TY - JOUR
AB - Cytosine DNA methylation regulates the expression of eukaryotic genes and transposons. Methylation is copied by methyltransferases after DNA replication, which results in faithful transmission of methylation patterns during cell division and, at least in flowering plants, across generations. Transgenerational inheritance is mediated by a small group of cells that includes gametes and their progenitors. However, methylation is usually analyzed in somatic tissues that do not contribute to the next generation, and the mechanisms of transgenerational inheritance are inferred from such studies. To gain a better understanding of how DNA methylation is inherited, we analyzed purified Arabidopsis thaliana sperm and vegetative cells-the cell types that comprise pollen-with mutations in the DRM, CMT2, and CMT3 methyltransferases. We find that DNA methylation dependency on these enzymes is similar in sperm, vegetative cells, and somatic tissues, although DRM activity extends into heterochromatin in vegetative cells, likely reflecting transcription of heterochromatic transposons in this cell type. We also show that lack of histone H1, which elevates heterochromatic DNA methylation in somatic tissues, does not have this effect in pollen. Instead, levels of CG methylation in wild-type sperm and vegetative cells, as well as in wild-type microspores from which both pollen cell types originate, are substantially higher than in wild-type somatic tissues and similar to those of H1-depleted roots. Our results demonstrate that the mechanisms of methylation maintenance are similar between pollen and somatic cells, but the efficiency of CG methylation is higher in pollen, allowing methylation patterns to be accurately inherited across generations.
AU - Hsieh, Ping-Hung
AU - He, Shengbo
AU - Buttress, Toby
AU - Gao, Hongbo
AU - Couchman, Matthew
AU - Fischer, Robert L.
AU - Zilberman, Daniel
AU - Feng, Xiaoqi
ID - 9473
IS - 52
JF - Proceedings of the National Academy of Sciences
SN - 0027-8424
TI - Arabidopsis male sexual lineage exhibits more robust maintenance of CG methylation than somatic tissues
VL - 113
ER -
TY - JOUR
AB - Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis. DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice—species that diverged 150 million years ago—as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis. However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm.
AU - Park, Kyunghyuk
AU - Kim, M. Yvonne
AU - Vickers, Martin
AU - Park, Jin-Sup
AU - Hyun, Youbong
AU - Okamoto, Takashi
AU - Zilberman, Daniel
AU - Fischer, Robert L.
AU - Feng, Xiaoqi
AU - Choi, Yeonhee
AU - Scholten, Stefan
ID - 9477
IS - 52
JF - Proceedings of the National Academy of Sciences
KW - Multidisciplinary
SN - 0027-8424
TI - DNA demethylation is initiated in the central cells of Arabidopsis and rice
VL - 113
ER -
TY - CONF
AB - Experience constantly shapes neural circuits through a variety of plasticity mechanisms. While the functional roles of some plasticity mechanisms are well-understood, it remains unclear how changes in neural excitability contribute to learning. Here, we develop a normative interpretation of intrinsic plasticity (IP) as a key component of unsupervised learning. We introduce a novel generative mixture model that accounts for the class-specific statistics of stimulus intensities, and we derive a neural circuit that learns the input classes and their intensities. We will analytically show that inference and learning for our generative model can be achieved by a neural circuit with intensity-sensitive neurons equipped with a specific form of IP. Numerical experiments verify our analytical derivations and show robust behavior for artificial and natural stimuli. Our results link IP to non-trivial input statistics, in particular the statistics of stimulus intensities for classes to which a neuron is sensitive. More generally, our work paves the way toward new classification algorithms that are robust to intensity variations.
AU - Monk, Travis
AU - Savin, Cristina
AU - Lücke, Jörg
ID - 948
TI - Neurons equipped with intrinsic plasticity learn stimulus intensity statistics
VL - 29
ER -
TY - GEN
AU - Roux, Camille
AU - Fraisse, Christelle
AU - Romiguier, Jonathan
AU - Anciaux, Youann
AU - Galtier, Nicolas
AU - Bierne, Nicolas
ID - 9862
TI - Simulation study to test the robustness of ABC in face of recent times of divergence
ER -
TY - GEN
AU - Roux, Camille
AU - Fraisse, Christelle
AU - Romiguier, Jonathan
AU - Anciaux, Youann
AU - Galtier, Nicolas
AU - Bierne, Nicolas
ID - 9863
TI - Accessions of surveyed individuals, geographic locations and summary statistics
ER -
TY - GEN
AU - Zagórski, Marcin P
AU - Burda, Zdzisław
AU - Wacław, Bartłomiej
ID - 9866
TI - ZIP-archived directory containing all data and computer programs
ER -
TY - GEN
AB - In the beginning of our experiment, subjects were asked to read a few pages on their computer screens that would explain the rules of the subsequent game. Here, we provide these instructions, translated from German.
AU - Hilbe, Christian
AU - Hagel, Kristin
AU - Milinski, Manfred
ID - 9867
TI - Experimental game instructions
ER -
TY - GEN
AB - The raw data file containing the experimental decisions of all our study subjects.
AU - Hilbe, Christian
AU - Hagel, Kristin
AU - Milinski, Manfred
ID - 9868
TI - Experimental data
ER -
TY - GEN
AB - A lower bound on the error of a positional estimator with limited positional information is derived.
AU - Hillenbrand, Patrick
AU - Gerland, Ulrich
AU - Tkačik, Gašper
ID - 9869
TI - Error bound on an estimator of position
ER -
TY - GEN
AB - The effect of noise in the input field on an Ising model is approximated. Furthermore, methods to compute positional information in an Ising model by transfer matrices and Monte Carlo sampling are outlined.
AU - Hillenbrand, Patrick
AU - Gerland, Ulrich
AU - Tkačik, Gašper
ID - 9870
TI - Computation of positional information in an Ising model
ER -
TY - GEN
AB - The positional information in a discrete morphogen field with Gaussian noise is computed.
AU - Hillenbrand, Patrick
AU - Gerland, Ulrich
AU - Tkačik, Gašper
ID - 9871
TI - Computation of positional information in a discrete morphogen field
ER -
TY - GEN
AU - Boehm, Alex
AU - Arnoldini, Markus
AU - Bergmiller, Tobias
AU - Röösli, Thomas
AU - Bigosch, Colette
AU - Ackermann, Martin
ID - 9873
TI - Quantification of the growth rate reduction as a consequence of age-specific mortality
ER -
TY - JOUR
AB - The inference of demographic history from genome data is hindered by a lack of efficient computational approaches. In particular, it has proved difficult to exploit the information contained in the distribution of genealogies across the genome. We have previously shown that the generating function (GF) of genealogies can be used to analytically compute likelihoods of demographic models from configurations of mutations in short sequence blocks (Lohse et al. 2011). Although the GF has a simple, recursive form, the size of such likelihood calculations explodes quickly with the number of individuals and applications of this framework have so far been mainly limited to small samples (pairs and triplets) for which the GF can be written by hand. Here we investigate several strategies for exploiting the inherent symmetries of the coalescent. In particular, we show that the GF of genealogies can be decomposed into a set of equivalence classes that allows likelihood calculations from nontrivial samples. Using this strategy, we automated blockwise likelihood calculations for a general set of demographic scenarios in Mathematica. These histories may involve population size changes, continuous migration, discrete divergence, and admixture between multiple populations. To give a concrete example, we calculate the likelihood for a model of isolation with migration (IM), assuming two diploid samples without phase and outgroup information. We demonstrate the new inference scheme with an analysis of two individual butterfly genomes from the sister species Heliconius melpomene rosina and H. cydno.
AU - Lohse, Konrad
AU - Chmelik, Martin
AU - Martin, Simon
AU - Barton, Nicholas H
ID - 1518
IS - 2
JF - Genetics
TI - Efficient strategies for calculating blockwise likelihoods under the coalescent
VL - 202
ER -
TY - JOUR
AB - Cytokinin is a phytohormone that is well known for its roles in numerous plant growth and developmental processes, yet it has also been linked to abiotic stress response in a less defined manner. Arabidopsis (Arabidopsis thaliana) Cytokinin Response Factor 6 (CRF6) is a cytokinin-responsive AP2/ERF-family transcription factor that, through the cytokinin signaling pathway, plays a key role in the inhibition of dark-induced senescence. CRF6 expression is also induced by oxidative stress, and here we show a novel function for CRF6 in relation to oxidative stress and identify downstream transcriptional targets of CRF6 that are repressed in response to oxidative stress. Analysis of transcriptomic changes in wild-type and crf6 mutant plants treated with H2O2 identified CRF6-dependent differentially expressed transcripts, many of which were repressed rather than induced. Moreover, many repressed genes also show decreased expression in 35S:CRF6 overexpressing plants. Together, these findings suggest that CRF6 functions largely as a transcriptional repressor. Interestingly, among the H2O2 repressed CRF6-dependent transcripts was a set of five genes associated with cytokinin processes: (signaling) ARR6, ARR9, ARR11, (biosynthesis) LOG7, and (transport) ABCG14. We have examined mutants of these cytokinin-associated target genes to reveal novel connections to oxidative stress. Further examination of CRF6-DNA interactions indicated that CRF6 may regulate its targets both directly and indirectly. Together, this shows that CRF6 functions during oxidative stress as a negative regulator to control this cytokinin-associated module of CRF6- dependent genes and establishes a novel connection between cytokinin and oxidative stress response.
AU - Zwack, Paul
AU - De Clercq, Inge
AU - Howton, Timothy
AU - Hallmark, H Tucker
AU - Hurny, Andrej
AU - Keshishian, Erika
AU - Parish, Alyssa
AU - Benková, Eva
AU - Mukhtar, M Shahid
AU - Van Breusegem, Frank
AU - Rashotte, Aaron
ID - 1331
IS - 2
JF - Plant Physiology
SN - 0032-0889
TI - Cytokinin response factor 6 represses cytokinin-associated genes during oxidative stress
VL - 172
ER -
TY - JOUR
AB - We study the homomorphism induced in homology by a closed correspondence between topological spaces, using projections from the graph of the correspondence to its domain and codomain. We provide assumptions under which the homomorphism induced by an outer approximation of a continuous map coincides with the homomorphism induced in homology by the map. In contrast to more classical results we do not require that the projection to the domain have acyclic preimages. Moreover, we show that it is possible to retrieve correct homological information from a correspondence even if some data is missing or perturbed. Finally, we describe an application to combinatorial maps that are either outer approximations of continuous maps or reconstructions of such maps from a finite set of data points.
AU - Harker, Shaun
AU - Kokubu, Hiroshi
AU - Mischaikow, Konstantin
AU - Pilarczyk, Pawel
ID - 1252
IS - 4
JF - Proceedings of the American Mathematical Society
SN - 1088-6826
TI - Inducing a map on homology from a correspondence
VL - 144
ER -
TY - JOUR
AB - Selection, mutation, and random drift affect the dynamics of allele frequencies and consequently of quantitative traits. While the macroscopic dynamics of quantitative traits can be measured, the underlying allele frequencies are typically unobserved. Can we understand how the macroscopic observables evolve without following these microscopic processes? This problem has been studied previously by analogy with statistical mechanics: the allele frequency distribution at each time point is approximated by the stationary form, which maximizes entropy. We explore the limitations of this method when mutation is small (4Nμ < 1) so that populations are typically close to fixation, and we extend the theory in this regime to account for changes in mutation strength. We consider a single diallelic locus either under directional selection or with overdominance and then generalize to multiple unlinked biallelic loci with unequal effects. We find that the maximum-entropy approximation is remarkably accurate, even when mutation and selection change rapidly.
AU - Bod'ová, Katarína
AU - Tkacik, Gasper
AU - Barton, Nicholas H
ID - 1420
IS - 4
JF - Genetics
TI - A general approximation for the dynamics of quantitative traits
VL - 202
ER -
TY - CONF
AB - Games on graphs provide the appropriate framework to study several central problems in computer science, such as verification and synthesis of reactive systems. One of the most basic objectives for games on graphs is the liveness (or Büchi) objective that given a target set of vertices requires that some vertex in the target set is visited infinitely often. We study generalized Büchi objectives (i.e., conjunction of liveness objectives), and implications between two generalized Büchi objectives (known as GR(1) objectives), that arise in numerous applications in computer-aided verification. We present improved algorithms and conditional super-linear lower bounds based on widely believed assumptions about the complexity of (A1) combinatorial Boolean matrix multiplication and (A2) CNF-SAT. We consider graph games with n vertices, m edges, and generalized Büchi objectives with k conjunctions. First, we present an algorithm with running time O(k*n^2), improving the previously known O(k*n*m) and O(k^2*n^2) worst-case bounds. Our algorithm is optimal for dense graphs under (A1). Second, we show that the basic algorithm for the problem is optimal for sparse graphs when the target sets have constant size under (A2). Finally, we consider GR(1) objectives, with k_1 conjunctions in the antecedent and k_2 conjunctions in the consequent, and present an O(k_1 k_2 n^{2.5})-time algorithm, improving the previously known O(k_1*k_2*n*m)-time algorithm for m > n^{1.5}.
AU - Chatterjee, Krishnendu
AU - Dvorák, Wolfgang
AU - Henzinger, Monika H
AU - Loitzenbauer, Veronika
ID - 1068
TI - Conditionally optimal algorithms for generalized Büchi Games
VL - 58
ER -
TY - JOUR
AB - Emerging infectious diseases (EIDs) have contributed significantly to the current biodiversity crisis, leading to widespread epidemics and population loss. Owing to genetic variation in pathogen virulence, a complete understanding of species decline requires the accurate identification and characterization of EIDs. We explore this issue in the Western honeybee, where increasing mortality of populations in the Northern Hemisphere has caused major concern. Specifically, we investigate the importance of genetic identity of the main suspect in mortality, deformed wing virus (DWV), in driving honeybee loss. Using laboratory experiments and a systematic field survey, we demonstrate that an emerging DWV genotype (DWV-B) is more virulent than the established DWV genotype (DWV-A) and is widespread in the landscape. Furthermore, we show in a simple model that colonies infected with DWV-B collapse sooner than colonies infected with DWV-A. We also identify potential for rapid DWV evolution by revealing extensive genome-wide recombination in vivo. The emergence of DWV-B in naive honeybee populations, including via recombination with DWV-A, could be of significant ecological and economic importance. Our findings emphasize that knowledge of pathogen genetic identity and diversity is critical to understanding drivers of species decline.
AU - Mcmahon, Dino
AU - Natsopoulou, Myrsini
AU - Doublet, Vincent
AU - Fürst, Matthias
AU - Weging, Silvio
AU - Brown, Mark
AU - Gogol Döring, Andreas
AU - Paxton, Robert
ID - 1262
IS - 1833
JF - Proceedings of the Royal Society of London Series B Biological Sciences
TI - Elevated virulence of an emerging viral genotype as a driver of honeybee loss
VL - 283
ER -
TY - GEN
AB - Emerging infectious diseases (EIDs) have contributed significantly to the current biodiversity crisis, leading to widespread epidemics and population loss. Owing to genetic variation in pathogen virulence, a complete understanding of species decline requires the accurate identification and characterization of EIDs. We explore this issue in the Western honeybee, where increasing mortality of populations in the Northern Hemisphere has caused major concern. Specifically, we investigate the importance of genetic identity of the main suspect in mortality, deformed wing virus (DWV), in driving honeybee loss. Using laboratory experiments and a systematic field survey, we demonstrate that an emerging DWV genotype (DWV-B) is more virulent than the established DWV genotype (DWV-A) and is widespread in the landscape. Furthermore, we show in a simple model that colonies infected with DWV-B collapse sooner than colonies infected with DWV-A. We also identify potential for rapid DWV evolution by revealing extensive genome-wide recombination in vivo. The emergence of DWV-B in naive honeybee populations, including via recombination with DWV-A, could be of significant ecological and economic importance. Our findings emphasize that knowledge of pathogen genetic identity and diversity is critical to understanding drivers of species decline.
AU - Mcmahon, Dino
AU - Natsopoulou, Myrsini
AU - Doublet, Vincent
AU - Fürst, Matthias
AU - Weging, Silvio
AU - Brown, Mark
AU - Gogol Döring, Andreas
AU - Paxton, Robert
ID - 9704
TI - Data from: Elevated virulence of an emerging viral genotype as a driver of honeybee loss
ER -
TY - JOUR
AB - Across the nervous system, certain population spiking patterns are observed far more frequently than others. A hypothesis about this structure is that these collective activity patterns function as population codewords–collective modes–carrying information distinct from that of any single cell. We investigate this phenomenon in recordings of ∼150 retinal ganglion cells, the retina’s output. We develop a novel statistical model that decomposes the population response into modes; it predicts the distribution of spiking activity in the ganglion cell population with high accuracy. We found that the modes represent localized features of the visual stimulus that are distinct from the features represented by single neurons. Modes form clusters of activity states that are readily discriminated from one another. When we repeated the same visual stimulus, we found that the same mode was robustly elicited. These results suggest that retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina.
AU - Prentice, Jason
AU - Marre, Olivier
AU - Ioffe, Mark
AU - Loback, Adrianna
AU - Tkacik, Gasper
AU - Berry, Michael
ID - 1197
IS - 11
JF - PLoS Computational Biology
TI - Error-robust modes of the retinal population code
VL - 12
ER -
TY - JOUR
AB - Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.
AU - Wielgoss, Sébastien
AU - Bergmiller, Tobias
AU - Bischofberger, Anna M.
AU - Hall, Alex R.
ID - 5749
IS - 3
JF - Molecular Biology and Evolution
SN - 0737-4038
TI - Adaptation to parasites and costs of parasite resistance in mutator and nonmutator bacteria
VL - 33
ER -
TY - GEN
AB - Summary: Declining populations of bee pollinators are a cause of concern, with major repercussions for biodiversity loss and food security. RNA viruses associated with honeybees represent a potential threat to other insect pollinators, but the extent of this threat is poorly understood. This study aims to attain a detailed understanding of the current and ongoing risk of emerging infectious disease (EID) transmission between managed and wild pollinator species across a wide range of RNA viruses. Within a structured large-scale national survey across 26 independent sites, we quantify the prevalence and pathogen loads of multiple RNA viruses in co-occurring managed honeybee (Apis mellifera) and wild bumblebee (Bombus spp.) populations. We then construct models that compare virus prevalence between wild and managed pollinators. Multiple RNA viruses associated with honeybees are widespread in sympatric wild bumblebee populations. Virus prevalence in honeybees is a significant predictor of virus prevalence in bumblebees, but we remain cautious in speculating over the principle direction of pathogen transmission. We demonstrate species-specific differences in prevalence, indicating significant variation in disease susceptibility or tolerance. Pathogen loads within individual bumblebees may be high and in the case of at least one RNA virus, prevalence is higher in wild bumblebees than in managed honeybee populations. Our findings indicate widespread transmission of RNA viruses between managed and wild bee pollinators, pointing to an interconnected network of potential disease pressures within and among pollinator species. In the context of the biodiversity crisis, our study emphasizes the importance of targeting a wide range of pathogens and defining host associations when considering potential drivers of population decline.
AU - Mcmahon, Dino
AU - Fürst, Matthias
AU - Caspar, Jesicca
AU - Theodorou, Panagiotis
AU - Brown, Mark
AU - Paxton, Robert
ID - 9720
TI - Data from: A sting in the spit: widespread cross-infection of multiple RNA viruses across wild and managed bees
ER -
TY - GEN
AB - Much of quantitative genetics is based on the ‘infinitesimal model’, under which selection has a negligible effect on the genetic variance. This is typically justified by assuming a very large number of loci with additive effects. However, it applies even when genes interact, provided that the number of loci is large enough that selection on each of them is weak relative to random drift. In the long term, directional selection will change allele frequencies, but even then, the effects of epistasis on the ultimate change in trait mean due to selection may be modest. Stabilising selection can maintain many traits close to their optima, even when the underlying alleles are weakly selected. However, the number of traits that can be optimised is apparently limited to ~4Ne by the ‘drift load’, and this is hard to reconcile with the apparent complexity of many organisms. Just as for the mutation load, this limit can be evaded by a particular form of negative epistasis. A more robust limit is set by the variance in reproductive success. This suggests that selection accumulates information most efficiently in the infinitesimal regime, when selection on individual alleles is weak, and comparable with random drift. A review of evidence on selection strength suggests that although most variance in fitness may be because of alleles with large Nes, substantial amounts of adaptation may be because of alleles in the infinitesimal regime, in which epistasis has modest effects.
AU - Barton, Nicholas H
ID - 9710
TI - Data from: How does epistasis influence the response to selection?
ER -
TY - JOUR
AU - Martin, Olivier
AU - Zagórski, Marcin P
ID - 1373
JF - Physics of Life Reviews
TI - Network architectures and operating principles. Reply to comments on "Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function"
VL - 17
ER -
TY - GEN
AB - Viral capsids are structurally constrained by interactions among the amino acids (AAs) of their constituent proteins. Therefore, epistasis is expected to evolve among physically interacting sites and to influence the rates of substitution. To study the evolution of epistasis, we focused on the major structural protein of the ϕX174 phage family by, first, reconstructing the ancestral protein sequences of 18 species using a Bayesian statistical framework. The inferred ancestral reconstruction differed at eight AAs, for a total of 256 possible ancestral haplotypes. For each ancestral haplotype and the extant species, we estimated, in silico, the distribution of free energies and epistasis of the capsid structure. We found that free energy has not significantly increased but epistasis has. We decomposed epistasis up to fifth order and found that higher-order epistasis sometimes compensates pairwise interactions making the free energy seem additive. The dN/dS ratio is low, suggesting strong purifying selection, and that structure is under stabilizing selection. We synthesized phages carrying ancestral haplotypes of the coat protein gene and measured their fitness experimentally. Our findings indicate that stabilizing mutations can have higher fitness, and that fitness optima do not necessarily coincide with energy minima.
AU - Fernandes Redondo, Rodrigo A
AU - de Vladar, Harold
AU - Włodarski, Tomasz
AU - Bollback, Jonathan P
ID - 9864
TI - Data from evolutionary interplay between structure, energy and epistasis in the coat protein of the ϕX174 phage family
ER -
TY - CONF
AB - We present a coherent microwave to telecom signal converter based on the electro-optical effect using a crystalline WGM-resonator coupled to a 3D microwave cavity, achieving high photon conversion efficiency of 0.1% with MHz bandwidth.
AU - Rueda, Alfredo
AU - Sedlmeir, Florian
AU - Collodo, Michele
AU - Vogl, Ulrich
AU - Stiller, Birgit
AU - Schunk, Georg
AU - Strekalov, Dimitry
AU - Marquardt, Christoph
AU - Fink, Johannes M
AU - Painter, Oskar
AU - Leuchs, Gerd
AU - Schwefel, Harald
ID - 1115
TI - Efficient single sideband microwave to optical conversion using a LiNbO₃ WGM-resonator
ER -
TY - CONF
AB - Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM.
AU - Chatterjee, Krishnendu
AU - Dvoák, Wolfgang
AU - Henzinger, Monika H
AU - Loitzenbauer, Veronika
ID - 1140
T2 - Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science
TI - Model and objective separation with conditional lower bounds: disjunction is harder than conjunction
ER -
TY - JOUR
AB - Most migrating cells extrude their front by the force of actin polymerization. Polymerization requires an initial nucleation step, which is mediated by factors establishing either parallel filaments in the case of filopodia or branched filaments that form the branched lamellipodial network. Branches are considered essential for regular cell motility and are initiated by the Arp2/3 complex, which in turn is activated by nucleation-promoting factors of the WASP and WAVE families. Here we employed rapid amoeboid crawling leukocytes and found that deletion of the WAVE complex eliminated actin branching and thus lamellipodia formation. The cells were left with parallel filaments at the leading edge, which translated, depending on the differentiation status of the cell, into a unipolar pointed cell shape or cells with multiple filopodia. Remarkably, unipolar cells migrated with increased speed and enormous directional persistence, while they were unable to turn towards chemotactic gradients. Cells with multiple filopodia retained chemotactic activity but their migration was progressively impaired with increasing geometrical complexity of the extracellular environment. These findings establish that diversified leading edge protrusions serve as explorative structures while they slow down actual locomotion.
AU - Leithner, Alexander F
AU - Eichner, Alexander
AU - Müller, Jan
AU - Reversat, Anne
AU - Brown, Markus
AU - Schwarz, Jan
AU - Merrin, Jack
AU - De Gorter, David
AU - Schur, Florian
AU - Bayerl, Jonathan
AU - De Vries, Ingrid
AU - Wieser, Stefan
AU - Hauschild, Robert
AU - Lai, Frank
AU - Moser, Markus
AU - Kerjaschki, Dontscho
AU - Rottner, Klemens
AU - Small, Victor
AU - Stradal, Theresia
AU - Sixt, Michael K
ID - 1321
JF - Nature Cell Biology
TI - Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes
VL - 18
ER -
TY - JOUR
AB - Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
AU - Tarlungeanu, Dora-Clara
AU - Deliu, Elena
AU - Dotter, Christoph
AU - Kara, Majdi
AU - Janiesch, Philipp
AU - Scalise, Mariafrancesca
AU - Galluccio, Michele
AU - Tesulov, Mateja
AU - Morelli, Emanuela
AU - Sönmez, Fatma
AU - Bilgüvar, Kaya
AU - Ohgaki, Ryuichi
AU - Kanai, Yoshikatsu
AU - Johansen, Anide
AU - Esharif, Seham
AU - Ben Omran, Tawfeg
AU - Topcu, Meral
AU - Schlessinger, Avner
AU - Indiveri, Cesare
AU - Duncan, Kent
AU - Caglayan, Ahmet
AU - Günel, Murat
AU - Gleeson, Joseph
AU - Novarino, Gaia
ID - 1183
IS - 6
JF - Cell
TI - Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder
VL - 167
ER -
TY - JOUR
AB - During metazoan development, the temporal pattern of morphogen signaling is critical for organizing cell fates in space and time. Yet, tools for temporally controlling morphogen signaling within the embryo are still scarce. Here, we developed a photoactivatable Nodal receptor to determine how the temporal pattern of Nodal signaling affects cell fate specification during zebrafish gastrulation. By using this receptor to manipulate the duration of Nodal signaling in vivo by light, we show that extended Nodal signaling within the organizer promotes prechordal plate specification and suppresses endoderm differentiation. Endoderm differentiation is suppressed by extended Nodal signaling inducing expression of the transcriptional repressor goosecoid (gsc) in prechordal plate progenitors, which in turn restrains Nodal signaling from upregulating the endoderm differentiation gene sox17 within these cells. Thus, optogenetic manipulation of Nodal signaling identifies a critical role of Nodal signaling duration for organizer cell fate specification during gastrulation.
AU - Sako, Keisuke
AU - Pradhan, Saurabh
AU - Barone, Vanessa
AU - Inglés Prieto, Álvaro
AU - Mueller, Patrick
AU - Ruprecht, Verena
AU - Capek, Daniel
AU - Galande, Sanjeev
AU - Janovjak, Harald L
AU - Heisenberg, Carl-Philipp J
ID - 1100
IS - 3
JF - Cell Reports
TI - Optogenetic control of nodal signaling reveals a temporal pattern of nodal signaling regulating cell fate specification during gastrulation
VL - 16
ER -
TY - CONF
AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural problems that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, a property satisfied by the controlflow graphs of most programs. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis. The study of multiple queries allows us to consider the tradeoff between the resource usage of the one-time preprocessing and for each individual query. The traditional approach constructs the product graph of all components and applies the best-known graph algorithm on the product. In this approach, even the answer to a single query requires the transitive closure (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results showing that the worst-case running time of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (i.e., improving the worst-case bound for the shortest path problem in general graphs). Preliminary experimental results show that our algorithms perform favorably on several benchmarks.
AU - Chatterjee, Krishnendu
AU - Goharshady, Amir
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
ID - 1437
TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components
VL - 20-22
ER -
TY - CONF
AB - We consider nondeterministic probabilistic programs with the most basic liveness property of termination. We present efficient methods for termination analysis of nondeterministic probabilistic programs with polynomial guards and assignments. Our approach is through synthesis of polynomial ranking supermartingales, that on one hand significantly generalizes linear ranking supermartingales and on the other hand is a counterpart of polynomial ranking-functions for proving termination of nonprobabilistic programs. The approach synthesizes polynomial ranking-supermartingales through Positivstellensatz's, yielding an efficient method which is not only sound, but also semi-complete over a large subclass of programs. We show experimental results to demonstrate that our approach can handle several classical programs with complex polynomial guards and assignments, and can synthesize efficient quadratic ranking-supermartingales when a linear one does not exist even for simple affine programs.
AU - Chatterjee, Krishnendu
AU - Fu, Hongfei
AU - Goharshady, Amir
ID - 1386
TI - Termination analysis of probabilistic programs through Positivstellensatz's
VL - 9779
ER -
TY - JOUR
AB - Glycoinositolphosphoceramides (GIPCs) are complex sphingolipids present at the plasma membrane of various eukaryotes with the important exception of mammals. In fungi, these glycosphingolipids commonly contain an alpha-mannose residue (Man) linked at position 2 of the inositol. However, several pathogenic fungi additionally synthesize zwitterionic GIPCs carrying an alpha-glucosamine residue (GlcN) at this position. In the human pathogen Aspergillus fumigatus, the GlcNalpha1,2IPC core (where IPC is inositolphosphoceramide) is elongated to Manalpha1,3Manalpha1,6GlcNalpha1,2IPC, which is the most abundant GIPC synthesized by this fungus. In this study, we identified an A. fumigatus N-acetylglucosaminyltransferase, named GntA, and demonstrate its involvement in the initiation of zwitterionic GIPC biosynthesis. Targeted deletion of the gene encoding GntA in A. fumigatus resulted in complete absence of zwitterionic GIPC; a phenotype that could be reverted by episomal expression of GntA in the mutant. The N-acetylhexosaminyltransferase activity of GntA was substantiated by production of N-acetylhexosamine-IPC in the yeast Saccharomyces cerevisiae upon GntA expression. Using an in vitro assay, GntA was furthermore shown to use UDP-N-acetylglucosamine as donor substrate to generate a glycolipid product resistant to saponification and to digestion by phosphatidylinositol-phospholipase C as expected for GlcNAcalpha1,2IPC. Finally, as the enzymes involved in mannosylation of IPC, GntA was localized to the Golgi apparatus, the site of IPC synthesis.
AU - Engel, Jakob
AU - Schmalhorst, Philipp S
AU - Kruger, Anke
AU - Muller, Christina
AU - Buettner, Falk
AU - Routier, Françoise
ID - 802
IS - 12
JF - Glycobiology
TI - Characterization of an N-acetylglucosaminyltransferase involved in Aspergillus fumigatus zwitterionic glycoinositolphosphoceramide biosynthesis
VL - 25
ER -
TY - JOUR
AB - We prove that nonlinear Gibbs measures can be obtained from the corresponding many-body, grand-canonical, quantum Gibbs states, in a mean-field limit where the temperature T diverges and the interaction strength behaves as 1/T. We proceed by characterizing the interacting Gibbs state as minimizing a functional counting the free-energy relatively to the non-interacting case. We then perform an infinite-dimensional analogue of phase-space semiclassical analysis, using fine properties of the quantum relative entropy, the link between quantum de Finetti measures and upper/lower symbols in a coherent state basis, as well as Berezin-Lieb type inequalities. Our results cover the measure built on the defocusing nonlinear Schrödinger functional on a finite interval, as well as smoother interactions in dimensions d 2.
AU - Lewin, Mathieu
AU - Phan Thanh, Nam
AU - Rougerie, Nicolas
ID - 473
JF - Journal de l'Ecole Polytechnique - Mathematiques
TI - Derivation of nonlinear gibbs measures from many-body quantum mechanics
VL - 2
ER -
TY - JOUR
AB - Dendritic cells are potent antigen-presenting cells endowed with the unique ability to initiate adaptive immune responses upon inflammation. Inflammatory processes are often associated with an increased production of serotonin, which operates by activating specific receptors. However, the functional role of serotonin receptors in regulation of dendritic cell functions is poorly understood. Here, we demonstrate that expression of serotonin receptor 5-HT7 (5-HT7TR) as well as its downstream effector Cdc42 is upregulated in dendritic cells upon maturation. Although dendritic cell maturation was independent of 5-HT7TR, receptor stimulation affected dendritic cell morphology through Cdc42-mediated signaling. In addition, basal activity of 5-HT7TR was required for the proper expression of the chemokine receptor CCR7, which is a key factor that controls dendritic cell migration. Consistent with this, we observed that 5-HT7TR enhances chemotactic motility of dendritic cells in vitro by modulating their directionality and migration velocity. Accordingly, migration of dendritic cells in murine colon explants was abolished after pharmacological receptor inhibition. Our results indicate that there is a crucial role for 5-HT7TR-Cdc42-mediated signaling in the regulation of dendritic cell morphology and motility, suggesting that 5-HT7TR could be a new target for treatment of a variety of inflammatory and immune disorders.
AU - Holst, Katrin
AU - Guseva, Daria
AU - Schindler, Susann
AU - Sixt, Michael K
AU - Braun, Armin
AU - Chopra, Himpriya
AU - Pabst, Oliver
AU - Ponimaskin, Evgeni
ID - 477
IS - 15
JF - Journal of Cell Science
TI - The serotonin receptor 5-HT7R regulates the morphology and migratory properties of dendritic cells
VL - 128
ER -
TY - JOUR
AB - We consider two-player games played on weighted directed graphs with mean-payoff and total-payoff objectives, two classical quantitative objectives. While for single-dimensional games the complexity and memory bounds for both objectives coincide, we show that in contrast to multi-dimensional mean-payoff games that are known to be coNP-complete, multi-dimensional total-payoff games are undecidable. We introduce conservative approximations of these objectives, where the payoff is considered over a local finite window sliding along a play, instead of the whole play. For single dimension, we show that (i) if the window size is polynomial, deciding the winner takes polynomial time, and (ii) the existence of a bounded window can be decided in NP ∩ coNP, and is at least as hard as solving mean-payoff games. For multiple dimensions, we show that (i) the problem with fixed window size is EXPTIME-complete, and (ii) there is no primitive-recursive algorithm to decide the existence of a bounded window.
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
AU - Randour, Mickael
AU - Raskin, Jean
ID - 523
IS - 6
JF - Information and Computation
TI - Looking at mean-payoff and total-payoff through windows
VL - 242
ER -
TY - JOUR
AB - We consider concurrent games played by two players on a finite-state graph, where in every round the players simultaneously choose a move, and the current state along with the joint moves determine the successor state. We study the most fundamental objective for concurrent games, namely, mean-payoff or limit-average objective, where a reward is associated to each transition, and the goal of player 1 is to maximize the long-run average of the rewards, and the objective of player 2 is strictly the opposite (i.e., the games are zero-sum). The path constraint for player 1 could be qualitative, i.e., the mean-payoff is the maximal reward, or arbitrarily close to it; or quantitative, i.e., a given threshold between the minimal and maximal reward. We consider the computation of the almost-sure (resp. positive) winning sets, where player 1 can ensure that the path constraint is satisfied with probability 1 (resp. positive probability). Almost-sure winning with qualitative constraint exactly corresponds to the question of whether there exists a strategy to ensure that the payoff is the maximal reward of the game. Our main results for qualitative path constraints are as follows: (1) we establish qualitative determinacy results that show that for every state either player 1 has a strategy to ensure almost-sure (resp. positive) winning against all player-2 strategies, or player 2 has a spoiling strategy to falsify almost-sure (resp. positive) winning against all player-1 strategies; (2) we present optimal strategy complexity results that precisely characterize the classes of strategies required for almost-sure and positive winning for both players; and (3) we present quadratic time algorithms to compute the almost-sure and the positive winning sets, matching the best known bound of the algorithms for much simpler problems (such as reachability objectives). For quantitative constraints we show that a polynomial time solution for the almost-sure or the positive winning set would imply a solution to a long-standing open problem (of solving the value problem of turn-based deterministic mean-payoff games) that is not known to be solvable in polynomial time.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
ID - 524
IS - 6
JF - Information and Computation
TI - Qualitative analysis of concurrent mean payoff games
VL - 242
ER -
TY - JOUR
AB - Ethylene is a gaseous phytohormone that plays vital roles in plant growth and development. Previous studies uncovered EIN2 as an essential signal transducer linking ethylene perception on ER to transcriptional regulation in the nucleus through a “cleave and shuttle” model. In this study, we report another mechanism of EIN2-mediated ethylene signaling, whereby EIN2 imposes the translational repression of EBF1 and EBF2 mRNA. We find that the EBF1/2 3′ UTRs mediate EIN2-directed translational repression and identify multiple poly-uridylates (PolyU) motifs as functional cis elements of 3′ UTRs. Furthermore, we demonstrate that ethylene induces EIN2 to associate with 3′ UTRs and target EBF1/2 mRNA to cytoplasmic processing-body (P-body) through interacting with multiple P-body factors, including EIN5 and PABs. Our study illustrates translational regulation as a key step in ethylene signaling and presents mRNA 3′ UTR functioning as a “signal transducer” to sense and relay cellular signaling in plants.
AU - Li, Wenyang
AU - Ma, Mengdi
AU - Feng, Ying
AU - Li, Hongjiang
AU - Wang, Yichuan
AU - Ma, Yutong
AU - Li, Mingzhe
AU - An, Fengying
AU - Guo, Hongwei
ID - 532
IS - 3
JF - Cell
TI - EIN2-directed translational regulation of ethylene signaling in arabidopsis
VL - 163
ER -
TY - GEN
AB - We consider Markov decision processes (MDPs) with multiple limit-average (or mean-payoff) objectives.
There have been two different views: (i) the expectation semantics, where the goal is to optimize the expected mean-payoff objective, and (ii) the satisfaction semantics, where the goal is to maximize the probability of runs such that the mean-payoff value stays above a given vector.
We consider the problem where the goal is to optimize the expectation under the constraint that the satisfaction semantics is ensured, and thus consider a generalization that unifies the existing semantics.
Our problem captures the notion of optimization with respect to strategies that are risk-averse (i.e., ensures certain probabilistic guarantee).
Our main results are algorithms for the decision problem which are always polynomial in the size of the MDP. We also show that an approximation of the Pareto-curve can be computed in time polynomial in the size of the MDP, and the approximation factor, but exponential in the number of dimensions.
Finally, we present a complete characterization of the strategy complexity (in terms of memory bounds and randomization) required to solve our problem.
AU - Chatterjee, Krishnendu
AU - Komarkova, Zuzana
AU - Kretinsky, Jan
ID - 5429
SN - 2664-1690
TI - Unifying two views on multiple mean-payoff objectives in Markov decision processes
ER -
TY - GEN
AB - We consider the core algorithmic problems related to verification of systems with respect to three classical quantitative properties, namely, the mean- payoff property, the ratio property, and the minimum initial credit for energy property. The algorithmic problem given a graph and a quantitative property asks to compute the optimal value (the infimum value over all traces) from every node of the graph. We consider graphs with constant treewidth, and it is well-known that the control-flow graphs of most programs have constant treewidth. Let n denote the number of nodes of a graph, m the number of edges (for constant treewidth graphs m = O ( n ) ) and W the largest absolute value of the weights. Our main theoretical results are as follows. First, for constant treewidth graphs we present an algorithm that approximates the mean-payoff value within a mul- tiplicative factor of ∊ in time O ( n · log( n/∊ )) and linear space, as compared to the classical algorithms that require quadratic time. Second, for the ratio property we present an algorithm that for constant treewidth graphs works in time O ( n · log( | a · b · n | )) = O ( n · log( n · W )) , when the output is a b , as compared to the previously best known algorithm with running time O ( n 2 · log( n · W )) . Third, for the minimum initial credit problem we show that (i) for general graphs the problem can be solved in O ( n 2 · m ) time and the associated decision problem can be solved in O ( n · m ) time, improving the previous known O ( n 3 · m · log( n · W )) and O ( n 2 · m ) bounds, respectively; and (ii) for constant treewidth graphs we present an algorithm that requires O ( n · log n ) time, improving the previous known O ( n 4 · log( n · W )) bound. We have implemented some of our algorithms and show that they present a significant speedup on standard benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
ID - 5430
SN - 2664-1690
TI - Faster algorithms for quantitative verification in constant treewidth graphs
ER -
TY - GEN
AB - We consider finite-state concurrent stochastic games, played by k>=2 players for an infinite number of rounds, where in every round, each player simultaneously and independently of the other players chooses an action, whereafter the successor state is determined by a probability distribution given by the current state and the chosen actions. We consider reachability objectives that given a target set of states require that some state in the target set is visited, and the dual safety objectives that given a target set require that only states in the target set are visited. We are interested in the complexity of stationary strategies measured by their patience, which is defined as the inverse of the smallest non-zero probability employed.
Our main results are as follows: We show that in two-player zero-sum concurrent stochastic games (with reachability objective for one player and the complementary safety objective for the other player): (i) the optimal bound on the patience of optimal and epsilon-optimal strategies, for both players is doubly exponential; and (ii) even in games with a single non-absorbing state exponential (in the number of actions) patience is necessary. In general we study the class of non-zero-sum games admitting epsilon-Nash equilibria. We show that if there is at least one player with reachability objective, then doubly-exponential patience is needed in general for epsilon-Nash equilibrium strategies, whereas in contrast if all players have safety objectives, then the optimal bound on patience for epsilon-Nash equilibrium strategies is only exponential.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Hansen, Kristoffer
ID - 5431
SN - 2664-1690
TI - The patience of concurrent stochastic games with safety and reachability objectives
ER -
TY - GEN
AB - Evolution occurs in populations of reproducing individuals. The structure of the population affects the outcome of the evolutionary process. Evolutionary graph theory is a powerful approach to study this phenomenon. There are two graphs. The interaction graph specifies who interacts with whom in the context of evolution.The replacement graph specifies who competes with whom for reproduction.
The vertices of the two graphs are the same, and each vertex corresponds to an individual of the population. A key quantity is the fixation probability of a new mutant. It is defined as the probability that a newly introduced mutant (on a single vertex) generates a lineage of offspring which eventually takes over the entire population of resident individuals. The basic computational questions are as follows: (i) the qualitative question asks whether the fixation probability is positive; and (ii) the quantitative approximation question asks for an approximation of the fixation probability.
Our main results are:
(1) We show that the qualitative question is NP-complete and the quantitative approximation question is #P-hard in the special case when the interaction and the replacement graphs coincide and even with the restriction that the resident individuals do not reproduce (which corresponds to an invading population taking over an empty structure).
(2) We show that in general the qualitative question is PSPACE-complete and the quantitative approximation question is PSPACE-hard and can be solved in exponential time.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Nowak, Martin
ID - 5432
SN - 2664-1690
TI - The complexity of evolutionary games on graphs
ER -
TY - GEN
AB - We consider Markov decision processes (MDPs) with multiple limit-average (or mean-payoff) objectives.
There have been two different views: (i) the expectation semantics, where the goal is to optimize the expected mean-payoff objective, and (ii) the satisfaction semantics, where the goal is to maximize the probability of runs such that the mean-payoff value stays above a given vector.
We consider the problem where the goal is to optimize the expectation under the constraint that the satisfaction semantics is ensured, and thus consider a generalization that unifies the existing semantics. Our problem captures the notion of optimization with respect to strategies that are risk-averse (i.e., ensures certain probabilistic guarantee).
Our main results are algorithms for the decision problem which are always polynomial in the size of the MDP.
We also show that an approximation of the Pareto-curve can be computed in time polynomial in the size of the MDP, and the approximation factor, but exponential in the number of dimensions. Finally, we present a complete characterization of the strategy complexity (in terms of memory bounds and randomization) required to solve our problem.
AU - Chatterjee, Krishnendu
AU - Komarkova, Zuzana
AU - Kretinsky, Jan
ID - 5435
SN - 2664-1690
TI - Unifying two views on multiple mean-payoff objectives in Markov decision processes
ER -
TY - GEN
AB - Recently there has been a significant effort to handle quantitative properties in formal verification and synthesis. While weighted automata over finite and infinite words provide a natural and flexible framework to express quantitative properties, perhaps surprisingly, some basic system properties such as average response time cannot be expressed using weighted automata, nor in any other know decidable formalism. In this work, we introduce nested weighted automata as a natural extension of weighted automata which makes it possible to express important quantitative properties such as average response time.
In nested weighted automata, a master automaton spins off and collects results from weighted slave automata, each of which computes a quantity along a finite portion of an infinite word. Nested weighted automata can be viewed as the quantitative analogue of monitor automata, which are used in run-time verification. We establish an almost complete decidability picture for the basic decision problems about nested weighted automata, and illustrate their applicability in several domains. In particular, nested weighted automata can be used to decide average response time properties.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Otop, Jan
ID - 5436
SN - 2664-1690
TI - Nested weighted automata
ER -
TY - GEN
AB - We consider the core algorithmic problems related to verification of systems with respect to three classical quantitative properties, namely, the mean-payoff property, the ratio property, and the minimum initial credit for energy property.
The algorithmic problem given a graph and a quantitative property asks to compute the optimal value (the infimum value over all traces) from every node of the graph. We consider graphs with constant treewidth, and it is well-known that the control-flow graphs of most programs have constant treewidth. Let $n$ denote the number of nodes of a graph, $m$ the number of edges (for constant treewidth graphs $m=O(n)$) and $W$ the largest absolute value of the weights.
Our main theoretical results are as follows.
First, for constant treewidth graphs we present an algorithm that approximates the mean-payoff value within a multiplicative factor of $\epsilon$ in time $O(n \cdot \log (n/\epsilon))$ and linear space, as compared to the classical algorithms that require quadratic time. Second, for the ratio property we present an algorithm that for constant treewidth graphs works in time $O(n \cdot \log (|a\cdot b|))=O(n\cdot\log (n\cdot W))$, when the output is $\frac{a}{b}$, as compared to the previously best known algorithm with running time $O(n^2 \cdot \log (n\cdot W))$. Third, for the minimum initial credit problem we show that (i)~for general graphs the problem can be solved in $O(n^2\cdot m)$ time and the associated decision problem can be solved in $O(n\cdot m)$ time, improving the previous known $O(n^3\cdot m\cdot \log (n\cdot W))$ and $O(n^2 \cdot m)$ bounds, respectively; and (ii)~for constant treewidth graphs we present an algorithm that requires $O(n\cdot \log n)$ time, improving the previous known $O(n^4 \cdot \log (n \cdot W))$ bound.
We have implemented some of our algorithms and show that they present a significant speedup on standard benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
ID - 5437
SN - 2664-1690
TI - Faster algorithms for quantitative verification in constant treewidth graphs
ER -
TY - GEN
AB - The edit distance between two words w1, w2 is the minimal number of word operations (letter insertions, deletions, and substitutions) necessary to transform w1 to w2. The edit distance generalizes to languages L1, L2, where the edit distance is the minimal number k such that for every word from L1 there exists a word in L2 with edit distance at most k. We study the edit distance computation problem between pushdown automata and their subclasses.
The problem of computing edit distance to a pushdown automaton is undecidable, and in practice, the interesting question is to compute the edit distance from a pushdown automaton (the implementation, a standard model for programs with recursion) to a regular language (the specification). In this work, we present a complete picture of decidability and complexity for deciding whether, for a given threshold k, the edit distance from a pushdown automaton to a finite automaton is at most k.
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Ibsen-Jensen, Rasmus
AU - Otop, Jan
ID - 5438
SN - 2664-1690
TI - Edit distance for pushdown automata
ER -
TY - GEN
AB - The target discounted-sum problem is the following: Given a rational discount factor 0 < λ < 1 and three rational values a, b, and t, does there exist a finite or an infinite sequence w ε(a, b)∗ or w ε(a, b)w, such that Σ|w| i=0 w(i)λi equals t? The problem turns out to relate to many fields of mathematics and computer science, and its decidability question is surprisingly hard to solve. We solve the finite version of the problem, and show the hardness of the infinite version, linking it to various areas and open problems in mathematics and computer science: β-expansions, discounted-sum automata, piecewise affine maps, and generalizations of the Cantor set. We provide some partial results to the infinite version, among which are solutions to its restriction to eventually-periodic sequences and to the cases that λ λ 1/2 or λ = 1/n, for every n ε N. We use our results for solving some open problems on discounted-sum automata, among which are the exact-value problem for nondeterministic automata over finite words and the universality and inclusion problems for functional automata.
AU - Boker, Udi
AU - Henzinger, Thomas A
AU - Otop, Jan
ID - 5439
SN - 2664-1690
TI - The target discounted-sum problem
ER -
TY - GEN
AB - Evolution occurs in populations of reproducing individuals. The structure of the population affects the outcome of the evolutionary process. Evolutionary graph theory is a powerful approach to study this phenomenon. There are two graphs. The interaction graph specifies who interacts with whom for payoff in the context of evolution. The replacement graph specifies who competes with whom for reproduction. The vertices of the two graphs are the same, and each vertex corresponds to an individual of the population. The fitness (or the reproductive rate) is a non-negative number, and depends on the payoff. A key quantity is the fixation probability of a new mutant. It is defined as the probability that a newly introduced mutant (on a single vertex) generates a lineage of offspring which eventually takes over the entire population of resident individuals. The basic computational questions are as follows: (i) the qualitative question asks whether the fixation probability is positive; and (ii) the quantitative approximation question asks for an approximation of the fixation probability. Our main results are as follows: First, we consider a special case of the general problem, where the residents do not reproduce. We show that the qualitative question is NP-complete, and the quantitative approximation question is #P-complete, and the hardness results hold even in the special case where the interaction and the replacement graphs coincide. Second, we show that in general both the qualitative and the quantitative approximation questions are PSPACE-complete. The PSPACE-hardness result for quantitative approximation holds even when the fitness is always positive.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Nowak, Martin
ID - 5440
SN - 2664-1690
TI - The complexity of evolutionary games on graphs
ER -
TY - GEN
AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural problems that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, a property satisfied by the controlflow graphs of most programs. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis. The study of multiple queries allows us to consider the tradeoff between the resource usage of the one-time preprocessing and for each individual query. The traditional approach constructs the product graph of all components and applies the best-known graph algorithm on the product. In this approach, even the answer to a single query requires the transitive closure (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results showing that the worst-case running time of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (i.e., improving the worst-case bound for the shortest path problem in general graphs). Preliminary experimental results show that our algorithms perform favorably on several benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Goharshady, Amir
AU - Pavlogiannis, Andreas
ID - 5441
SN - 2664-1690
TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components
ER -
TY - GEN
AB - POMDPs are standard models for probabilistic planning problems, where an agent interacts with an uncertain environment. We study the problem of almost-sure reachability, where given a set of target states, the question is to decide whether there is a policy to ensure that the target set is reached with probability 1 (almost-surely). While in general the problem is EXPTIME-complete, in many practical cases policies with a small amount of memory suffice. Moreover, the existing solution to the problem is explicit, which first requires to construct explicitly an exponential reduction to a belief-support MDP. In this work, we first study the existence of observation-stationary strategies, which is NP-complete, and then small-memory strategies. We present a symbolic algorithm by an efficient encoding to SAT and using a SAT solver for the problem. We report experimental results demonstrating the scalability of our symbolic (SAT-based) approach.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Davies, Jessica
ID - 5443
SN - 2664-1690
TI - A symbolic SAT-based algorithm for almost-sure reachability with small strategies in POMDPs
ER -
TY - GEN
AB - A comprehensive understanding of the clonal evolution of cancer is critical for understanding neoplasia. Genome-wide sequencing data enables evolutionary studies at unprecedented depth. However, classical phylogenetic methods often struggle with noisy sequencing data of impure DNA samples and fail to detect subclones that have different evolutionary trajectories. We have developed a tool, called Treeomics, that allows us to reconstruct the phylogeny of a cancer with commonly available sequencing technologies. Using Bayesian inference and Integer Linear Programming, robust phylogenies consistent with the biological processes underlying cancer evolution were obtained for pancreatic, ovarian, and prostate cancers. Furthermore, Treeomics correctly identified sequencing artifacts such as those resulting from low statistical power; nearly 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumor heterogeneity among distinct samples. Importantly, we show that the evolutionary trees generated with Treeomics are mathematically optimal.
AU - Reiter, Johannes
AU - Makohon-Moore, Alvin
AU - Gerold, Jeffrey
AU - Bozic, Ivana
AU - Chatterjee, Krishnendu
AU - Iacobuzio-Donahue, Christine
AU - Vogelstein, Bert
AU - Nowak, Martin
ID - 5444
SN - 2664-1690
TI - Reconstructing robust phylogenies of metastatic cancers
ER -
TY - DATA
AB - This repository contains the experimental part of the CAV 2015 publication Counterexample Explanation by Learning Small Strategies in Markov Decision Processes.
We extended the probabilistic model checker PRISM to represent strategies of Markov Decision Processes as Decision Trees.
The archive contains a java executable version of the extended tool (prism_dectree.jar) together with a few examples of the PRISM benchmark library.
To execute the program, please have a look at the README.txt, which provides instructions and further information on the archive.
The archive contains scripts that (if run often enough) reproduces the data presented in the publication.
AU - Fellner, Andreas
ID - 5549
KW - Markov Decision Process
KW - Decision Tree
KW - Probabilistic Verification
KW - Counterexample Explanation
TI - Experimental part of CAV 2015 publication: Counterexample Explanation by Learning Small Strategies in Markov Decision Processes
ER -
TY - JOUR
AB - Mathematical models are of fundamental importance in the understanding of complex population dynamics. For instance, they can be used to predict the population evolution starting from different initial conditions or to test how a system responds to external perturbations. For this analysis to be meaningful in real applications, however, it is of paramount importance to choose an appropriate model structure and to infer the model parameters from measured data. While many parameter inference methods are available for models based on deterministic ordinary differential equations, the same does not hold for more detailed individual-based models. Here we consider, in particular, stochastic models in which the time evolution of the species abundances is described by a continuous-time Markov chain. These models are governed by a master equation that is typically difficult to solve. Consequently, traditional inference methods that rely on iterative evaluation of parameter likelihoods are computationally intractable. The aim of this paper is to present recent advances in parameter inference for continuous-time Markov chain models, based on a moment closure approximation of the parameter likelihood, and to investigate how these results can help in understanding, and ultimately controlling, complex systems in ecology. Specifically, we illustrate through an agricultural pest case study how parameters of a stochastic individual-based model can be identified from measured data and how the resulting model can be used to solve an optimal control problem in a stochastic setting. In particular, we show how the matter of determining the optimal combination of two different pest control methods can be formulated as a chance constrained optimization problem where the control action is modeled as a state reset, leading to a hybrid system formulation.
AU - Parise, Francesca
AU - Lygeros, John
AU - Ruess, Jakob
ID - 10794
JF - Frontiers in Environmental Science
KW - General Environmental Science
SN - 2296-665X
TI - Bayesian inference for stochastic individual-based models of ecological systems: a pest control simulation study
VL - 3
ER -
TY - CONF
AB - We consider concurrent mean-payoff games, a very well-studied class of two-player (player 1 vs player 2) zero-sum games on finite-state graphs where every transition is assigned a reward between 0 and 1, and the payoff function is the long-run average of the rewards. The value is the maximal expected payoff that player 1 can guarantee against all strategies of player 2. We consider the computation of the set of states with value 1 under finite-memory strategies for player 1, and our main results for the problem are as follows: (1) we present a polynomial-time algorithm; (2) we show that whenever there is a finite-memory strategy, there is a stationary strategy that does not need memory at all; and (3) we present an optimal bound (which is double exponential) on the patience of stationary strategies (where patience of a distribution is the inverse of the smallest positive probability and represents a complexity measure of a stationary strategy).
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
ID - 10796
IS - 1
SN - 978-161197374-7
T2 - Proceedings of the Twenty-Sixth Annual ACM-SIAM Symposium on Discrete Algorithms
TI - The value 1 problem under finite-memory strategies for concurrent mean-payoff games
VL - 2015
ER -
TY - JOUR
AB - This paper addresses the problem of semantic segmentation, where the possible class labels are from a predefined set. We exploit top-down guidance, i.e., the coarse localization of the objects and their class labels provided by object detectors. For each detected bounding box, figure-ground segmentation is performed and the final result is achieved by merging the figure-ground segmentations. The main idea of the proposed approach, which is presented in our preliminary work, is to reformulate the figure-ground segmentation problem as sparse reconstruction pursuing the object mask in a nonparametric manner. The latent segmentation mask should be coherent subject to sparse error caused by intra-category diversity; thus, the object mask is inferred by making use of sparse representations over the training set. To handle local spatial deformations, local patch-level masks are also considered and inferred by sparse representations over the spatially nearby patches. The sparse reconstruction coefficients and the latent mask are alternately optimized by applying the Lasso algorithm and the accelerated proximal gradient method. The proposed formulation results in a convex optimization problem; thus, the global optimal solution is achieved. In this paper, we provide theoretical analysis of the convergence and optimality. We also give an extended numerical analysis of the proposed algorithm and a comprehensive comparison with the related semantic segmentation methods on the challenging PASCAL visual object class object segmentation datasets and the Weizmann horse dataset. The experimental results demonstrate that the proposed algorithm achieves a competitive performance when compared with the state of the arts.
AU - Xia, Wei
AU - Domokos, Csaba
AU - Xiong, Junjun
AU - Cheong, Loongfah
AU - Yan, Shuicheng
ID - 1533
IS - 8
JF - IEEE Transactions on Circuits and Systems for Video Technology
TI - Segmentation over detection via optimal sparse reconstructions
VL - 25
ER -
TY - JOUR
AB - PIN proteins are auxin export carriers that direct intercellular auxin flow and in turn regulate many aspects of plant growth and development including responses to environmental changes. The Arabidopsis R2R3-MYB transcription factor FOUR LIPS (FLP) and its paralogue MYB88 regulate terminal divisions during stomatal development, as well as female reproductive development and stress responses. Here we show that FLP and MYB88 act redundantly but differentially in regulating the transcription of PIN3 and PIN7 in gravity-sensing cells of primary and lateral roots. On the one hand, FLP is involved in responses to gravity stimulation in primary roots, whereas on the other, FLP and MYB88 function complementarily in establishing the gravitropic set-point angles of lateral roots. Our results support a model in which FLP and MYB88 expression specifically determines the temporal-spatial patterns of PIN3 and PIN7 transcription that are closely associated with their preferential functions during root responses to gravity.
AU - Wang, Hongzhe
AU - Yang, Kezhen
AU - Zou, Junjie
AU - Zhu, Lingling
AU - Xie, Zidian
AU - Morita, Miyoterao
AU - Tasaka, Masao
AU - Friml, Jirí
AU - Grotewold, Erich
AU - Beeckman, Tom
AU - Vanneste, Steffen
AU - Sack, Fred
AU - Le, Jie
ID - 1534
JF - Nature Communications
TI - Transcriptional regulation of PIN genes by FOUR LIPS and MYB88 during Arabidopsis root gravitropism
VL - 6
ER -
TY - JOUR
AB - Neuronal and neuroendocrine L-type calcium channels (Cav1.2, Cav1.3) open readily at relatively low membrane potentials and allow Ca2+ to enter the cells near resting potentials. In this way, Cav1.2 and Cav1.3 shape the action potential waveform, contribute to gene expression, synaptic plasticity, neuronal differentiation, hormone secretion and pacemaker activity. In the chromaffin cells (CCs) of the adrenal medulla, Cav1.3 is highly expressed and is shown to support most of the pacemaking current that sustains action potential (AP) firings and part of the catecholamine secretion. Cav1.3 forms Ca2+-nanodomains with the fast inactivating BK channels and drives the resting SK currents. These latter set the inter-spike interval duration between consecutive spikes during spontaneous firing and the rate of spike adaptation during sustained depolarizations. Cav1.3 plays also a primary role in the switch from “tonic” to “burst” firing that occurs in mouse CCs when either the availability of voltage-gated Na channels (Nav) is reduced or the β2 subunit featuring the fast inactivating BK channels is deleted. Here, we discuss the functional role of these “neuronlike” firing modes in CCs and how Cav1.3 contributes to them. The open issue is to understand how these novel firing patterns are adapted to regulate the quantity of circulating catecholamines during resting condition or in response to acute and chronic stress.
AU - Vandael, David H
AU - Marcantoni, Andrea
AU - Carbone, Emilio
ID - 1535
IS - 2
JF - Current Molecular Pharmacology
TI - Cav1.3 channels as key regulators of neuron-like firings and catecholamine release in chromaffin cells
VL - 8
ER -
TY - JOUR
AB - Strigolactones, first discovered as germination stimulants for parasitic weeds [1], are carotenoid-derived phytohormones that play major roles in inhibiting lateral bud outgrowth and promoting plant-mycorrhizal symbiosis [2-4]. Furthermore, strigolactones are involved in the regulation of lateral and adventitious root development, root cell division [5, 6], secondary growth [7], and leaf senescence [8]. Recently, we discovered the strigolactone transporter Petunia axillaris PLEIOTROPIC DRUG RESISTANCE 1 (PaPDR1), which is required for efficient mycorrhizal colonization and inhibition of lateral bud outgrowth [9]. However, how strigolactones are transported through the plant remained unknown. Here we show that PaPDR1 exhibits a cell-type-specific asymmetric localization in different root tissues. In root tips, PaPDR1 is co-expressed with the strigolactone biosynthetic gene DAD1 (CCD8), and it is localized at the apical membrane of root hypodermal cells, presumably mediating the shootward transport of strigolactone. Above the root tip, in the hypodermal passage cells that form gates for the entry of mycorrhizal fungi, PaPDR1 is present in the outer-lateral membrane, compatible with its postulated function as strigolactone exporter from root to soil. Transport studies are in line with our localization studies since (1) a papdr1 mutant displays impaired transport of strigolactones out of the root tip to the shoot as well as into the rhizosphere and (2) DAD1 expression and PIN1/PIN2 levels change in plants deregulated for PDR1 expression, suggestive of variations in endogenous strigolactone contents. In conclusion, our results indicate that the polar localizations of PaPDR1 mediate directional shootward strigolactone transport as well as localized exudation into the soil.
AU - Sasse, Joëlle
AU - Simon, Sibu
AU - Gübeli, Christian
AU - Liu, Guowei
AU - Cheng, Xi
AU - Friml, Jirí
AU - Bouwmeester, Harro
AU - Martinoia, Enrico
AU - Borghi, Lorenzo
ID - 1536
IS - 5
JF - Current Biology
TI - Asymmetric localizations of the ABC transporter PaPDR1 trace paths of directional strigolactone transport
VL - 25
ER -
TY - JOUR
AB - 3D amoeboid cell migration is central to many developmental and disease-related processes such as cancer metastasis. Here, we identify a unique prototypic amoeboid cell migration mode in early zebrafish embryos, termed stable-bleb migration. Stable-bleb cells display an invariant polarized balloon-like shape with exceptional migration speed and persistence. Progenitor cells can be reversibly transformed into stable-bleb cells irrespective of their primary fate and motile characteristics by increasing myosin II activity through biochemical or mechanical stimuli. Using a combination of theory and experiments, we show that, in stable-bleb cells, cortical contractility fluctuations trigger a stochastic switch into amoeboid motility, and a positive feedback between cortical flows and gradients in contractility maintains stable-bleb cell polarization. We further show that rearward cortical flows drive stable-bleb cell migration in various adhesive and non-adhesive environments, unraveling a highly versatile amoeboid migration phenotype.
AU - Ruprecht, Verena
AU - Wieser, Stefan
AU - Callan Jones, Andrew
AU - Smutny, Michael
AU - Morita, Hitoshi
AU - Sako, Keisuke
AU - Barone, Vanessa
AU - Ritsch Marte, Monika
AU - Sixt, Michael K
AU - Voituriez, Raphaël
AU - Heisenberg, Carl-Philipp J
ID - 1537
IS - 4
JF - Cell
TI - Cortical contractility triggers a stochastic switch to fast amoeboid cell motility
VL - 160
ER -
TY - JOUR
AB - Systems biology rests on the idea that biological complexity can be better unraveled through the interplay of modeling and experimentation. However, the success of this approach depends critically on the informativeness of the chosen experiments, which is usually unknown a priori. Here, we propose a systematic scheme based on iterations of optimal experiment design, flow cytometry experiments, and Bayesian parameter inference to guide the discovery process in the case of stochastic biochemical reaction networks. To illustrate the benefit of our methodology, we apply it to the characterization of an engineered light-inducible gene expression circuit in yeast and compare the performance of the resulting model with models identified from nonoptimal experiments. In particular, we compare the parameter posterior distributions and the precision to which the outcome of future experiments can be predicted. Moreover, we illustrate how the identified stochastic model can be used to determine light induction patterns that make either the average amount of protein or the variability in a population of cells follow a desired profile. Our results show that optimal experiment design allows one to derive models that are accurate enough to precisely predict and regulate the protein expression in heterogeneous cell populations over extended periods of time.
AU - Ruess, Jakob
AU - Parise, Francesca
AU - Milias Argeitis, Andreas
AU - Khammash, Mustafa
AU - Lygeros, John
ID - 1538
IS - 26
JF - PNAS
TI - Iterative experiment design guides the characterization of a light-inducible gene expression circuit
VL - 112
ER -
TY - JOUR
AB - Many stochastic models of biochemical reaction networks contain some chemical species for which the number of molecules that are present in the system can only be finite (for instance due to conservation laws), but also other species that can be present in arbitrarily large amounts. The prime example of such networks are models of gene expression, which typically contain a small and finite number of possible states for the promoter but an infinite number of possible states for the amount of mRNA and protein. One of the main approaches to analyze such models is through the use of equations for the time evolution of moments of the chemical species. Recently, a new approach based on conditional moments of the species with infinite state space given all the different possible states of the finite species has been proposed. It was argued that this approach allows one to capture more details about the full underlying probability distribution with a smaller number of equations. Here, I show that the result that less moments provide more information can only stem from an unnecessarily complicated description of the system in the classical formulation. The foundation of this argument will be the derivation of moment equations that describe the complete probability distribution over the finite state space but only low-order moments over the infinite state space. I will show that the number of equations that is needed is always less than what was previously claimed and always less than the number of conditional moment equations up to the same order. To support these arguments, a symbolic algorithm is provided that can be used to derive minimal systems of unconditional moment equations for models with partially finite state space.
AU - Ruess, Jakob
ID - 1539
IS - 24
JF - Journal of Chemical Physics
TI - Minimal moment equations for stochastic models of biochemical reaction networks with partially finite state space
VL - 143
ER -
TY - JOUR
AB - Plant sexual reproduction involves highly structured and specialized organs: stamens (male) and gynoecia (female, containing ovules). These organs synchronously develop within protective flower buds, until anthesis, via tightly coordinated mechanisms that are essential for effective fertilization and production of viable seeds. The phytohormone auxin is one of the key endogenous signalling molecules controlling initiation and development of these, and other, plant organs. In particular, its uneven distribution, resulting from tightly controlled production, metabolism and directional transport, is an important morphogenic factor. In this review we discuss how developmentally controlled and localized auxin biosynthesis and transport contribute to the coordinated development of plants' reproductive organs, and their fertilized derivatives (embryos) via the regulation of auxin levels and distribution within and around them. Current understanding of the links between de novo local auxin biosynthesis, auxin transport and/or signalling is presented to highlight the importance of the non-cell autonomous action of auxin production on development and morphogenesis of reproductive organs and embryos. An overview of transcription factor families, which spatiotemporally define local auxin production by controlling key auxin biosynthetic enzymes, is also presented.
AU - Robert, Hélène
AU - Crhák Khaitová, Lucie
AU - Mroue, Souad
AU - Benková, Eva
ID - 1540
IS - 16
JF - Journal of Experimental Botany
TI - The importance of localized auxin production for morphogenesis of reproductive organs and embryos in Arabidopsis
VL - 66
ER -
TY - CONF
AB - We present XSpeed a parallel state-space exploration algorithm for continuous systems with linear dynamics and nondeterministic inputs. The motivation of having parallel algorithms is to exploit the computational power of multi-core processors to speed-up performance. The parallelization is achieved on two fronts. First, we propose a parallel implementation of the support function algorithm by sampling functions in parallel. Second, we propose a parallel state-space exploration by slicing the time horizon and computing the reachable states in the time slices in parallel. The second method can be however applied only to a class of linear systems with invertible dynamics and fixed input. A GP-GPU implementation is also presented following a lazy evaluation strategy on support functions. The parallel algorithms are implemented in the tool XSpeed. We evaluated the performance on two benchmarks including an 28 dimension Helicopter model. Comparison with the sequential counterpart shows a maximum speed-up of almost 7× on a 6 core, 12 thread Intel Xeon CPU E5-2420 processor. Our GP-GPU implementation shows a maximum speed-up of 12× over the sequential implementation and 53× over SpaceEx (LGG scenario), the state of the art tool for reachability analysis of linear hybrid systems. Experiments illustrate that our parallel algorithm with time slicing not only speeds-up performance but also improves precision.
AU - Ray, Rajarshi
AU - Gurung, Amit
AU - Das, Binayak
AU - Bartocci, Ezio
AU - Bogomolov, Sergiy
AU - Grosu, Radu
ID - 1541
TI - XSpeed: Accelerating reachability analysis on multi-core processors
VL - 9434
ER -
TY - JOUR
AB - The theory of population genetics and evolutionary computation have been evolving separately for nearly 30 years. Many results have been independently obtained in both fields and many others are unique to its respective field. We aim to bridge this gap by developing a unifying framework for evolutionary processes that allows both evolutionary algorithms and population genetics models to be cast in the same formal framework. The framework we present here decomposes the evolutionary process into its several components in order to facilitate the identification of similarities between different models. In particular, we propose a classification of evolutionary operators based on the defining properties of the different components. We cast several commonly used operators from both fields into this common framework. Using this, we map different evolutionary and genetic algorithms to different evolutionary regimes and identify candidates with the most potential for the translation of results between the fields. This provides a unified description of evolutionary processes and represents a stepping stone towards new tools and results to both fields.
AU - Paixao, Tiago
AU - Badkobeh, Golnaz
AU - Barton, Nicholas H
AU - Çörüş, Doğan
AU - Dang, Duccuong
AU - Friedrich, Tobias
AU - Lehre, Per
AU - Sudholt, Dirk
AU - Sutton, Andrew
AU - Trubenova, Barbora
ID - 1542
JF - Journal of Theoretical Biology
TI - Toward a unifying framework for evolutionary processes
VL - 383
ER -
TY - JOUR
AB - A plethora of diverse programmed cell death (PCD) processes has been described in living organisms. In animals and plants, different forms of PCD play crucial roles in development, immunity, and responses to the environment. While the molecular control of some animal PCD forms such as apoptosis is known in great detail, we still know comparatively little about the regulation of the diverse types of plant PCD. In part, this deficiency in molecular understanding is caused by the lack of reliable reporters to detect PCD processes. Here, we addressed this issue by using a combination of bioinformatics approaches to identify commonly regulated genes during diverse plant PCD processes in Arabidopsis (Arabidopsis thaliana). Our results indicate that the transcriptional signatures of developmentally controlled cell death are largely distinct from the ones associated with environmentally induced cell death. Moreover, different cases of developmental PCD share a set of cell death-associated genes. Most of these genes are evolutionary conserved within the green plant lineage, arguing for an evolutionary conserved core machinery of developmental PCD. Based on this information, we established an array of specific promoter-reporter lines for developmental PCD in Arabidopsis. These PCD indicators represent a powerful resource that can be used in addition to established morphological and biochemical methods to detect and analyze PCD processes in vivo and in planta.
AU - Olvera Carrillo, Yadira
AU - Van Bel, Michiel
AU - Van Hautegem, Tom
AU - Fendrych, Matyas
AU - Huysmans, Marlies
AU - Šimášková, Mária
AU - Van Durme, Matthias
AU - Buscaill, Pierre
AU - Rivas, Susana
AU - Coll, Núria
AU - Coppens, Frederik
AU - Maere, Steven
AU - Nowack, Moritz
ID - 1543
IS - 4
JF - Plant Physiology
TI - A conserved core of programmed cell death indicator genes discriminates developmentally and environmentally induced programmed cell death in plants
VL - 169
ER -
TY - CHAP
AB - Cell division in prokaryotes and eukaryotes is commonly initiated by the well-controlled binding of proteins to the cytoplasmic side of the cell membrane. However, a precise characterization of the spatiotemporal dynamics of membrane-bound proteins is often difficult to achieve in vivo. Here, we present protocols for the use of supported lipid bilayers to rebuild the cytokinetic machineries of cells with greatly different dimensions: the bacterium Escherichia coli and eggs of the vertebrate Xenopus laevis. Combined with total internal reflection fluorescence microscopy, these experimental setups allow for precise quantitative analyses of membrane-bound proteins. The protocols described to obtain glass-supported membranes from bacterial and vertebrate lipids can be used as starting points for other reconstitution experiments. We believe that similar biochemical assays will be instrumental to study the biochemistry and biophysics underlying a variety of complex cellular tasks, such as signaling, vesicle trafficking, and cell motility.
AU - Nguyen, Phuong
AU - Field, Christine
AU - Groen, Aaron
AU - Mitchison, Timothy
AU - Loose, Martin
ID - 1544
T2 - Building a Cell from its Components Parts
TI - Using supported bilayers to study the spatiotemporal organization of membrane-bound proteins
VL - 128
ER -
TY - JOUR
AB - Synaptic efficacy and precision are influenced by the coupling of voltage-gated Ca2+ channels (VGCCs) to vesicles. But because the topography of VGCCs and their proximity to vesicles is unknown, a quantitative understanding of the determinants of vesicular release at nanometer scale is lacking. To investigate this, we combined freeze-fracture replica immunogold labeling of Cav2.1 channels, local [Ca2+] imaging, and patch pipette perfusion of EGTA at the calyx of Held. Between postnatal day 7 and 21, VGCCs formed variable sized clusters and vesicular release became less sensitive to EGTA, whereas fixed Ca2+ buffer properties remained constant. Experimentally constrained reaction-diffusion simulations suggest that Ca2+ sensors for vesicular release are located at the perimeter of VGCC clusters (<30nm) and predict that VGCC number per cluster determines vesicular release probability without altering release time course. This "perimeter release model" provides a unifying framework accounting for developmental changes in both synaptic efficacy and time course.
AU - Nakamura, Yukihiro
AU - Harada, Harumi
AU - Kamasawa, Naomi
AU - Matsui, Ko
AU - Rothman, Jason
AU - Shigemoto, Ryuichi
AU - Silver, R Angus
AU - Digregorio, David
AU - Takahashi, Tomoyuki
ID - 1546
IS - 1
JF - Neuron
TI - Nanoscale distribution of presynaptic Ca2+ channels and its impact on vesicular release during development
VL - 85
ER -
TY - JOUR
AB - Let G be a graph on the vertex set V(G) = {x1,…,xn} with the edge set E(G), and let R = K[x1,…, xn] be the polynomial ring over a field K. Two monomial ideals are associated to G, the edge ideal I(G) generated by all monomials xixj with {xi,xj} ∈ E(G), and the vertex cover ideal IG generated by monomials ∏xi∈Cxi for all minimal vertex covers C of G. A minimal vertex cover of G is a subset C ⊂ V(G) such that each edge has at least one vertex in C and no proper subset of C has the same property. Indeed, the vertex cover ideal of G is the Alexander dual of the edge ideal of G. In this paper, for an unmixed bipartite graph G we consider the lattice of vertex covers LG and we explicitly describe the minimal free resolution of the ideal associated to LG which is exactly the vertex cover ideal of G. Then we compute depth, projective dimension, regularity and extremal Betti numbers of R/I(G) in terms of the associated lattice.
AU - Mohammadi, Fatemeh
AU - Moradi, Somayeh
ID - 1547
IS - 3
JF - Bulletin of the Korean Mathematical Society
TI - Resolution of unmixed bipartite graphs
VL - 52
ER -
TY - JOUR
AB - Reproduction within a host and transmission to the next host are crucial for the virulence and fitness of pathogens. Nevertheless, basic knowledge about such parameters is often missing from the literature, even for well-studied bacteria, such as Bacillus thuringiensis, an endospore-forming insect pathogen, which infects its hosts via the oral route. To characterize bacterial replication success, we made use of an experimental oral infection system for the red flour beetle Tribolium castaneum and developed a flow cytometric assay for the quantification of both spore ingestion by the individual beetle larvae and the resulting spore load after bacterial replication and resporulation within cadavers. On average, spore numbers increased 460-fold, showing that Bacillus thuringiensis grows and replicates successfully in insect cadavers. By inoculating cadaver-derived spores and spores from bacterial stock cultures into nutrient medium, we next investigated outgrowth characteristics of vegetative cells and found that cadaver- derived bacteria showed reduced growth compared to bacteria from the stock cultures. Interestingly, this reduced growth was a consequence of inhibited spore germination, probably originating from the host and resulting in reduced host mortality in subsequent infections by cadaver-derived spores. Nevertheless, we further showed that Bacillus thuringiensis transmission was possible via larval cannibalism when no other food was offered. These results contribute to our understanding of the ecology of Bacillus thuringiensis as an insect pathogen.
AU - Milutinovic, Barbara
AU - Höfling, Christina
AU - Futo, Momir
AU - Scharsack, Jörn
AU - Kurtz, Joachim
ID - 1548
IS - 23
JF - Applied and Environmental Microbiology
TI - Infection of Tribolium castaneum with Bacillus thuringiensis: Quantification of bacterial replication within cadavers, transmission via cannibalism, and inhibition of spore germination
VL - 81
ER -
TY - CHAP
AB - Nature has incorporated small photochromic molecules, colloquially termed 'photoswitches', in photoreceptor proteins to sense optical cues in photo-taxis and vision. While Nature's ability to employ light-responsive functionalities has long been recognized, it was not until recently that scientists designed, synthesized and applied synthetic photochromes to manipulate many of which open rapidly and locally in their native cell types, biological processes with the temporal and spatial resolution of light. Ion channels in particular have come to the forefront of proteins that can be put under the designer control of synthetic photochromes. Photochromic ion channel controllers are comprised of three classes, photochromic soluble ligands (PCLs), photochromic tethered ligands (PTLs) and photochromic crosslinkers (PXs), and in each class ion channel functionality is controlled through reversible changes in photochrome structure. By acting as light-dependent ion channel agonists, antagonist or modulators, photochromic controllers effectively converted a wide range of ion channels, including voltage-gated ion channels, 'leak channels', tri-, tetra- and pentameric ligand-gated ion channels, and temperaturesensitive ion channels, into man-made photoreceptors. Control by photochromes can be reversible, unlike in the case of 'caged' compounds, and non-invasive with high spatial precision, unlike pharmacology and electrical manipulation. Here, we introduce design principles of emerging photochromic molecules that act on ion channels and discuss the impact that these molecules are beginning to have on ion channel biophysics and neuronal physiology.
AU - Mckenzie, Catherine
AU - Sanchez Romero, Inmaculada
AU - Janovjak, Harald L
ID - 1549
SN - 978-1-4939-2844-6
T2 - Novel chemical tools to study ion channel biology
TI - Flipping the photoswitch: Ion channels under light control
VL - 869
ER -
TY - JOUR
AB - The medial ganglionic eminence (MGE) gives rise to the majority of mouse forebrain interneurons. Here, we examine the lineage relationship among MGE-derived interneurons using a replication-defective retroviral library containing a highly diverse set of DNA barcodes. Recovering the barcodes from the mature progeny of infected progenitor cells enabled us to unambiguously determine their respective lineal relationship. We found that clonal dispersion occurs across large areas of the brain and is not restricted by anatomical divisions. As such, sibling interneurons can populate the cortex, hippocampus striatum, and globus pallidus. The majority of interneurons appeared to be generated from asymmetric divisions of MGE progenitor cells, followed by symmetric divisions within the subventricular zone. Altogether, our findings uncover that lineage relationships do not appear to determine interneuron allocation to particular regions. As such, it is likely that clonally related interneurons have considerable flexibility as to the particular forebrain circuits to which they can contribute.
AU - Mayer, Christian
AU - Jaglin, Xavier
AU - Cobbs, Lucy
AU - Bandler, Rachel
AU - Streicher, Carmen
AU - Cepko, Constance
AU - Hippenmeyer, Simon
AU - Fishell, Gord
ID - 1550
IS - 5
JF - Neuron
TI - Clonally related forebrain interneurons disperse broadly across both functional areas and structural boundaries
VL - 87
ER -
TY - JOUR
AB - Reciprocal coevolution between host and pathogen is widely seen as a major driver of evolution and biological innovation. Yet, to date, the underlying genetic mechanisms and associated trait functions that are unique to rapid coevolutionary change are generally unknown. We here combined experimental evolution of the bacterial biocontrol agent Bacillus thuringiensis and its nematode host Caenorhabditis elegans with large-scale phenotyping, whole genome analysis, and functional genetics to demonstrate the selective benefit of pathogen virulence and the underlying toxin genes during the adaptation process. We show that: (i) high virulence was specifically favoured during pathogen–host coevolution rather than pathogen one-sided adaptation to a nonchanging host or to an environment without host; (ii) the pathogen genotype BT-679 with known nematocidal toxin genes and high virulence specifically swept to fixation in all of the independent replicate populations under coevolution but only some under one-sided adaptation; (iii) high virulence in the BT-679-dominated populations correlated with elevated copy numbers of the plasmid containing the nematocidal toxin genes; (iv) loss of virulence in a toxin-plasmid lacking BT-679 isolate was reconstituted by genetic reintroduction or external addition of the toxins.We conclude that sustained coevolution is distinct from unidirectional selection in shaping the pathogen's genome and life history characteristics. To our knowledge, this study is the first to characterize the pathogen genes involved in coevolutionary adaptation in an animal host–pathogen interaction system.
AU - El Masri, Leila
AU - Branca, Antoine
AU - Sheppard, Anna
AU - Papkou, Andrei
AU - Laehnemann, David
AU - Guenther, Patrick
AU - Prahl, Swantje
AU - Saebelfeld, Manja
AU - Hollensteiner, Jacqueline
AU - Liesegang, Heiko
AU - Brzuszkiewicz, Elzbieta
AU - Daniel, Rolf
AU - Michiels, Nico
AU - Schulte, Rebecca
AU - Kurtz, Joachim
AU - Rosenstiel, Philip
AU - Telschow, Arndt
AU - Bornberg Bauer, Erich
AU - Schulenburg, Hinrich
ID - 1551
IS - 6
JF - PLoS Biology
TI - Host–pathogen coevolution: The selective advantage of Bacillus thuringiensis virulence and its cry toxin genes
VL - 13
ER -
TY - JOUR
AB - Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns.
AU - Maiuri, Paolo
AU - Rupprecht, Jean
AU - Wieser, Stefan
AU - Ruprecht, Verena
AU - Bénichou, Olivier
AU - Carpi, Nicolas
AU - Coppey, Mathieu
AU - De Beco, Simon
AU - Gov, Nir
AU - Heisenberg, Carl-Philipp J
AU - Lage Crespo, Carolina
AU - Lautenschlaeger, Franziska
AU - Le Berre, Maël
AU - Lennon Duménil, Ana
AU - Raab, Matthew
AU - Thiam, Hawa
AU - Piel, Matthieu
AU - Sixt, Michael K
AU - Voituriez, Raphaël
ID - 1553
IS - 2
JF - Cell
TI - Actin flows mediate a universal coupling between cell speed and cell persistence
VL - 161
ER -
TY - JOUR
AB - The visualization of hormonal signaling input and output is key to understanding how multicellular development is regulated. The plant signaling molecule auxin triggers many growth and developmental responses, but current tools lack the sensitivity or precision to visualize these. We developed a set of fluorescent reporters that allow sensitive and semiquantitative readout of auxin responses at cellular resolution in Arabidopsis thaliana. These generic tools are suitable for any transformable plant species.
AU - Liao, Cheyang
AU - Smet, Wouter
AU - Brunoud, Géraldine
AU - Yoshida, Saiko
AU - Vernoux, Teva
AU - Weijers, Dolf
ID - 1554
IS - 3
JF - Nature Methods
TI - Reporters for sensitive and quantitative measurement of auxin response
VL - 12
ER -
TY - JOUR
AB - We show that incorporating spatial dispersal of individuals into a simple vaccination epidemic model may give rise to a model that exhibits rich dynamical behavior. Using an SIVS (susceptible-infected-vaccinated-susceptible) model as a basis, we describe the spread of an infectious disease in a population split into two regions. In each subpopulation, both forward and backward bifurcations can occur. This implies that for disconnected regions the two-patch system may admit several steady states. We consider traveling between the regions and investigate the impact of spatial dispersal of individuals on the model dynamics. We establish conditions for the existence of multiple nontrivial steady states in the system, and we study the structure of the equilibria. The mathematical analysis reveals an unusually rich dynamical behavior, not normally found in the simple epidemic models. In addition to the disease-free equilibrium, eight endemic equilibria emerge from backward transcritical and saddle-node bifurcation points, forming an interesting bifurcation diagram. Stability of steady states, their bifurcations, and the global dynamics are investigated with analytical tools, numerical simulations, and rigorous set-oriented numerical computations.
AU - Knipl, Diána
AU - Pilarczyk, Pawel
AU - Röst, Gergely
ID - 1555
IS - 2
JF - SIAM Journal on Applied Dynamical Systems
TI - Rich bifurcation structure in a two patch vaccination model
VL - 14
ER -
TY - JOUR
AB - The elongator complex subunit 2 (ELP2) protein, one subunit of an evolutionarily conserved histone acetyltransferase complex, has been shown to participate in leaf patterning, plant immune and abiotic stress responses in Arabidopsis thaliana. Here, its role in root development was explored. Compared to the wild type, the elp2 mutant exhibited an accelerated differentiation of its root stem cells and cell division was more active in its quiescent centre (QC). The key transcription factors responsible for maintaining root stem cell and QC identity, such as AP2 transcription factors PLT1 (PLETHORA1) and PLT2 (PLETHORA2), GRAS transcription factors such as SCR (SCARECROW) and SHR (SHORT ROOT) and WUSCHEL-RELATED HOMEOBOX5 transcription factor WOX5, were all strongly down-regulated in the mutant. On the other hand, expression of the G2/M transition activator CYCB1 was substantially induced in elp2. The auxin efflux transporters PIN1 and PIN2 showed decreased protein levels and PIN1 also displayed mild polarity alterations in elp2, which resulted in a reduced auxin content in the root tip. Either the acetylation or methylation level of each of these genes differed between the mutant and the wild type, suggesting that the ELP2 regulation of root development involves the epigenetic modification of a range of transcription factors and other developmental regulators.
AU - Jia, Yuebin
AU - Tian, Huiyu
AU - Li, Hongjiang
AU - Yu, Qianqian
AU - Wang, Lei
AU - Friml, Jirí
AU - Ding, Zhaojun
ID - 1556
IS - 15
JF - Journal of Experimental Botany
TI - The Arabidopsis thaliana elongator complex subunit 2 epigenetically affects root development
VL - 66
ER -
TY - JOUR
AB - γ-Aminobutyric acid (GABA)- and glycine-mediated hyperpolarizing inhibition is associated with a chloride influx that depends on the inwardly directed chloride electrochemical gradient. In neurons, the extrusion of chloride from the cytosol primarily depends on the expression of an isoform of potassium-chloride cotransporters (KCC2s). KCC2 is crucial in the regulation of the inhibitory tone of neural circuits, including pain processing neural assemblies. Thus we investigated the cellular distribution of KCC2 in neurons underlying pain processing in the superficial spinal dorsal horn of rats by using high-resolution immunocytochemical methods. We demonstrated that perikarya and dendrites widely expressed KCC2, but axon terminals proved to be negative for KCC2. In single ultrathin sections, silver deposits labeling KCC2 molecules showed different densities on the surface of dendritic profiles, some of which were negative for KCC2. In freeze fracture replicas and tissue sections double stained for the β3-subunit of GABAA receptors and KCC2, GABAA receptors were revealed on dendritic segments with high and also with low KCC2 densities. By measuring the distances between spots immunoreactive for gephyrin (a scaffolding protein of GABAA and glycine receptors) and KCC2 on the surface of neurokinin 1 (NK1) receptor-immunoreactive dendrites, we found that gephyrin-immunoreactive spots were located at various distances from KCC2 cotransporters; 5.7 % of them were recovered in the middle of 4-10-μm-long dendritic segments that were free of KCC2 immunostaining. The variable local densities of KCC2 may result in variable postsynaptic potentials evoked by the activation of GABAA and glycine receptors along the dendrites of spinal neurons.
AU - Javdani, Fariba
AU - Holló, Krisztina
AU - Hegedűs, Krisztina
AU - Kis, Gréta
AU - Hegyi, Zoltán
AU - Dócs, Klaudia
AU - Kasugai, Yu
AU - Fukazawa, Yugo
AU - Shigemoto, Ryuichi
AU - Antal, Miklós
ID - 1557
IS - 13
JF - Journal of Comparative Neurology
TI - Differential expression patterns of K+Cl- cotransporter 2 in neurons within the superficial spinal dorsal horn of rats
VL - 523
ER -
TY - JOUR
AB - CyclophilinAis a conserved peptidyl-prolyl cis-trans isomerase (PPIase) best known as the cellular receptor of the immunosuppressant cyclosporine A. Despite significant effort, evidence of developmental functions of cyclophilin A in non-plant systems has remained obscure. Mutations in a tomato (Solanum lycopersicum) cyclophilin A ortholog, DIAGEOTROPICA (DGT), have been shown to abolish the organogenesis of lateral roots; however, a mechanistic explanation of the phenotype is lacking. Here, we show that the dgt mutant lacks auxin maxima relevant to priming and specification of lateral root founder cells. DGT is expressed in shoot and root, and localizes to both the nucleus and cytoplasm during lateral root organogenesis. Mutation of ENTIRE/ IAA9, a member of the auxin-responsive Aux/IAA protein family of transcriptional repressors, partially restores the inability of dgt to initiate lateral root primordia but not the primordia outgrowth. By comparison, grafting of a wild-type scion restores the process of lateral root formation, consistent with participation of a mobile signal. Antibodies do not detect movement of the DGT protein into the dgt rootstock; however, experiments with radiolabeled auxin and an auxin-specific microelectrode demonstrate abnormal auxin fluxes. Functional studies of DGT in heterologous yeast and tobacco-leaf auxin-transport systems demonstrate that DGT negatively regulates PIN-FORMED (PIN) auxin efflux transporters by affecting their plasma membrane localization. Studies in tomato support complex effects of the dgt mutation on PIN expression level, expression domain and plasma membrane localization. Our data demonstrate that DGT regulates auxin transport in lateral root formation.
AU - Ivanchenko, Maria
AU - Zhu, Jinsheng
AU - Wang, Bangjun
AU - Medvecka, Eva
AU - Du, Yunlong
AU - Azzarello, Elisa
AU - Mancuso, Stefano
AU - Megraw, Molly
AU - Filichkin, Sergei
AU - Dubrovsky, Joseph
AU - Friml, Jirí
AU - Geisler, Markus
ID - 1558
IS - 4
JF - Development
TI - The cyclophilin a DIAGEOTROPICA gene affects auxin transport in both root and shoot to control lateral root formation
VL - 142
ER -
TY - JOUR
AB - There are deep, yet largely unexplored, connections between computer science and biology. Both disciplines examine how information proliferates in time and space. Central results in computer science describe the complexity of algorithms that solve certain classes of problems. An algorithm is deemed efficient if it can solve a problem in polynomial time, which means the running time of the algorithm is a polynomial function of the length of the input. There are classes of harder problems for which the fastest possible algorithm requires exponential time. Another criterion is the space requirement of the algorithm. There is a crucial distinction between algorithms that can find a solution, verify a solution, or list several distinct solutions in given time and space. The complexity hierarchy that is generated in this way is the foundation of theoretical computer science. Precise complexity results can be notoriously difficult. The famous question whether polynomial time equals nondeterministic polynomial time (i.e., P = NP) is one of the hardest open problems in computer science and all of mathematics. Here, we consider simple processes of ecological and evolutionary spatial dynamics. The basic question is: What is the probability that a new invader (or a new mutant)will take over a resident population?We derive precise complexity results for a variety of scenarios. We therefore show that some fundamental questions in this area cannot be answered by simple equations (assuming that P is not equal to NP).
AU - Ibsen-Jensen, Rasmus
AU - Chatterjee, Krishnendu
AU - Nowak, Martin
ID - 1559
IS - 51
JF - PNAS
TI - Computational complexity of ecological and evolutionary spatial dynamics
VL - 112
ER -
TY - JOUR
AB - Stromal cells in the subcapsular sinus of the lymph node 'decide' which cells and molecules are allowed access to the deeper parenchyma. The glycoprotein PLVAP is a crucial component of this selector function.
AU - Hons, Miroslav
AU - Sixt, Michael K
ID - 1560
IS - 4
JF - Nature Immunology
TI - The lymph node filter revealed
VL - 16
ER -
TY - JOUR
AB - Replication-deficient recombinant adenoviruses are potent vectors for the efficient transient expression of exogenous genes in resting immune cells. However, most leukocytes are refractory to efficient adenoviral transduction as they lack expression of the coxsackie/adenovirus receptor (CAR). To circumvent this obstacle, we generated the R26/CAG-CARΔ1StopF (where R26 is ROSA26 and CAG is CMV early enhancer/chicken β actin promoter) knock-in mouse line. This strain allows monitoring of in situ Cre recombinase activity through expression of CARΔ1. Simultaneously, CARΔ1 expression permits selective and highly efficient adenoviral transduction of immune cell populations, such as mast cells or T cells, directly ex vivo in bulk cultures without prior cell purification or activation. Furthermore, we show that CARΔ1 expression dramatically improves adenoviral infection of in vitro differentiated conventional and plasmacytoid dendritic cells (DCs), basophils, mast cells, as well as Hoxb8-immortalized hematopoietic progenitor cells. This novel dual function mouse strain will hence be a valuable tool to rapidly dissect the function of specific genes in leukocyte physiology.
AU - Heger, Klaus
AU - Kober, Maike
AU - Rieß, David
AU - Drees, Christoph
AU - De Vries, Ingrid
AU - Bertossi, Arianna
AU - Roers, Axel
AU - Sixt, Michael K
AU - Schmidt Supprian, Marc
ID - 1561
IS - 6
JF - European Journal of Immunology
TI - A novel Cre recombinase reporter mouse strain facilitates selective and efficient infection of primary immune cells with adenoviral vectors
VL - 45
ER -
TY - JOUR
AB - The plant hormone auxin is a key regulator of plant growth and development. Auxin levels are sensed and interpreted by distinct receptor systems that activate a broad range of cellular responses. The Auxin-Binding Protein1 (ABP1) that has been identified based on its ability to bind auxin with high affinity is a prime candidate for the extracellular receptor responsible for mediating a range of auxin effects, in particular, the fast non-transcriptional ones. Contradictory genetic studies suggested prominent or no importance of ABP1 in many developmental processes. However, how crucial the role of auxin binding to ABP1 is for its functions has not been addressed. Here, we show that the auxin-binding pocket of ABP1 is essential for its gain-of-function cellular and developmental roles. In total, 16 different abp1 mutants were prepared that possessed substitutions in the metal core or in the hydrophobic amino acids of the auxin-binding pocket as well as neutral mutations. Their analysis revealed that an intact auxin-binding pocket is a prerequisite for ABP1 to activate downstream components of the ABP1 signalling pathway, such as Rho of Plants (ROPs) and to mediate the clathrin association with membranes for endocytosis regulation. In planta analyses demonstrated the importance of the auxin binding pocket for all known ABP1-mediated postembryonic developmental processes, including morphology of leaf epidermal cells, root growth and root meristem activity, and vascular tissue differentiation. Taken together, these findings suggest that auxin binding to ABP1 is central to its function, supporting the role of ABP1 as auxin receptor.
AU - Grones, Peter
AU - Chen, Xu
AU - Simon, Sibu
AU - Kaufmann, Walter
AU - De Rycke, Riet
AU - Nodzyński, Tomasz
AU - Zažímalová, Eva
AU - Friml, Jirí
ID - 1562
IS - 16
JF - Journal of Experimental Botany
TI - Auxin-binding pocket of ABP1 is crucial for its gain-of-function cellular and developmental roles
VL - 66
ER -
TY - JOUR
AB - For a given self-map $f$ of $M$, a closed smooth connected and simply-connected manifold of dimension $m\geq 4$, we provide an algorithm for estimating the values of the topological invariant $D^m_r[f]$, which equals the minimal number of $r$-periodic points in the smooth homotopy class of $f$. Our results are based on the combinatorial scheme for computing $D^m_r[f]$ introduced by G. Graff and J. Jezierski [J. Fixed Point Theory Appl. 13 (2013), 63-84]. An open-source implementation of the algorithm programmed in C++ is publicly available at {\tt http://www.pawelpilarczyk.com/combtop/}.
AU - Graff, Grzegorz
AU - Pilarczyk, Pawel
ID - 1563
IS - 1
JF - Topological Methods in Nonlinear Analysis
TI - An algorithmic approach to estimating the minimal number of periodic points for smooth self-maps of simply-connected manifolds
VL - 45
ER -
TY - JOUR
AU - Gilson, Matthieu
AU - Savin, Cristina
AU - Zenke, Friedemann
ID - 1564
IS - 11
JF - Frontiers in Computational Neuroscience
TI - Editorial: Emergent neural computation from the interaction of different forms of plasticity
VL - 9
ER -
TY - JOUR
AB - Leptin is an adipokine produced by the adipose tissue regulating body weight through its appetite-suppressing effect. Besides being expressed in the hypothalamus and hippocampus, leptin receptors (ObRs) are also present in chromaffin cells of the adrenal medulla. In the present study, we report the effect of leptin on mouse chromaffin cell (MCC) functionality, focusing on cell excitability and catecholamine secretion. Acute application of leptin (1 nm) on spontaneously firing MCCs caused a slowly developing membrane hyperpolarization followed by complete blockade of action potential (AP) firing. This inhibitory effect at rest was abolished by the BK channel blocker paxilline (1 μm), suggesting the involvement of BK potassium channels. Single-channel recordings in 'perforated microvesicles' confirmed that leptin increased BK channel open probability without altering its unitary conductance. BK channel up-regulation was associated with the phosphoinositide 3-kinase (PI3K) signalling cascade because the PI3K specific inhibitor wortmannin (100 nm) fully prevented BK current increase. We also tested the effect of leptin on evoked AP firing and Ca2+-driven exocytosis. Although leptin preserves well-adapted AP trains of lower frequency, APs are broader and depolarization-evoked exocytosis is increased as a result of the larger size of the ready-releasable pool and higher frequency of vesicle release. The kinetics and quantal size of single secretory events remained unaltered. Leptin had no effect on firing and secretion in db-/db- mice lacking the ObR gene, confirming its specificity. In conclusion, leptin exhibits a dual action on MCC activity. It dampens AP firing at rest but preserves AP firing and increases catecholamine secretion during sustained stimulation, highlighting the importance of the adipo-adrenal axis in the leptin-mediated increase of sympathetic tone and catecholamine release.
AU - Gavello, Daniela
AU - Vandael, David H
AU - Gosso, Sara
AU - Carbone, Emilio
AU - Carabelli, Valentina
ID - 1565
IS - 22
JF - Journal of Physiology
TI - Dual action of leptin on rest-firing and stimulated catecholamine release via phosphoinositide 3-kinase-riven BK channel up-regulation in mouse chromaffin cells
VL - 593
ER -
TY - JOUR
AB - Deposits of misfolded proteins in the human brain are associated with the development of many neurodegenerative diseases. Recent studies show that these proteins have common traits even at the monomer level. Among them, a polyglutamine region that is present in huntingtin is known to exhibit a correlation between the length of the chain and the severity as well as the earliness of the onset of Huntington disease. Here, we apply bias exchange molecular dynamics to generate structures of polyglutamine expansions of several lengths and characterize the resulting independent conformations. We compare the properties of these conformations to those of the standard proteins, as well as to other homopolymeric tracts. We find that, similar to the previously studied polyvaline chains, the set of possible transient folds is much broader than the set of known-to-date folds, although the conformations have different structures. We show that the mechanical stability is not related to any simple geometrical characteristics of the structures. We demonstrate that long polyglutamine expansions result in higher mechanical stability than the shorter ones. They also have a longer life span and are substantially more prone to form knotted structures. The knotted region has an average length of 35 residues, similar to the typical threshold for most polyglutamine-related diseases. Similarly, changes in shape and mechanical stability appear once the total length of the peptide exceeds this threshold of 35 glutamine residues. We suggest that knotted conformers may also harm the cellular machinery and thus lead to disease.
AU - Gómez Sicilia, Àngel
AU - Sikora, Mateusz K
AU - Cieplak, Marek
AU - Carrión Vázquez, Mariano
ID - 1566
IS - 10
JF - PLoS Computational Biology
TI - An exploration of the universe of polyglutamine structures
VL - 11
ER -
TY - CONF
AB - My personal journey to the fascinating world of geometric forms started more than 30 years ago with the invention of alpha shapes in the plane. It took about 10 years before we generalized the concept to higher dimensions, we produced working software with a graphics interface for the three-dimensional case. At the same time, we added homology to the computations. Needless to say that this foreshadowed the inception of persistent homology, because it suggested the study of filtrations to capture the scale of a shape or data set. Importantly, this method has fast algorithms. The arguably most useful result on persistent homology is the stability of its diagrams under perturbations.
AU - Edelsbrunner, Herbert
ID - 1567
T2 - 23rd International Symposium
TI - Shape, homology, persistence, and stability
VL - 9411
ER -
TY - CONF
AB - Aiming at the automatic diagnosis of tumors from narrow band imaging (NBI) magnifying endoscopy (ME) images of the stomach, we combine methods from image processing, computational topology, and machine learning to classify patterns into normal, tubular, vessel. Training the algorithm on a small number of images of each type, we achieve a high rate of correct classifications. The analysis of the learning algorithm reveals that a handful of geometric and topological features are responsible for the overwhelming majority of decisions.
AU - Dunaeva, Olga
AU - Edelsbrunner, Herbert
AU - Lukyanov, Anton
AU - Machin, Michael
AU - Malkova, Daria
ID - 1568
T2 - Proceedings - 16th International Symposium on Symbolic and Numeric Algorithms for Scientific Computing
TI - The classification of endoscopy images with persistent homology
ER -
TY - JOUR
AB - Spatial regulation of the plant hormone indole-3-acetic acid (IAA, or auxin) is essential for plant development. Auxin gradient establishment is mediated by polarly localized auxin transporters, including PIN-FORMED (PIN) proteins. Their localization and abundance at the plasma membrane are tightly regulated by endomembrane machinery, especially the endocytic and recycling pathways mediated by the ADP ribosylation factor guanine nucleotide exchange factor (ARF-GEF) GNOM. We assessed the role of the early secretory pathway in establishing PIN1 polarity in Arabidopsis thaliana by pharmacological and genetic approaches. We identified the compound endosidin 8 (ES8), which selectively interferes with PIN1 basal polarity without altering the polarity of apical proteins. ES8 alters the auxin distribution pattern in the root and induces a strong developmental phenotype, including reduced root length. The ARF-GEF- defective mutants gnom-like 1 ( gnl1-1) and gnom ( van7) are significantly resistant to ES8. The compound does not affect recycling or vacuolar trafficking of PIN1 but leads to its intracellular accumulation, resulting in loss of PIN1 basal polarity at the plasma membrane. Our data confirm a role for GNOM in endoplasmic reticulum (ER) - Golgi trafficking and reveal that a GNL1/GNOM-mediated early secretory pathway selectively regulates PIN1 basal polarity establishment in a manner essential for normal plant development.
AU - Doyle, Siamsa
AU - Haegera, Ash
AU - Vain, Thomas
AU - Rigala, Adeline
AU - Viotti, Corrado
AU - Łangowskaa, Małgorzata
AU - Maa, Qian
AU - Friml, Jirí
AU - Raikhel, Natasha
AU - Hickse, Glenn
AU - Robert, Stéphanie
ID - 1569
IS - 7
JF - PNAS
TI - An early secretory pathway mediated by gnom-like 1 and gnom is essential for basal polarity establishment in Arabidopsis thaliana
VL - 112
ER -
TY - JOUR
AB - Grounding autonomous behavior in the nervous system is a fundamental challenge for neuroscience. In particular, self-organized behavioral development provides more questions than answers. Are there special functional units for curiosity, motivation, and creativity? This paper argues that these features can be grounded in synaptic plasticity itself, without requiring any higher-level constructs. We propose differential extrinsic plasticity (DEP) as a new synaptic rule for self-learning systems and apply it to a number of complex robotic systems as a test case. Without specifying any purpose or goal, seemingly purposeful and adaptive rhythmic behavior is developed, displaying a certain level of sensorimotor intelligence. These surprising results require no systemspecific modifications of the DEP rule. They rather arise from the underlying mechanism of spontaneous symmetry breaking,which is due to the tight brain body environment coupling. The new synaptic rule is biologically plausible and would be an interesting target for neurobiological investigation. We also argue that this neuronal mechanism may have been a catalyst in natural evolution.
AU - Der, Ralf
AU - Martius, Georg S
ID - 1570
IS - 45
JF - PNAS
TI - Novel plasticity rule can explain the development of sensorimotor intelligence
VL - 112
ER -
TY - JOUR
AB - Epistatic interactions can frustrate and shape evolutionary change. Indeed, phenotypes may fail to evolve when essential mutations are only accessible through positive selection if they are fixed simultaneously. How environmental variability affects such constraints is poorly understood. Here, we studied genetic constraints in fixed and fluctuating environments using the Escherichia coli lac operon as a model system for genotype-environment interactions. We found that, in different fixed environments, all trajectories that were reconstructed by applying point mutations within the transcription factor-operator interface became trapped at suboptima, where no additional improvements were possible. Paradoxically, repeated switching between these same environments allows unconstrained adaptation by continuous improvements. This evolutionary mode is explained by pervasive cross-environmental tradeoffs that reposition the peaks in such a way that trapped genotypes can repeatedly climb ascending slopes and hence, escape adaptive stasis. Using a Markov approach, we developed a mathematical framework to quantify the landscape-crossing rates and show that this ratchet-like adaptive mechanism is robust in a wide spectrum of fluctuating environments. Overall, this study shows that genetic constraints can be overcome by environmental change and that crossenvironmental tradeoffs do not necessarily impede but also, can facilitate adaptive evolution. Because tradeoffs and environmental variability are ubiquitous in nature, we speculate this evolutionary mode to be of general relevance.
AU - De Vos, Marjon
AU - Dawid, Alexandre
AU - Šunderlíková, Vanda
AU - Tans, Sander
ID - 1571
IS - 48
JF - PNAS
TI - Breaking evolutionary constraint with a tradeoff ratchet
VL - 112
ER -
TY - JOUR
AB - We consider the quantum ferromagnetic Heisenberg model in three dimensions, for all spins S ≥ 1/2. We rigorously prove the validity of the spin-wave approximation for the excitation spectrum, at the level of the first non-trivial contribution to the free energy at low temperatures. Our proof comes with explicit, constructive upper and lower bounds on the error term. It uses in an essential way the bosonic formulation of the model in terms of the Holstein-Primakoff representation. In this language, the model describes interacting bosons with a hard-core on-site repulsion and a nearest-neighbor attraction. This attractive interaction makes the lower bound on the free energy particularly tricky: the key idea there is to prove a differential inequality for the two-particle density, which is thereby shown to be smaller than the probability density of a suitably weighted two-particle random process on the lattice.
AU - Correggi, Michele
AU - Giuliani, Alessandro
AU - Seiringer, Robert
ID - 1572
IS - 1
JF - Communications in Mathematical Physics
TI - Validity of the spin-wave approximation for the free energy of the Heisenberg ferromagnet
VL - 339
ER -
TY - JOUR
AB - We present a new, simpler proof of the unconditional uniqueness of solutions to the cubic Gross-Pitaevskii hierarchy in ℝ3. One of the main tools in our analysis is the quantum de Finetti theorem. Our uniqueness result is equivalent to the one established in the celebrated works of Erdos, Schlein, and Yau.
AU - Chen, Thomas
AU - Hainzl, Christian
AU - Pavlović, Nataša
AU - Seiringer, Robert
ID - 1573
IS - 10
JF - Communications on Pure and Applied Mathematics
TI - Unconditional uniqueness for the cubic gross pitaevskii hierarchy via quantum de finetti
VL - 68
ER -
TY - JOUR
AB - Multiple plant developmental processes, such as lateral root development, depend on auxin distribution patterns that are in part generated by the PIN-formed family of auxin-efflux transporters. Here we propose that AUXIN RESPONSE FACTOR7 (ARF7) and the ARF7-regulated FOUR LIPS/MYB124 (FLP) transcription factors jointly form a coherent feed-forward motif that mediates the auxin-responsive PIN3 transcription in planta to steer the early steps of lateral root formation. This regulatory mechanism might endow the PIN3 circuitry with a temporal 'memory' of auxin stimuli, potentially maintaining and enhancing the robustness of the auxin flux directionality during lateral root development. The cooperative action between canonical auxin signalling and other transcription factors might constitute a general mechanism by which transcriptional auxin-sensitivity can be regulated at a tissue-specific level.
AU - Chen, Qian
AU - Liu, Yang
AU - Maere, Steven
AU - Lee, Eunkyoung
AU - Van Isterdael, Gert
AU - Xie, Zidian
AU - Xuan, Wei
AU - Lucas, Jessica
AU - Vassileva, Valya
AU - Kitakura, Saeko
AU - Marhavy, Peter
AU - Wabnik, Krzysztof T
AU - Geldner, Niko
AU - Benková, Eva
AU - Le, Jie
AU - Fukaki, Hidehiro
AU - Grotewold, Erich
AU - Li, Chuanyou
AU - Friml, Jirí
AU - Sack, Fred
AU - Beeckman, Tom
AU - Vanneste, Steffen
ID - 1574
JF - Nature Communications
TI - A coherent transcriptional feed-forward motif model for mediating auxin-sensitive PIN3 expression during lateral root development
VL - 6
ER -
TY - JOUR
AB - The immune response relies on the migration of leukocytes and on their ability to stop in precise anatomical locations to fulfil their task. How leukocyte migration and function are coordinated is unknown. Here we show that in immature dendritic cells, which patrol their environment by engulfing extracellular material, cell migration and antigen capture are antagonistic. This antagonism results from transient enrichment of myosin IIA at the cell front, which disrupts the back-to-front gradient of the motor protein, slowing down locomotion but promoting antigen capture. We further highlight that myosin IIA enrichment at the cell front requires the MHC class II-associated invariant chain (Ii). Thus, by controlling myosin IIA localization, Ii imposes on dendritic cells an intermittent antigen capture behaviour that might facilitate environment patrolling. We propose that the requirement for myosin II in both cell migration and specific cell functions may provide a general mechanism for their coordination in time and space.
AU - Chabaud, Mélanie
AU - Heuzé, Mélina
AU - Bretou, Marine
AU - Vargas, Pablo
AU - Maiuri, Paolo
AU - Solanes, Paola
AU - Maurin, Mathieu
AU - Terriac, Emmanuel
AU - Le Berre, Maël
AU - Lankar, Danielle
AU - Piolot, Tristan
AU - Adelstein, Robert
AU - Zhang, Yingfan
AU - Sixt, Michael K
AU - Jacobelli, Jordan
AU - Bénichou, Olivier
AU - Voituriez, Raphaël
AU - Piel, Matthieu
AU - Lennon Duménil, Ana
ID - 1575
JF - Nature Communications
TI - Cell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells
VL - 6
ER -
TY - JOUR
AB - Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that noncognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here, we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibrium models of TF binding, and propose an alternative nonequilibrium scheme that implements kinetic proofreading to suppress erroneous initiation. This proposal is consistent with the observed covalent modifications of the transcriptional apparatus and predicts increased noise in gene expression as a trade-off for improved specificity. Using information theory, we quantify this trade-off to find when optimal proofreading architectures are favored over their equilibrium counterparts. Such architectures exhibit significant super-Poisson noise at low expression in steady state.
AU - Cepeda Humerez, Sarah A
AU - Rieckh, Georg
AU - Tkacik, Gasper
ID - 1576
IS - 24
JF - Physical Review Letters
TI - Stochastic proofreading mechanism alleviates crosstalk in transcriptional regulation
VL - 115
ER -
TY - JOUR
AB - Contrary to the pattern seen in mammalian sex chromosomes, where most Y-linked genes have X-linked homologs, the Drosophila X and Y chromosomes appear to be unrelated. Most of the Y-linked genes have autosomal paralogs, so autosome-to-Y transposition must be the main source of Drosophila Y-linked genes. Here we show how these genes were acquired. We found a previously unidentified gene (flagrante delicto Y, FDY) that originated from a recent duplication of the autosomal gene vig2 to the Y chromosome of Drosophila melanogaster. Four contiguous genes were duplicated along with vig2, but they became pseudogenes through the accumulation of deletions and transposable element insertions, whereas FDY remained functional, acquired testis-specific expression, and now accounts for ∼20% of the vig2-like mRNA in testis. FDY is absent in the closest relatives of D. melanogaster, and DNA sequence divergence indicates that the duplication to the Y chromosome occurred ∼2 million years ago. Thus, FDY provides a snapshot of the early stages of the establishment of a Y-linked gene and demonstrates how the Drosophila Y has been accumulating autosomal genes.
AU - Carvalho, Antonio
AU - Vicoso, Beatriz
AU - Russo, Claudia
AU - Swenor, Bonnielin
AU - Clark, Andrew
ID - 1577
IS - 40
JF - PNAS
TI - Birth of a new gene on the Y chromosome of Drosophila melanogaster
VL - 112
ER -
TY - JOUR
AB - We prove that the dual of the digital Voronoi diagram constructed by flooding the plane from the data points gives a geometrically and topologically correct dual triangulation. This provides the proof of correctness for recently developed GPU algorithms that outperform traditional CPU algorithms for constructing two-dimensional Delaunay triangulations.
AU - Cao, Thanhtung
AU - Edelsbrunner, Herbert
AU - Tan, Tiowseng
ID - 1578
IS - 7
JF - Computational Geometry
TI - Triangulations from topologically correct digital Voronoi diagrams
VL - 48
ER -
TY - JOUR
AB - We show that the Galois group of any Schubert problem involving lines in projective space contains the alternating group. This constitutes the largest family of enumerative problems whose Galois groups have been largely determined. Using a criterion of Vakil and a special position argument due to Schubert, our result follows from a particular inequality among Kostka numbers of two-rowed tableaux. In most cases, a combinatorial injection proves the inequality. For the remaining cases, we use the Weyl integral formulas to obtain an integral formula for these Kostka numbers. This rewrites the inequality as an integral, which we estimate to establish the inequality.
AU - Brooks, Christopher
AU - Martin Del Campo Sanchez, Abraham
AU - Sottile, Frank
ID - 1579
IS - 6
JF - Transactions of the American Mathematical Society
TI - Galois groups of Schubert problems of lines are at least alternating
VL - 367
ER -
TY - JOUR
AB - Synapsins (Syns) are an evolutionarily conserved family of presynaptic proteins crucial for the fine-tuning of synaptic function. A large amount of experimental evidences has shown that Syns are involved in the development of epileptic phenotypes and several mutations in Syn genes have been associated with epilepsy in humans and animal models. Syn mutations induce alterations in circuitry and neurotransmitter release, differentially affecting excitatory and inhibitory synapses, thus causing an excitation/inhibition imbalance in network excitability toward hyperexcitability that may be a determinant with regard to the development of epilepsy. Another approach to investigate epileptogenic mechanisms is to understand how silencing Syn affects the cellular behavior of single neurons and is associated with the hyperexcitable phenotypes observed in epilepsy. Here, we examined the functional effects of antisense-RNA inhibition of Syn expression on individually identified and isolated serotonergic cells of the Helix land snail. We found that Helix synapsin silencing increases cell excitability characterized by a slightly depolarized resting membrane potential, decreases the rheobase, reduces the threshold for action potential (AP) firing and increases the mean and instantaneous firing rates, with respect to control cells. The observed increase of Ca2+ and BK currents in Syn-silenced cells seems to be related to changes in the shape of the AP waveform. These currents sustain the faster spiking in Syn-deficient cells by increasing the after hyperpolarization and limiting the Na+ and Ca2+ channel inactivation during repetitive firing. This in turn speeds up the depolarization phase by reaching the AP threshold faster. Our results provide evidence that Syn silencing increases intrinsic cell excitability associated with increased Ca2+ and Ca2+-dependent BK currents in the absence of excitatory or inhibitory inputs.
AU - Brenes, Oscar
AU - Vandael, David H
AU - Carbone, Emilio
AU - Montarolo, Pier
AU - Ghirardi, Mirella
ID - 1580
JF - Neuroscience
TI - Knock-down of synapsin alters cell excitability and action potential waveform by potentiating BK and voltage gated Ca2 currents in Helix serotonergic neurons
VL - 311
ER -