TY - JOUR AB - Recently it was shown that a molecule rotating in a quantum solvent can be described in terms of the “angulon” quasiparticle [M. Lemeshko, Phys. Rev. Lett. 118, 095301 (2017)]. Here we extend the angulon theory to the case of molecules possessing an additional spin-1/2 degree of freedom and study the behavior of the system in the presence of a static magnetic field. We show that exchange of angular momentum between the molecule and the solvent can be altered by the field, even though the solvent itself is non-magnetic. In particular, we demonstrate a possibility to control resonant emission of phonons with a given angular momentum using a magnetic field. AU - Rzadkowski, Wojciech AU - Lemeshko, Mikhail ID - 415 IS - 10 JF - The Journal of Chemical Physics TI - Effect of a magnetic field on molecule–solvent angular momentum transfer VL - 148 ER - TY - JOUR AB - The current state of the art in real-time two-dimensional water wave simulation requires developers to choose between efficient Fourier-based methods, which lack interactions with moving obstacles, and finite-difference or finite element methods, which handle environmental interactions but are significantly more expensive. This paper attempts to bridge this long-standing gap between complexity and performance, by proposing a new wave simulation method that can faithfully simulate wave interactions with moving obstacles in real time while simultaneously preserving minute details and accommodating very large simulation domains. Previous methods for simulating 2D water waves directly compute the change in height of the water surface, a strategy which imposes limitations based on the CFL condition (fast moving waves require small time steps) and Nyquist's limit (small wave details require closely-spaced simulation variables). This paper proposes a novel wavelet transformation that discretizes the liquid motion in terms of amplitude-like functions that vary over space, frequency, and direction, effectively generalizing Fourier-based methods to handle local interactions. Because these new variables change much more slowly over space than the original water height function, our change of variables drastically reduces the limitations of the CFL condition and Nyquist limit, allowing us to simulate highly detailed water waves at very large visual resolutions. Our discretization is amenable to fast summation and easy to parallelize. We also present basic extensions like pre-computed wave paths and two-way solid fluid coupling. Finally, we argue that our discretization provides a convenient set of variables for artistic manipulation, which we illustrate with a novel wave-painting interface. AU - Jeschke, Stefan AU - Skrivan, Tomas AU - Mueller Fischer, Matthias AU - Chentanez, Nuttapong AU - Macklin, Miles AU - Wojtan, Christopher J ID - 134 IS - 4 JF - ACM Transactions on Graphics TI - Water surface wavelets VL - 37 ER - TY - JOUR AB - We introduce a diagrammatic Monte Carlo approach to angular momentum properties of quantum many-particle systems possessing a macroscopic number of degrees of freedom. The treatment is based on a diagrammatic expansion that merges the usual Feynman diagrams with the angular momentum diagrams known from atomic and nuclear structure theory, thereby incorporating the non-Abelian algebra inherent to quantum rotations. Our approach is applicable at arbitrary coupling, is free of systematic errors and of finite-size effects, and naturally provides access to the impurity Green function. We exemplify the technique by obtaining an all-coupling solution of the angulon model; however, the method is quite general and can be applied to a broad variety of systems in which particles exchange quantum angular momentum with their many-body environment. AU - Bighin, Giacomo AU - Tscherbul, Timur AU - Lemeshko, Mikhail ID - 6339 IS - 16 JF - Physical Review Letters TI - Diagrammatic Monte Carlo approach to angular momentum in quantum many-particle systems VL - 121 ER - TY - JOUR AB - We introduce a Diagrammatic Monte Carlo (DiagMC) approach to complex molecular impurities with rotational degrees of freedom interacting with a many-particle environment. The treatment is based on the diagrammatic expansion that merges the usual Feynman diagrams with the angular momentum diagrams known from atomic and nuclear structure theory, thereby incorporating the non-Abelian algebra inherent to quantum rotations. Our approach works at arbitrary coupling, is free of systematic errors and of finite size effects, and naturally provides access to the impurity Green function. We exemplify the technique by obtaining an all-coupling solution of the angulon model, however, the method is quite general and can be applied to a broad variety of quantum impurities possessing angular momentum degrees of freedom. AU - Bighin, Giacomo AU - Tscherbul, Timur AU - Lemeshko, Mikhail ID - 417 IS - 16 JF - Physical Review Letters TI - Diagrammatic Monte Carlo approach to rotating molecular impurities VL - 121 ER - TY - JOUR AB - Clathrin-mediated endocytosis (CME) is a cellular trafficking process in which cargoes and lipids are internalized from the plasma membrane into vesicles coated with clathrin and adaptor proteins. CME is essential for many developmental and physiological processes in plants, but its underlying mechanism is not well characterised compared to that in yeast and animal systems. Here, we searched for new factors involved in CME in Arabidopsis thaliana by performing Tandem Affinity Purification of proteins that interact with clathrin light chain, a principal component of the clathrin coat. Among the confirmed interactors, we found two putative homologues of the clathrin-coat uncoating factor auxilin previously described in non-plant systems. Overexpression of AUXILIN-LIKE1 and AUXILIN-LIKE2 in A. thaliana caused an arrest of seedling growth and development. This was concomitant with inhibited endocytosis due to blocking of clathrin recruitment after the initial step of adaptor protein binding to the plasma membrane. By contrast, auxilin-like(1/2) loss-of-function lines did not present endocytosis-related developmental or cellular phenotypes under normal growth conditions. This work contributes to the on-going characterization of the endocytotic machinery in plants and provides a robust tool for conditionally and specifically interfering with CME in A. thaliana. AU - Adamowski, Maciek AU - Narasimhan, Madhumitha AU - Kania, Urszula AU - Glanc, Matous AU - De Jaeger, Geert AU - Friml, Jirí ID - 412 IS - 3 JF - The Plant Cell SN - 1040-4651 TI - A functional study of AUXILIN LIKE1 and 2 two putative clathrin uncoating factors in Arabidopsis VL - 30 ER - TY - JOUR AB - With the advent of optogenetics, it became possible to change the activity of a targeted population of neurons in a temporally controlled manner. To combine the advantages of 60-channel in vivo tetrode recording and laser-based optogenetics, we have developed a closed-loop recording system that allows for the actual electrophysiological signal to be used as a trigger for the laser light mediating the optogenetic intervention. We have optimized the weight, size, and shape of the corresponding implant to make it compatible with the size, force, and movements of a behaving mouse, and we have shown that the system can efficiently block sharp wave ripple (SWR) events using those events themselves as a trigger. To demonstrate the full potential of the optogenetic recording system we present a pilot study addressing the contribution of SWR events to learning in a complex behavioral task. AU - Rangel Guerrero, Dámaris K AU - Donnett, James G. AU - Csicsvari, Jozsef L AU - Kovács, Krisztián ID - 5914 IS - 4 JF - eNeuro TI - Tetrode recording from the hippocampus of behaving mice coupled with four-point-irradiation closed-loop optogenetics: A technique to study the contribution of Hippocampal SWR events to learning VL - 5 ER - TY - JOUR AB - 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. AU - Brown, Markus AU - Assen, Frank P AU - Leithner, Alexander F AU - Abe, Jun AU - Schachner, Helga AU - Asfour, Gabriele AU - Bagó Horváth, Zsuzsanna AU - Stein, Jens AU - Uhrin, Pavel AU - Sixt, Michael K AU - Kerjaschki, Dontscho ID - 402 IS - 6382 JF - Science TI - Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice VL - 359 ER - TY - THES AB - Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly 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 neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. AU - Tarlungeanu, Dora-Clara ID - 395 SN - 2663-337X TI - The branched chain amino acids in autism spectrum disorders ER - TY - THES AB - 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. AU - Case, Matthew J ID - 51 SN - 2663-337X TI - From the left to the right: A tale of asymmetries, environments, and hippocampal development ER - TY - THES AB - 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. AU - Laukoter, Susanne ID - 10 SN - 2663-337X TI - Role of genomic imprinting in cerebral cortex development ER - TY - THES AB - In the here presented thesis, we explore the role of branched actin networks in cell migration and antigen presentation, the two most relevant processes in dendritic cell biology. Branched actin networks construct lamellipodial protrusions at the leading edge of migrating cells. These are typically seen as adhesive structures, which mediate force transduction to the extracellular matrix that leads to forward locomotion. We ablated Arp2/3 nucleation promoting factor WAVE in DCs and found that the resulting cells lack lamellipodial protrusions. Instead, depending on the maturation state, one or multiple filopodia were formed. By challenging these cells in a variety of migration assays we found that lamellipodial protrusions are dispensable for the locomotion of leukocytes and actually dampen the speed of migration. However, lamellipodia are critically required to negotiate complex environments that DCs experience while they travel to the next draining lymph node. Taken together our results suggest that leukocyte lamellipodia have rather a sensory- than a force transducing function. Furthermore, we show for the first time structure and dynamics of dendritic cell F-actin at the immunological synapse with naïve T cells. Dendritic cell F-actin appears as dynamic foci that are nucleated by the Arp2/3 complex. WAVE ablated dendritic cells show increased membrane tension, leading to an altered ultrastructure of the immunological synapse and severe T cell priming defects. These results point towards a previously unappreciated role of the cellular mechanics of dendritic cells in T cell activation. Additionally, we present a novel cell culture based system for the differentiation of dendritic cells from conditionally immortalized hematopoietic precursors. These precursor cells are genetically tractable via the CRISPR/Cas9 system while they retain their ability to differentiate into highly migratory dendritic cells and other immune cells. This will foster the study of all aspects of dendritic cell biology and beyond. AU - Leithner, Alexander F ID - 323 SN - 2663-337X TI - Branched actin networks in dendritic cell biology ER - TY - THES AB - 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. AU - Hurny, Andrej ID - 539 SN - 2663-337X TI - Identification and characterization of novel auxin-cytokinin cross-talk components ER - TY - THES AB - The hippocampus is a key brain region for spatial memory and navigation and is needed at all stages of memory, including encoding, consolidation, and recall. Hippocampal place cells selectively discharge at specific locations of the environment to form a cognitive map of the space. During the rest period and sleep following spatial navigation and/or learning, the waking activity of the place cells is reactivated within high synchrony events. This reactivation is thought to be important for memory consolidation and stabilization of the spatial representations. The aim of my thesis was to directly test whether the reactivation content encoded in firing patterns of place cells is important for consolidation of spatial memories. In particular, I aimed to test whether, in cases when multiple spatial memory traces are acquired during learning, the specific disruption of the reactivation of a subset of these memories leads to the selective disruption of the corresponding memory traces or through memory interference the other learned memories are disrupted as well. In this thesis, using a modified cheeseboard paradigm and a closed-loop recording setup with feedback optogenetic stimulation, I examined how the disruption of the reactivation of specific spiking patterns affects consolidation of the corresponding memory traces. To obtain multiple distinctive memories, animals had to perform a spatial task in two distinct cheeseboard environments and the reactivation of spiking patterns associated with one of the environments (target) was disrupted after learning during four hours rest period using a real-time decoding method. This real-time decoding method was capable of selectively affecting the firing rates and cofiring correlations of the target environment-encoding cells. The selective disruption led to behavioural impairment in the memory tests after the rest periods in the target environment but not in the other undisrupted control environment. In addition, the map of the target environment was less stable in the impaired memory tests compared to the learning session before than the map of the control environment. However, when the animal relearned the task, the same map recurred in the target environment that was present during learning before the disruption. Altogether my work demonstrated that the reactivation content is important: assembly-related disruption of reactivation can lead to a selective memory impairment and deficiency in map stability. These findings indeed suggest that reactivated assembly patterns reflect processes associated with the consolidation of memory traces. AU - Gridchyn, Igor ID - 48 SN - 2663-337X TI - Reactivation content is important for consolidation of spatial memory ER - TY - THES AB - Immune cells migrating to the sites of infection navigate through diverse tissue architectures and switch their migratory mechanisms upon demand. However, little is known about systemic regulators that could allow the acquisition of these mechanisms. We performed a genetic screen in Drosophila melanogaster to identify regulators of germband invasion by embryonic macrophages into the confined space between the ectoderm and mesoderm. We have found that bZIP circadian transcription factors (TFs) Kayak (dFos) and Vrille (dNFIL3) have opposite effects on macrophage germband infiltration: Kayak facilitated and Vrille inhibited it. These TFs are enriched in the macrophages during migration and genetically interact to control it. Kayak sets a less coordinated mode of migration of the macrophage group and increases the probability and length of Levy walks. Intriguingly, the motility of kayak mutant macrophages was also strongly affected during initial germband invasion but not along another less confined route. Inhibiting Rho1 signaling within the tail ectoderm partially rescued the Kayak mutant phenotype, strongly suggesting that migrating macrophages have to overcome a barrier imposed by the stiffness of the ectoderm. Also, Kayak appeared to be important for the maintenance of the round cell shape and the rear edge translocation of the macrophages invading the germband. Complementary to this, the cortical actin cytoskeleton of Kayak- deficient macrophages was strongly affected. RNA sequencing revealed the filamin Cheerio and tetraspanin TM4SF to be downstream of Kayak. Chromatin immunoprecipitation and immunostaining revealed that the formin Diaphanous is another downstream target of Kayak. Immunostaining revealed that the formin Diaphanous is another downstream target of Kayak. Indeed, Cheerio, TM4SF and Diaphanous are required within macrophages for germband invasion, and expression of constitutively active Diaphanous in macrophages was able to rescue the kayak mutant phenotype. Moreover, Cher and Diaphanous are also reduced in the macrophages overexpressing Vrille. We hypothesize that Kayak, through its targets, increases actin polymerization and cortical tension in macrophages and thus allows extra force generation necessary for macrophage dissemination and migration through confined stiff tissues, while Vrille counterbalances it. AU - Belyaeva, Vera ID - 9 SN - 2663-337X TI - Transcriptional regulation of macrophage migration in the Drosophila melanogaster embryo ER - TY - THES AB - A major challenge in neuroscience research is to dissect the circuits that orchestrate behavior in health and disease. Proteins from a wide range of non-mammalian species, such as microbial opsins, have been successfully transplanted to specific neuronal targets to override their natural communication patterns. The goal of our work is to manipulate synaptic communication in a manner that closely incorporates the functional intricacies of synapses by preserving temporal encoding (i.e. the firing pattern of the presynaptic neuron) and connectivity (i.e. target specific synapses rather than specific neurons). Our strategy to achieve this goal builds on the use of non-mammalian transplants to create a synthetic synapse. The mode of modulation comes from pre-synaptic uptake of a synthetic neurotransmitter (SN) into synaptic vesicles by means of a genetically targeted transporter selective for the SN. Upon natural vesicular release, exposure of the SN to the synaptic cleft will modify the post-synaptic potential through an orthogonal ligand gated ion channel. To achieve this goal we have functionally characterized a mixed cationic methionine-gated ion channel from Arabidopsis thaliana, designed a method to functionally characterize a synthetic transporter in isolated synaptic vesicles without the need for transgenic animals, identified and extracted multiple prokaryotic uptake systems that are substrate specific for methionine (Met), and established a primary/cell line co-culture system that would allow future combinatorial testing of this orthogonal transmitter-transporter-channel trifecta. Synthetic synapses will provide a unique opportunity to manipulate synaptic communication while maintaining the electrophysiological integrity of the pre-synaptic cell. In this way, information may be preserved that was generated in upstream circuits and that could be essential for concerted function and information processing. AU - Mckenzie, Catherine ID - 6266 SN - 2663-337X TI - Design and characterization of methods and biological components to realize synthetic neurotransmission ER - TY - THES AB - The Wnt/planar cell polarity (Wnt/PCP) pathway determines planar polarity of epithelial cells in both vertebrates and invertebrates. The role that Wnt/PCP signaling plays in mesenchymal contexts, however, is only poorly understood. While previous studies have demonstrated the capacity of Wnt/PCP signaling to polarize and guide directed migration of mesenchymal cells, it remains unclear whether endogenous Wnt/PCP signaling performs these functions instructively, as it does in epithelial cells. Here we developed a light-switchable version of the Wnt/PCP receptor Frizzled 7 (Fz7) to unambiguously distinguish between an instructive and a permissive role of Wnt/PCP signaling for the directional collective migration of mesendoderm progenitor cells during zebrafish gastrulation. We show that prechordal plate (ppl) cell migration is defective in maternal-zygotic fz7a and fz7b (MZ fz7a,b) double mutant embryos, and that Fz7 functions cell-autonomously in this process by promoting ppl cell protrusion formation and directed migration. We further show that local activation of Fz7 can direct ppl cell migration both in vitro and in vivo. Surprisingly, however, uniform Fz7 activation is sufficient to fully rescue the ppl cell migration defect in MZ fz7a,b mutant embryos, indicating that Wnt/PCP signaling functions permissively rather than instructively in directed mesendoderm cell migration during zebrafish gastrulation. AU - Capek, Daniel ID - 50 SN - 2663-337X TI - Optogenetic Frizzled 7 reveals a permissive function of Wnt/PCP signaling in directed mesenchymal cell migration ER - TY - THES AB - Expression of genes is a fundamental molecular phenotype that is subject to evolution by different types of mutations. Both the rate and the effect of mutations may depend on the DNA sequence context of a particular gene or a particular promoter sequence. In this thesis I investigate the nature of this dependence using simple genetic systems in Escherichia coli. With these systems I explore the evolution of constitutive gene expression from random starting sequences at different loci on the chromosome and at different locations in sequence space. First, I dissect chromosomal neighborhood effects that underlie locus-dependent differences in the potential of a gene under selection to become more highly expressed. Next, I find that the effects of point mutations in promoter sequences are dependent on sequence context, and that an existing energy matrix model performs poorly in predicting relative expression of unrelated sequences. Finally, I show that a substantial fraction of random sequences contain functional promoters and I present an extended thermodynamic model that predicts promoter strength in full sequence space. Taken together, these results provide new insights and guides on how to integrate information on sequence context to improve our qualitative and quantitative understanding of bacterial gene expression, with implications for rapid evolution of drug resistance, de novo evolution of genes, and horizontal gene transfer. AU - Steinrück, Magdalena ID - 26 SN - 2663-337X TI - The influence of sequence context on the evolution of bacterial gene expression ER - TY - JOUR AB - Solid-state qubit manipulation and read-out fidelities are reaching fault-tolerance, but quantum error correction requires millions of physical qubits and therefore a scalable quantum computer architecture. To solve signal-line bandwidth and fan-out problems, microwave sources required for qubit manipulation might be embedded close to the qubit chip, typically operating at temperatures below 4 K. Here, we perform the first low temperature measurements of a 130 nm BiCMOS based SiGe voltage controlled oscillator at cryogenic temperature. We determined the frequency and output power dependence on temperature and magnetic field up to 5 T and measured the temperature influence on its noise performance. The device maintains its full functionality from 300 K to 4 K. The carrier frequency at 4 K increases by 3% with respect to the carrier frequency at 300 K, and the output power at 4 K increases by 10 dB relative to the output power at 300 K. The frequency tuning range of approximately 20% remains unchanged between 300 K and 4 K. In an in-plane magnetic field of 5 T, the carrier frequency shifts by only 0.02% compared to the frequency at zero magnetic field. AU - Hollmann, Arne AU - Jirovec, Daniel AU - Kucharski, Maciej AU - Kissinger, Dietmar AU - Fischer, Gunter AU - Schreiber, Lars R. ID - 5816 IS - 11 JF - Review of Scientific Instruments SN - 00346748 TI - 30 GHz-voltage controlled oscillator operating at 4 K VL - 89 ER - TY - THES AB - 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. AU - Lukacisinova, Marta ID - 6263 SN - 2663-337X TI - Genetic determinants of antibiotic resistance evolution ER - TY - JOUR AB - Drosophila melanogaster plasmatocytes, the phagocytic cells among hemocytes, are essential for immune responses, but also play key roles from early development to death through their interactions with other cell types. They regulate homeostasis and signaling during development, stem cell proliferation, metabolism, cancer, wound responses and aging, displaying intriguing molecular and functional conservation with vertebrate macrophages. Given the relative ease of genetics in Drosophila compared to vertebrates, tools permitting visualization and genetic manipulation of plasmatocytes and surrounding tissues independently at all stages would greatly aid in fully understanding these processes, but are lacking. Here we describe a comprehensive set of transgenic lines that allow this. These include extremely brightly fluorescing mCherry-based lines that allow GAL4-independent visualization of plasmatocyte nuclei, cytoplasm or actin cytoskeleton from embryonic Stage 8 through adulthood in both live and fixed samples even as heterozygotes, greatly facilitating screening. These lines allow live visualization and tracking of embryonic plasmatocytes, as well as larval plasmatocytes residing at the body wall or flowing with the surrounding hemolymph. With confocal imaging, interactions of plasmatocytes and inner tissues can be seen in live or fixed embryos, larvae and adults. They permit efficient GAL4-independent FACS analysis/sorting of plasmatocytes throughout life. To facilitate genetic analysis of reciprocal signaling, we have also made a plasmatocyte-expressing QF2 line that in combination with extant GAL4 drivers allows independent genetic manipulation of both plasmatocytes and surrounding tissues, and a GAL80 line that blocks GAL4 drivers from affecting plasmatocytes, both of which function from the early embryo to the adult. AU - György, Attila AU - Roblek, Marko AU - Ratheesh, Aparna AU - Valosková, Katarina AU - Belyaeva, Vera AU - Wachner, Stephanie AU - Matsubayashi, Yutaka AU - Sanchez Sanchez, Besaiz AU - Stramer, Brian AU - Siekhaus, Daria E ID - 544 IS - 3 JF - G3: Genes, Genomes, Genetics TI - Tools allowing independent visualization and genetic manipulation of Drosophila melanogaster macrophages and surrounding tissues VL - 8 ER - TY - JOUR AB - 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. AU - Luján, Rafael AU - Aguado, Carolina AU - Ciruela, Francisco AU - Cózar, Javier AU - Kleindienst, David AU - De La Ossa, Luis AU - Bettler, Bernhard AU - Wickman, Kevin AU - Watanabe, Masahiko AU - Shigemoto, Ryuichi AU - Fukazawa, Yugo ID - 612 IS - 3 JF - Brain Structure and Function TI - Differential association of GABAB receptors with their effector ion channels in Purkinje cells VL - 223 ER - TY - JOUR AB - Parvalbumin-positive (PV+) GABAergic interneurons in hippocampal microcircuits are thought to play a key role in several higher network functions, such as feedforward and feedback inhibition, network oscillations, and pattern separation. Fast lateral inhibition mediated by GABAergic interneurons may implement a winner-takes-all mechanism in the hippocampal input layer. However, it is not clear whether the functional connectivity rules of granule cells (GCs) and interneurons in the dentate gyrus are consistent with such a mechanism. Using simultaneous patch-clamp recordings from up to seven GCs and up to four PV+ interneurons in the dentate gyrus, we find that connectivity is structured in space, synapse-specific, and enriched in specific disynaptic motifs. In contrast to the neocortex, lateral inhibition in the dentate gyrus (in which a GC inhibits neighboring GCs via a PV+ interneuron) is ~ 10-times more abundant than recurrent inhibition (in which a GC inhibits itself). Thus, unique connectivity rules may enable the dentate gyrus to perform specific higher-order computations AU - Espinoza Martinez, Claudia AU - Guzmán, José AU - Zhang, Xiaomin AU - Jonas, Peter M ID - 21 IS - 1 JF - Nature Communications TI - Parvalbumin+ interneurons obey unique connectivity rules and establish a powerful lateral-inhibition microcircuit in dentate gyrus VL - 9 ER - TY - CONF AB - Crypto-currencies are digital assets designed to work as a medium of exchange, e.g., Bitcoin, but they are susceptible to attacks (dishonest behavior of participants). A framework for the analysis of attacks in crypto-currencies requires (a) modeling of game-theoretic aspects to analyze incentives for deviation from honest behavior; (b) concurrent interactions between participants; and (c) analysis of long-term monetary gains. Traditional game-theoretic approaches for the analysis of security protocols consider either qualitative temporal properties such as safety and termination, or the very special class of one-shot (stateless) games. However, to analyze general attacks on protocols for crypto-currencies, both stateful analysis and quantitative objectives are necessary. In this work our main contributions are as follows: (a) we show how a class of concurrent mean-payo games, namely ergodic games, can model various attacks that arise naturally in crypto-currencies; (b) we present the first practical implementation of algorithms for ergodic games that scales to model realistic problems for crypto-currencies; and (c) we present experimental results showing that our framework can handle games with thousands of states and millions of transitions. AU - Chatterjee, Krishnendu AU - Goharshady, Amir AU - Ibsen-Jensen, Rasmus AU - Velner, Yaron ID - 66 SN - 978-3-95977-087-3 TI - Ergodic mean-payoff games for the analysis of attacks in crypto-currencies VL - 118 ER - TY - CONF AB - Smart contracts are computer programs that are executed by a network of mutually distrusting agents, without the need of an external trusted authority. Smart contracts handle and transfer assets of considerable value (in the form of crypto-currency like Bitcoin). Hence, it is crucial that their implementation is bug-free. We identify the utility (or expected payoff) of interacting with such smart contracts as the basic and canonical quantitative property for such contracts. We present a framework for such quantitative analysis of smart contracts. Such a formal framework poses new and novel research challenges in programming languages, as it requires modeling of game-theoretic aspects to analyze incentives for deviation from honest behavior and modeling utilities which are not specified as standard temporal properties such as safety and termination. While game-theoretic incentives have been analyzed in the security community, their analysis has been restricted to the very special case of stateless games. However, to analyze smart contracts, stateful analysis is required as it must account for the different program states of the protocol. Our main contributions are as follows: we present (i)~a simplified programming language for smart contracts; (ii)~an automatic translation of the programs to state-based games; (iii)~an abstraction-refinement approach to solve such games; and (iv)~experimental results on real-world-inspired smart contracts. AU - Chatterjee, Krishnendu AU - Goharshady, Amir AU - Velner, Yaron ID - 311 TI - Quantitative analysis of smart contracts VL - 10801 ER - TY - CONF AB - We present a secure approach for maintaining andreporting credit history records on the Blockchain. Our ap-proach removes third-parties such as credit reporting agen-cies from the lending process and replaces them with smartcontracts. This allows customers to interact directly with thelenders or banks while ensuring the integrity, unmalleabilityand privacy of their credit data. Additionally, each customerhas full control over complete or selective disclosure of hercredit records, eliminating the risk of privacy violations or databreaches. Moreover, our approach provides strong guaranteesfor the lenders as well. A lender can check both correctness andcompleteness of the credit data disclosed to her. This is the firstapproach that can perform all credit reporting tasks withouta central authority or changing the financial mechanisms*. AU - Goharshady, Amir Kafshdar AU - Behrouz, Ali AU - Chatterjee, Krishnendu ID - 6340 SN - 978-1-5386-7975-3 T2 - Proceedings of the IEEE International Conference on Blockchain TI - Secure Credit Reporting on the Blockchain ER - TY - JOUR AB - We study algorithmic questions wrt algebraic path properties in concurrent systems, where the transitions of the system are labeled from a complete, closed semiring. 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 Kafshdar AU - Pavlogiannis, Andreas ID - 6009 IS - 3 JF - ACM Transactions on Programming Languages and Systems SN - 0164-0925 TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components VL - 40 ER - TY - CONF AB - We consider the stochastic shortest path (SSP)problem for succinct Markov decision processes(MDPs), where the MDP consists of a set of vari-ables, and a set of nondeterministic rules that up-date the variables. First, we show that several ex-amples from the AI literature can be modeled assuccinct MDPs. Then we present computationalapproaches for upper and lower bounds for theSSP problem: (a) for computing upper bounds, ourmethod is polynomial-time in the implicit descrip-tion of the MDP; (b) for lower bounds, we present apolynomial-time (in the size of the implicit descrip-tion) reduction to quadratic programming. Our ap-proach is applicable even to infinite-state MDPs.Finally, we present experimental results to demon-strate the effectiveness of our approach on severalclassical examples from the AI literature. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Goharshady, Amir AU - Okati, Nastaran ID - 5977 SN - 10450823 T2 - Proceedings of the Twenty-Seventh International Joint Conference on Artificial Intelligence TI - Computational approaches for stochastic shortest path on succinct MDPs VL - 2018 ER - TY - JOUR AB - We show that a rather simple, steady modification of the streamwise velocity profile in a pipe can lead to a complete collapse of turbulence and the flow fully relaminarizes. Two different devices, a stationary obstacle (inset) and a device which injects fluid through an annular gap close to the wall, are used to control the flow. Both devices modify the streamwise velocity profile such that the flow in the center of the pipe is decelerated and the flow in the near wall region is accelerated. We present measurements with stereoscopic particle image velocimetry to investigate and capture the development of the relaminarizing flow downstream these devices and the specific circumstances responsible for relaminarization. We find total relaminarization up to Reynolds numbers of 6000, where the skin friction in the far downstream distance is reduced by a factor of 3.4 due to relaminarization. In a smooth straight pipe the flow remains completely laminar downstream of the control. Furthermore, we show that transient (temporary) relaminarization in a spatially confined region right downstream the devices occurs also at much higher Reynolds numbers, accompanied by a significant local skin friction drag reduction. The underlying physical mechanism of relaminarization is attributed to a weakening of the near-wall turbulence production cycle. AU - Kühnen, Jakob AU - Scarselli, Davide AU - Schaner, Markus AU - Hof, Björn ID - 422 IS - 4 JF - Flow Turbulence and Combustion TI - Relaminarization by steady modification of the streamwise velocity profile in a pipe VL - 100 ER - TY - JOUR AB - Turbulence is the major cause of friction losses in transport processes and it is responsible for a drastic drag increase in flows over bounding surfaces. While much effort is invested into developing ways to control and reduce turbulence intensities, so far no methods exist to altogether eliminate turbulence if velocities are sufficiently large. We demonstrate for pipe flow that appropriate distortions to the velocity profile lead to a complete collapse of turbulence and subsequently friction losses are reduced by as much as 90%. Counterintuitively, the return to laminar motion is accomplished by initially increasing turbulence intensities or by transiently amplifying wall shear. Since neither the Reynolds number nor the shear stresses decrease (the latter often increase), these measures are not indicative of turbulence collapse. Instead, an amplification mechanism measuring the interaction between eddies and the mean shear is found to set a threshold below which turbulence is suppressed beyond recovery. AU - Kühnen, Jakob AU - Song, Baofang AU - Scarselli, Davide AU - Budanur, Nazmi B AU - Riedl, Michael AU - Willis, Ashley AU - Avila, Marc AU - Hof, Björn ID - 461 JF - Nature Physics TI - Destabilizing turbulence in pipe flow VL - 14 ER - TY - JOUR AB - Auxin is unique among plant hormones due to its directional transport that is mediated by the polarly distributed PIN auxin transporters at the plasma membrane. The canalization hypothesis proposes that the auxin feedback on its polar flow is a crucial, plant-specific mechanism mediating multiple self-organizing developmental processes. Here, we used the auxin effect on the PIN polar localization in Arabidopsis thaliana roots as a proxy for the auxin feedback on the PIN polarity during canalization. We performed microarray experiments to find regulators of this process that act downstream of auxin. We identified genes that were transcriptionally regulated by auxin in an AXR3/IAA17- and ARF7/ARF19-dependent manner. Besides the known components of the PIN polarity, such as PID and PIP5K kinases, a number of potential new regulators were detected, among which the WRKY23 transcription factor, which was characterized in more detail. Gain- and loss-of-function mutants confirmed a role for WRKY23 in mediating the auxin effect on the PIN polarity. Accordingly, processes requiring auxin-mediated PIN polarity rearrangements, such as vascular tissue development during leaf venation, showed a higher WRKY23 expression and required the WRKY23 activity. Our results provide initial insights into the auxin transcriptional network acting upstream of PIN polarization and, potentially, canalization-mediated plant development. AU - Prat, Tomas AU - Hajny, Jakub AU - Grunewald, Wim AU - Vasileva, Mina K AU - Molnar, Gergely AU - Tejos, Ricardo AU - Schmid, Markus AU - Sauer, Michael AU - Friml, Jirí ID - 449 IS - 1 JF - PLoS Genetics TI - WRKY23 is a component of the transcriptional network mediating auxin feedback on PIN polarity VL - 14 ER - TY - JOUR AB - Intercellular distribution of the plant hormone auxin largely depends on the polar subcellular distribution of the plasma membrane PIN-FORMED (PIN) auxin transporters. PIN polarity switches in response to different developmental and environmental signals have been shown to redirect auxin fluxes mediating certain developmental responses. PIN phosphorylation at different sites and by different kinases is crucial for PIN function. Here we investigate the role of PIN phosphorylation during gravitropic response. Loss- and gain-of-function mutants in PINOID and related kinases but not in D6PK kinase as well as mutations mimicking constitutive dephosphorylated or phosphorylated status of two clusters of predicted phosphorylation sites partially disrupted PIN3 phosphorylation and caused defects in gravitropic bending in roots and hypocotyls. In particular, they impacted PIN3 polarity rearrangements in response to gravity and during feed-back regulation by auxin itself. Thus PIN phosphorylation, besides regulating transport activity and apical-basal targeting, is also important for the rapid polarity switches in response to environmental and endogenous signals. AU - Grones, Peter AU - Abas, Melinda F AU - Hajny, Jakub AU - Jones, Angharad AU - Waidmann, Sascha AU - Kleine Vehn, Jürgen AU - Friml, Jirí ID - 191 IS - 1 JF - Scientific Reports TI - PID/WAG-mediated phosphorylation of the Arabidopsis PIN3 auxin transporter mediates polarity switches during gravitropism VL - 8 ER - TY - JOUR AB - Plant hormones as signalling molecules play an essential role in the control of plant growth and development. Typically, sites of hormonal action are usually distant from the site of biosynthesis thus relying on efficient transport mechanisms. Over the last decades, molecular identification of proteins and protein complexes involved in hormonal transport has started. Advanced screens for genes involved in hormonal transport in combination with transport assays using heterologous systems such as yeast, insect, or tobacco BY2 cells or Xenopus oocytes provided important insights into mechanisms underlying distribution of hormones in plant body and led to identification of principal transporters for each hormone. This review gives a short overview of the mechanisms of hormonal transport and transporters identified in Arabidopsis thaliana. AU - Abualia, Rashed AU - Benková, Eva AU - Lacombe, Benoît ID - 47 JF - Advances in Botanical Research TI - Transporters and mechanisms of hormone transport in arabidopsis VL - 87 ER - TY - JOUR AB - Although much is known about the physiological framework of T cell motility, and numerous rate-limiting molecules have been identified through loss-of-function approaches, an integrated functional concept of T cell motility is lacking. Here, we used in vivo precision morphometry together with analysis of cytoskeletal dynamics in vitro to deconstruct the basic mechanisms of T cell migration within lymphatic organs. We show that the contributions of the integrin LFA-1 and the chemokine receptor CCR7 are complementary rather than positioned in a linear pathway, as they are during leukocyte extravasation from the blood vasculature. Our data demonstrate that CCR7 controls cortical actin flows, whereas integrins mediate substrate friction that is sufficient to drive locomotion in the absence of considerable surface adhesions and plasma membrane flux. AU - Hons, Miroslav AU - Kopf, Aglaja AU - Hauschild, Robert AU - Leithner, Alexander F AU - Gärtner, Florian R AU - Abe, Jun AU - Renkawitz, Jörg AU - Stein, Jens AU - Sixt, Michael K ID - 15 IS - 6 JF - Nature Immunology TI - Chemokines and integrins independently tune actin flow and substrate friction during intranodal migration of T cells VL - 19 ER - TY - JOUR AB - This scientific commentary refers to ‘NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice’ by Szczurkowska et al. AU - Contreras, Ximena AU - Hippenmeyer, Simon ID - 28 IS - 9 JF - Brain a journal of neurology TI - Incorrect trafficking route leads to autism VL - 141 ER - TY - JOUR AB - The rapid auxin-triggered growth of the Arabidopsis hypocotyls involves the nuclear TIR1/AFB-Aux/IAA signaling and is accompanied by acidification of the apoplast and cell walls (Fendrych et al., 2016). Here, we describe in detail the method for analysis of the elongation and the TIR1/AFB-Aux/IAA-dependent auxin response in hypocotyl segments as well as the determination of relative values of the cell wall pH. AU - Li, Lanxin AU - Krens, Gabriel AU - Fendrych, Matyas AU - Friml, Jirí ID - 442 IS - 1 JF - Bio-protocol TI - Real-time analysis of auxin response, cell wall pH and elongation in Arabidopsis thaliana Hypocotyls VL - 8 ER - TY - JOUR AB - SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder. AU - Deliu, Elena AU - Arecco, Niccoló AU - Morandell, Jasmin AU - Dotter, Christoph AU - Contreras, Ximena AU - Girardot, Charles AU - Käsper, Eva AU - Kozlova, Alena AU - Kishi, Kasumi AU - Chiaradia, Ilaria AU - Noh, Kyung AU - Novarino, Gaia ID - 3 IS - 12 JF - Nature Neuroscience TI - Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition VL - 21 ER - TY - JOUR AB - Indirect reciprocity explores how humans act when their reputation is at stake, and which social norms they use to assess the actions of others. A crucial question in indirect reciprocity is which social norms can maintain stable cooperation in a society. Past research has highlighted eight such norms, called “leading-eight” strategies. This past research, however, is based on the assumption that all relevant information about other population members is publicly available and that everyone agrees on who is good or bad. Instead, here we explore the reputation dynamics when information is private and noisy. We show that under these conditions, most leading-eight strategies fail to evolve. Those leading-eight strategies that do evolve are unable to sustain full cooperation.Indirect reciprocity is a mechanism for cooperation based on shared moral systems and individual reputations. It assumes that members of a community routinely observe and assess each other and that they use this information to decide who is good or bad, and who deserves cooperation. When information is transmitted publicly, such that all community members agree on each other’s reputation, previous research has highlighted eight crucial moral systems. These “leading-eight” strategies can maintain cooperation and resist invasion by defectors. However, in real populations individuals often hold their own private views of others. Once two individuals disagree about their opinion of some third party, they may also see its subsequent actions in a different light. Their opinions may further diverge over time. Herein, we explore indirect reciprocity when information transmission is private and noisy. We find that in the presence of perception errors, most leading-eight strategies cease to be stable. Even if a leading-eight strategy evolves, cooperation rates may drop considerably when errors are common. Our research highlights the role of reliable information and synchronized reputations to maintain stable moral systems. AU - Hilbe, Christian AU - Schmid, Laura AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 2 IS - 48 JF - PNAS TI - Indirect reciprocity with private, noisy, and incomplete information VL - 115 ER - TY - JOUR AB - Gene regulatory networks evolve through rewiring of individual components—that is, through changes in regulatory connections. However, the mechanistic basis of regulatory rewiring is poorly understood. Using a canonical gene regulatory system, we quantify the properties of transcription factors that determine the evolutionary potential for rewiring of regulatory connections: robustness, tunability and evolvability. In vivo repression measurements of two repressors at mutated operator sites reveal their contrasting evolutionary potential: while robustness and evolvability were positively correlated, both were in trade-off with tunability. Epistatic interactions between adjacent operators alleviated this trade-off. A thermodynamic model explains how the differences in robustness, tunability and evolvability arise from biophysical characteristics of repressor–DNA binding. The model also uncovers that the energy matrix, which describes how mutations affect repressor–DNA binding, encodes crucial information about the evolutionary potential of a repressor. The biophysical determinants of evolutionary potential for regulatory rewiring constitute a mechanistic framework for understanding network evolution. AU - Igler, Claudia AU - Lagator, Mato AU - Tkacik, Gasper AU - Bollback, Jonathan P AU - Guet, Calin C ID - 67 IS - 10 JF - Nature Ecology and Evolution TI - Evolutionary potential of transcription factors for gene regulatory rewiring VL - 2 ER - TY - DATA AB - Mean repression values and standard error of the mean are given for all operator mutant libraries. AU - Igler, Claudia AU - Lagator, Mato AU - Tkacik, Gasper AU - Bollback, Jonathan P AU - Guet, Calin C ID - 5585 TI - Data for the paper Evolutionary potential of transcription factors for gene regulatory rewiring ER - TY - JOUR AB - From microwave ovens to satellite television to the GPS and data services on our mobile phones, microwave technology is everywhere today. But one technology that has so far failed to prove its worth in this wavelength regime is quantum communication that uses the states of single photons as information carriers. This is because single microwave photons, as opposed to classical microwave signals, are extremely vulnerable to noise from thermal excitations in the channels through which they travel. Two new independent studies, one by Ze-Liang Xiang at Technische Universität Wien (Vienna), Austria, and colleagues [1] and another by Benoît Vermersch at the University of Innsbruck, also in Austria, and colleagues [2] now describe a theoretical protocol for microwave quantum communication that is resilient to thermal and other types of noise. Their approach could become a powerful technique to establish fast links between superconducting data processors in a future all-microwave quantum network. AU - Fink, Johannes M ID - 1013 IS - 32 JF - Physics TI - Viewpoint: Microwave quantum states beat the heat VL - 10 ER - TY - JOUR AB - We present a new proof rule for proving almost-sure termination of probabilistic programs, including those that contain demonic non-determinism. An important question for a probabilistic program is whether the probability mass of all its diverging runs is zero, that is that it terminates "almost surely". Proving that can be hard, and this paper presents a new method for doing so. It applies directly to the program's source code, even if the program contains demonic choice. Like others, we use variant functions (a.k.a. "super-martingales") that are real-valued and decrease randomly on each loop iteration; but our key innovation is that the amount as well as the probability of the decrease are parametric. We prove the soundness of the new rule, indicate where its applicability goes beyond existing rules, and explain its connection to classical results on denumerable (non-demonic) Markov chains. AU - Mciver, Annabelle AU - Morgan, Carroll AU - Kaminski, Benjamin Lucien AU - Katoen, Joost P ID - 10418 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - A new proof rule for almost-sure termination VL - 2 ER - TY - CONF AB - 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). AU - Paixao, Tiago AU - Pérez Heredia, Jorge ID - 1112 SN - 978-145034651-1 T2 - Proceedings of the 14th ACM/SIGEVO Conference on Foundations of Genetic Algorithms TI - An application of stochastic differential equations to evolutionary algorithms ER - TY - CONF AB - We study space complexity and time-space trade-offs with a focus not on peak memory usage but on overall memory consumption throughout the computation. Such a cumulative space measure was introduced for the computational model of parallel black pebbling by [Alwen and Serbinenko ’15] as a tool for obtaining results in cryptography. We consider instead the non- deterministic black-white pebble game and prove optimal cumulative space lower bounds and trade-offs, where in order to minimize pebbling time the space has to remain large during a significant fraction of the pebbling. We also initiate the study of cumulative space in proof complexity, an area where other space complexity measures have been extensively studied during the last 10–15 years. Using and extending the connection between proof complexity and pebble games in [Ben-Sasson and Nordström ’08, ’11] we obtain several strong cumulative space results for (even parallel versions of) the resolution proof system, and outline some possible future directions of study of this, in our opinion, natural and interesting space measure. AU - Alwen, Joel F AU - De Rezende, Susanna AU - Nordstrom, Jakob AU - Vinyals, Marc ED - Papadimitriou, Christos ID - 1175 SN - 18688969 TI - Cumulative space in black-white pebbling and resolution VL - 67 ER - TY - JOUR AB - Variation in genotypes may be responsible for differences in dispersal rates, directional biases, and growth rates of individuals. These traits may favor certain genotypes and enhance their spatiotemporal spreading into areas occupied by the less advantageous genotypes. We study how these factors influence the speed of spreading in the case of two competing genotypes under the assumption that spatial variation of the total population is small compared to the spatial variation of the frequencies of the genotypes in the population. In that case, the dynamics of the frequency of one of the genotypes is approximately described by a generalized Fisher–Kolmogorov–Petrovskii–Piskunov (F–KPP) equation. This generalized F–KPP equation with (nonlinear) frequency-dependent diffusion and advection terms admits traveling wave solutions that characterize the invasion of the dominant genotype. Our existence results generalize the classical theory for traveling waves for the F–KPP with constant coefficients. Moreover, in the particular case of the quadratic (monostable) nonlinear growth–decay rate in the generalized F–KPP we study in detail the influence of the variance in diffusion and mean displacement rates of the two genotypes on the minimal wave propagation speed. AU - Kollár, Richard AU - Novak, Sebastian ID - 1191 IS - 3 JF - Bulletin of Mathematical Biology TI - Existence of traveling waves for the generalized F–KPP equation VL - 79 ER - TY - JOUR AB - Systems such as fluid flows in channels and pipes or the complex Ginzburg–Landau system, defined over periodic domains, exhibit both continuous symmetries, translational and rotational, as well as discrete symmetries under spatial reflections or complex conjugation. The simplest, and very common symmetry of this type is the equivariance of the defining equations under the orthogonal group O(2). We formulate a novel symmetry reduction scheme for such systems by combining the method of slices with invariant polynomial methods, and show how it works by applying it to the Kuramoto–Sivashinsky system in one spatial dimension. As an example, we track a relative periodic orbit through a sequence of bifurcations to the onset of chaos. Within the symmetry-reduced state space we are able to compute and visualize the unstable manifolds of relative periodic orbits, their torus bifurcations, a transition to chaos via torus breakdown, and heteroclinic connections between various relative periodic orbits. It would be very hard to carry through such analysis in the full state space, without a symmetry reduction such as the one we present here. AU - Budanur, Nazmi B AU - Cvitanović, Predrag ID - 1211 IS - 3-4 JF - Journal of Statistical Physics TI - Unstable manifolds of relative periodic orbits in the symmetry reduced state space of the Kuramoto–Sivashinsky system VL - 167 ER - TY - JOUR AB - 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. AU - Fulek, Radoslav AU - Pelsmajer, Michael AU - Schaefer, Marcus ID - 1113 IS - 1 JF - Journal of Graph Algorithms and Applications TI - Hanani-Tutte for radial planarity VL - 21 ER - TY - CHAP AB - Complex I (NADH:ubiquinone oxidoreductase) plays a central role in cellular energy generation, contributing to the proton motive force used to produce ATP. It couples the transfer of two electrons between NADH and quinone to translocation of four protons across the membrane. It is the largest protein assembly of bacterial and mitochondrial respiratory chains, composed, in mammals, of up to 45 subunits with a total molecular weight of ∼1 MDa. Bacterial enzyme is about half the size, providing the important “minimal” model of complex I. The l-shaped complex consists of a hydrophilic arm, where electron transfer occurs, and a membrane arm, where proton translocation takes place. Previously, we have solved the crystal structures of the hydrophilic domain of complex I from Thermus thermophilus and of the membrane domain from Escherichia coli, followed by the atomic structure of intact, entire complex I from T. thermophilus. Recently, we have solved by cryo-EM a first complete atomic structure of mammalian (ovine) mitochondrial complex I. Core subunits are well conserved from the bacterial version, whilst supernumerary subunits form an interlinked, stabilizing shell around the core. Subunits containing additional cofactors, including Zn ion, NADPH and phosphopantetheine, probably have regulatory roles. Dysfunction of mitochondrial complex I is implicated in many human neurodegenerative diseases. The structure of mammalian enzyme provides many insights into complex I mechanism, assembly, maturation and dysfunction, allowing detailed molecular analysis of disease-causing mutations. AU - Sazanov, Leonid A ED - Wikström, Mårten ID - 444 SN - 978-1-78262-865-1 T2 - Mechanisms of primary energy transduction in biology TI - Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions ER - TY - JOUR AB - Most kinesin motors move in only one direction along microtubules. Members of the kinesin-5 subfamily were initially described as unidirectional plus-end-directed motors and shown to produce piconewton forces. However, some fungal kinesin-5 motors are bidirectional. The force production of a bidirectional kinesin-5 has not yet been measured. Therefore, it remains unknown whether the mechanism of the unconventional minus-end-directed motility differs fundamentally from that of plus-end-directed stepping. Using force spectroscopy, we have measured here the forces that ensembles of purified budding yeast kinesin-5 Cin8 produce in microtubule gliding assays in both plus- and minus-end direction. Correlation analysis of pause forces demonstrated that individual Cin8 molecules produce additive forces in both directions of movement. In ensembles, Cin8 motors were able to produce single-motor forces up to a magnitude of ∼1.5 pN. Hence, these properties appear to be conserved within the kinesin-5 subfamily. Force production was largely independent of the directionality of movement, indicating similarities between the motility mechanisms for both directions. These results provide constraints for the development of models for the bidirectional motility mechanism of fission yeast kinesin-5 and provide insight into the function of this mitotic motor. AU - Fallesen, Todd AU - Roostalu, Johanna AU - Düllberg, Christian F AU - Pruessner, Gunnar AU - Surrey, Thomas ID - 453 IS - 9 JF - Biophysical Journal TI - Ensembles of bidirectional kinesin Cin8 produce additive forces in both directions of movement VL - 113 ER - TY - JOUR AB - The computation of the winning set for parity objectives and for Streett objectives in graphs as well as in game graphs are central problems in computer-aided verification, with application to the verification of closed systems with strong fairness conditions, the verification of open systems, checking interface compatibility, well-formedness of specifications, and the synthesis of reactive systems. We show how to compute the winning set on n vertices for (1) parity-3 (aka one-pair Streett) objectives in game graphs in time O(n5/2) and for (2) k-pair Streett objectives in graphs in time O(n2+nklogn). For both problems this gives faster algorithms for dense graphs and represents the first improvement in asymptotic running time in 15 years. AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Loitzenbauer, Veronika ID - 464 IS - 3 JF - Logical Methods in Computer Science SN - 1860-5974 TI - Improved algorithms for parity and Streett objectives VL - 13 ER - TY - JOUR AB - This paper presents a method for simulating water surface waves as a displacement field on a 2D domain. Our method relies on Lagrangian particles that carry packets of water wave energy; each packet carries information about an entire group of wave trains, as opposed to only a single wave crest. Our approach is unconditionally stable and can simulate high resolution geometric details. This approach also presents a straightforward interface for artistic control, because it is essentially a particle system with intuitive parameters like wavelength and amplitude. Our implementation parallelizes well and runs in real time for moderately challenging scenarios. AU - Jeschke, Stefan AU - Wojtan, Christopher J ID - 470 IS - 4 JF - ACM Transactions on Graphics SN - 07300301 TI - Water wave packets VL - 36 ER - TY - JOUR AB - We present a new algorithm for the statistical model checking of Markov chains with respect to unbounded temporal properties, including full linear temporal logic. The main idea is that we monitor each simulation run on the fly, in order to detect quickly if a bottom strongly connected component is entered with high probability, in which case the simulation run can be terminated early. As a result, our simulation runs are often much shorter than required by termination bounds that are computed a priori for a desired level of confidence on a large state space. In comparison to previous algorithms for statistical model checking our method is not only faster in many cases but also requires less information about the system, namely, only the minimum transition probability that occurs in the Markov chain. In addition, our method can be generalised to unbounded quantitative properties such as mean-payoff bounds. AU - Daca, Przemyslaw AU - Henzinger, Thomas A AU - Kretinsky, Jan AU - Petrov, Tatjana ID - 471 IS - 2 JF - ACM Transactions on Computational Logic (TOCL) SN - 15293785 TI - Faster statistical model checking for unbounded temporal properties VL - 18 ER - TY - JOUR AB - We introduce planar matchings on directed pseudo-line arrangements, which yield a planar set of pseudo-line segments such that only matching-partners are adjacent. By translating the planar matching problem into a corresponding stable roommates problem we show that such matchings always exist. Using our new framework, we establish, for the first time, a complete, rigorous definition of weighted straight skeletons, which are based on a so-called wavefront propagation process. We present a generalized and unified approach to treat structural changes in the wavefront that focuses on the restoration of weak planarity by finding planar matchings. AU - Biedl, Therese AU - Huber, Stefan AU - Palfrader, Peter ID - 481 IS - 3-4 JF - International Journal of Computational Geometry and Applications TI - Planar matchings for weighted straight skeletons VL - 26 ER - TY - JOUR AB - We consider the dynamics of a large quantum system of N identical bosons in 3D interacting via a two-body potential of the form N3β-1w(Nβ(x - y)). For fixed 0 = β < 1/3 and large N, we obtain a norm approximation to the many-body evolution in the Nparticle Hilbert space. The leading order behaviour of the dynamics is determined by Hartree theory while the second order is given by Bogoliubov theory. AU - Nam, Phan AU - Napiórkowski, Marcin M ID - 484 IS - 3 JF - Advances in Theoretical and Mathematical Physics SN - 10950761 TI - Bogoliubov correction to the mean-field dynamics of interacting bosons VL - 21 ER - TY - JOUR AB - We prove the universality for the eigenvalue gap statistics in the bulk of the spectrum for band matrices, in the regime where the band width is comparable with the dimension of the matrix, W ~ N. All previous results concerning universality of non-Gaussian random matrices are for mean-field models. By relying on a new mean-field reduction technique, we deduce universality from quantum unique ergodicity for band matrices. AU - Bourgade, Paul AU - Erdös, László AU - Yau, Horng AU - Yin, Jun ID - 483 IS - 3 JF - Advances in Theoretical and Mathematical Physics SN - 10950761 TI - Universality for a class of random band matrices VL - 21 ER - TY - CONF AB - In this paper we study network architecture for unlicensed cellular networking for outdoor coverage in TV white spaces. The main technology proposed for TV white spaces is 802.11af, a Wi-Fi variant adapted for TV frequencies. However, 802.11af is originally designed for improved indoor propagation. We show that long links, typical for outdoor use, exacerbate known Wi-Fi issues, such as hidden and exposed terminal, and significantly reduce its efficiency. Instead, we propose CellFi, an alternative architecture based on LTE. LTE is designed for long-range coverage and throughput efficiency, but it is also designed to operate in tightly controlled and centrally managed networks. CellFi overcomes these problems by designing an LTE-compatible spectrum database component, mandatory for TV white space networking, and introducing an interference management component for distributed coordination. CellFi interference management is compatible with existing LTE mechanisms, requires no explicit communication between base stations, and is more efficient than CSMA for long links. We evaluate our design through extensive real world evaluation on of-the-shelf LTE equipment and simulations. We show that, compared to 802.11af, it increases coverage by 40% and reduces median flow completion times by 2.3x. AU - Baig, Ghufran AU - Radunovic, Bozidar AU - Alistarh, Dan-Adrian AU - Balkwill, Matthew AU - Karagiannis, Thomas AU - Qiu, Lili ID - 487 SN - 978-145035422-6 T2 - Proceedings of the 2017 13th International Conference on emerging Networking EXperiments and Technologies TI - Towards unlicensed cellular networks in TV white spaces ER - TY - JOUR AB - Orientation in space is represented in specialized brain circuits. Persistent head direction signals are transmitted from anterior thalamus to the presubiculum, but the identity of the presubicular target neurons, their connectivity and function in local microcircuits are unknown. Here, we examine how thalamic afferents recruit presubicular principal neurons and Martinotti interneurons, and the ensuing synaptic interactions between these cells. Pyramidal neuron activation of Martinotti cells in superficial layers is strongly facilitating such that high-frequency head directional stimulation efficiently unmutes synaptic excitation. Martinotti-cell feedback plays a dual role: precisely timed spikes may not inhibit the firing of in-tune head direction cells, while exerting lateral inhibition. Autonomous attractor dynamics emerge from a modelled network implementing wiring motifs and timing sensitive synaptic interactions in the pyramidal - Martinotti-cell feedback loop. This inhibitory microcircuit is therefore tuned to refine and maintain head direction information in the presubiculum. AU - Simonnet, Jean AU - Nassar, Mérie AU - Stella, Federico AU - Cohen, Ivan AU - Mathon, Bertrand AU - Boccara, Charlotte AU - Miles, Richard AU - Fricker, Desdemona ID - 514 JF - Nature Communications SN - 20411723 TI - Activity dependent feedback inhibition may maintain head direction signals in mouse presubiculum VL - 8 ER - TY - JOUR AB - The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII2 and CIV (SC I+III2+IV, known as the respirasome), as well as with CIII2 alone (SC I+III2). CIII2 forms a supercomplex with CIV (SC III2+IV) and CV forms dimers (CV2). Recent cryo-EM studies have revealed the structures of SC I+III2+IV and SC I+III2. Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport. AU - Letts, James A AU - Sazanov, Leonid A ID - 515 IS - 10 JF - Nature Structural and Molecular Biology SN - 15459993 TI - Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain VL - 24 ER - TY - JOUR AB - We present an experimental setup that creates a shear flow with zero mean advection velocity achieved by counterbalancing the nonzero streamwise pressure gradient by moving boundaries, which generates plane Couette-Poiseuille flow. We obtain experimental results in the transitional regime for this flow. Using flow visualization, we characterize the subcritical transition to turbulence in Couette-Poiseuille flow and show the existence of turbulent spots generated by a permanent perturbation. Due to the zero mean advection velocity of the base profile, these turbulent structures are nearly stationary. We distinguish two regions of the turbulent spot: the active turbulent core, which is characterized by waviness of the streaks similar to traveling waves, and the surrounding region, which includes in addition the weak undisturbed streaks and oblique waves at the laminar-turbulent interface. We also study the dependence of the size of these two regions on Reynolds number. Finally, we show that the traveling waves move in the downstream (Poiseuille) direction. AU - Klotz, Lukasz AU - Lemoult, Grégoire M AU - Frontczak, Idalia AU - Tuckerman, Laurette AU - Wesfreid, José ID - 513 IS - 4 JF - Physical Review Fluids TI - Couette-Poiseuille flow experiment with zero mean advection velocity: Subcritical transition to turbulence VL - 2 ER - TY - JOUR AB - Cyanobacteria are mostly engineered to be sustainable cell-factories by genetic manipulations alone. Here, by modulating the concentration of allosteric effectors, we focus on increasing product formation without further burdening the cells with increased expression of enzymes. Resorting to a novel 96-well microplate cultivation system for cyanobacteria, and using lactate-producing strains of Synechocystis PCC6803 expressing different l-lactate dehydrogenases (LDH), we titrated the effect of 2,5-anhydro-mannitol supplementation. The latter acts in cells as a nonmetabolizable analogue of fructose 1,6-bisphosphate, a known allosteric regulator of one of the tested LDHs. In this strain (SAA023), we achieved over 2-fold increase of lactate productivity. Furthermore, we observed that as carbon is increasingly deviated during growth toward product formation, there is an increased fixation rate in the population of spontaneous mutants harboring an impaired production pathway. This is a challenge in the development of green cell factories, which may be countered by the incorporation in biotechnological processes of strategies such as the one pioneered here. AU - Du, Wei AU - Angermayr, Andreas AU - Jongbloets, Joeri AU - Molenaar, Douwe AU - Bachmann, Herwig AU - Hellingwerf, Klaas AU - Branco Dos Santos, Filipe ID - 520 IS - 3 JF - ACS Synthetic Biology SN - 21615063 TI - Nonhierarchical flux regulation exposes the fitness burden associated with lactate production in Synechocystis sp. PCC6803 VL - 6 ER - TY - JOUR AB - Let X and Y be proper metric spaces. We show that a coarsely n-to-1 map f:X→Y induces an n-to-1 map of Higson coronas. This viewpoint turns out to be successful in showing that the classical dimension raising theorems hold in large scale; that is, if f:X→Y is a coarsely n-to-1 map between proper metric spaces X and Y then asdim(Y)≤asdim(X)+n−1. Furthermore we introduce coarsely open coarsely n-to-1 maps, which include the natural quotient maps via a finite group action, and prove that they preserve the asymptotic dimension. AU - Austin, Kyle AU - Virk, Ziga ID - 521 JF - Topology and its Applications SN - 01668641 TI - Higson compactification and dimension raising VL - 215 ER - TY - JOUR AB - We investigate the complexity of finding an embedded non-orientable surface of Euler genus g in a triangulated 3-manifold. This problem occurs both as a natural question in low-dimensional topology, and as a first non-trivial instance of embeddability of complexes into 3-manifolds. We prove that the problem is NP-hard, thus adding to the relatively few hardness results that are currently known in 3-manifold topology. In addition, we show that the problem lies in NP when the Euler genus g is odd, and we give an explicit algorithm in this case. AU - Burton, Benjamin AU - De Mesmay, Arnaud N AU - Wagner, Uli ID - 534 IS - 4 JF - Discrete & Computational Geometry SN - 01795376 TI - Finding non-orientable surfaces in 3-Manifolds VL - 58 ER - TY - JOUR AB - Optogenetik und Photopharmakologie ermöglichen präzise räumliche und zeitliche Kontrolle von Proteinwechselwirkung und -funktion in Zellen und Tieren. Optogenetische Methoden, die auf grünes Licht ansprechen und zum Trennen von Proteinkomplexen geeignet sind, sind nichtweitläufig verfügbar, würden jedoch mehrfarbige Experimente zur Beantwortung von biologischen Fragestellungen ermöglichen. Hier demonstrieren wir die Verwendung von Cobalamin(Vitamin B12)-bindenden Domänen von bakteriellen CarH-Transkriptionsfaktoren zur Grünlicht-induzierten Dissoziation von Rezeptoren. Fusioniert mit dem Fibroblasten-W achstumsfaktor-Rezeptor 1 führten diese im Dunkeln in kultivierten Zellen zu Signalaktivität durch Oligomerisierung, welche durch Beleuchten umgehend aufgehoben wurde. In Zebrafischembryonen, die einen derartigen Rezeptor exprimieren, ermöglichte grünes Licht die Kontrolle über abnormale Signalaktivität während der Embryonalentwicklung. AU - Kainrath, Stephanie AU - Stadler, Manuela AU - Gschaider-Reichhart, Eva AU - Distel, Martin AU - Janovjak, Harald L ID - 538 IS - 16 JF - Angewandte Chemie TI - Grünlicht-induzierte Rezeptorinaktivierung durch Cobalamin-bindende Domänen VL - 129 ER - TY - JOUR AB - RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass-spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/-mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host. AU - Khamina, Kseniya AU - Lercher, Alexander AU - Caldera, Michael AU - Schliehe, Christopher AU - Vilagos, Bojan AU - Sahin, Mehmet AU - Kosack, Lindsay AU - Bhattacharya, Anannya AU - Májek, Peter AU - Stukalov, Alexey AU - Sacco, Roberto AU - James, Leo AU - Pinschewer, Daniel AU - Bennett, Keiryn AU - Menche, Jörg AU - Bergthaler, Andreas ID - 540 IS - 12 JF - PLoS Pathogens SN - 15537366 TI - Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein VL - 13 ER - TY - JOUR AB - We consider Markov decision processes (MDPs) with multiple limit-average (or mean-payoff) objectives. There exist 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 optimization with respect to both objectives at once, thus unifying the existing semantics. Precisely, the goal is to optimize the expectation while ensuring the satisfaction constraint. Our problem captures the notion of optimization with respect to strategies that are risk-averse (i.e., ensure certain probabilistic guarantee). Our main results are as follows: First, we present algorithms for the decision problems 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. Second, 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 - Křetínská, Zuzana AU - Kretinsky, Jan ID - 466 IS - 2 JF - Logical Methods in Computer Science SN - 18605974 TI - Unifying two views on multiple mean-payoff objectives in Markov decision processes VL - 13 ER - TY - JOUR 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 or in any other known 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 runtime 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 - 467 IS - 4 JF - ACM Transactions on Computational Logic (TOCL) SN - 15293785 TI - Nested weighted automata VL - 18 ER - TY - JOUR AB - The edit distance between two words w 1 , w 2 is the minimal number of word operations (letter insertions, deletions, and substitutions) necessary to transform w 1 to w 2 . The edit distance generalizes to languages L 1 , L 2 , where the edit distance from L 1 to L 2 is the minimal number k such that for every word from L 1 there exists a word in L 2 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 the following problems: (1) deciding whether, for a given threshold k , the edit distance from a pushdown automaton to a finite automaton is at most k , and (2) deciding whether the edit distance from a pushdown automaton to a finite automaton is finite. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Ibsen-Jensen, Rasmus AU - Otop, Jan ID - 465 IS - 3 JF - Logical Methods in Computer Science SN - 18605974 TI - Edit distance for pushdown automata VL - 13 ER - TY - JOUR AB - The fixation probability is the probability that a new mutant introduced in a homogeneous population eventually takes over the entire population. The fixation probability is a fundamental quantity of natural selection, and known to depend on the population structure. Amplifiers of natural selection are population structures which increase the fixation probability of advantageous mutants, as compared to the baseline case of well-mixed populations. In this work we focus on symmetric population structures represented as undirected graphs. In the regime of undirected graphs, the strongest amplifier known has been the Star graph, and the existence of undirected graphs with stronger amplification properties has remained open for over a decade. In this work we present the Comet and Comet-swarm families of undirected graphs. We show that for a range of fitness values of the mutants, the Comet and Cometswarm graphs have fixation probability strictly larger than the fixation probability of the Star graph, for fixed population size and at the limit of large populations, respectively. AU - Pavlogiannis, Andreas AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 512 IS - 1 JF - Scientific Reports SN - 20452322 TI - Amplification on undirected population structures: Comets beat stars VL - 7 ER - TY - JOUR AB - A fundamental algorithmic problem at the heart of static analysis is Dyck reachability. The input is a graph where the edges are labeled with different types of opening and closing parentheses, and the reachability information is computed via paths whose parentheses are properly matched. We present new results for Dyck reachability problems with applications to alias analysis and data-dependence analysis. Our main contributions, that include improved upper bounds as well as lower bounds that establish optimality guarantees, are as follows: First, we consider Dyck reachability on bidirected graphs, which is the standard way of performing field-sensitive points-to analysis. Given a bidirected graph with n nodes and m edges, we present: (i) an algorithm with worst-case running time O(m + n · α(n)), where α(n) is the inverse Ackermann function, improving the previously known O(n2) time bound; (ii) a matching lower bound that shows that our algorithm is optimal wrt to worst-case complexity; and (iii) an optimal average-case upper bound of O(m) time, improving the previously known O(m · logn) bound. Second, we consider the problem of context-sensitive data-dependence analysis, where the task is to obtain analysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almost linear time, after which the contribution of the library in the complexity of the client analysis is only linear, and only wrt the number of call sites. Third, we prove that combinatorial algorithms for Dyck reachability on general graphs with truly sub-cubic bounds cannot be obtained without obtaining sub-cubic combinatorial algorithms for Boolean Matrix Multiplication, which is a long-standing open problem. Thus we establish that the existing combinatorial algorithms for Dyck reachability are (conditionally) optimal for general graphs. We also show that the same hardness holds for graphs of constant treewidth. Finally, we provide a prototype implementation of our algorithms for both alias analysis and data-dependence analysis. Our experimental evaluation demonstrates that the new algorithms significantly outperform all existing methods on the two problems, over real-world benchmarks. AU - Chatterjee, Krishnendu AU - Choudhary, Bhavya AU - Pavlogiannis, Andreas ID - 10416 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - Optimal Dyck reachability for data-dependence and Alias analysis VL - 2 ER - TY - GEN AB - A fundamental algorithmic problem at the heart of static analysis is Dyck reachability. The input is a graphwhere the edges are labeled with different types of opening and closing parentheses, and the reachabilityinformation is computed via paths whose parentheses are properly matched. We present new results for Dyckreachability problems with applications to alias analysis and data-dependence analysis. Our main contributions,that include improved upper bounds as well as lower bounds that establish optimality guarantees, are asfollows:First, we consider Dyck reachability on bidirected graphs, which is the standard way of performing field-sensitive points-to analysis. Given a bidirected graph withnnodes andmedges, we present: (i) an algorithmwith worst-case running timeO(m+n·α(n)), whereα(n)is the inverse Ackermann function, improving thepreviously knownO(n2)time bound; (ii) a matching lower bound that shows that our algorithm is optimalwrt to worst-case complexity; and (iii) an optimal average-case upper bound ofO(m)time, improving thepreviously knownO(m·logn)bound.Second, we consider the problem of context-sensitive data-dependence analysis, where the task is to obtainanalysis summaries of library code in the presence of callbacks. Our algorithm preprocesses libraries in almostlinear time, after which the contribution of the library in the complexity of the client analysis is only linear,and only wrt the number of call sites.Third, we prove that combinatorial algorithms for Dyck reachability on general graphs with truly sub-cubic bounds cannot be obtained without obtaining sub-cubic combinatorial algorithms for Boolean MatrixMultiplication, which is a long-standing open problem. Thus we establish that the existing combinatorialalgorithms for Dyck reachability are (conditionally) optimal for general graphs. We also show that the samehardness holds for graphs of constant treewidth.Finally, we provide a prototype implementation of our algorithms for both alias analysis and data-dependenceanalysis. Our experimental evaluation demonstrates that the new algorithms significantly outperform allexisting methods on the two problems, over real-world benchmarks. AU - Chatterjee, Krishnendu AU - Choudhary, Bhavya AU - Pavlogiannis, Andreas ID - 5455 SN - 2664-1690 TI - Optimal Dyck reachability for data-dependence and alias analysis ER - TY - GEN AB - In this report the implementation of the institutional data repository IST DataRep at IST Austria will be covered: Starting with the research phase when requirements for a repository were established, the procedure of choosing a repository-software and its customization based on the results of user-testings will be discussed. Followed by reflections on the marketing strategies in regard of impact, and at the end sharing some experiences of one year operating IST DataRep. AU - Barbara Petritsch ID - 5450 TI - Implementing the institutional data repository IST DataRep ER - TY - JOUR AB - We present a new dynamic partial-order reduction method for stateless model checking of concurrent programs. A common approach for exploring program behaviors relies on enumerating the traces of the program, without storing the visited states (aka stateless exploration). As the number of distinct traces grows exponentially, dynamic partial-order reduction (DPOR) techniques have been successfully used to partition the space of traces into equivalence classes (Mazurkiewicz partitioning), with the goal of exploring only few representative traces from each class. We introduce a new equivalence on traces under sequential consistency semantics, which we call the observation equivalence. Two traces are observationally equivalent if every read event observes the same write event in both traces. While the traditional Mazurkiewicz equivalence is control-centric, our new definition is data-centric. We show that our observation equivalence is coarser than the Mazurkiewicz equivalence, and in many cases even exponentially coarser. We devise a DPOR exploration of the trace space, called data-centric DPOR, based on the observation equivalence. AU - Chalupa, Marek AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Sinha, Nishant AU - Vaidya, Kapil ID - 10417 IS - POPL JF - Proceedings of the ACM on Programming Languages TI - Data-centric dynamic partial order reduction VL - 2 ER - TY - GEN AB - We present a new dynamic partial-order reduction method for stateless model checking of concurrent programs. A common approach for exploring program behaviors relies on enumerating the traces of the program, without storing the visited states (aka stateless exploration). As the number of distinct traces grows exponentially, dynamic partial-order reduction (DPOR) techniques have been successfully used to partition the space of traces into equivalence classes (Mazurkiewicz partitioning), with the goal of exploring only few representative traces from each class. We introduce a new equivalence on traces under sequential consistency semantics, which we call the observation equivalence. Two traces are observationally equivalent if every read event observes the same write event in both traces. While the traditional Mazurkiewicz equivalence is control-centric, our new definition is data-centric. We show that our observation equivalence is coarser than the Mazurkiewicz equivalence, and in many cases even exponentially coarser. We devise a DPOR exploration of the trace space, called data-centric DPOR, based on the observation equivalence. 1. For acyclic architectures, our algorithm is guaranteed to explore exactly one representative trace from each observation class, while spending polynomial time per class. Hence, our algorithm is optimal wrt the observation equivalence, and in several cases explores exponentially fewer traces than any enumerative method based on the Mazurkiewicz equivalence. 2. For cyclic architectures, we consider an equivalence between traces which is finer than the observation equivalence; but coarser than the Mazurkiewicz equivalence, and in some cases is exponentially coarser. Our data-centric DPOR algorithm remains optimal under this trace equivalence. Finally, we perform a basic experimental comparison between the existing Mazurkiewicz-based DPOR and our data-centric DPOR on a set of academic benchmarks. Our results show a significant reduction in both running time and the number of explored equivalence classes. AU - Chalupa, Marek AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Sinha, Nishant AU - Vaidya, Kapil ID - 5456 SN - 2664-1690 TI - Data-centric dynamic partial order reduction ER - TY - CONF AB - Evolutionary graph theory studies the evolutionary dynamics in a population structure given as a connected graph. Each node of the graph represents an individual of the population, and edges determine how offspring are placed. We consider the classical birth-death Moran process where there are two types of individuals, namely, the residents with fitness 1 and mutants with fitness r. The fitness indicates the reproductive strength. The evolutionary dynamics happens as follows: in the initial step, in a population of all resident individuals a mutant is introduced, and then at each step, an individual is chosen proportional to the fitness of its type to reproduce, and the offspring replaces a neighbor uniformly at random. The process stops when all individuals are either residents or mutants. The probability that all individuals in the end are mutants is called the fixation probability, which is a key factor in the rate of evolution. We consider the problem of approximating the fixation probability. The class of algorithms that is extremely relevant for approximation of the fixation probabilities is the Monte-Carlo simulation of the process. Previous results present a polynomial-time Monte-Carlo algorithm for undirected graphs when r is given in unary. First, we present a simple modification: instead of simulating each step, we discard ineffective steps, where no node changes type (i.e., either residents replace residents, or mutants replace mutants). Using the above simple modification and our result that the number of effective steps is concentrated around the expected number of effective steps, we present faster polynomial-time Monte-Carlo algorithms for undirected graphs. Our algorithms are always at least a factor O(n2/ log n) faster as compared to the previous algorithms, where n is the number of nodes, and is polynomial even if r is given in binary. We also present lower bounds showing that the upper bound on the expected number of effective steps we present is asymptotically tight for undirected graphs. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus AU - Nowak, Martin ID - 551 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Faster Monte Carlo algorithms for fixation probability of the Moran process on undirected graphs VL - 83 ER - TY - CONF AB - Graph games provide the foundation for modeling and synthesis of reactive processes. Such games are played over graphs where the vertices are controlled by two adversarial players. We consider graph games where the objective of the first player is the conjunction of a qualitative objective (specified as a parity condition) and a quantitative objective (specified as a meanpayoff condition). There are two variants of the problem, namely, the threshold problem where the quantitative goal is to ensure that the mean-payoff value is above a threshold, and the value problem where the quantitative goal is to ensure the optimal mean-payoff value; in both cases ensuring the qualitative parity objective. The previous best-known algorithms for game graphs with n vertices, m edges, parity objectives with d priorities, and maximal absolute reward value W for mean-payoff objectives, are as follows: O(nd+1 . m . w) for the threshold problem, and O(nd+2 · m · W) for the value problem. Our main contributions are faster algorithms, and the running times of our algorithms are as follows: O(nd-1 · m ·W) for the threshold problem, and O(nd · m · W · log(n · W)) for the value problem. For mean-payoff parity objectives with two priorities, our algorithms match the best-known bounds of the algorithms for mean-payoff games (without conjunction with parity objectives). Our results are relevant in synthesis of reactive systems with both functional requirement (given as a qualitative objective) and performance requirement (given as a quantitative objective). AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Svozil, Alexander ID - 552 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Faster algorithms for mean-payoff parity games VL - 83 ER - TY - CONF AB - We consider two player, zero-sum, finite-state concurrent reachability games, played 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. Player 1 wins iff a designated goal state is eventually 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: (i) the optimal bound on the patience of optimal and -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. AU - Chatterjee, Krishnendu AU - Hansen, Kristofer AU - Ibsen-Jensen, Rasmus ID - 553 SN - 978-395977046-0 T2 - Leibniz International Proceedings in Informatics TI - Strategy complexity of concurrent safety games VL - 83 ER - TY - JOUR AB - In a recent article (Jentzen et al. 2016 Commun. Math. Sci. 14, 1477–1500 (doi:10.4310/CMS.2016.v14. n6.a1)), it has been established that, for every arbitrarily slow convergence speed and every natural number d ? {4, 5, . . .}, there exist d-dimensional stochastic differential equations with infinitely often differentiable and globally bounded coefficients such that no approximation method based on finitely many observations of the driving Brownian motion can converge in absolute mean to the solution faster than the given speed of convergence. In this paper, we strengthen the above result by proving that this slow convergence phenomenon also arises in two (d = 2) and three (d = 3) space dimensions. AU - Gerencser, Mate AU - Jentzen, Arnulf AU - Salimova, Diyora ID - 560 IS - 2207 JF - Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences SN - 13645021 TI - On stochastic differential equations with arbitrarily slow convergence rates for strong approximation in two space dimensions VL - 473 ER - TY - BOOK AB - This book is a concise and self-contained introduction of recent techniques to prove local spectral universality for large random matrices. Random matrix theory is a fast expanding research area, and this book mainly focuses on the methods that the authors participated in developing over the past few years. Many other interesting topics are not included, and neither are several new developments within the framework of these methods. The authors have chosen instead to present key concepts that they believe are the core of these methods and should be relevant for future applications. They keep technicalities to a minimum to make the book accessible to graduate students. With this in mind, they include in this book the basic notions and tools for high-dimensional analysis, such as large deviation, entropy, Dirichlet form, and the logarithmic Sobolev inequality. AU - Erdös, László AU - Yau, Horng ID - 567 SN - 9-781-4704-3648-3 TI - A Dynamical Approach to Random Matrix Theory VL - 28 ER - TY - JOUR AB - We study robust properties of zero sets of continuous maps f: X → ℝn. Formally, we analyze the family Z< r(f) := (g-1(0): ||g - f|| < r) of all zero sets of all continuous maps g closer to f than r in the max-norm. All of these sets are outside A := (x: |f(x)| ≥ r) and we claim that Z< r(f) is fully determined by A and an element of a certain cohomotopy group which (by a recent result) is computable whenever the dimension of X is at most 2n - 3. By considering all r > 0 simultaneously, the pointed cohomotopy groups form a persistence module-a structure leading to persistence diagrams as in the case of persistent homology or well groups. Eventually, we get a descriptor of persistent robust properties of zero sets that has better descriptive power (Theorem A) and better computability status (Theorem B) than the established well diagrams. Moreover, if we endow every point of each zero set with gradients of the perturbation, the robust description of the zero sets by elements of cohomotopy groups is in some sense the best possible (Theorem C). AU - Franek, Peter AU - Krcál, Marek ID - 568 IS - 2 JF - Homology, Homotopy and Applications SN - 15320073 TI - Persistence of zero sets VL - 19 ER - TY - JOUR AB - Most phenotypes are determined by molecular systems composed of specifically interacting molecules. However, unlike for individual components, little is known about the distributions of mutational effects of molecular systems as a whole. We ask how the distribution of mutational effects of a transcriptional regulatory system differs from the distributions of its components, by first independently, and then simultaneously, mutating a transcription factor and the associated promoter it represses. We find that the system distribution exhibits increased phenotypic variation compared to individual component distributions - an effect arising from intermolecular epistasis between the transcription factor and its DNA-binding site. In large part, this epistasis can be qualitatively attributed to the structure of the transcriptional regulatory system and could therefore be a common feature in prokaryotes. Counter-intuitively, intermolecular epistasis can alleviate the constraints of individual components, thereby increasing phenotypic variation that selection could act on and facilitating adaptive evolution. AU - Lagator, Mato AU - Sarikas, Srdjan AU - Acar, Hande AU - Bollback, Jonathan P AU - Guet, Calin C ID - 570 JF - eLife SN - 2050084X TI - Regulatory network structure determines patterns of intermolecular epistasis VL - 6 ER - TY - JOUR AB - The actomyosin ring generates force to ingress the cytokinetic cleavage furrow in animal cells, yet its filament organization and the mechanism of contractility is not well understood. We quantified actin filament order in human cells using fluorescence polarization microscopy and found that cleavage furrow ingression initiates by contraction of an equatorial actin network with randomly oriented filaments. The network subsequently gradually reoriented actin filaments along the cell equator. This strictly depended on myosin II activity, suggesting local network reorganization by mechanical forces. Cortical laser microsurgery revealed that during cytokinesis progression, mechanical tension increased substantially along the direction of the cell equator, while the network contracted laterally along the pole-to-pole axis without a detectable increase in tension. Our data suggest that an asymmetric increase in cortical tension promotes filament reorientation along the cytokinetic cleavage furrow, which might have implications for diverse other biological processes involving actomyosin rings. AU - Spira, Felix AU - Cuylen Haering, Sara AU - Mehta, Shalin AU - Samwer, Matthias AU - Reversat, Anne AU - Verma, Amitabh AU - Oldenbourg, Rudolf AU - Sixt, Michael K AU - Gerlich, Daniel ID - 569 JF - eLife SN - 2050084X TI - Cytokinesis in vertebrate cells initiates by contraction of an equatorial actomyosin network composed of randomly oriented filaments VL - 6 ER - TY - JOUR AB - Blood platelets are critical for hemostasis and thrombosis and play diverse roles during immune responses. Despite these versatile tasks in mammalian biology, their skills on a cellular level are deemed limited, mainly consisting in rolling, adhesion, and aggregate formation. Here, we identify an unappreciated asset of platelets and show that adherent platelets use adhesion receptors to mechanically probe the adhesive substrate in their local microenvironment. When actomyosin-dependent traction forces overcome substrate resistance, platelets migrate and pile up the adhesive substrate together with any bound particulate material. They use this ability to act as cellular scavengers, scanning the vascular surface for potential invaders and collecting deposited bacteria. Microbe collection by migrating platelets boosts the activity of professional phagocytes, exacerbating inflammatory tissue injury in sepsis. This assigns platelets a central role in innate immune responses and identifies them as potential targets to dampen inflammatory tissue damage in clinical scenarios of severe systemic infection. In addition to their role in thrombosis and hemostasis, platelets can also migrate to sites of infection to help trap bacteria and clear the vascular surface. AU - Gärtner, Florian R AU - Ahmad, Zerkah AU - Rosenberger, Gerhild AU - Fan, Shuxia AU - Nicolai, Leo AU - Busch, Benjamin AU - Yavuz, Gökce AU - Luckner, Manja AU - Ishikawa Ankerhold, Hellen AU - Hennel, Roman AU - Benechet, Alexandre AU - Lorenz, Michael AU - Chandraratne, Sue AU - Schubert, Irene AU - Helmer, Sebastian AU - Striednig, Bianca AU - Stark, Konstantin AU - Janko, Marek AU - Böttcher, Ralph AU - Verschoor, Admar AU - Leon, Catherine AU - Gachet, Christian AU - Gudermann, Thomas AU - Mederos Y Schnitzler, Michael AU - Pincus, Zachary AU - Iannacone, Matteo AU - Haas, Rainer AU - Wanner, Gerhard AU - Lauber, Kirsten AU - Sixt, Michael K AU - Massberg, Steffen ID - 571 IS - 6 JF - Cell Press SN - 00928674 TI - Migrating platelets are mechano scavengers that collect and bundle bacteria VL - 171 ER - TY - JOUR AB - In this review, we summarize the different biosynthesis-related pathways that contribute to the regulation of endogenous auxin in plants. We demonstrate that all known genes involved in auxin biosynthesis also have a role in root formation, from the initiation of a root meristem during embryogenesis to the generation of a functional root system with a primary root, secondary lateral root branches and adventitious roots. Furthermore, the versatile adaptation of root development in response to environmental challenges is mediated by both local and distant control of auxin biosynthesis. In conclusion, auxin homeostasis mediated by spatial and temporal regulation of auxin biosynthesis plays a central role in determining root architecture. AU - Olatunji, Damilola AU - Geelen, Danny AU - Verstraeten, Inge ID - 572 IS - 12 JF - International Journal of Molecular Sciences TI - Control of endogenous auxin levels in plant root development VL - 18 ER - TY - CHAP AB - Different distance metrics produce Voronoi diagrams with different properties. It is a well-known that on the (real) 2D plane or even on any 3D plane, a Voronoi diagram (VD) based on the Euclidean distance metric produces convex Voronoi regions. In this paper, we first show that this metric produces a persistent VD on the 2D digital plane, as it comprises digitally convex Voronoi regions and hence correctly approximates the corresponding VD on the 2D real plane. Next, we show that on a 3D digital plane D, the Euclidean metric spanning over its voxel set does not guarantee a digital VD which is persistent with the real-space VD. As a solution, we introduce a novel concept of functional-plane-convexity, which is ensured by the Euclidean metric spanning over the pedal set of D. Necessary proofs and some visual result have been provided to adjudge the merit and usefulness of the proposed concept. AU - Biswas, Ranita AU - Bhowmick, Partha ID - 5803 SN - 0302-9743 T2 - Combinatorial image analysis TI - Construction of persistent Voronoi diagram on 3D digital plane VL - 10256 ER - TY - CONF AB - Tunneling of a particle through a potential barrier remains one of the most remarkable quantum phenomena. Owing to advances in laser technology, electric fields comparable to those electrons experience in atoms are readily generated and open opportunities to dynamically investigate the process of electron tunneling through the potential barrier formed by the superposition of both laser and atomic fields. Attosecond-time and angstrom-space resolution of the strong laser-field technique allow to address fundamental questions related to tunneling, which are still open and debated: Which time is spent under the barrier and what momentum is picked up by the particle in the meantime? In this combined experimental and theoretical study we demonstrate that for strong-field ionization the leading quantum mechanical Wigner treatment for the time resolved description of tunneling is valid. We achieve a high sensitivity on the tunneling barrier and unambiguously isolate its effects by performing a differential study of two systems with almost identical tunneling geometry. Moreover, working with a low frequency laser, we essentially limit the non-adiabaticity of the process as a major source of uncertainty. The agreement between experiment and theory implies two substantial corrections with respect to the widely employed quasiclassical treatment: In addition to a non-vanishing longitudinal momentum along the laser field-direction we provide clear evidence for a non-zero tunneling time delay. This addresses also the fundamental question how the transition occurs from the tunnel barrier to free space classical evolution of the ejected electron. AU - Camus, Nicolas AU - Yakaboylu, Enderalp AU - Fechner, Lutz AU - Klaiber, Michael AU - Laux, Martin AU - Mi, Yonghao AU - Hatsagortsyan, Karen AU - Pfeifer, Thomas AU - Keitel, Cristoph AU - Moshammer, Robert ID - 313 IS - 1 SN - 17426588 TI - Experimental evidence for Wigner's tunneling time VL - 999 ER - TY - JOUR AB - The first hundred attoseconds of the electron dynamics during strong field tunneling ionization are investigated. We quantify theoretically how the electron’s classical trajectories in the continuum emerge from the tunneling process and test the results with those achieved in parallel from attoclock measurements. An especially high sensitivity on the tunneling barrier is accomplished here by comparing the momentum distributions of two atomic species of slightly deviating atomic potentials (argon and krypton) being ionized under absolutely identical conditions with near-infrared laser pulses (1300 nm). The agreement between experiment and theory provides clear evidence for a nonzero tunneling time delay and a nonvanishing longitudinal momentum of the electron at the “tunnel exit.” AU - Camus, Nicolas AU - Yakaboylu, Enderalp AU - Fechner, Lutz AU - Klaiber, Michael AU - Laux, Martin AU - Mi, Yonghao AU - Hatsagortsyan, Karen Z. AU - Pfeifer, Thomas AU - Keitel, Christoph H. AU - Moshammer, Robert ID - 6013 IS - 2 JF - Physical Review Letters SN - 0031-9007 TI - Experimental evidence for quantum tunneling time VL - 119 ER - TY - CONF AB - Position based cryptography (PBC), proposed in the seminal work of Chandran, Goyal, Moriarty, and Ostrovsky (SIAM J. Computing, 2014), aims at constructing cryptographic schemes in which the identity of the user is his geographic position. Chandran et al. construct PBC schemes for secure positioning and position-based key agreement in the bounded-storage model (Maurer, J. Cryptology, 1992). Apart from bounded memory, their security proofs need a strong additional restriction on the power of the adversary: he cannot compute joint functions of his inputs. Removing this assumption is left as an open problem. We show that an answer to this question would resolve a long standing open problem in multiparty communication complexity: finding a function that is hard to compute with low communication complexity in the simultaneous message model, but easy to compute in the fully adaptive model. On a more positive side: we also show some implications in the other direction, i.e.: we prove that lower bounds on the communication complexity of certain multiparty problems imply existence of PBC primitives. Using this result we then show two attractive ways to “bypass” our hardness result: the first uses the random oracle model, the second weakens the locality requirement in the bounded-storage model to online computability. The random oracle construction is arguably one of the simplest proposed so far in this area. Our results indicate that constructing improved provably secure protocols for PBC requires a better understanding of multiparty communication complexity. This is yet another example where negative results in one area (in our case: lower bounds in multiparty communication complexity) can be used to construct secure cryptographic schemes. AU - Brody, Joshua AU - Dziembowski, Stefan AU - Faust, Sebastian AU - Pietrzak, Krzysztof Z ED - Kalai, Yael ED - Reyzin, Leonid ID - 605 SN - 978-331970499-9 TI - Position based cryptography and multiparty communication complexity VL - 10677 ER - TY - CHAP AB - In several settings of physics and chemistry one has to deal with molecules interacting with some kind of an external environment, be it a gas, a solution, or a crystal surface. Understanding molecular processes in the presence of such a many-particle bath is inherently challenging, and usually requires large-scale numerical computations. Here, we present an alternative approach to the problem, based on the notion of the angulon quasiparticle. We show that molecules rotating inside superfluid helium nanodroplets and Bose–Einstein condensates form angulons, and therefore can be described by straightforward solutions of a simple microscopic Hamiltonian. Casting the problem in the language of angulons allows us not only to greatly simplify it, but also to gain insights into the origins of the observed phenomena and to make predictions for future experimental studies. AU - Lemeshko, Mikhail AU - Schmidt, Richard ED - Dulieu, Oliver ED - Osterwalder, Andreas ID - 604 SN - 20413181 T2 - Cold Chemistry: Molecular Scattering and Reactivity Near Absolute Zero TI - Molecular impurities interacting with a many-particle environment: From ultracold gases to helium nanodroplets VL - 11 ER - TY - CONF AB - Several cryptographic schemes and applications are based on functions that are both reasonably efficient to compute and moderately hard to invert, including client puzzles for Denial-of-Service protection, password protection via salted hashes, or recent proof-of-work blockchain systems. Despite their wide use, a definition of this concept has not yet been distilled and formalized explicitly. Instead, either the applications are proven directly based on the assumptions underlying the function, or some property of the function is proven, but the security of the application is argued only informally. The goal of this work is to provide a (universal) definition that decouples the efforts of designing new moderately hard functions and of building protocols based on them, serving as an interface between the two. On a technical level, beyond the mentioned definitions, we instantiate the model for four different notions of hardness. We extend the work of Alwen and Serbinenko (STOC 2015) by providing a general tool for proving security for the first notion of memory-hard functions that allows for provably secure applications. The tool allows us to recover all of the graph-theoretic techniques developed for proving security under the older, non-composable, notion of security used by Alwen and Serbinenko. As an application of our definition of moderately hard functions, we prove the security of two different schemes for proofs of effort (PoE). We also formalize and instantiate the concept of a non-interactive proof of effort (niPoE), in which the proof is not bound to a particular communication context but rather any bit-string chosen by the prover. AU - Alwen, Joel F AU - Tackmann, Björn ED - Kalai, Yael ED - Reyzin, Leonid ID - 609 SN - 978-331970499-9 TI - Moderately hard functions: Definition, instantiations, and applications VL - 10677 ER - TY - JOUR AB - The fact that the complete graph K5 does not embed in the plane has been generalized in two independent directions. On the one hand, the solution of the classical Heawood problem for graphs on surfaces established that the complete graph Kn embeds in a closed surface M (other than the Klein bottle) if and only if (n−3)(n−4) ≤ 6b1(M), where b1(M) is the first Z2-Betti number of M. On the other hand, van Kampen and Flores proved that the k-skeleton of the n-dimensional simplex (the higher-dimensional analogue of Kn+1) embeds in R2k if and only if n ≤ 2k + 1. Two decades ago, Kühnel conjectured that the k-skeleton of the n-simplex embeds in a compact, (k − 1)-connected 2k-manifold with kth Z2-Betti number bk only if the following generalized Heawood inequality holds: (k+1 n−k−1) ≤ (k+1 2k+1)bk. This is a common generalization of the case of graphs on surfaces as well as the van Kampen–Flores theorem. In the spirit of Kühnel’s conjecture, we prove that if the k-skeleton of the n-simplex embeds in a compact 2k-manifold with kth Z2-Betti number bk, then n ≤ 2bk(k 2k+2)+2k+4. This bound is weaker than the generalized Heawood inequality, but does not require the assumption that M is (k−1)-connected. Our results generalize to maps without q-covered points, in the spirit of Tverberg’s theorem, for q a prime power. Our proof uses a result of Volovikov about maps that satisfy a certain homological triviality condition. AU - Goaoc, Xavier AU - Mabillard, Isaac AU - Paták, Pavel AU - Patakova, Zuzana AU - Tancer, Martin AU - Wagner, Uli ID - 610 IS - 2 JF - Israel Journal of Mathematics TI - On generalized Heawood inequalities for manifolds: A van Kampen–Flores type nonembeddability result VL - 222 ER - TY - JOUR AB - Small RNAs (sRNAs) regulate genes in plants and animals. Here, we show that population-wide differences in color patterns in snapdragon flowers are caused by an inverted duplication that generates sRNAs. The complexity and size of the transcripts indicate that the duplication represents an intermediate on the pathway to microRNA evolution. The sRNAs repress a pigment biosynthesis gene, creating a yellow highlight at the site of pollinator entry. The inverted duplication exhibits steep clines in allele frequency in a natural hybrid zone, showing that the allele is under selection. Thus, regulatory interactions of evolutionarily recent sRNAs can be acted upon by selection and contribute to the evolution of phenotypic diversity. AU - Bradley, Desmond AU - Xu, Ping AU - Mohorianu, Irina AU - Whibley, Annabel AU - Field, David AU - Tavares, Hugo AU - Couchman, Matthew AU - Copsey, Lucy AU - Carpenter, Rosemary AU - Li, Miaomiao AU - Li, Qun AU - Xue, Yongbiao AU - Dalmay, Tamas AU - Coen, Enrico ID - 611 IS - 6365 JF - Science SN - 00368075 TI - Evolution of flower color pattern through selection on regulatory small RNAs VL - 358 ER - TY - JOUR AB - Bacteria in groups vary individually, and interact with other bacteria and the environment to produce population-level patterns of gene expression. Investigating such behavior in detail requires measuring and controlling populations at the single-cell level alongside precisely specified interactions and environmental characteristics. Here we present an automated, programmable platform that combines image-based gene expression and growth measurements with on-line optogenetic expression control for hundreds of individual Escherichia coli cells over days, in a dynamically adjustable environment. This integrated platform broadly enables experiments that bridge individual and population behaviors. We demonstrate: (i) population structuring by independent closed-loop control of gene expression in many individual cells, (ii) cell-cell variation control during antibiotic perturbation, (iii) hybrid bio-digital circuits in single cells, and freely specifiable digital communication between individual bacteria. These examples showcase the potential for real-time integration of theoretical models with measurement and control of many individual cells to investigate and engineer microbial population behavior. AU - Chait, Remy P AU - Ruess, Jakob AU - Bergmiller, Tobias AU - Tkacik, Gasper AU - Guet, Calin C ID - 613 IS - 1 JF - Nature Communications SN - 20411723 TI - Shaping bacterial population behavior through computer interfaced control of individual cells VL - 8 ER - TY - JOUR AB - We show that the Dyson Brownian Motion exhibits local universality after a very short time assuming that local rigidity and level repulsion of the eigenvalues hold. These conditions are verified, hence bulk spectral universality is proven, for a large class of Wigner-like matrices, including deformed Wigner ensembles and ensembles with non-stochastic variance matrices whose limiting densities differ from Wigner's semicircle law. AU - Erdös, László AU - Schnelli, Kevin ID - 615 IS - 4 JF - Annales de l'institut Henri Poincare (B) Probability and Statistics SN - 02460203 TI - Universality for random matrix flows with time dependent density VL - 53 ER - TY - CHAP AB - Genetic factors might be largely responsible for the development of autism spectrum disorder (ASD) that alone or in combination with specific environmental risk factors trigger the pathology. Multiple mutations identified in ASD patients that impair synaptic function in the central nervous system are well studied in animal models. How these mutations might interact with other risk factors is not fully understood though. Additionally, how systems outside of the brain are altered in the context of ASD is an emerging area of research. Extracerebral influences on the physiology could begin in utero and contribute to changes in the brain and in the development of other body systems and further lead to epigenetic changes. Therefore, multiple recent studies have aimed at elucidating the role of gene-environment interactions in ASD. Here we provide an overview on the extracerebral systems that might play an important associative role in ASD and review evidence regarding the potential roles of inflammation, trace metals, metabolism, genetic susceptibility, enteric nervous system function and the microbiota of the gastrointestinal (GI) tract on the development of endophenotypes in animal models of ASD. By influencing environmental conditions, it might be possible to reduce or limit the severity of ASD pathology. AU - Hill Yardin, Elisa AU - Mckeown, Sonja AU - Novarino, Gaia AU - Grabrucker, Andreas ED - Schmeisser, Michael ED - Boekers, Tobias ID - 623 SN - 03015556 T2 - Translational Anatomy and Cell Biology of Autism Spectrum Disorder TI - Extracerebral dysfunction in animal models of autism spectrum disorder VL - 224 ER - TY - JOUR AB - Our focus here is on the infinitesimal model. In this model, one or several quantitative traits are described as the sum of a genetic and a non-genetic component, the first being distributed within families as a normal random variable centred at the average of the parental genetic components, and with a variance independent of the parental traits. Thus, the variance that segregates within families is not perturbed by selection, and can be predicted from the variance components. This does not necessarily imply that the trait distribution across the whole population should be Gaussian, and indeed selection or population structure may have a substantial effect on the overall trait distribution. One of our main aims is to identify some general conditions on the allelic effects for the infinitesimal model to be accurate. We first review the long history of the infinitesimal model in quantitative genetics. Then we formulate the model at the phenotypic level in terms of individual trait values and relationships between individuals, but including different evolutionary processes: genetic drift, recombination, selection, mutation, population structure, …. We give a range of examples of its application to evolutionary questions related to stabilising selection, assortative mating, effective population size and response to selection, habitat preference and speciation. We provide a mathematical justification of the model as the limit as the number M of underlying loci tends to infinity of a model with Mendelian inheritance, mutation and environmental noise, when the genetic component of the trait is purely additive. We also show how the model generalises to include epistatic effects. We prove in particular that, within each family, the genetic components of the individual trait values in the current generation are indeed normally distributed with a variance independent of ancestral traits, up to an error of order 1∕M. Simulations suggest that in some cases the convergence may be as fast as 1∕M. AU - Barton, Nicholas H AU - Etheridge, Alison AU - Véber, Amandine ID - 626 JF - Theoretical Population Biology SN - 00405809 TI - The infinitesimal model: Definition derivation and implications VL - 118 ER - TY - CHAP AB - In the analysis of reactive systems a quantitative objective assigns a real value to every trace of the system. The value decision problem for a quantitative objective requires a trace whose value is at least a given threshold, and the exact value decision problem requires a trace whose value is exactly the threshold. We compare the computational complexity of the value and exact value decision problems for classical quantitative objectives, such as sum, discounted sum, energy, and mean-payoff for two standard models of reactive systems, namely, graphs and graph games. AU - Chatterjee, Krishnendu AU - Doyen, Laurent AU - Henzinger, Thomas A ED - Aceto, Luca ED - Bacci, Giorgio ED - Ingólfsdóttir, Anna ED - Legay, Axel ED - Mardare, Radu ID - 625 SN - 0302-9743 T2 - Models, Algorithms, Logics and Tools TI - The cost of exactness in quantitative reachability VL - 10460 ER - TY - JOUR AB - Bacteria adapt to adverse environmental conditions by altering gene expression patterns. Recently, a novel stress adaptation mechanism has been described that allows Escherichia coli to alter gene expression at the post-transcriptional level. The key player in this regulatory pathway is the endoribonuclease MazF, the toxin component of the toxin-antitoxin module mazEF that is triggered by various stressful conditions. In general, MazF degrades the majority of transcripts by cleaving at ACA sites, which results in the retardation of bacterial growth. Furthermore, MazF can process a small subset of mRNAs and render them leaderless by removing their ribosome binding site. MazF concomitantly modifies ribosomes, making them selective for the translation of leaderless mRNAs. In this study, we employed fluorescent reporter-systems to investigate mazEF expression during stressful conditions, and to infer consequences of the mRNA processing mediated by MazF on gene expression at the single-cell level. Our results suggest that mazEF transcription is maintained at low levels in single cells encountering adverse conditions, such as antibiotic stress or amino acid starvation. Moreover, using the grcA mRNA as a model for MazF-mediated mRNA processing, we found that MazF activation promotes heterogeneity in the grcA reporter expression, resulting in a subpopulation of cells with increased levels of GrcA reporter protein. AU - Nikolic, Nela AU - Didara, Zrinka AU - Moll, Isabella ID - 624 IS - 9 JF - PeerJ SN - 21678359 TI - MazF activation promotes translational heterogeneity of the grcA mRNA in Escherichia coli populations VL - 2017 ER - TY - CONF AB - We consider the problem of developing automated techniques for solving recurrence relations to aid the expected-runtime analysis of programs. The motivation is that several classical textbook algorithms have quite efficient expected-runtime complexity, whereas the corresponding worst-case bounds are either inefficient (e.g., Quick-Sort), or completely ineffective (e.g., Coupon-Collector). Since the main focus of expected-runtime analysis is to obtain efficient bounds, we consider bounds that are either logarithmic, linear or almost-linear (O(log n), O(n), O(n · log n), respectively, where n represents the input size). Our main contribution is an efficient (simple linear-time algorithm) sound approach for deriving such expected-runtime bounds for the analysis of recurrence relations induced by randomized algorithms. The experimental results show that our approach can efficiently derive asymptotically optimal expected-runtime bounds for recurrences of classical randomized algorithms, including Randomized-Search, Quick-Sort, Quick-Select, Coupon-Collector, where the worst-case bounds are either inefficient (such as linear as compared to logarithmic expected-runtime complexity, or quadratic as compared to linear or almost-linear expected-runtime complexity), or ineffective. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Murhekar, Aniket ED - Majumdar, Rupak ED - Kunčak, Viktor ID - 628 SN - 978-331963386-2 TI - Automated recurrence analysis for almost linear expected runtime bounds VL - 10426 ER - TY - CHAP AB - Even simple cells like bacteria have precisely regulated cellular anatomies, which allow them to grow, divide and to respond to internal or external cues with high fidelity. How spatial and temporal intracellular organization in prokaryotic cells is achieved and maintained on the basis of locally interacting proteins still remains largely a mystery. Bulk biochemical assays with purified components and in vivo experiments help us to approach key cellular processes from two opposite ends, in terms of minimal and maximal complexity. However, to understand how cellular phenomena emerge, that are more than the sum of their parts, we have to assemble cellular subsystems step by step from the bottom up. Here, we review recent in vitro reconstitution experiments with proteins of the bacterial cell division machinery and illustrate how they help to shed light on fundamental cellular mechanisms that constitute spatiotemporal order and regulate cell division. AU - Loose, Martin AU - Zieske, Katja AU - Schwille, Petra ID - 629 T2 - Prokaryotic Cytoskeletons TI - Reconstitution of protein dynamics involved in bacterial cell division VL - 84 ER - TY - CONF AB - Background: Standards have become available to share semantically encoded vital parameters from medical devices, as required for example by personal healthcare records. Standardised sharing of biosignal data largely remains open. Objectives: The goal of this work is to explore available biosignal file format and data exchange standards and profiles, and to conceptualise end-To-end solutions. Methods: The authors reviewed and discussed available biosignal file format standards with other members of international standards development organisations (SDOs). Results: A raw concept for standards based acquisition, storage, archiving and sharing of biosignals was developed. The GDF format may serve for storing biosignals. Signals can then be shared using FHIR resources and may be stored on FHIR servers or in DICOM archives, with DICOM waveforms as one possible format. Conclusion: Currently a group of international SDOs (e.g. HL7, IHE, DICOM, IEEE) is engaged in intensive discussions. This discussion extends existing work that already was adopted by large implementer communities. The concept presented here only reports the current status of the discussion in Austria. The discussion will continue internationally, with results to be expected over the coming years. AU - Sauermann, Stefan AU - David, Veronika AU - Schlögl, Alois AU - Egelkraut, Reinhard AU - Frohner, Matthias AU - Pohn, Birgit AU - Urbauer, Philipp AU - Mense, Alexander ID - 630 SN - 978-161499758-0 TI - Biosignals standards and FHIR: The way to go VL - 236 ER - TY - JOUR AB - We consider a 2D quantum system of N bosons in a trapping potential |x|s, interacting via a pair potential of the form N2β−1 w(Nβ x). We show that for all 0 < β < (s + 1)/(s + 2), the leading order behavior of ground states of the many-body system is described in the large N limit by the corresponding cubic nonlinear Schrödinger energy functional. Our result covers the focusing case (w < 0) where even the stability of the many-body system is not obvious. This answers an open question mentioned by X. Chen and J. Holmer for harmonic traps (s = 2). Together with the BBGKY hierarchy approach used by these authors, our result implies the convergence of the many-body quantum dynamics to the focusing NLS equation with harmonic trap for all 0 < β < 3/4. AU - Lewin, Mathieu AU - Nam, Phan AU - Rougerie, Nicolas ID - 632 IS - 6 JF - Proceedings of the American Mathematical Society TI - A note on 2D focusing many boson systems VL - 145 ER -