of auxin transporters at the plasma membrane and thereby enable rapid modification of the auxin flow to coordinate plant growth and development. AU - Semeradova, Hana AU - Montesinos López, Juan C AU - Benková, Eva ID - 9160 IS - 3 JF - Plant Communications SN - 2590-3462 TI - All roads lead to auxin: Post-translational regulation of auxin transport by multiple hormonal pathways VL - 1 ER - TY - CONF AB - This report presents the results of a friendly competition for formal verification of continuous and hybrid systems with piecewise constant dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In this third edition, six tools have been applied to solve five different benchmark problems in the category for piecewise constant dynamics: BACH, Lyse, Hy- COMP, PHAVer/SX, PHAVerLite, and VeriSiMPL. Compared to last year, a new tool has participated (HyCOMP) and PHAVerLite has replaced PHAVer-lite. The result is a snap- shot of the current landscape of tools and the types of benchmarks they are particularly suited for. Due to the diversity of problems, we are not ranking tools, yet the presented results probably provide the most complete assessment of tools for the safety verification of continuous and hybrid systems with piecewise constant dynamics up to this date. AU - Frehse, Goran AU - Abate, Alessandro AU - Adzkiya, Dieky AU - Becchi, Anna AU - Bu, Lei AU - Cimatti, Alessandro AU - Giacobbe, Mirco AU - Griggio, Alberto AU - Mover, Sergio AU - Mufid, Muhammad Syifa'ul AU - Riouak, Idriss AU - Tonetta, Stefano AU - Zaffanella, Enea ED - Frehse, Goran ED - Althoff, Matthias ID - 10877 SN - 2398-7340 T2 - ARCH19. 6th International Workshop on Applied Verification of Continuous and Hybrid Systems TI - ARCH-COMP19 Category Report: Hybrid systems with piecewise constant dynamics VL - 61 ER - TY - JOUR AU - Kalinin, Nikita AU - Shkolnikov, Mikhail ID - 441 IS - 3 JF - European Journal of Mathematics SN - 2199-675X TI - Tropical formulae for summation over a part of SL(2,Z) VL - 5 ER - TY - CHAP AB - The transcription coactivator, Yes-associated protein (YAP), which is a nuclear effector of the Hippo signaling pathway, has been shown to be a mechano-transducer. By using mutant fish and human 3D spheroids, we have recently demonstrated that YAP is also a mechano-effector. YAP functions in three-dimensional (3D) morphogenesis of organ and global body shape by controlling actomyosin-mediated tissue tension. In this chapter, we present a platform that links the findings in fish embryos with human cells. The protocols for analyzing tissue tension-mediated global body shape/organ morphogenesis in vivo and ex vivo using medaka fish embryos and in vitro using human cell spheroids represent useful tools for unraveling the molecular mechanisms by which YAP functions in regulating global body/organ morphogenesis. AU - Asaoka, Yoichi AU - Morita, Hitoshi AU - Furumoto, Hiroko AU - Heisenberg, Carl-Philipp J AU - Furutani-Seiki, Makoto ED - Hergovich, Alexander ID - 5793 SN - 978-1-4939-8909-6 T2 - The hippo pathway TI - Studying YAP-mediated 3D morphogenesis using fish embryos and human spheroids VL - 1893 ER - TY - JOUR AB - Cryptographic security is usually defined as a guarantee that holds except when a bad event with negligible probability occurs, and nothing is guaranteed in that bad case. However, in settings where such failure can happen with substantial probability, one needs to provide guarantees even for the bad case. A typical example is where a (possibly weak) password is used instead of a secure cryptographic key to protect a session, the bad event being that the adversary correctly guesses the password. In a situation with multiple such sessions, a per-session guarantee is desired: any session for which the password has not been guessed remains secure, independently of whether other sessions have been compromised. A new formalism for stating such gracefully degrading security guarantees is introduced and applied to analyze the examples of password-based message authentication and password-based encryption. While a natural per-message guarantee is achieved for authentication, the situation of password-based encryption is more delicate: a per-session confidentiality guarantee only holds against attackers for which the distribution of password-guessing effort over the sessions is known in advance. In contrast, for more general attackers without such a restriction, a strong, composable notion of security cannot be achieved. AU - Demay, Gregory AU - Gazi, Peter AU - Maurer, Ueli AU - Tackmann, Bjorn ID - 5887 IS - 1 JF - Journal of Computer Security SN - 0926227X TI - Per-session security: Password-based cryptography revisited VL - 27 ER - TY - JOUR AB - We give non-degeneracy criteria for Riemannian simplices based on simplices in spaces of constant sectional curvature. It extends previous work on Riemannian simplices, where we developed Riemannian simplices with respect to Euclidean reference simplices. The criteria we give in this article are in terms of quality measures for spaces of constant curvature that we develop here. We see that simplices in spaces that have nearly constant curvature, are already non-degenerate under very weak quality demands. This is of importance because it allows for sampling of Riemannian manifolds based on anisotropy of the manifold and not (absolute) curvature. AU - Dyer, Ramsay AU - Vegter, Gert AU - Wintraecken, Mathijs ID - 6515 IS - 1 JF - Journal of Computational Geometry SN - 1920-180X TI - Simplices modelled on spaces of constant curvature VL - 10 ER - TY - CONF AB - We construct a verifiable delay function (VDF) by showing how the Rivest-Shamir-Wagner time-lock puzzle can be made publicly verifiable. Concretely, we give a statistically sound public-coin protocol to prove that a tuple (N,x,T,y) satisfies y=x2T (mod N) where the prover doesn’t know the factorization of N and its running time is dominated by solving the puzzle, that is, compute x2T, which is conjectured to require T sequential squarings. To get a VDF we make this protocol non-interactive using the Fiat-Shamir heuristic.The motivation for this work comes from the Chia blockchain design, which uses a VDF as akey ingredient. For typical parameters (T≤2 40, N= 2048), our proofs are of size around 10K B, verification cost around three RSA exponentiations and computing the proof is 8000 times faster than solving the puzzle even without any parallelism. AU - Pietrzak, Krzysztof Z ID - 6528 SN - 1868-8969 T2 - 10th Innovations in Theoretical Computer Science Conference TI - Simple verifiable delay functions VL - 124 ER - TY - CONF AB - In this paper, we address the problem of synthesizing periodic switching controllers for stabilizing a family of linear systems. Our broad approach consists of constructing a finite game graph based on the family of linear systems such that every winning strategy on the game graph corresponds to a stabilizing switching controller for the family of linear systems. The construction of a (finite) game graph, the synthesis of a winning strategy and the extraction of a stabilizing controller are all computationally feasible. We illustrate our method on an example. AU - Kundu, Atreyee AU - Garcia Soto, Miriam AU - Prabhakar, Pavithra ID - 6565 SN - 978-153866246-5 T2 - 5th Indian Control Conference Proceedings TI - Formal synthesis of stabilizing controllers for periodically controlled linear switched systems ER - TY - CONF AB - Fejes Tóth [5] and Schneider [9] studied approximations of smooth convex hypersurfaces in Euclidean space by piecewise flat triangular meshes with a given number of vertices on the hypersurface that are optimal with respect to Hausdorff distance. They proved that this Hausdorff distance decreases inversely proportional with m 2/(d−1), where m is the number of vertices and d is the dimension of Euclidean space. Moreover the pro-portionality constant can be expressed in terms of the Gaussian curvature, an intrinsic quantity. In this short note, we prove the extrinsic nature of this constant for manifolds of sufficiently high codimension. We do so by constructing an family of isometric embeddings of the flat torus in Euclidean space. AU - Vegter, Gert AU - Wintraecken, Mathijs ID - 6628 T2 - The 31st Canadian Conference in Computational Geometry TI - The extrinsic nature of the Hausdorff distance of optimal triangulations of manifolds ER - TY - CONF AB - Various kinds of data are routinely represented as discrete probability distributions. Examples include text documents summarized by histograms of word occurrences and images represented as histograms of oriented gradients. Viewing a discrete probability distribution as a point in the standard simplex of the appropriate dimension, we can understand collections of such objects in geometric and topological terms. Importantly, instead of using the standard Euclidean distance, we look into dissimilarity measures with information-theoretic justification, and we develop the theory needed for applying topological data analysis in this setting. In doing so, we emphasize constructions that enable the usage of existing computational topology software in this context. AU - Edelsbrunner, Herbert AU - Virk, Ziga AU - Wagner, Hubert ID - 6648 SN - 9783959771047 T2 - 35th International Symposium on Computational Geometry TI - Topological data analysis in information space VL - 129 ER - TY - JOUR AB - Chemical labeling of proteins with synthetic molecular probes offers the possibility to probe the functions of proteins of interest in living cells. However, the methods for covalently labeling targeted proteins using complementary peptide tag-probe pairs are still limited, irrespective of the versatility of such pairs in biological research. Herein, we report the new CysHis tag-Ni(II) probe pair for the specific covalent labeling of proteins. A broad-range evaluation of the reactivity profiles of the probe and the CysHis peptide tag afforded a tag-probe pair with an optimized and high labeling selectivity and reactivity. In particular, the labeling specificity of this pair was notably improved compared to the previously reported one. This pair was successfully utilized for the fluorescence imaging of membrane proteins on the surfaces of living cells, demonstrating its potential utility in biological research. AU - Zenmyo, Naoki AU - Tokumaru, Hiroki AU - Uchinomiya, Shohei AU - Fuchida, Hirokazu AU - Tabata, Shigekazu AU - Hamachi, Itaru AU - Shigemoto, Ryuichi AU - Ojida, Akio ID - 6659 IS - 5 JF - Bulletin of the Chemical Society of Japan SN - 00092673 TI - Optimized reaction pair of the CysHis tag and Ni(II)-NTA probe for highly selective chemical labeling of membrane proteins VL - 92 ER - TY - CONF AB - A Valued Constraint Satisfaction Problem (VCSP) provides a common framework that can express a wide range of discrete optimization problems. A VCSP instance is given by a finite set of variables, a finite domain of labels, and an objective function to be minimized. This function is represented as a sum of terms where each term depends on a subset of the variables. To obtain different classes of optimization problems, one can restrict all terms to come from a fixed set Γ of cost functions, called a language. Recent breakthrough results have established a complete complexity classification of such classes with respect to language Γ: if all cost functions in Γ satisfy a certain algebraic condition then all Γ-instances can be solved in polynomial time, otherwise the problem is NP-hard. Unfortunately, testing this condition for a given language Γ is known to be NP-hard. We thus study exponential algorithms for this meta-problem. We show that the tractability condition of a finite-valued language Γ can be tested in O(3‾√3|D|⋅poly(size(Γ))) time, where D is the domain of Γ and poly(⋅) is some fixed polynomial. We also obtain a matching lower bound under the Strong Exponential Time Hypothesis (SETH). More precisely, we prove that for any constant δ<1 there is no O(3‾√3δ|D|) algorithm, assuming that SETH holds. AU - Kolmogorov, Vladimir ID - 6725 SN - 1868-8969 T2 - 46th International Colloquium on Automata, Languages and Programming TI - Testing the complexity of a valued CSP language VL - 132 ER - TY - CHAP AB - Randomness is an essential part of any secure cryptosystem, but many constructions rely on distributions that are not uniform. This is particularly true for lattice based cryptosystems, which more often than not make use of discrete Gaussian distributions over the integers. For practical purposes it is crucial to evaluate the impact that approximation errors have on the security of a scheme to provide the best possible trade-off between security and performance. Recent years have seen surprising results allowing to use relatively low precision while maintaining high levels of security. A key insight in these results is that sampling a distribution with low relative error can provide very strong security guarantees. Since floating point numbers provide guarantees on the relative approximation error, they seem a suitable tool in this setting, but it is not obvious which sampling algorithms can actually profit from them. While previous works have shown that inversion sampling can be adapted to provide a low relative error (Pöppelmann et al., CHES 2014; Prest, ASIACRYPT 2017), other works have called into question if this is possible for other sampling techniques (Zheng et al., Eprint report 2018/309). In this work, we consider all sampling algorithms that are popular in the cryptographic setting and analyze the relationship of floating point precision and the resulting relative error. We show that all of the algorithms either natively achieve a low relative error or can be adapted to do so. AU - Walter, Michael ED - Buchmann, J ED - Nitaj, A ED - Rachidi, T ID - 6726 SN - 0302-9743 T2 - Progress in Cryptology – AFRICACRYPT 2019 TI - Sampling the integers with low relative error VL - 11627 ER - TY - JOUR AB - Polar codes have gained extensive attention during the past few years and recently they have been selected for the next generation of wireless communications standards (5G). Successive-cancellation-based (SC-based) decoders, such as SC list (SCL) and SC flip (SCF), provide a reasonable error performance for polar codes at the cost of low decoding speed. Fast SC-based decoders, such as Fast-SSC, Fast-SSCL, and Fast-SSCF, identify the special constituent codes in a polar code graph off-line, produce a list of operations, store the list in memory, and feed the list to the decoder to decode the constituent codes in order efficiently, thus increasing the decoding speed. However, the list of operations is dependent on the code rate and as the rate changes, a new list is produced, making fast SC-based decoders not rate-flexible. In this paper, we propose a completely rate-flexible fast SC-based decoder by creating the list of operations directly in hardware, with low implementation complexity. We further propose a hardware architecture implementing the proposed method and show that the area occupation of the rate-flexible fast SC-based decoder in this paper is only 38% of the total area of the memory-based base-line decoder when 5G code rates are supported. AU - Hashemi, Seyyed Ali AU - Condo, Carlo AU - Mondelli, Marco AU - Gross, Warren J ID - 6750 IS - 22 JF - IEEE Transactions on Signal Processing SN - 1053587X TI - Rate-flexible fast polar decoders VL - 67 ER - TY - JOUR AB - We consider the graph class Grounded-L corresponding to graphs that admit an intersection representation by L-shaped curves, where additionally the topmost points of each curve are assumed to belong to a common horizontal line. We prove that Grounded-L graphs admit an equivalent characterisation in terms of vertex ordering with forbidden patterns. We also compare this class to related intersection classes, such as the grounded segment graphs, the monotone L-graphs (a.k.a. max point-tolerance graphs), or the outer-1-string graphs. We give constructions showing that these classes are all distinct and satisfy only trivial or previously known inclusions. AU - Jelínek, Vít AU - Töpfer, Martin ID - 6759 IS - 3 JF - Electronic Journal of Combinatorics TI - On grounded L-graphs and their relatives VL - 26 ER - TY - CONF AB - In two-player games on graphs, the players move a token through a graph to produce an infinite path, which determines the qualitative winner or quantitative payoff of the game. In bidding games, in each turn, we hold an auction between the two players to determine which player moves the token. Bidding games have largely been studied with concrete bidding mechanisms that are variants of a first-price auction: in each turn both players simultaneously submit bids, the higher bidder moves the token, and pays his bid to the lower bidder in Richman bidding, to the bank in poorman bidding, and in taxman bidding, the bid is split between the other player and the bank according to a predefined constant factor. Bidding games are deterministic games. They have an intriguing connection with a fragment of stochastic games called randomturn games. We study, for the first time, a combination of bidding games with probabilistic behavior; namely, we study bidding games that are played on Markov decision processes, where the players bid for the right to choose the next action, which determines the probability distribution according to which the next vertex is chosen. We study parity and meanpayoff bidding games on MDPs and extend results from the deterministic bidding setting to the probabilistic one. AU - Avni, Guy AU - Henzinger, Thomas A AU - Ibsen-Jensen, Rasmus AU - Novotny, Petr ID - 6822 SN - 0302-9743 T2 - Proceedings of the 13th International Conference of Reachability Problems TI - Bidding games on Markov decision processes VL - 11674 ER - TY - CONF AB - The fundamental model-checking problem, given as input a model and a specification, asks for the algorithmic verification of whether the model satisfies the specification. Two classical models for reactive systems are graphs and Markov decision processes (MDPs). A basic specification formalism in the verification of reactive systems is the strong fairness (aka Streett) objective, where given different types of requests and corresponding grants, the requirement is that for each type, if the request event happens infinitely often, then the corresponding grant event must also happen infinitely often. All omega-regular objectives can be expressed as Streett objectives and hence they are canonical in verification. Consider graphs/MDPs with n vertices, m edges, and a Streett objectives with k pairs, and let b denote the size of the description of the Streett objective for the sets of requests and grants. The current best-known algorithm for the problem requires time O(min(n^2, m sqrt{m log n}) + b log n). In this work we present randomized near-linear time algorithms, with expected running time O~(m + b), where the O~ notation hides poly-log factors. Our randomized algorithms are near-linear in the size of the input, and hence optimal up to poly-log factors. AU - Chatterjee, Krishnendu AU - Dvorák, Wolfgang AU - Henzinger, Monika H AU - Svozil, Alexander ID - 6887 T2 - Leibniz International Proceedings in Informatics TI - Near-linear time algorithms for Streett objectives in graphs and MDPs VL - 140 ER - TY - CONF AB - In this paper, we design novel liquid time-constant recurrent neural networks for robotic control, inspired by the brain of the nematode, C. elegans. In the worm's nervous system, neurons communicate through nonlinear time-varying synaptic links established amongst them by their particular wiring structure. This property enables neurons to express liquid time-constants dynamics and therefore allows the network to originate complex behaviors with a small number of neurons. We identify neuron-pair communication motifs as design operators and use them to configure compact neuronal network structures to govern sequential robotic tasks. The networks are systematically designed to map the environmental observations to motor actions, by their hierarchical topology from sensory neurons, through recurrently-wired interneurons, to motor neurons. The networks are then parametrized in a supervised-learning scheme by a search-based algorithm. We demonstrate that obtained networks realize interpretable dynamics. We evaluate their performance in controlling mobile and arm robots, and compare their attributes to other artificial neural network-based control agents. Finally, we experimentally show their superior resilience to environmental noise, compared to the existing machine learning-based methods. AU - Lechner, Mathias AU - Hasani, Ramin AU - Zimmer, Manuel AU - Henzinger, Thomas A AU - Grosu, Radu ID - 6888 SN - 9781538660270 T2 - Proceedings - IEEE International Conference on Robotics and Automation TI - Designing worm-inspired neural networks for interpretable robotic control VL - 2019-May ER - TY - CONF AB - In two-player games on graphs, the players move a token through a graph to produce an infinite path, which determines the winner of the game. Such games are central in formal methods since they model the interaction between a non-terminating system and its environment. In bidding games the players bid for the right to move the token: in each round, the players simultaneously submit bids, and the higher bidder moves the token and pays the other player. Bidding games are known to have a clean and elegant mathematical structure that relies on the ability of the players to submit arbitrarily small bids. Many applications, however, require a fixed granularity for the bids, which can represent, for example, the monetary value expressed in cents. We study, for the first time, the combination of discrete-bidding and infinite-duration games. Our most important result proves that these games form a large determined subclass of concurrent games, where determinacy is the strong property that there always exists exactly one player who can guarantee winning the game. In particular, we show that, in contrast to non-discrete bidding games, the mechanism with which tied bids are resolved plays an important role in discrete-bidding games. We study several natural tie-breaking mechanisms and show that, while some do not admit determinacy, most natural mechanisms imply determinacy for every pair of initial budgets. AU - Aghajohari, Milad AU - Avni, Guy AU - Henzinger, Thomas A ID - 6886 TI - Determinacy in discrete-bidding infinite-duration games VL - 140 ER - TY - CONF AB - A vector addition system with states (VASS) consists of a finite set of states and counters. A configuration is a state and a value for each counter; a transition changes the state and each counter is incremented, decremented, or left unchanged. While qualitative properties such as state and configuration reachability have been studied for VASS, we consider the long-run average cost of infinite computations of VASS. The cost of a configuration is for each state, a linear combination of the counter values. In the special case of uniform cost functions, the linear combination is the same for all states. The (regular) long-run emptiness problem is, given a VASS, a cost function, and a threshold value, if there is a (lasso-shaped) computation such that the long-run average value of the cost function does not exceed the threshold. For uniform cost functions, we show that the regular long-run emptiness problem is (a) decidable in polynomial time for integer-valued VASS, and (b) decidable but nonelementarily hard for natural-valued VASS (i.e., nonnegative counters). For general cost functions, we show that the problem is (c) NP-complete for integer-valued VASS, and (d) undecidable for natural-valued VASS. Our most interesting result is for (c) integer-valued VASS with general cost functions, where we establish a connection between the regular long-run emptiness problem and quadratic Diophantine inequalities. The general (nonregular) long-run emptiness problem is equally hard as the regular problem in all cases except (c), where it remains open. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ID - 6885 TI - Long-run average behavior of vector addition systems with states VL - 140 ER - TY - CONF AB - We study Markov decision processes and turn-based stochastic games with parity conditions. There are three qualitative winning criteria, namely, sure winning, which requires all paths to satisfy the condition, almost-sure winning, which requires the condition to be satisfied with probability 1, and limit-sure winning, which requires the condition to be satisfied with probability arbitrarily close to 1. We study the combination of two of these criteria for parity conditions, e.g., there are two parity conditions one of which must be won surely, and the other almost-surely. The problem has been studied recently by Berthon et al. for MDPs with combination of sure and almost-sure winning, under infinite-memory strategies, and the problem has been established to be in NP cap co-NP. Even in MDPs there is a difference between finite-memory and infinite-memory strategies. Our main results for combination of sure and almost-sure winning are as follows: (a) we show that for MDPs with finite-memory strategies the problem is in NP cap co-NP; (b) we show that for turn-based stochastic games the problem is co-NP-complete, both for finite-memory and infinite-memory strategies; and (c) we present algorithmic results for the finite-memory case, both for MDPs and turn-based stochastic games, by reduction to non-stochastic parity games. In addition we show that all the above complexity results also carry over to combination of sure and limit-sure winning, and results for all other combinations can be derived from existing results in the literature. Thus we present a complete picture for the study of combinations of two qualitative winning criteria for parity conditions in MDPs and turn-based stochastic games. AU - Chatterjee, Krishnendu AU - Piterman, Nir ID - 6889 TI - Combinations of Qualitative Winning for Stochastic Parity Games VL - 140 ER - TY - CONF AB - Consider a distributed system with n processors out of which f can be Byzantine faulty. In the approximate agreement task, each processor i receives an input value xi and has to decide on an output value yi such that 1. the output values are in the convex hull of the non-faulty processors’ input values, 2. the output values are within distance d of each other. Classically, the values are assumed to be from an m-dimensional Euclidean space, where m ≥ 1. In this work, we study the task in a discrete setting, where input values with some structure expressible as a graph. Namely, the input values are vertices of a finite graph G and the goal is to output vertices that are within distance d of each other in G, but still remain in the graph-induced convex hull of the input values. For d = 0, the task reduces to consensus and cannot be solved with a deterministic algorithm in an asynchronous system even with a single crash fault. For any d ≥ 1, we show that the task is solvable in asynchronous systems when G is chordal and n > (ω + 1)f, where ω is the clique number of G. In addition, we give the first Byzantine-tolerant algorithm for a variant of lattice agreement. For synchronous systems, we show tight resilience bounds for the exact variants of these and related tasks over a large class of combinatorial structures. AU - Nowak, Thomas AU - Rybicki, Joel ID - 6931 KW - consensus KW - approximate agreement KW - Byzantine faults KW - chordal graphs KW - lattice agreement T2 - 33rd International Symposium on Distributed Computing TI - Byzantine approximate agreement on graphs VL - 146 ER - TY - CONF AB - In this paper, we introduce a novel method to interpret recurrent neural networks (RNNs), particularly long short-term memory networks (LSTMs) at the cellular level. We propose a systematic pipeline for interpreting individual hidden state dynamics within the network using response characterization methods. The ranked contribution of individual cells to the network's output is computed by analyzing a set of interpretable metrics of their decoupled step and sinusoidal responses. As a result, our method is able to uniquely identify neurons with insightful dynamics, quantify relationships between dynamical properties and test accuracy through ablation analysis, and interpret the impact of network capacity on a network's dynamical distribution. Finally, we demonstrate the generalizability and scalability of our method by evaluating a series of different benchmark sequential datasets. AU - Hasani, Ramin AU - Amini, Alexander AU - Lechner, Mathias AU - Naser, Felix AU - Grosu, Radu AU - Rus, Daniela ID - 6985 SN - 9781728119854 T2 - Proceedings of the International Joint Conference on Neural Networks TI - Response characterization for auditing cell dynamics in long short-term memory networks ER - TY - JOUR AB - We consider the primitive relay channel, where the source sends a message to the relay and to the destination, and the relay helps the communication by transmitting an additional message to the destination via a separate channel. Two well-known coding techniques have been introduced for this setting: decode-and-forward and compress-and-forward. In decode-and-forward, the relay completely decodes the message and sends some information to the destination; in compress-and-forward, the relay does not decode, and it sends a compressed version of the received signal to the destination using Wyner–Ziv coding. In this paper, we present a novel coding paradigm that provides an improved achievable rate for the primitive relay channel. The idea is to combine compress-and-forward and decode-and-forward via a chaining construction. We transmit over pairs of blocks: in the first block, we use compress-and-forward; and, in the second block, we use decode-and-forward. More specifically, in the first block, the relay does not decode, it compresses the received signal via Wyner–Ziv, and it sends only part of the compression to the destination. In the second block, the relay completely decodes the message, it sends some information to the destination, and it also sends the remaining part of the compression coming from the first block. By doing so, we are able to strictly outperform both compress-and-forward and decode-and-forward. Note that the proposed coding scheme can be implemented with polar codes. As such, it has the typical attractive properties of polar coding schemes, namely, quasi-linear encoding and decoding complexity, and error probability that decays at super-polynomial speed. As a running example, we take into account the special case of the erasure relay channel, and we provide a comparison between the rates achievable by our proposed scheme and the existing upper and lower bounds. AU - Mondelli, Marco AU - Hassani, S. Hamed AU - Urbanke, Rüdiger ID - 7007 IS - 10 JF - Algorithms SN - 1999-4893 TI - A new coding paradigm for the primitive relay channel VL - 12 ER - TY - CONF AB - The aim of this short note is to expound one particular issue that was discussed during the talk [10] given at the symposium ”Researches on isometries as preserver problems and related topics” at Kyoto RIMS. That is, the role of Dirac masses by describing the isometry group of various metric spaces of probability measures. This article is of survey character, and it does not contain any essentially new results.From an isometric point of view, in some cases, metric spaces of measures are similar to C(K)-type function spaces. Similarity means here that their isometries are driven by some nice transformations of the underlying space. Of course, it depends on the particular choice of the metric how nice these transformations should be. Sometimes, as we will see, being a homeomorphism is enough to generate an isometry. But sometimes we need more: the transformation must preserve the underlying distance as well. Statements claiming that isometries in questions are necessarily induced by homeomorphisms are called Banach-Stone-type results, while results asserting that the underlying transformation is necessarily an isometry are termed as isometric rigidity results.As Dirac masses can be considered as building bricks of the set of all Borel measures, a natural question arises:Is it enough to understand how an isometry acts on the set of Dirac masses? Does this action extend uniquely to all measures?In what follows, we will thoroughly investigate this question. AU - Geher, Gyorgy Pal AU - Titkos, Tamas AU - Virosztek, Daniel ID - 7035 T2 - Kyoto RIMS Kôkyûroku TI - Dirac masses and isometric rigidity VL - 2125 ER - TY - BOOK AB - Wissen Sie, was sich hinter künstlicher Intelligenz und maschinellem Lernen verbirgt? Dieses Sachbuch erklärt Ihnen leicht verständlich und ohne komplizierte Formeln die grundlegenden Methoden und Vorgehensweisen des maschinellen Lernens. Mathematisches Vorwissen ist dafür nicht nötig. Kurzweilig und informativ illustriert Lisa, die Protagonistin des Buches, diese anhand von Alltagssituationen. Ein Buch für alle, die in Diskussionen über Chancen und Risiken der aktuellen Entwicklung der künstlichen Intelligenz und des maschinellen Lernens mit Faktenwissen punkten möchten. Auch für Schülerinnen und Schüler geeignet! ED - Kersting, Kristian ED - Lampert, Christoph ED - Rothkopf, Constantin ID - 7171 SN - 978-3-658-26762-9 TI - Wie Maschinen Lernen: Künstliche Intelligenz Verständlich Erklärt ER - TY - CONF AB - The genus g(G) of a graph G is the minimum g such that G has an embedding on the orientable surface M_g of genus g. A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The Z_2-genus of a graph G, denoted by g_0(G), is the minimum g such that G has an independently even drawing on M_g. By a result of Battle, Harary, Kodama and Youngs from 1962, the graph genus is additive over 2-connected blocks. In 2013, Schaefer and Stefankovic proved that the Z_2-genus of a graph is additive over 2-connected blocks as well, and asked whether this result can be extended to so-called 2-amalgamations, as an analogue of results by Decker, Glover, Huneke, and Stahl for the genus. We give the following partial answer. If G=G_1 cup G_2, G_1 and G_2 intersect in two vertices u and v, and G-u-v has k connected components (among which we count the edge uv if present), then |g_0(G)-(g_0(G_1)+g_0(G_2))|<=k+1. For complete bipartite graphs K_{m,n}, with n >= m >= 3, we prove that g_0(K_{m,n})/g(K_{m,n})=1-O(1/n). Similar results are proved also for the Euler Z_2-genus. We express the Z_2-genus of a graph using the minimum rank of partial symmetric matrices over Z_2; a problem that might be of independent interest. AU - Fulek, Radoslav AU - Kyncl, Jan ID - 7401 SN - 1868-8969 T2 - 35th International Symposium on Computational Geometry (SoCG 2019) TI - Z_2-Genus of graphs and minimum rank of partial symmetric matrices VL - 129 ER - TY - CHAP AB - We illustrate the ingredients of the state-of-the-art of model-based approach for the formal design and verification of cyber-physical systems. To capture the interaction between a discrete controller and its continuously evolving environment, we use the formal models of timed and hybrid automata. We explain the steps of modeling and verification in the tools Uppaal and SpaceEx using a case study based on a dual-chamber implantable pacemaker monitoring a human heart. We show how to design a model as a composition of components, how to construct models at varying levels of detail, how to establish that one model is an abstraction of another, how to specify correctness requirements using temporal logic, and how to verify that a model satisfies a logical requirement. AU - Alur, Rajeev AU - Giacobbe, Mirco AU - Henzinger, Thomas A AU - Larsen, Kim G. AU - Mikučionis, Marius ED - Steffen, Bernhard ED - Woeginger, Gerhard ID - 7453 SN - 1611-3349 T2 - Computing and Software Science TI - Continuous-time models for system design and analysis VL - 10000 ER - TY - JOUR AB - We consider an optimal control problem for an abstract nonlinear dissipative evolution equation. The differential constraint is penalized by augmenting the target functional by a nonnegative global-in-time functional which is null-minimized in the evolution equation is satisfied. Different variational settings are presented, leading to the convergence of the penalization method for gradient flows, noncyclic and semimonotone flows, doubly nonlinear evolutions, and GENERIC systems. AU - Portinale, Lorenzo AU - Stefanelli, Ulisse ID - 7550 IS - 2 JF - Advances in Mathematical Sciences and Applications SN - 1343-4373 TI - Penalization via global functionals of optimal-control problems for dissipative evolution VL - 28 ER - TY - GEN AB - There is increasing evidence that protein binding to specific sites along DNA can activate the reading out of genetic information without coming into direct physical contact with the gene. There also is evidence that these distant but interacting sites are embedded in a liquid droplet of proteins which condenses out of the surrounding solution. We argue that droplet-mediated interactions can account for crucial features of gene regulation only if the droplet is poised at a non-generic point in its phase diagram. We explore a minimal model that embodies this idea, show that this model has a natural mechanism for self-tuning, and suggest direct experimental tests. AU - Bialek, William AU - Gregor, Thomas AU - Tkačik, Gašper ID - 7552 T2 - arXiv:1912.08579 TI - Action at a distance in transcriptional regulation ER - TY - CONF AB - We present the results of a friendly competition for formal verification of continuous and hybrid systems with nonlinear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In this year, 6 tools Ariadne, CORA, DynIbex, Flow*, Isabelle/HOL, and JuliaReach (in alphabetic order) participated. They are applied to solve reachability analysis problems on four benchmark problems, one of them with hybrid dynamics. We do not rank the tools based on the results, but show the current status and discover the potential advantages of different tools. AU - Immler, Fabian AU - Althoff, Matthias AU - Benet, Luis AU - Chapoutot, Alexandre AU - Chen, Xin AU - Forets, Marcelo AU - Geretti, Luca AU - Kochdumper, Niklas AU - Sanders, David P. AU - Schilling, Christian ID - 7576 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with nonlinear dynamics VL - 61 ER - TY - CONF AB - We study edge asymptotics of poissonized Plancherel-type measures on skew Young diagrams (integer partitions). These measures can be seen as generalizations of those studied by Baik--Deift--Johansson and Baik--Rains in resolving Ulam's problem on longest increasing subsequences of random permutations and the last passage percolation (corner growth) discrete versions thereof. Moreover they interpolate between said measures and the uniform measure on partitions. In the new KPZ-like 1/3 exponent edge scaling limit with logarithmic corrections, we find new probability distributions generalizing the classical Tracy--Widom GUE, GOE and GSE distributions from the theory of random matrices. AU - Betea, Dan AU - Bouttier, Jérémie AU - Nejjar, Peter AU - Vuletíc, Mirjana ID - 8175 T2 - Proceedings on the 31st International Conference on Formal Power Series and Algebraic Combinatorics TI - New edge asymptotics of skew Young diagrams via free boundaries ER - TY - CONF AB - This report presents the results of a friendly competition for formal verification of continuous and hybrid systems with linear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In its third edition, seven tools have been applied to solve six different benchmark problems in the category for linear continuous dynamics (in alphabetical order): CORA, CORA/SX, HyDRA, Hylaa, JuliaReach, SpaceEx, and XSpeed. This report is a snapshot of the current landscape of tools and the types of benchmarks they are particularly suited for. Due to the diversity of problems, we are not ranking tools, yet the presented results provide one of the most complete assessments of tools for the safety verification of continuous and hybrid systems with linear continuous dynamics up to this date. AU - Althoff, Matthias AU - Bak, Stanley AU - Forets, Marcelo AU - Frehse, Goran AU - Kochdumper, Niklas AU - Ray, Rajarshi AU - Schilling, Christian AU - Schupp, Stefan ID - 8570 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with linear continuous dynamics VL - 61 ER - TY - JOUR AB - Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING 1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion. AU - Kim, M. Yvonne AU - Ono, Akemi AU - Scholten, Stefan AU - Kinoshita, Tetsu AU - Zilberman, Daniel AU - Okamoto, Takashi AU - Fischer, Robert L. ID - 9460 IS - 19 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - DNA demethylation by ROS1a in rice vegetative cells promotes methylation in sperm VL - 116 ER - TY - JOUR AB - Glyphosate (N-phosphonomethyl glycine) and its commercial herbicide formulations have been shown to exert toxicity via various mechanisms. It has been asserted that glyphosate substitutes for glycine in polypeptide chains leading to protein misfolding and toxicity. However, as no direct evidence exists for glycine to glyphosate substitution in proteins, including in mammalian organisms, we tested this claim by conducting a proteomics analysis of MDA-MB-231 human breast cancer cells grown in the presence of 100 mg/L glyphosate for 6 days. Protein extracts from three treated and three untreated cell cultures were analysed as one TMT-6plex labelled sample, to highlight a specific pattern (+/+/+/−/−/−) of reporter intensities for peptides bearing true glyphosate treatment induced-post translational modifications as well as allowing an investigation of the total proteome. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 6819 JF - BMC Research Notes TI - Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells VL - 12 ER - TY - GEN AB - Additional file 1: Table S1. Kinetics of MDA-MB-231 cell growth in either the presence or absence of 100Â mg/L glyphosate. Cell counts are given at day-1 of seeding flasks and following 6-days of continuous culture. Note: no differences in cell numbers were observed between negative control and glyphosate treated cultures. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 9784 TI - MOESM1 of Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells ER - TY - GEN AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 9839 TI - Data from: Is the sky the limit? On the expansion threshold of a species' range ER - TY - JOUR AB - Background DNA methylation of active genes, also known as gene body methylation, is found in many animal and plant genomes. Despite this, the transcriptional and developmental role of such methylation remains poorly understood. Here, we explore the dynamic range of DNA methylation in honey bee, a model organism for gene body methylation. Results Our data show that CG methylation in gene bodies globally fluctuates during honey bee development. However, these changes cause no gene expression alterations. Intriguingly, despite the global alterations, tissue-specific CG methylation patterns of complete genes or exons are rare, implying robust maintenance of genic methylation during development. Additionally, we show that CG methylation maintenance fluctuates in somatic cells, while reaching maximum fidelity in sperm cells. Finally, unlike universally present CG methylation, we discovered non-CG methylation specifically in bee heads that resembles such methylation in mammalian brain tissue. Conclusions Based on these results, we propose that gene body CG methylation can oscillate during development if it is kept to a level adequate to preserve function. Additionally, our data suggest that heightened non-CG methylation is a conserved regulator of animal nervous systems. AU - Harris, Keith D. AU - Lloyd, James P. B. AU - Domb, Katherine AU - Zilberman, Daniel AU - Zemach, Assaf ID - 9530 JF - Epigenetics and Chromatin TI - DNA methylation is maintained with high fidelity in the honey bee germline and exhibits global non-functional fluctuations during somatic development VL - 12 ER - TY - JOUR AB - Transposable elements (TEs), the movement of which can damage the genome, are epigenetically silenced in eukaryotes. Intriguingly, TEs are activated in the sperm companion cell – vegetative cell (VC) – of the flowering plant Arabidopsis thaliana. However, the extent and mechanism of this activation are unknown. Here we show that about 100 heterochromatic TEs are activated in VCs, mostly by DEMETER-catalyzed DNA demethylation. We further demonstrate that DEMETER access to some of these TEs is permitted by the natural depletion of linker histone H1 in VCs. Ectopically expressed H1 suppresses TEs in VCs by reducing DNA demethylation and via a methylation-independent mechanism. We demonstrate that H1 is required for heterochromatin condensation in plant cells and show that H1 overexpression creates heterochromatic foci in the VC progenitor cell. Taken together, our results demonstrate that the natural depletion of H1 during male gametogenesis facilitates DEMETER-directed DNA demethylation, heterochromatin relaxation, and TE activation. AU - He, Shengbo AU - Vickers, Martin AU - Zhang, Jingyi AU - Feng, Xiaoqi ID - 12192 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Natural depletion of histone H1 in sex cells causes DNA demethylation, heterochromatin decondensation and transposon activation VL - 8 ER - TY - JOUR AB - Meiotic crossover frequency varies within genomes, which influences genetic diversity and adaptation. In turn, genetic variation within populations can act to modify crossover frequency in cis and trans. To identify genetic variation that controls meiotic crossover frequency, we screened Arabidopsis accessions using fluorescent recombination reporters. We mapped a genetic modifier of crossover frequency in Col × Bur populations of Arabidopsis to a premature stop codon within TBP-ASSOCIATED FACTOR 4b (TAF4b), which encodes a subunit of the RNA polymerase II general transcription factor TFIID. The Arabidopsis taf4b mutation is a rare variant found in the British Isles, originating in South-West Ireland. Using genetics, genomics, and immunocytology, we demonstrate a genome-wide decrease in taf4b crossovers, with strongest reduction in the sub-telomeric regions. Using RNA sequencing (RNA-seq) from purified meiocytes, we show that TAF4b expression is meiocyte enriched, whereas its paralog TAF4 is broadly expressed. Consistent with the role of TFIID in promoting gene expression, RNA-seq of wild-type and taf4b meiocytes identified widespread transcriptional changes, including in genes that regulate the meiotic cell cycle and recombination. Therefore, TAF4b duplication is associated with acquisition of meiocyte-specific expression and promotion of germline transcription, which act directly or indirectly to elevate crossovers. This identifies a novel mode of meiotic recombination control via a general transcription factor. AU - Lawrence, Emma J. AU - Gao, Hongbo AU - Tock, Andrew J. AU - Lambing, Christophe AU - Blackwell, Alexander R. AU - Feng, Xiaoqi AU - Henderson, Ian R. ID - 12190 IS - 16 JF - Current Biology KW - General Agricultural and Biological Sciences KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0960-9822 TI - Natural variation in TBP-ASSOCIATED FACTOR 4b controls meiotic crossover and germline transcription in Arabidopsis VL - 29 ER - TY - GEN AU - Schlögl, Alois AU - Kiss, Janos AU - Elefante, Stefano ID - 12901 T2 - AHPC19 - Austrian HPC Meeting 2019 TI - Is Debian suitable for running an HPC Cluster? ER - TY - CONF AB - When can a polyomino piece of paper be folded into a unit cube? Prior work studied tree-like polyominoes, but polyominoes with holes remain an intriguing open problem. We present sufficient conditions for a polyomino with hole(s) to fold into a cube, and conditions under which cube folding is impossible. In particular, we show that all but five special simple holes guarantee foldability. AU - Aichholzer, Oswin AU - Akitaya, Hugo A AU - Cheung, Kenneth C AU - Demaine, Erik D AU - Demaine, Martin L AU - Fekete, Sandor P AU - Kleist, Linda AU - Kostitsyna, Irina AU - Löffler, Maarten AU - Masárová, Zuzana AU - Mundilova, Klara AU - Schmidt, Christiane ID - 6989 T2 - Proceedings of the 31st Canadian Conference on Computational Geometry TI - Folding polyominoes with holes into a cube ER - TY - CONF AB - In two-player games on graphs, the players move a token through a graph to produce a finite or infinite path, which determines the qualitative winner or quantitative payoff of the game. We study bidding games in which the players bid for the right to move the token. Several bidding rules were studied previously. In Richman bidding, in each round, the players simultaneously submit bids, and the higher bidder moves the token and pays the other player. Poorman bidding is similar except that the winner of the bidding pays the "bank" rather than the other player. Taxman bidding spans the spectrum between Richman and poorman bidding. They are parameterized by a constant tau in [0,1]: portion tau of the winning bid is paid to the other player, and portion 1-tau to the bank. While finite-duration (reachability) taxman games have been studied before, we present, for the first time, results on infinite-duration taxman games. It was previously shown that both Richman and poorman infinite-duration games with qualitative objectives reduce to reachability games, and we show a similar result here. Our most interesting results concern quantitative taxman games, namely mean-payoff games, where poorman and Richman bidding differ significantly. A central quantity in these games is the ratio between the two players' initial budgets. While in poorman mean-payoff games, the optimal payoff of a player depends on the initial ratio, in Richman bidding, the payoff depends only on the structure of the game. In both games the optimal payoffs can be found using (different) probabilistic connections with random-turn games in which in each turn, instead of bidding, a coin is tossed to determine which player moves. While the value with Richman bidding equals the value of a random-turn game with an un-biased coin, with poorman bidding, the bias in the coin is the initial ratio of the budgets. We give a complete classification of mean-payoff taxman games that is based on a probabilistic connection: the value of a taxman bidding game with parameter tau and initial ratio r, equals the value of a random-turn game that uses a coin with bias F(tau, r) = (r+tau * (1-r))/(1+tau). Thus, we show that Richman bidding is the exception; namely, for every tau <1, the value of the game depends on the initial ratio. Our proof technique simplifies and unifies the previous proof techniques for both Richman and poorman bidding. AU - Avni, Guy AU - Henzinger, Thomas A AU - Zikelic, Dorde ID - 6884 TI - Bidding mechanisms in graph games VL - 138 ER - TY - GEN AB - A detailed description of the two stochastic models, table of parameters, supplementary data for Figures 4 and 5, parameter dependence of the results, and an analysis on motors with different force–velocity functions (PDF) AU - Ucar, Mehmet C AU - Lipowsky, Reinhard ID - 9726 TI - Supplementary information - Collective force generation by molecular motors is determined by strain-induced unbinding ER - TY - JOUR AB - In this paper we discuss three results. The first two concern general sets of positive reach: we first characterize the reach of a closed set by means of a bound on the metric distortion between the distance measured in the ambient Euclidean space and the shortest path distance measured in the set. Secondly, we prove that the intersection of a ball with radius less than the reach with the set is geodesically convex, meaning that the shortest path between any two points in the intersection lies itself in the intersection. For our third result we focus on manifolds with positive reach and give a bound on the angle between tangent spaces at two different points in terms of the reach and the distance between the two points. AU - Boissonnat, Jean-Daniel AU - Lieutier, André AU - Wintraecken, Mathijs ID - 6671 IS - 1-2 JF - Journal of Applied and Computational Topology SN - 2367-1726 TI - The reach, metric distortion, geodesic convexity and the variation of tangent spaces VL - 3 ER - TY - JOUR AB - A representation formula for solutions of stochastic partial differential equations with Dirichlet boundary conditions is proved. The scope of our setting is wide enough to cover the general situation when the backward characteristics that appear in the usual formulation are not even defined in the Itô sense. AU - Gerencser, Mate AU - Gyöngy, István ID - 301 IS - 3 JF - Stochastic Processes and their Applications TI - A Feynman–Kac formula for stochastic Dirichlet problems VL - 129 ER - TY - JOUR AB - We consider an interacting, dilute Bose gas trapped in a harmonic potential at a positive temperature. The system is analyzed in a combination of a thermodynamic and a Gross–Pitaevskii (GP) limit where the trap frequency ω, the temperature T, and the particle number N are related by N∼ (T/ ω) 3→ ∞ while the scattering length is so small that the interaction energy per particle around the center of the trap is of the same order of magnitude as the spectral gap in the trap. We prove that the difference between the canonical free energy of the interacting gas and the one of the noninteracting system can be obtained by minimizing the GP energy functional. We also prove Bose–Einstein condensation in the following sense: The one-particle density matrix of any approximate minimizer of the canonical free energy functional is to leading order given by that of the noninteracting gas but with the free condensate wavefunction replaced by the GP minimizer. AU - Deuchert, Andreas AU - Seiringer, Robert AU - Yngvason, Jakob ID - 80 IS - 2 JF - Communications in Mathematical Physics TI - Bose–Einstein condensation in a dilute, trapped gas at positive temperature VL - 368 ER - TY - JOUR AB - Empirical data suggest that inversions in many species contain genes important for intraspecific divergence and speciation, yet mechanisms of evolution remain unclear. While genes inside an inversion are tightly linked, inversions are not static but evolve separately from the rest of the genome by new mutations, recombination within arrangements, and gene flux between arrangements. Inversion polymorphisms are maintained by different processes, for example, divergent or balancing selection, or a mix of multiple processes. Moreover, the relative roles of selection, drift, mutation, and recombination will change over the lifetime of an inversion and within its area of distribution. We believe inversions are central to the evolution of many species, but we need many more data and new models to understand the complex mechanisms involved. AU - Faria, Rui AU - Johannesson, Kerstin AU - Butlin, Roger K. AU - Westram, Anja M ID - 5911 IS - 3 JF - Trends in Ecology and Evolution SN - 01695347 TI - Evolving inversions VL - 34 ER -