@article{402, abstract = {During metastasis, malignant cells escape the primary tumor, intravasate lymphatic vessels, and reach draining sentinel lymph nodes before they colonize distant organs via the blood circulation. Although lymph node metastasis in cancer patients correlates with poor prognosis, evidence is lacking as to whether and how tumor cells enter the bloodstream via lymph nodes. To investigate this question, we delivered carcinoma cells into the lymph nodes of mice by microinfusing the cells into afferent lymphatic vessels. We found that tumor cells rapidly infiltrated the lymph node parenchyma, invaded blood vessels, and seeded lung metastases without involvement of the thoracic duct. These results suggest that the lymph node blood vessels can serve as an exit route for systemic dissemination of cancer cells in experimental mouse models. Whether this form of tumor cell spreading occurs in cancer patients remains to be determined.}, author = {Brown, Markus and Assen, Frank P and Leithner, Alexander F and Abe, Jun and Schachner, Helga and Asfour, Gabriele and Bagó Horváth, Zsuzsanna and Stein, Jens and Uhrin, Pavel and Sixt, Michael K and Kerjaschki, Dontscho}, journal = {Science}, number = {6382}, pages = {1408 -- 1411}, publisher = {American Association for the Advancement of Science}, title = {{Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice}}, doi = {10.1126/science.aal3662}, volume = {359}, year = {2018}, } @article{612, abstract = {Metabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically through the modulation of different effector signalling pathways. Here, we analysed the distribution of GABAB receptors using highly sensitive SDS-digested freeze-fracture replica labelling in mouse cerebellar Purkinje cells. Immunoreactivity for GABAB1 was observed on presynaptic and, more abundantly, on postsynaptic compartments, showing both scattered and clustered distribution patterns. Quantitative analysis of immunoparticles revealed a somato-dendritic gradient, with the density of immunoparticles increasing 26-fold from somata to dendritic spines. To understand the spatial relationship of GABAB receptors with two key effector ion channels, the G protein-gated inwardly rectifying K+ (GIRK/Kir3) channel and the voltage-dependent Ca2+ channel, biochemical and immunohistochemical approaches were performed. Co-immunoprecipitation analysis demonstrated that GABAB receptors co-assembled with GIRK and CaV2.1 channels in the cerebellum. Using double-labelling immunoelectron microscopic techniques, co-clustering between GABAB1 and GIRK2 was detected in dendritic spines, whereas they were mainly segregated in the dendritic shafts. In contrast, co-clustering of GABAB1 and CaV2.1 was detected in dendritic shafts but not spines. Presynaptically, although no significant co-clustering of GABAB1 and GIRK2 or CaV2.1 channels was detected, inter-cluster distance for GABAB1 and GIRK2 was significantly smaller in the active zone than in the dendritic shafts, and that for GABAB1 and CaV2.1 was significantly smaller in the active zone than in the dendritic shafts and spines. Thus, GABAB receptors are associated with GIRK and CaV2.1 channels in different subcellular compartments. These data provide a better framework for understanding the different roles played by GABAB receptors and their effector ion channels in the cerebellar network.}, author = {Luján, Rafael and Aguado, Carolina and Ciruela, Francisco and Cózar, Javier and Kleindienst, David and De La Ossa, Luis and Bettler, Bernhard and Wickman, Kevin and Watanabe, Masahiko and Shigemoto, Ryuichi and Fukazawa, Yugo}, journal = {Brain Structure and Function}, number = {3}, pages = {1565 -- 1587}, publisher = {Springer}, title = {{Differential association of GABAB receptors with their effector ion channels in Purkinje cells}}, doi = {10.1007/s00429-017-1568-y}, volume = {223}, year = {2018}, } @phdthesis{6263, abstract = {Antibiotic resistance can emerge spontaneously through genomic mutation and render treatment ineffective. To counteract this process, in addition to the discovery and description of resistance mechanisms,a deeper understanding of resistanceevolvabilityand its determinantsis needed. To address this challenge, this thesisuncoversnew genetic determinants of resistance evolvability using a customized robotic setup, exploressystematic ways in which resistance evolution is perturbed due to dose-responsecharacteristics of drugs and mutation rate differences,and mathematically investigates the evolutionary fate of one specific type of evolvability modifier -a stress-induced mutagenesis allele.We find severalgenes which strongly inhibit or potentiate resistance evolution. In order to identify them, we first developedan automated high-throughput feedback-controlled protocol whichkeeps the population size and selection pressure approximately constant for hundreds of cultures by dynamically re-diluting the cultures and adjusting the antibiotic concentration. We implementedthis protocol on a customized liquid handling robot and propagated 100 different gene deletion strains of Escherichia coliin triplicate for over 100 generations in tetracycline and in chloramphenicol, and comparedtheir adaptation rates.We find a diminishing returns pattern, where initially sensitive strains adapted more compared to less sensitive ones. Our data uncover that deletions of certain genes which do not affect mutation rate,including efflux pump components, a chaperone and severalstructural and regulatory genes can strongly and reproducibly alterresistance evolution. Sequencing analysis of evolved populations indicates that epistasis with resistance mutations is the most likelyexplanation. This work could inspire treatment strategies in which targeted inhibitors of evolvability mechanisms will be given alongside antibiotics to slow down resistance evolution and extend theefficacy of antibiotics.We implemented astochasticpopulation genetics model, toverifyways in which general properties, namely, dose-response characteristics of drugs and mutation rates, influence evolutionary dynamics. In particular, under the exposure to antibiotics with shallow dose-response curves,bacteria have narrower distributions of fitness effects of new mutations. We show that in silicothis also leads to slower resistance evolution. We see and confirm with experiments that increased mutation rates, apart from speeding up evolution, also leadto high reproducibility of phenotypic adaptation in a context of continually strong selection pressure.Knowledge of these patterns can aid in predicting the dynamics of antibiotic resistance evolutionand adapting treatment schemes accordingly.Focusing on a previously described type of evolvability modifier –a stress-induced mutagenesis allele –we find conditions under which it can persist in a population under periodic selectionakin to clinical treatment. We set up a deterministic infinite populationcontinuous time model tracking the frequencies of a mutator and resistance allele and evaluate various treatment schemes in how well they maintain a stress-induced mutator allele. In particular,a high diversity of stresses is crucial for the persistence of the mutator allele. This leads to a general trade-off where exactly those diversifying treatment schemes which are likely to decrease levels of resistance could lead to stronger selection of highly evolvable genotypes.In the long run, this work will lead to a deeper understanding of the genetic and cellular mechanisms involved in antibiotic resistance evolution and could inspire new strategies for slowing down its rate. }, author = {Lukacisinova, Marta}, issn = {2663-337X}, pages = {91}, publisher = {Institute of Science and Technology Austria}, title = {{Genetic determinants of antibiotic resistance evolution}}, doi = {10.15479/AT:ISTA:th1072}, year = {2018}, } @phdthesis{51, abstract = {Asymmetries have long been known about in the central nervous system. From gross anatomical differences, such as the presence of the parapineal organ in only one hemisphere of the developing zebrafish, to more subtle differences in activity between both hemispheres, as seen in freely roaming animals or human participants under PET and fMRI imaging analysis. The presence of asymmetries has been demonstrated to have huge behavioural implications, with their disruption often leading to the generation of neurological disorders, memory problems, changes in personality, and in an organism's health and well-being. For my Ph.D. work I aimed to tackle two important avenues of research. The first being the process of input-side dependency in the hippocampus, with the goal of finding a key gene responsible for its development (Gene X). The second project was to do with experience-induced laterality formation in the hippocampus. Specifically, how laterality in the synapse density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental enrichment. Through unilateral tracer injections into the CA3, I was able to selectively measure the properties of synapses within the CA1 and investigate how they differed based upon which hemisphere the presynaptic neurone originated. Having found the existence of a previously unreported reversed (left-isomerism) i.v. mutant, through morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate a key gene responsible for the process of left or right determination of inputs to the CA1 s.r.. This work relates to the previous finding of input-side dependent asymmetry in the wild-type rodent, where the origin of the projecting neurone to the CA1 will determine the morphology of a synapse, to a greater degree than the hemisphere in which the projection terminates. Using left- and right-isomerism i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like (Evl) as a potential target for Gene X. In relation to this topic, I also highlight my work in the recently published paper of how knockout of PirB can lead to a lack of input-side dependency in the murine hippocampus. For the second question, I show that the environmental enrichment paradigm will lead to an asymmetry in the synapse densities in the hippocampus of mice. I also highlight that the nature of the enrichment is of less consequence than the process of enrichment itself. I demonstrate that the CA3 region will dramatically alter its projection targets, in relation to environmental stimulation, with the asymmetry in synaptic density, caused by enrichment, relying heavily on commissural fibres. I also highlight the vital importance of input-side dependent asymmetry, as a necessary component of experience-dependent laterality formation in the CA1 s.r.. However, my results suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism also at play. Upon further investigation, I highlight the significant, and highly important, finding that the changes seen in the CA1 s.r. were predominantly caused through projections from the left-CA3, with the right-CA3 having less involvement in this mechanism.}, author = {Case, Matthew J}, issn = {2663-337X}, pages = {186}, publisher = {Institute of Science and Technology Austria}, title = {{From the left to the right: A tale of asymmetries, environments, and hippocampal development}}, doi = {10.15479/AT:ISTA:th_1032}, year = {2018}, } @phdthesis{10, abstract = {Genomic imprinting is an epigenetic process that leads to parent of origin-specific gene expression in a subset of genes. Imprinted genes are essential for brain development, and deregulation of imprinting is associated with neurodevelopmental diseases and the pathogenesis of psychiatric disorders. However, the cell-type specificity of imprinting at single cell resolution, and how imprinting and thus gene dosage regulates neuronal circuit assembly is still largely unknown. Here, MADM (Mosaic Analysis with Double Markers) technology was employed to assess genomic imprinting at single cell level. By visualizing MADM-induced uniparental disomies (UPDs) in distinct colors at single cell level in genetic mosaic animals, this experimental paradigm provides a unique quantitative platform to systematically assay the UPD-mediated imbalances in imprinted gene expression at unprecedented resolution. An experimental pipeline based on FACS, RNA-seq and bioinformatics analysis was established and applied to systematically map cell-type-specific ‘imprintomes’ in the mouse brain. The results revealed that parental-specific expression of imprinted genes per se is rarely cell-type-specific even at the individual cell level. Conversely, when we extended the comparison to downstream responses resulting from imbalanced imprinted gene expression, we discovered an unexpectedly high degree of cell-type specificity. Furthermore, we determined a novel function of genomic imprinting in cortical astrocyte production and in olfactory bulb (OB) granule cell generation. These results suggest important functional implication of genomic imprinting for generating cell-type diversity in the brain. In addition, MADM provides a powerful tool to study candidate genes by concomitant genetic manipulation and fluorescent labelling of single cells. MADM-based candidate gene approach was utilized to identify potential imprinted genes involved in the generation of cortical astrocytes and OB granule cells. We investigated p57Kip2, a maternally expressed gene and known cell cycle regulator. Although we found that p57Kip2 does not play a role in these processes, we detected an unexpected function of the paternal allele previously thought to be silent. Finally, we took advantage of a key property of MADM which is to allow unambiguous investigation of environmental impact on single cells. The experimental pipeline based on FACS and RNA-seq analysis of MADM-labeled cells was established to probe the functional differences of single cell loss of gene function compared to global loss of function on a transcriptional level. With this method, both common and distinct responses were isolated due to cell-autonomous and non-autonomous effects acting on genotypically identical cells. As a result, transcriptional changes were identified which result solely from the surrounding environment. Using the MADM technology to study genomic imprinting at single cell resolution, we have identified cell-type-specific gene expression, novel gene function and the impact of environment on single cell transcriptomes. Together, these provide important insights to the understanding of mechanisms regulating cell-type specificity and thus diversity in the brain.}, author = {Laukoter, Susanne}, issn = {2663-337X}, pages = {1 -- 139}, publisher = {Institute of Science and Technology Austria}, title = {{Role of genomic imprinting in cerebral cortex development}}, doi = {10.15479/AT:ISTA:th1057}, year = {2018}, } @phdthesis{539, abstract = {The whole life cycle of plants as well as their responses to environmental stimuli is governed by a complex network of hormonal regulations. A number of studies have demonstrated an essential role of both auxin and cytokinin in the regulation of many aspects of plant growth and development including embryogenesis, postembryonic organogenic processes such as root, and shoot branching, root and shoot apical meristem activity and phyllotaxis. Over the last decades essential knowledge on the key molecular factors and pathways that spatio-temporally define auxin and cytokinin activities in the plant body has accumulated. However, how both hormonal pathways are interconnected by a complex network of interactions and feedback circuits that determines the final outcome of the individual hormone actions is still largely unknown. Root system architecture establishment and in particular formation of lateral organs is prime example of developmental process at whose regulation both auxin and cytokinin pathways converge. To dissect convergence points and pathways that tightly balance auxin - cytokinin antagonistic activities that determine the root branching pattern transcriptome profiling was applied. Genome wide expression analyses of the xylem pole pericycle, a tissue giving rise to lateral roots, led to identification of genes that are highly responsive to combinatorial auxin and cytokinin treatments and play an essential function in the auxin-cytokinin regulated root branching. SYNERGISTIC AUXIN CYTOKININ 1 (SYAC1) gene, which encodes for a protein of unknown function, was detected among the top candidate genes of which expression was synergistically up-regulated by simultaneous hormonal treatment. Plants with modulated SYAC1 activity exhibit severe defects in the root system establishment and attenuate developmental responses to both auxin and cytokinin. To explore the biological function of the SYAC1, we employed different strategies including expression pattern analysis, subcellular localization and phenotypic analyses of the syac1 loss-of-function and gain-of-function transgenic lines along with the identification of the SYAC1 interaction partners. Detailed functional characterization revealed that SYAC1 acts as a developmentally specific regulator of the secretory pathway to control deposition of cell wall components and thereby rapidly fine tune elongation growth.}, author = {Hurny, Andrej}, issn = {2663-337X}, pages = {147}, publisher = {Institute of Science and Technology Austria}, title = {{Identification and characterization of novel auxin-cytokinin cross-talk components}}, doi = {10.15479/AT:ISTA:th_930}, year = {2018}, } @article{1084, abstract = {BceRS and PsdRS are paralogous two-component systems in Bacillus subtilis controlling the response to antimicrobial peptides. In the presence of extracellular bacitracin and nisin, respectively, the two response regulators (RRs) bind their target promoters, PbceA or PpsdA, resulting in a strong up-regulation of target gene expression and ultimately antibiotic resistance. Despite high sequence similarity between the RRs BceR and PsdR and their known binding sites, no cross-regulation has been observed between them. We therefore investigated the specificity determinants of PbceA and PpsdA that ensure the insulation of these two paralogous pathways at the RR–promoter interface. In vivo and in vitro analyses demonstrate that the regulatory regions within these two promoters contain three important elements: in addition to the known (main) binding site, we identified a linker region and a secondary binding site that are crucial for functionality. Initial binding to the high-affinity, low-specificity main binding site is a prerequisite for the subsequent highly specific binding of a second RR dimer to the low-affinity secondary binding site. In addition to this hierarchical cooperative binding, discrimination requires a competition of the two RRs for their respective binding site mediated by only slight differences in binding affinities.}, author = {Fang, Chong and Nagy-Staron, Anna A and Grafe, Martin and Heermann, Ralf and Jung, Kirsten and Gebhard, Susanne and Mascher, Thorsten}, issn = { 0950-382X}, journal = {Molecular Microbiology}, number = {1}, pages = {16 -- 31}, publisher = {Wiley-Blackwell}, title = {{Insulation and wiring specificity of BceR like response regulators and their target promoters in Bacillus subtilis}}, doi = {10.1111/mmi.13597}, volume = {104}, year = {2017}, } @article{1085, abstract = {Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution.}, author = {Wright, Alison and Darolti, Iulia and Bloch, Natasha and Oostra, Vicencio and Sandkam, Benjamin and Buechel, Séverine and Kolm, Niclas and Breden, Felix and Vicoso, Beatriz and Mank, Judith}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation}}, doi = {10.1038/ncomms14251}, volume = {8}, year = {2017}, } @article{1087, abstract = {Using extensive direct numerical simulations, the dynamics of laminar-turbulent fronts in pipe flow is investigated for Reynolds numbers between and 5500. We here investigate the physical distinction between the fronts of weak and strong slugs both by analysing the turbulent kinetic energy budget and by comparing the downstream front motion to the advection speed of bulk turbulent structures. Our study shows that weak downstream fronts travel slower than turbulent structures in the bulk and correspond to decaying turbulence at the front. At the downstream front speed becomes faster than the advection speed, marking the onset of strong fronts. In contrast to weak fronts, turbulent eddies are generated at strong fronts by feeding on the downstream laminar flow. Our study also suggests that temporal fluctuations of production and dissipation at the downstream laminar-turbulent front drive the dynamical switches between the two types of front observed up to.}, author = {Song, Baofang and Barkley, Dwight and Hof, Björn and Avila, Marc}, issn = {0022-1120}, journal = {Journal of Fluid Mechanics}, pages = {1045 -- 1059}, publisher = {Cambridge University Press}, title = {{Speed and structure of turbulent fronts in pipe flow}}, doi = {10.1017/jfm.2017.14}, volume = {813}, year = {2017}, } @article{1089, abstract = {We discuss properties of distributions that are multivariate totally positive of order two (MTP2) related to conditional independence. In particular, we show that any independence model generated by an MTP2 distribution is a compositional semigraphoid which is upward-stable and singleton-transitive. In addition, we prove that any MTP2 distribution satisfying an appropriate support condition is faithful to its concentration graph. Finally, we analyze factorization properties of MTP2 distributions and discuss ways of constructing MTP2 distributions; in particular we give conditions on the log-linear parameters of a discrete distribution which ensure MTP2 and characterize conditional Gaussian distributions which satisfy MTP2.}, author = {Fallat, Shaun and Lauritzen, Steffen and Sadeghi, Kayvan and Uhler, Caroline and Wermuth, Nanny and Zwiernik, Piotr}, issn = {0090-5364}, journal = {Annals of Statistics}, number = {3}, pages = {1152 -- 1184}, publisher = {Institute of Mathematical Statistics}, title = {{Total positivity in Markov structures}}, doi = {10.1214/16-AOS1478}, volume = {45}, year = {2017}, } @article{1104, abstract = {In the early visual system, cells of the same type perform the same computation in different places of the visual field. How these cells code together a complex visual scene is unclear. A common assumption is that cells of a single-type extract a single-stimulus feature to form a feature map, but this has rarely been observed directly. Using large-scale recordings in the rat retina, we show that a homogeneous population of fast OFF ganglion cells simultaneously encodes two radically different features of a visual scene. Cells close to a moving object code quasilinearly for its position, while distant cells remain largely invariant to the object's position and, instead, respond nonlinearly to changes in the object's speed. We develop a quantitative model that accounts for this effect and identify a disinhibitory circuit that mediates it. Ganglion cells of a single type thus do not code for one, but two features simultaneously. This richer, flexible neural map might also be present in other sensory systems.}, author = {Deny, Stephane and Ferrari, Ulisse and Mace, Emilie and Yger, Pierre and Caplette, Romain and Picaud, Serge and Tkacik, Gasper and Marre, Olivier}, issn = {2041-1723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Multiplexed computations in retinal ganglion cells of a single type}}, doi = {10.1038/s41467-017-02159-y}, volume = {8}, year = {2017}, } @inproceedings{1108, abstract = {In this work we study the learnability of stochastic processes with respect to the conditional risk, i.e. the existence of a learning algorithm that improves its next-step performance with the amount of observed data. We introduce a notion of pairwise discrepancy between conditional distributions at different times steps and show how certain properties of these discrepancies can be used to construct a successful learning algorithm. Our main results are two theorems that establish criteria for learnability for many classes of stochastic processes, including all special cases studied previously in the literature.}, author = {Zimin, Alexander and Lampert, Christoph}, location = {Fort Lauderdale, FL, United States}, pages = {213 -- 222}, publisher = {ML Research Press}, title = {{Learning theory for conditional risk minimization}}, volume = {54}, year = {2017}, } @article{1109, abstract = {Rotation of molecules embedded in He nanodroplets is explored by a combination of fs laser-induced alignment experiments and angulon quasiparticle theory. We demonstrate that at low fluence of the fs alignment pulse, the molecule and its solvation shell can be set into coherent collective rotation lasting long enough to form revivals. With increasing fluence, however, the revivals disappear -- instead, rotational dynamics as rapid as for an isolated molecule is observed during the first few picoseconds. Classical calculations trace this phenomenon to transient decoupling of the molecule from its He shell. Our results open novel opportunities for studying non-equilibrium solute-solvent dynamics and quantum thermalization. }, author = {Shepperson, Benjamin and Søndergaard, Anders and Christiansen, Lars and Kaczmarczyk, Jan and Zillich, Robert and Lemeshko, Mikhail and Stapelfeldt, Henrik}, journal = {Physical Review Letters}, number = {20}, publisher = {American Physical Society}, title = {{Laser-induced rotation of iodine molecules in helium nanodroplets: Revivals and breaking-free}}, doi = {10.1103/PhysRevLett.118.203203}, volume = {118}, year = {2017}, } @article{1110, abstract = {The phytohormone auxin is a major determinant and regulatory component important for plant development. Auxin transport between cells is mediated by a complex system of transporters such as AUX1/LAX, PIN, and ABCB proteins, and their localization and activity is thought to be influenced by phosphatases and kinases. Flavonols have been shown to alter auxin transport activity and changes in flavonol accumulation in the Arabidopsis thaliana rol1-2 mutant cause defects in auxin transport and seedling development. A new mutation in ROOTS CURL IN NPA 1 (RCN1), encoding a regulatory subunit of the phosphatase PP2A, was found to suppress the growth defects of rol1-2 without changing the flavonol content. rol1-2 rcn1-3 double mutants show wild type-like auxin transport activity while levels of free auxin are not affected by rcn1-3. In the rol1-2 mutant, PIN2 shows a flavonol-induced basal-to-apical shift in polar localization which is reversed in the rol1-2 rcn1-3 to basal localization. In vivo analysis of PINOID action, a kinase known to influence PIN protein localization in a PP2A-antagonistic manner, revealed a negative impact of flavonols on PINOID activity. Together, these data suggest that flavonols affect auxin transport by modifying the antagonistic kinase/phosphatase equilibrium.}, author = {Kuhn, Benjamin and Nodzyński, Tomasz and Errafi, Sanae and Bucher, Rahel and Gupta, Shibu and Aryal, Bibek and Dobrev, Petre and Bigler, Laurent and Geisler, Markus and Zažímalová, Eva and Friml, Jirí and Ringli, Christoph}, issn = {2045-2322}, journal = {Scientific Reports}, publisher = {Nature Publishing Group}, title = {{Flavonol-induced changes in PIN2 polarity and auxin transport in the Arabidopsis thaliana rol1-2 mutant require phosphatase activity}}, doi = {10.1038/srep41906}, volume = {7}, year = {2017}, } @article{1111, abstract = {Adaptation depends critically on the effects of new mutations and their dependency on the genetic background in which they occur. These two factors can be summarized by the fitness landscape. However, it would require testing all mutations in all backgrounds, making the definition and analysis of fitness landscapes mostly inaccessible. Instead of postulating a particular fitness landscape, we address this problem by considering general classes of landscapes and calculating an upper limit for the time it takes for a population to reach a fitness peak, circumventing the need to have full knowledge about the fitness landscape. We analyze populations in the weak-mutation regime and characterize the conditions that enable them to quickly reach the fitness peak as a function of the number of sites under selection. We show that for additive landscapes there is a critical selection strength enabling populations to reach high-fitness genotypes, regardless of the distribution of effects. This threshold scales with the number of sites under selection, effectively setting a limit to adaptation, and results from the inevitable increase in deleterious mutational pressure as the population adapts in a space of discrete genotypes. Furthermore, we show that for the class of all unimodal landscapes this condition is sufficient but not necessary for rapid adaptation, as in some highly epistatic landscapes the critical strength does not depend on the number of sites under selection; effectively removing this barrier to adaptation.}, author = {Heredia, Jorge and Trubenova, Barbora and Sudholt, Dirk and Paixao, Tiago}, issn = {0016-6731}, journal = {Genetics}, number = {2}, pages = {803 -- 825}, publisher = {Genetics Society of America}, title = {{Selection limits to adaptive walks on correlated landscapes}}, doi = {10.1534/genetics.116.189340}, volume = {205}, year = {2017}, } @inproceedings{1112, abstract = {There has been renewed interest in modelling the behaviour of evolutionary algorithms by more traditional mathematical objects, such as ordinary differential equations or Markov chains. The advantage is that the analysis becomes greatly facilitated due to the existence of well established methods. However, this typically comes at the cost of disregarding information about the process. Here, we introduce the use of stochastic differential equations (SDEs) for the study of EAs. SDEs can produce simple analytical results for the dynamics of stochastic processes, unlike Markov chains which can produce rigorous but unwieldy expressions about the dynamics. On the other hand, unlike ordinary differential equations (ODEs), they do not discard information about the stochasticity of the process. We show that these are especially suitable for the analysis of fixed budget scenarios and present analogs of the additive and multiplicative drift theorems for SDEs. We exemplify the use of these methods for two model algorithms ((1+1) EA and RLS) on two canonical problems(OneMax and LeadingOnes).}, author = {Paixao, Tiago and Pérez Heredia, Jorge}, booktitle = {Proceedings of the 14th ACM/SIGEVO Conference on Foundations of Genetic Algorithms}, isbn = {978-145034651-1}, location = {Copenhagen, Denmark}, pages = {3 -- 11}, publisher = {ACM}, title = {{An application of stochastic differential equations to evolutionary algorithms}}, doi = {10.1145/3040718.3040729}, year = {2017}, } @article{1113, abstract = {A drawing of a graph G is radial if the vertices of G are placed on concentric circles C 1 , . . . , C k with common center c , and edges are drawn radially : every edge intersects every circle centered at c at most once. G is radial planar if it has a radial embedding, that is, a crossing-free radial drawing. If the vertices of G are ordered or partitioned into ordered levels (as they are for leveled graphs), we require that the assignment of vertices to circles corresponds to the given ordering or leveling. We show that a graph G is radial planar if G has a radial drawing in which every two edges cross an even number of times; the radial embedding has the same leveling as the radial drawing. In other words, we establish the weak variant of the Hanani-Tutte theorem for radial planarity. This generalizes a result by Pach and Toth.}, author = {Fulek, Radoslav and Pelsmajer, Michael and Schaefer, Marcus}, journal = {Journal of Graph Algorithms and Applications}, number = {1}, pages = {135 -- 154}, publisher = {Brown University}, title = {{Hanani-Tutte for radial planarity}}, doi = {10.7155/jgaa.00408}, volume = {21}, year = {2017}, } @article{1114, abstract = {Nonequilibrium phase transitions exist in damped-driven open quantum systems when the continuous tuning of an external parameter leads to a transition between two robust steady states. In second-order transitions this change is abrupt at a critical point, whereas in first-order transitions the two phases can coexist in a critical hysteresis domain. Here, we report the observation of a first-order dissipative quantum phase transition in a driven circuit quantum electrodynamics system. It takes place when the photon blockade of the driven cavity-atom system is broken by increasing the drive power. The observed experimental signature is a bimodal phase space distribution with varying weights controlled by the drive strength. Our measurements show an improved stabilization of the classical attractors up to the millisecond range when the size of the quantum system is increased from one to three artificial atoms. The formation of such robust pointer states could be used for new quantum measurement schemes or to investigate multiphoton phases of finite-size, nonlinear, open quantum systems.}, author = {Fink, Johannes M and Dombi, András and Vukics, András and Wallraff, Andreas and Domokos, Peter}, issn = {2160-3308}, journal = {Physical Review X}, number = {1}, publisher = {American Physical Society}, title = {{Observation of the photon blockade breakdown phase transition}}, doi = {10.1103/PhysRevX.7.011012}, volume = {7}, year = {2017}, } @inproceedings{1116, abstract = {Time-triggered switched networks are a deterministic communication infrastructure used by real-time distributed embedded systems. Due to the criticality of the applications running over them, developers need to ensure that end-to-end communication is dependable and predictable. Traditional approaches assume static networks that are not flexible to changes caused by reconfigurations or, more importantly, faults, which are dealt with in the application using redundancy. We adopt the concept of handling faults in the switches from non-real-time networks while maintaining the required predictability. We study a class of forwarding schemes that can handle various types of failures. We consider probabilistic failures. We study a class of forwarding schemes that can handle various types of failures. We consider probabilistic failures. For a given network with a forwarding scheme and a constant ℓ, we compute the {\em score} of the scheme, namely the probability (induced by faults) that at least ℓ messages arrive on time. We reduce the scoring problem to a reachability problem on a Markov chain with a "product-like" structure. Its special structure allows us to reason about it symbolically, and reduce the scoring problem to #SAT. Our solution is generic and can be adapted to different networks and other contexts. Also, we show the computational complexity of the scoring problem is #P-complete, and we study methods to estimate the score. We evaluate the effectiveness of our techniques with an implementation. }, author = {Avni, Guy and Goel, Shubham and Henzinger, Thomas A and Rodríguez Navas, Guillermo}, issn = {0302-9743}, location = {Uppsala, Sweden}, pages = {169 -- 187}, publisher = {Springer}, title = {{Computing scores of forwarding schemes in switched networks with probabilistic faults}}, doi = {10.1007/978-3-662-54580-5_10}, volume = {10206}, year = {2017}, } @article{1117, abstract = {GABAergic synapses in brain circuits generate inhibitory output signals with submillisecond latency and temporal precision. Whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Here, we examined the Ca^2+ sensor of exocytosis at GABAergic basket cell (BC) to Purkinje cell (PC) synapses in cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ∼10%, identifying Syt2 as the major Ca^2+ sensor at BC-PC synapses. Differential adenovirus-mediated rescue revealed that Syt2 triggered release with shorter latency and higher temporal precision and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as release sensor at BC-PC synapses ensures fast and efficient feedforward inhibition in cerebellar microcircuits. #bioimagingfacility-author}, author = {Chen, Chong and Arai, Itaru and Satterield, Rachel and Young, Samuel and Jonas, Peter M}, issn = {2211-1247}, journal = {Cell Reports}, number = {3}, pages = {723 -- 736}, publisher = {Cell Press}, title = {{Synaptotagmin 2 is the fast Ca2+ sensor at a central inhibitory synapse}}, doi = {10.1016/j.celrep.2016.12.067}, volume = {18}, year = {2017}, }