TY - DATA AB - Input files and scripts from "Evolution of gene dosage on the Z-chromosome of schistosome parasites" by Picard M.A.L., et al (2018). AU - Vicoso, Beatriz ID - 5586 KW - schistosoma KW - Z-chromosome KW - gene expression TI - Input files and scripts from "Evolution of gene dosage on the Z-chromosome of schistosome parasites" by Picard M.A.L., et al (2018) ER - TY - DATA AB - Data and scripts are provided in support of the manuscript "Efficient inference of paternity and sibship inference given known maternity via hierarchical clustering", and the associated Python package FAPS, available from www.github.com/ellisztamas/faps. Simulation scripts cover: 1. Performance under different mating scenarios. 2. Comparison with Colony2. 3. Effect of changing the number of Monte Carlo draws The final script covers the analysis of half-sib arrays from wild-pollinated seed in an Antirrhinum majus hybrid zone. AU - Ellis, Thomas ID - 5583 TI - Data and Python scripts supporting Python package FAPS ER - TY - DATA AB - Nela Nikolic, Tobias Bergmiller, Alexandra Vandervelde, Tanino G. Albanese, Lendert Gelens, and Isabella Moll (2018) “Autoregulation of mazEF expression underlies growth heterogeneity in bacterial populations” Nucleic Acids Research, doi: 10.15479/AT:ISTA:74; microscopy experiments by Tobias Bergmiller; image and data analysis by Nela Nikolic. AU - Bergmiller, Tobias AU - Nikolic, Nela ID - 5569 KW - microscopy KW - microfluidics TI - Time-lapse microscopy data ER - TY - JOUR AB - Which properties of metabolic networks can be derived solely from stoichiometry? Predictive results have been obtained by flux balance analysis (FBA), by postulating that cells set metabolic fluxes to maximize growth rate. Here we consider a generalization of FBA to single-cell level using maximum entropy modeling, which we extend and test experimentally. Specifically, we define for Escherichia coli metabolism a flux distribution that yields the experimental growth rate: the model, containing FBA as a limit, provides a better match to measured fluxes and it makes a wide range of predictions: on flux variability, regulation, and correlations; on the relative importance of stoichiometry vs. optimization; on scaling relations for growth rate distributions. We validate the latter here with single-cell data at different sub-inhibitory antibiotic concentrations. The model quantifies growth optimization as emerging from the interplay of competitive dynamics in the population and regulation of metabolism at the level of single cells. AU - De Martino, Daniele AU - Mc, Andersson Anna AU - Bergmiller, Tobias AU - Guet, Calin C AU - Tkacik, Gasper ID - 161 IS - 1 JF - Nature Communications TI - Statistical mechanics for metabolic networks during steady state growth VL - 9 ER - TY - DATA AB - Supporting material to the article STATISTICAL MECHANICS FOR METABOLIC NETWORKS IN STEADY-STATE GROWTH boundscoli.dat Flux Bounds of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium. polcoli.dat Matrix enconding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium, obtained from the soichiometric matrix by standard linear algebra (reduced row echelon form). ellis.dat Approximate Lowner-John ellipsoid rounding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium obtained with the Lovasz method. point0.dat Center of the approximate Lowner-John ellipsoid rounding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium obtained with the Lovasz method. lovasz.cpp This c++ code file receives in input the polytope of the feasible steady states of a metabolic network, (matrix and bounds), and it gives in output an approximate Lowner-John ellipsoid rounding the polytope with the Lovasz method NB inputs are referred by defaults to the catabolic core of the E.Coli network iAF1260. For further details we refer to PLoS ONE 10.4 e0122670 (2015). sampleHRnew.cpp This c++ code file receives in input the polytope of the feasible steady states of a metabolic network, (matrix and bounds), the ellipsoid rounding the polytope, a point inside and it gives in output a max entropy sampling at fixed average growth rate of the steady states by performing an Hit-and-Run Monte Carlo Markov chain. NB inputs are referred by defaults to the catabolic core of the E.Coli network iAF1260. For further details we refer to PLoS ONE 10.4 e0122670 (2015). AU - De Martino, Daniele AU - Tkacik, Gasper ID - 5587 KW - metabolic networks KW - e.coli core KW - maximum entropy KW - monte carlo markov chain sampling KW - ellipsoidal rounding TI - Supporting materials "STATISTICAL MECHANICS FOR METABOLIC NETWORKS IN STEADY-STATE GROWTH" ER - TY - JOUR AB - The t-haplotype, a mouse meiotic driver found on chromosome 17, has been a model for autosomal segregation distortion for close to a century, but several questions remain regarding its biology and evolutionary history. A recently published set of population genomics resources for wild mice includes several individuals heterozygous for the t-haplotype, which we use to characterize this selfish element at the genomic and transcriptomic level. Our results show that large sections of the t-haplotype have been replaced by standard homologous sequences, possibly due to occasional events of recombination, and that this complicates the inference of its history. As expected for a long genomic segment of very low recombination, the t-haplotype carries an excess of fixed nonsynonymous mutations compared to the standard chromosome. This excess is stronger for regions that have not undergone recent recombination, suggesting that occasional gene flow between the t and the standard chromosome may provide a mechanism to regenerate coding sequences that have accumulated deleterious mutations. Finally, we find that t-complex genes with altered expression largely overlap with deleted or amplified regions, and that carrying a t-haplotype alters the testis expression of genes outside of the t-complex, providing new leads into the pathways involved in the biology of this segregation distorter. AU - Kelemen, Réka K AU - Vicoso, Beatriz ID - 542 IS - 1 JF - Genetics TI - Complex history and differentiation patterns of the t-haplotype, a mouse meiotic driver VL - 208 ER - TY - JOUR AB - Because of the intrinsic randomness of the evolutionary process, a mutant with a fitness advantage has some chance to be selected but no certainty. Any experiment that searches for advantageous mutants will lose many of them due to random drift. It is therefore of great interest to find population structures that improve the odds of advantageous mutants. Such structures are called amplifiers of natural selection: they increase the probability that advantageous mutants are selected. Arbitrarily strong amplifiers guarantee the selection of advantageous mutants, even for very small fitness advantage. Despite intensive research over the past decade, arbitrarily strong amplifiers have remained rare. Here we show how to construct a large variety of them. Our amplifiers are so simple that they could be useful in biotechnology, when optimizing biological molecules, or as a diagnostic tool, when searching for faster dividing cells or viruses. They could also occur in natural population structures. AU - Pavlogiannis, Andreas AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin A. ID - 5751 IS - 1 JF - Communications Biology SN - 2399-3642 TI - Construction of arbitrarily strong amplifiers of natural selection using evolutionary graph theory VL - 1 ER - TY - DATA AB - File S1. Variant Calling Format file of the ingroup: 197 haploid sequences of D. melanogaster from Zambia (Africa) aligned to the D. melanogaster 5.57 reference genome. File S2. Variant Calling Format file of the outgroup: 1 haploid sequence of D. simulans aligned to the D. melanogaster 5.57 reference genome. File S3. Annotations of each transcript in coding regions with SNPeff: Ps (# of synonymous polymorphic sites); Pn (# of non-synonymous polymorphic sites); Ds (# of synonymous divergent sites); Dn (# of non-synonymous divergent sites); DoS; ⍺ MK . All variants were included. File S4. Annotations of each transcript in non-coding regions with SNPeff: Ps (# of synonymous polymorphic sites); Pu (# of UTR polymorphic sites); Ds (# of synonymous divergent sites); Du (# of UTR divergent sites); DoS; ⍺ MK . All variants were included. File S5. Annotations of each transcript in coding regions with SNPGenie: Ps (# of synonymous polymorphic sites); πs (synonymous diversity); Ss_p (total # of synonymous sites in the polymorphism data); Pn (# of non-synonymous polymorphic sites); πn (non-synonymous diversity); Sn_p (total # of non-synonymous sites in the polymorphism data); Ds (# of synonymous divergent sites); ks (synonymous evolutionary rate); Ss_d (total # of synonymous sites in the divergence data); Dn (# of non-synonymous divergent sites); kn (non-synonymous evolutionary rate); Sn_d (total # of non- synonymous sites in the divergence data); DoS; ⍺ MK . All variants were included. File S6. Gene expression values (RPKM summed over all transcripts) for each sample. Values were quantile-normalized across all samples. File S7. Final dataset with all covariates, ⍺ MK , ωA MK and DoS for coding sites, excluding variants below 5% frequency. File S8. Final dataset with all covariates, ⍺ MK , ωA MK and DoS for non-coding sites, excluding variants below 5% frequency. File S9. Final dataset with all covariates, ⍺ EWK , ωA EWK and deleterious SFS for coding sites obtained with the Eyre-Walker and Keightley method on binned data and using all variants. AU - Fraisse, Christelle ID - 5757 KW - (mal)adaptation KW - pleiotropy KW - selective constraint KW - evo-devo KW - gene expression KW - Drosophila melanogaster TI - Supplementary Files for "Pleiotropy modulates the efficacy of selection in Drosophila melanogaster" ER - TY - THES AB - The eigenvalue density of many large random matrices is well approximated by a deterministic measure, the self-consistent density of states. In the present work, we show this behaviour for several classes of random matrices. In fact, we establish that, in each of these classes, the self-consistent density of states approximates the eigenvalue density of the random matrix on all scales slightly above the typical eigenvalue spacing. For large classes of random matrices, the self-consistent density of states exhibits several universal features. We prove that, under suitable assumptions, random Gram matrices and Hermitian random matrices with decaying correlations have a 1/3-Hölder continuous self-consistent density of states ρ on R, which is analytic, where it is positive, and has either a square root edge or a cubic root cusp, where it vanishes. We, thus, extend the validity of the corresponding result for Wigner-type matrices from [4, 5, 7]. We show that ρ is determined as the inverse Stieltjes transform of the normalized trace of the unique solution m(z) to the Dyson equation −m(z) −1 = z − a + S[m(z)] on C N×N with the constraint Im m(z) ≥ 0. Here, z lies in the complex upper half-plane, a is a self-adjoint element of C N×N and S is a positivity-preserving operator on C N×N encoding the first two moments of the random matrix. In order to analyze a possible limit of ρ for N → ∞ and address some applications in free probability theory, we also consider the Dyson equation on infinite dimensional von Neumann algebras. We present two applications to random matrices. We first establish that, under certain assumptions, large random matrices with independent entries have a rotationally symmetric self-consistent density of states which is supported on a centered disk in C. Moreover, it is infinitely often differentiable apart from a jump on the boundary of this disk. Second, we show edge universality at all regular (not necessarily extreme) spectral edges for Hermitian random matrices with decaying correlations. AU - Alt, Johannes ID - 149 SN - 2663-337X TI - Dyson equation and eigenvalue statistics of random matrices ER - 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 - CONF AB - We prove that, at least for the binary erasure channel, the polar-coding paradigm gives rise to codes that not only approach the Shannon limit but, in fact, do so under the best possible scaling of their block length as a function of the gap to capacity. This result exhibits the first known family of binary codes that attain both optimal scaling and quasi-linear complexity of encoding and decoding. Specifically, for any fixed δ > 0, we exhibit binary linear codes that ensure reliable communication at rates within ε > 0 of capacity with block length n = O(1/ε 2+δ ), construction complexity Θ(n), and encoding/decoding complexity Θ(n log n). AU - Fazeli, Arman AU - Hassani, Hamed AU - Mondelli, Marco AU - Vardy, Alexander ID - 6665 T2 - 2018 IEEE Information Theory Workshop TI - Binary linear codes with optimal scaling: Polar codes with large kernels ER - TY - JOUR AB - To maintain genome integrity, segmented double-stranded RNA viruses of the Reoviridae family must accurately select and package a complete set of up to a dozen distinct genomic RNAs. It is thought that the high fidelity segmented genome assembly involves multiple sequence-specific RNA–RNA interactions between single-stranded RNA segment precursors. These are mediated by virus-encoded non-structural proteins with RNA chaperone-like activities, such as rotavirus (RV) NSP2 and avian reovirus σNS. Here, we compared the abilities of NSP2 and σNS to mediate sequence-specific interactions between RV genomic segment precursors. Despite their similar activities, NSP2 successfully promotes inter-segment association, while σNS fails to do so. To understand the mechanisms underlying such selectivity in promoting inter-molecular duplex formation, we compared RNA-binding and helix-unwinding activities of both proteins. We demonstrate that octameric NSP2 binds structured RNAs with high affinity, resulting in efficient intramolecular RNA helix disruption. Hexameric σNS oligomerizes into an octamer that binds two RNAs, yet it exhibits only limited RNA-unwinding activity compared to NSP2. Thus, the formation of intersegment RNA–RNA interactions is governed by both helix-unwinding capacity of the chaperones and stability of RNA structure. We propose that this protein-mediated RNA selection mechanism may underpin the high fidelity assembly of multi-segmented RNA genomes in Reoviridae. AU - Bravo, Jack Peter Kelly AU - Borodavka, Alexander AU - Barth, Anders AU - Calabrese, Antonio N AU - Mojzes, Peter AU - Cockburn, Joseph J B AU - Lamb, Don C AU - Tuma, Roman ID - 15143 IS - 15 JF - Nucleic Acids Research KW - Genetics SN - 0305-1048 TI - Stability of local secondary structure determines selectivity of viral RNA chaperones VL - 46 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 - 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 - 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 AU - Vahid Belarghou, Afshin AU - Šarić, Anđela AU - Idema, Timon ID - 10126 IS - 3 JF - Biophysical Journal KW - biophysics SN - 0006-3495 TI - Curvature mediated interactions in highly curved membranes VL - 112 ER - TY - JOUR AB - We study periodic homogenization by Γ-convergence of integral functionals with integrands W(x,ξ) having no polynomial growth and which are both not necessarily continuous with respect to the space variable and not necessarily convex with respect to the matrix variable. This allows to deal with homogenization of composite hyperelastic materials consisting of two or more periodic components whose the energy densities tend to infinity as the volume of matter tends to zero, i.e., W(x,ξ)=∑j∈J1Vj(x)Hj(ξ) where {Vj}j∈J is a finite family of open disjoint subsets of RN, with |∂Vj|=0 for all j∈J and ∣∣RN∖⋃j∈JVj|=0, and, for each j∈J, Hj(ξ)→∞ as detξ→0. In fact, our results apply to integrands of type W(x,ξ)=a(x)H(ξ) when H(ξ)→∞ as detξ→0 and a∈L∞(RN;[0,∞[) is 1-periodic and is either continuous almost everywhere or not continuous. When a is not continuous, we obtain a density homogenization formula which is a priori different from the classical one by Braides–Müller. Although applications to hyperelasticity are limited due to the fact that our framework is not consistent with the constraint of noninterpenetration of the matter, our results can be of technical interest to analysis of homogenization of integral functionals. AU - Anza Hafsa, Omar AU - Clozeau, Nicolas AU - Mandallena, Jean-Philippe ID - 10175 IS - 2 JF - Annales mathématiques Blaise Pascal SN - 1259-1734 TI - Homogenization of nonconvex unbounded singular integrals VL - 24 ER - TY - JOUR AB - We investigate effects of quasiparticle poisoning in a Majorana island with strong tunnel coupling to normal-metal leads. In addition to the main Coulomb blockade diamonds, "shadow" diamonds appear, shifted by 1e in gate voltage, consistent with transport through an excited (poisoned) state of the island. Comparison to a simple model yields an estimate of parity lifetime for the strongly coupled island (∼1 μs) and sets a bound for a weakly coupled island (>10 μs). Fluctuations in the gate-voltage spacing of Coulomb peaks at high field, reflecting Majorana hybridization, are enhanced by the reduced lever arm at strong coupling. When converted from gate voltage to energy units, fluctuations are consistent with previous measurements. AU - Albrecht, S M AU - Hansen, Esben AU - Higginbotham, Andrew P AU - Kuemmeth, Ferdinand AU - Jespersen, Thomas AU - Nygård, Jesper AU - Krogstrup, Peter AU - Danon, Jeroen AU - Flensberg, Karsten AU - Marcus, Charles ID - 103 IS - 13 JF - APS Physics, Physical Review Letters TI - Transport signatures of quasiparticle poisoning in a majorana island VL - 118 ER - TY - JOUR AB - Eukaryotic cells are densely packed with macromolecular complexes and intertwining organelles, continually transported and reshaped. Intriguingly, organelles avoid clashing and entangling with each other in such limited space. Mitochondria form extensive networks constantly remodeled by fission and fusion. Here, we show that mitochondrial fission is triggered by mechanical forces. Mechano-stimulation of mitochondria – via encounter with motile intracellular pathogens, via external pressure applied by an atomic force microscope, or via cell migration across uneven microsurfaces – results in the recruitment of the mitochondrial fission machinery, and subsequent division. We propose that MFF, owing to affinity for narrow mitochondria, acts as a membrane-bound force sensor to recruit the fission machinery to mechanically strained sites. Thus, mitochondria adapt to the environment by sensing and responding to biomechanical cues. Our findings that mechanical triggers can be coupled to biochemical responses in membrane dynamics may explain how organelles orderly cohabit in the crowded cytoplasm. AU - Helle, Sebastian Carsten Johannes AU - Feng, Qian AU - Aebersold, Mathias J AU - Hirt, Luca AU - Grüter, Raphael R AU - Vahid, Afshin AU - Sirianni, Andrea AU - Mostowy, Serge AU - Snedeker, Jess G AU - Šarić, Anđela AU - Idema, Timon AU - Zambelli, Tomaso AU - Kornmann, Benoît ID - 10370 JF - eLife KW - general immunology and microbiology KW - general biochemistry KW - genetics and molecular biology KW - general medicine KW - general neuroscience SN - 2050-084X TI - Mechanical force induces mitochondrial fission VL - 6 ER - TY - JOUR AB - Biological membranes have a central role in mediating the organization of membrane-curving proteins, a dynamic process that has proven to be challenging to probe experimentally. Using atomic force microscopy, we capture the hierarchically organized assemblies of Bin/amphiphysin/Rvs (BAR) proteins on supported lipid membranes. Their structure reveals distinct long linear aggregates of proteins, regularly spaced by up to 300 nm. Employing accurate free-energy calculations from large-scale coarse-grained computer simulations, we found that the membrane mediates the interaction among protein filaments as a combination of short- and long-ranged interactions. The long-ranged component acts at strikingly long distances, giving rise to a variety of micron-sized ordered patterns. This mechanism may contribute to the long-ranged spatiotemporal control of membrane remodeling by proteins in the cell. AU - Simunovic, Mijo AU - Šarić, Anđela AU - Henderson, J. Michael AU - Lee, Ka Yee C. AU - Voth, Gregory A. ID - 10369 IS - 12 JF - ACS Central Science KW - general chemical engineering KW - general chemistry SN - 2374-7943 TI - Long-range organization of membrane-curving proteins VL - 3 ER - TY - JOUR AB - Electric charges are conserved. The same would be expected to hold for magnetic charges, yet magnetic monopoles have never been observed. It is therefore surprising that the laws of nonequilibrium thermodynamics, combined with Maxwell’s equations, suggest that colloidal particles heated or cooled in certain polar or paramagnetic solvents may behave as if they carry an electric/magnetic charge. Here, we present numerical simulations that show that the field distribution around a pair of such heated/cooled colloidal particles agrees quantitatively with the theoretical predictions for a pair of oppositely charged electric or magnetic monopoles. However, in other respects, the nonequilibrium colloidal particles do not behave as monopoles: They cannot be moved by a homogeneous applied field. The numerical evidence for the monopole-like fields around heated/cooled colloidal particles is crucial because the experimental and numerical determination of forces between such colloidal particles would be complicated by the presence of other effects, such as thermophoresis. AU - Wirnsberger, Peter AU - Fijan, Domagoj AU - Lightwood, Roger A. AU - Šarić, Anđela AU - Dellago, Christoph AU - Frenkel, Daan ID - 10373 IS - 19 JF - Proceedings of the National Academy of Sciences KW - multidisciplinary SN - 0027-8424 TI - Numerical evidence for thermally induced monopoles VL - 114 ER - TY - JOUR AB - The formation of filaments from naturally occurring protein molecules is a process at the core of a range of functional and aberrant biological phenomena, such as the assembly of the cytoskeleton or the appearance of aggregates in Alzheimer's disease. The macroscopic behaviour associated with such processes is remarkably diverse, ranging from simple nucleated growth to highly cooperative processes with a well-defined lagtime. Thus, conventionally, different molecular mechanisms have been used to explain the self-assembly of different proteins. Here we show that this range of behaviour can be quantitatively captured by a single unifying Petri net that describes filamentous growth in terms of aggregate number and aggregate mass concentrations. By considering general features associated with a particular network connectivity, we are able to establish directly the rate-determining steps of the overall aggregation reaction from the system's scaling behaviour. We illustrate the power of this framework on a range of different experimental and simulated aggregating systems. The approach is general and will be applicable to any future extensions of the reaction network of filamentous self-assembly. AU - Meisl, Georg AU - Rajah, Luke AU - Cohen, Samuel A. I. AU - Pfammatter, Manuela AU - Šarić, Anđela AU - Hellstrand, Erik AU - Buell, Alexander K. AU - Aguzzi, Adriano AU - Linse, Sara AU - Vendruscolo, Michele AU - Dobson, Christopher M. AU - Knowles, Tuomas P. J. ID - 10374 IS - 10 JF - Chemical Science KW - general chemistry SN - 2041-6520 TI - Scaling behaviour and rate-determining steps in filamentous self-assembly VL - 8 ER - TY - JOUR AB - Cellular membranes exhibit a large variety of shapes, strongly coupled to their function. Many biological processes involve dynamic reshaping of membranes, usually mediated by proteins. This interaction works both ways: while proteins influence the membrane shape, the membrane shape affects the interactions between the proteins. To study these membrane-mediated interactions on closed and anisotropically curved membranes, we use colloids adhered to ellipsoidal membrane vesicles as a model system. We find that two particles on a closed system always attract each other, and tend to align with the direction of largest curvature. Multiple particles form arcs, or, at large enough numbers, a complete ring surrounding the vesicle in its equatorial plane. The resulting vesicle shape resembles a snowman. Our results indicate that these physical interactions on membranes with anisotropic shapes can be exploited by cells to drive macromolecules to preferred regions of cellular or intracellular membranes, and utilized to initiate dynamic processes such as cell division. The same principle could be used to find the midplane of an artificial vesicle, as a first step towards dividing it into two equal parts. AU - Vahid, Afshin AU - Šarić, Anđela AU - Idema, Timon ID - 10375 IS - 28 JF - Soft Matter KW - condensed matter physics KW - general chemistry SN - 1744-683X TI - Curvature variation controls particle aggregation on fluid vesicles VL - 13 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 - THES AB - The superconducting state of matter enables one to observe quantum effects on the macroscopic scale and hosts many fascinating phenomena. Topological defects of the superconducting order parameter, such as vortices and fluxoid states in multiply connected structures, are often the key ingredients of these phenomena. This dissertation describes a new mode of magnetic force microscopy (Φ0-MFM) for investigating vortex and fluxoid sates in mesoscopic superconducting (SC) structures. The technique relies on the magneto-mechanical coupling of a MFM cantilever to the motion of fluxons. The novelty of the technique is that a magnetic particle attached to the cantilever is used not only to sense the state of a SC structure, but also as a primary source of the inhomogeneous magnetic field which induces that state. Φ0-MFM enables us to map the transitions between tip-induced states during a scan: at the positions of the tip, where the two lowest energy states become degenerate, small oscillations of the tip drive the transitions between these states, which causes a significant shift in the resonant frequency and dissipation of the cantilever. For narrow-wall aluminum rings, the mapped fluxoid transitions form concentric contours on a scan. We show that the changes in the cantilever resonant frequency and dissipation are well-described by a stochastic resonance (SR) of cantilever-driven thermally activated phase slips (TAPS). The SR model allows us to experimentally determine the rate of TAPS and compare it to the Langer-Ambegaokar-McCumber-Halperin (LAMH) theory for TAPS in 1D superconducting structures. Further, we use the SR model to qualitatively study the effects of a locally applied magnetic field on the phase slip rate in rings containing constrictions. The states with multiple vortices or winding numbers could be useful for the development of novel superconducting devices, or the study of vortex interactions and interference effects. Using Φ0-MFM allows us to induce, probe and control fluxoid states in thin wall structures comprised of multiple loops. We show that Φ0-MFM images of the fluxoid transitions allow us to identify the underlying states and to investigate their energetics and dynamics even in complicated structures. AU - Polshyn, Hryhoriy ID - 10663 KW - physics KW - superconductivity KW - magnetic force microscopy KW - phase slips TI - Magnetic force microscopy studies of mesoscopic superconducting structures ER - TY - CONF AB - New ways to investigate and manipulate fluxoid and vortex states of mesoscopic superconducting structures are of great interest. The states with multiple vortices or winding numbers could be useful for the study of vortex interactions and interference effects, the braiding of Majorana bound states by winding vortices, and the development of novel superconducting devices. We demonstrate a methodology based on magnetic force microscopy that allows us to induce, probe and control fluxoid states in thin wall structures comprised of multiple loops. By using micro-magnet as a source of inhomogeneous magnetic field, we can efficiently explore the configuration space of fluxoid states. Scanning over the structure reveals the energy crossing points of the lowest laying fluxoid states. This is due the strong interaction of cantilever with thermally activated fluxoid transitions at points of degeneracy. We show that measured patterns of fluxoid transitions allow to identify the states, investigate their energetics, and manipulate them. Further, we show that the dynamics of driven fluxoid transitions can be described by stochastic resonance model, which provides a unique way of measuring fluxoid transition rate and related energy barrier for chosen transitions even in complicated structures AU - Polshyn, Hryhoriy AU - Naibert, Tyler AU - Budakian, Raffi ID - 10745 IS - 4 SN - 0003-0503 T2 - APS March Meeting 2017 TI - Probing and controlling fluxoid states in multiply-connected mesoscopic superconducting structures VL - 62 ER - TY - CHAP AU - Wenzl, Bernhard ED - Parker, Joshua ED - Poole, Ralph ID - 1075 SN - 978-3643908124 T2 - Austria and America: 20th-Century Cross-Cultural Encounters TI - An American in Allied-occupied Austria: John Dos Passos Reports on "The Vienna Frontier" VL - 15 ER - TY - JOUR AB - Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML. AU - Franks, Tobias M. AU - McCloskey, Asako AU - Shokhirev, Maxim Nikolaievich AU - Benner, Chris AU - Rathore, Annie AU - HETZER, Martin W ID - 11066 IS - 22 JF - Genes & Development KW - Developmental Biology KW - Genetics SN - 0890-9369 TI - Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells VL - 31 ER - TY - JOUR AB - Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate. AU - Toda, Tomohisa AU - Hsu, Jonathan Y. AU - Linker, Sara B. AU - Hu, Lauren AU - Schafer, Simon T. AU - Mertens, Jerome AU - Jacinto, Filipe V. AU - HETZER, Martin W AU - Gage, Fred H. ID - 11067 IS - 5 JF - Cell Stem Cell KW - Cell Biology KW - Genetics KW - Molecular Medicine SN - 1934-5909 TI - Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells VL - 21 ER - TY - JOUR AB - Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging. AU - Buchwalter, Abigail AU - HETZER, Martin W ID - 11065 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry SN - 2041-1723 TI - Nucleolar expansion and elevated protein translation in premature aging VL - 8 ER - TY - JOUR AB - We present spectroscopic follow-up observations of CR7 with ALMA, targeted at constraining the infrared (IR) continuum and [C II]158 mm line-emission at high spatial resolution matched to the HST/WFC3 imaging. CR7 is a luminous Lyα emitting galaxy at z = 6.6 that consists of three separated UV-continuum components. Our observations reveal several well-separated components of [C II] emission. The two most luminous components in [C II] coincide with the brightest UV components (A and B), blueshifted by »150 km s−1 with respect to the peak of Lyα emission. Other [C II] components are observed close to UV clumps B and C and are blueshifted by »300 and ≈80 km s−1 with respect to the systemic redshift. We do not detect FIR continuum emission due to dust with a 3σ limiting luminosity LIR T L d 35 K 3.1 10 = <´ 10 ( ) . This allows us to mitigate uncertainties in the dust-corrected SFR and derive SFRs for the three UV clumps A, B, and C of 28, 5, and 7 M yr−1. All clumps have [C II] luminosities consistent within the scatter observed in the local relation between SFR and L[ ] C II , implying that strong Lyα emission does not necessarily anti-correlate with [C II] luminosity. Combining our measurements with the literature, we show that galaxies with blue UV slopes have weaker [C II] emission at fixed SFR, potentially due to their lower metallicities and/or higher photoionization. Comparison with hydrodynamical simulations suggests that CR7ʼs clumps have metallicities of 0.1 Z Z 0.2 < < . The observed ISM structure of CR7 indicates that we are likely witnessing the build up of a central galaxy in the early universe through complex accretion of satellites. AU - Matthee, Jorryt J AU - Sobral, D. AU - Boone, F. AU - Röttgering, H. AU - Schaerer, D. AU - Girard, M. AU - Pallottini, A. AU - Vallini, L. AU - Ferrara, A. AU - Darvish, B. AU - Mobasher, B. ID - 11518 IS - 2 JF - The Astrophysical Journal KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - dark ages KW - reionization KW - first stars – galaxies: formation – galaxies: high-redshift – galaxies: ISM – galaxies: kinematics and dynamics SN - 0004-637X TI - ALMA reveals metals yet no dust within multiple components in CR7 VL - 851 ER - TY - JOUR AB - We present the CAlibrating LYMan-α with Hα (CALYMHA) pilot survey and new results on Lyman α (Lyα) selected galaxies at z ∼ 2. We use a custom-built Lyα narrow-band filter at the Isaac Newton Telescope, designed to provide a matched volume coverage to the z = 2.23 Hα HiZELS survey. Here, we present the first results for the COSMOS and UDS fields. Our survey currently reaches a 3σ line flux limit of ∼4 × 10−17 erg s−1 cm−2, and a Lyα luminosity limit of ∼1042.3 erg s−1. We find 188 Lyα emitters over 7.3 × 105 Mpc3, but also find significant numbers of other line-emitting sources corresponding to He II, C III] and C IV emission lines. These sources are important contaminants, and we carefully remove them, unlike most previous studies. We find that the Lyα luminosity function at z = 2.23 is very well described by a Schechter function up to LLy α ≈ 1043 erg s−1 with L∗=1042.59+0.16−0.08 erg s−1, ϕ∗=10−3.09+0.14−0.34 Mpc−3 and α = −1.75 ± 0.25. Above LLy α ≈ 1043 erg s−1, the Lyα luminosity function becomes power-law like, driven by X-ray AGN. We find that Lyα-selected emitters have a high escape fraction of 37 ± 7 per cent, anticorrelated with Lyα luminosity and correlated with Lyα equivalent width. Lyα emitters have ubiquitous large (≈40 kpc) Lyα haloes, ∼2 times larger than their Hα extents. By directly comparing our Lyα and Hα luminosity functions, we find that the global/overall escape fraction of Lyα photons (within a 13 kpc radius) from the full population of star-forming galaxies is 5.1 ± 0.2 per cent at the peak of the star formation history. An extra 3.3 ± 0.3 per cent of Lyα photons likely still escape, but at larger radii. AU - Sobral, David AU - Matthee, Jorryt J AU - Best, Philip AU - Stroe, Andra AU - Röttgering, Huub AU - Oteo, Iván AU - Smail, Ian AU - Morabito, Leah AU - Paulino-Afonso, Ana ID - 11562 IS - 1 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: haloes KW - galaxies: high-redshift KW - galaxies: luminosity function KW - mass function KW - galaxies: statistics KW - cosmology: observations SN - 0035-8711 TI - The CALYMHA survey: Lyα luminosity function and global escape fraction of Lyα photons at z = 2.23 VL - 466 ER - TY - JOUR AB - While traditionally associated with active galactic nuclei (AGN), the properties of the C II] (λ = 2326 Å), C III] (λ, λ = 1907, 1909 Å) and C IV (λ, λ = 1549, 1551 Å) emission lines are still uncertain as large, unbiased samples of sources are scarce. We present the first blind, statistical study of C II], C III] and C IV emitters at z ∼ 0.68, 1.05, 1.53, respectively, uniformly selected down to a flux limit of ∼4 × 10−17 erg s−1 cm−1 through a narrow-band survey covering an area of ∼1.4 deg2 over COSMOS and UDS. We detect 16 C II], 35 C III] and 17 C IV emitters, whose nature we investigate using optical colours as well as Hubble Space Telescope (HST), X-ray, radio and far-infrared data. We find that z ∼ 0.7 C II] emitters are consistent with a mixture of blue (UV slope β = −2.0 ± 0.4) star-forming (SF) galaxies with discy HST structure and AGN with Seyfert-like morphologies. Bright C II] emitters have individual X-ray detections as well as high average black hole accretion rates (BHARs) of ∼0.1 M⊙ yr−1. C III] emitters at z ∼ 1.05 trace a general population of SF galaxies, with β = −0.8 ± 1.1, a variety of optical morphologies, including isolated and interacting galaxies and low BHAR (<0.02 M⊙ yr−1). Our C IV emitters at z ∼ 1.5 are consistent with young, blue quasars (β ∼ −1.9) with point-like optical morphologies, bright X-ray counterparts and large BHAR (0.8  M⊙ yr−1). We also find some surprising C II], C III] and C IV emitters with rest-frame equivalent widths (EWs) that could be as large as 50–100 Å. AGN or spatial offsets between the UV continuum stellar disc and the line-emitting regions may explain the large EW. These bright C II], C III] and C IV emitters are ideal candidates for spectroscopic follow-up to fully unveil their nature. AU - Stroe, Andra AU - Sobral, David AU - Matthee, Jorryt J AU - Calhau, João AU - Oteo, Ivan ID - 11566 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: active KW - galaxies: high-redshift KW - quasars: emission lines KW - galaxies: star formation KW - cosmology: observations SN - 0035-8711 TI - A 1.4 deg2 blind survey for C II], C III] and C IV at z ∼ 0.7–1.5 – I. Nature, morphologies and equivalent widths VL - 471 ER - TY - JOUR AB - We study the production rate of ionizing photons of a sample of 588 Hα emitters (HAEs) and 160 Lyman-α emitters (LAEs) at z = 2.2 in the COSMOS field in order to assess the implied emissivity from galaxies, based on their ultraviolet (UV) luminosity. By exploring the rest-frame Lyman Continuum (LyC) with GALEX/NUV data, we find fesc < 2.8 (6.4) per cent through median (mean) stacking. By combining the Hα luminosity density with intergalactic medium emissivity measurements from absorption studies, we find a globally averaged 〈fesc〉 of 5.9+14.5−4.2 per cent at z = 2.2 if we assume HAEs are the only source of ionizing photons. We find similarly low values of the global 〈fesc〉 at z ≈ 3–5, also ruling out a high 〈fesc〉 at z < 5. These low escape fractions allow us to measure ξion, the number of produced ionizing photons per unit UV luminosity, and investigate how this depends on galaxy properties. We find a typical ξion ≈ 1024.77 ± 0.04 Hz erg−1 for HAEs and ξion ≈ 1025.14 ± 0.09 Hz erg−1 for LAEs. LAEs and low-mass HAEs at z = 2.2 show similar values of ξion as typically assumed in the reionization era, while the typical HAE is three times less ionizing. Due to an increasing ξion with increasing EW(Hα), ξion likely increases with redshift. This evolution alone is fully in line with the observed evolution of ξion between z ≈ 2 and 5, indicating a typical value of ξion ≈ 1025.4 Hz erg−1 in the reionization era. AU - Matthee, Jorryt J AU - Sobral, David AU - Best, Philip AU - Khostovan, Ali Ahmad AU - Oteo, Iván AU - Bouwens, Rychard AU - Röttgering, Huub ID - 11564 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - cosmology: observations KW - dark ages KW - reionization KW - first stars SN - 0035-8711 TI - The production and escape of Lyman-Continuum radiation from star-forming galaxies at z ∼ 2 and their redshift evolution VL - 465 ER - TY - JOUR AB - Recently, the C III] and C IV emission lines have been observed in galaxies in the early Universe (z > 5), providing new ways to measure their redshift and study their stellar populations and active galactic nuclei (AGN). We explore the first blind C II], C III] and C IV survey (z ∼ 0.68, 1.05, 1.53, respectively) presented in Stroe et al. (2017). We derive luminosity functions (LF) and study properties of C II], C III] and C IV line emitters through comparisons to the LFs of H α and Ly α emitters, UV selected star-forming (SF) galaxies and quasars at similar redshifts. The C II] LF at z ∼ 0.68 is equally well described by a Schechter or a power-law LF, characteristic of a mixture of SF and AGN activity. The C III] LF (z ∼ 1.05) is consistent to a scaled down version of the Schechter H α and Ly α LF at their redshift, indicating a SF origin. In stark contrast, the C IV LF at z ∼ 1.53 is well fit by a power-law, quasar-like LF. We find that the brightest UV sources (MUV < −22) will universally have C III] and C IV emission. However, on average, C III] and C IV are not as abundant as H α or Ly α emitters at the same redshift, with cosmic average ratios of ∼0.02–0.06 to H α and ∼0.01–0.1 to intrinsic Ly α. We predict that the C III] and C IV lines can only be truly competitive in confirming high-redshift candidates when the hosts are intrinsically bright and the effective Ly α escape fraction is below 1 per cent. While C III] and C IV were proposed as good tracers of young, relatively low-metallicity galaxies typical of the early Universe, we find that, at least at z ∼ 1.5, C IV is exclusively hosted by AGN/quasars, especially at large line equivalent widths. AU - Stroe, Andra AU - Sobral, David AU - Matthee, Jorryt J AU - Calhau, João AU - Oteo, Ivan ID - 11567 IS - 3 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: active KW - galaxies: high redshift KW - galaxies: luminosity function KW - mass function KW - quasars: emission lines KW - star formation KW - cosmology: observations SN - 0035-8711 TI - A 1.4 deg2 blind survey for C II], C III] and C IV at z ∼ 0.7–1.5 – II. Luminosity functions and cosmic average line ratios VL - 471 ER - TY - JOUR AB - We use the hydrodynamical EAGLE simulation to study the magnitude and origin of the scatter in the stellar mass–halo mass relation for central galaxies. We separate cause and effect by correlating stellar masses in the baryonic simulation with halo properties in a matched dark matter only (DMO) simulation. The scatter in stellar mass increases with redshift and decreases with halo mass. At z = 0.1, it declines from 0.25 dex at M200, DMO ≈ 1011 M⊙ to 0.12 dex at M200, DMO ≈ 1013 M⊙, but the trend is weak above 1012 M⊙. For M200, DMO < 1012.5 M⊙ up to 0.04 dex of the scatter is due to scatter in the halo concentration. At fixed halo mass, a larger stellar mass corresponds to a more concentrated halo. This is likely because higher concentrations imply earlier formation times and hence more time for accretion and star formation, and/or because feedback is less efficient in haloes with higher binding energies. The maximum circular velocity, Vmax, DMO, and binding energy are therefore more fundamental properties than halo mass, meaning that they are more accurate predictors of stellar mass, and we provide fitting formulae for their relations with stellar mass. However, concentration alone cannot explain the total scatter in the Mstar−M200,DMO relation, and it does not explain the scatter in Mstar–Vmax, DMO. Halo spin, sphericity, triaxiality, substructure and environment are also not responsible for the remaining scatter, which thus could be due to more complex halo properties or non-linear/stochastic baryonic effects. AU - Matthee, Jorryt J AU - Schaye, Joop AU - Crain, Robert A. AU - Schaller, Matthieu AU - Bower, Richard AU - Theuns, Tom ID - 11565 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: formation KW - galaxies: haloes KW - cosmology: theory SN - 0035-8711 TI - The origin of scatter in the stellar mass–halo mass relation of central galaxies in the EAGLE simulation VL - 465 ER - TY - JOUR AB - We present a sample of ∼1000 emission-line galaxies at z = 0.4–4.7 from the ∼0.7deg2 High-z Emission-Line Survey in the Boötes field identified with a suite of six narrow-band filters at ≈0.4–2.1 μm. These galaxies have been selected on their Ly α (73), [O II] (285), H β/[O III] (387) or H α (362) emission line, and have been classified with optical to near-infrared colours. A subsample of 98 sources have reliable redshifts from multiple narrow-band (e.g. [O II]–H α) detections and/or spectroscopy. In this survey paper, we present the observations, selection and catalogues of emitters. We measure number densities of Ly α, [O II], H β/[O III] and H α and confirm strong luminosity evolution in star-forming galaxies from z ∼ 0.4 to ∼5, in agreement with previous results. To demonstrate the usefulness of dual-line emitters, we use the sample of dual [O II]–H α emitters to measure the observed [O II]/H α ratio at z = 1.47. The observed [O II]/H α ratio increases significantly from 0.40 ± 0.01 at z = 0.1 to 0.52 ± 0.05 at z = 1.47, which we attribute to either decreasing dust attenuation with redshift, or due to a bias in the (typically) fibre measurements in the local Universe that only measure the central kpc regions. At the bright end, we find that both the H α and Ly α number densities at z ≈ 2.2 deviate significantly from a Schechter form, following a power law. We show that this is driven entirely by an increasing X-ray/active galactic nucleus fraction with line luminosity, which reaches ≈100 per cent at line luminosities L ≳ 3 × 1044 erg s−1. AU - Matthee, Jorryt J AU - Sobral, David AU - Best, Philip AU - Smail, Ian AU - Bian, Fuyan AU - Darvish, Behnam AU - Röttgering, Huub AU - Fan, Xiaohui ID - 11561 IS - 1 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics galaxies KW - active KW - galaxies KW - evolution KW - galaxies KW - high-redshift KW - galaxies KW - luminosity function KW - mass function KW - galaxies: star formation SN - 0035-8711 TI - Boötes-HiZELS: An optical to near-infrared survey of emission-line galaxies at z = 0.4–4.7 VL - 471 ER - TY - JOUR AB - We present spectroscopic follow-up of candidate luminous Ly α emitters (LAEs) at z = 5.7–6.6 in the SA22 field with VLT/X-SHOOTER. We confirm two new luminous LAEs at z = 5.676 (SR6) and z = 6.532 (VR7), and also present HST follow-up of both sources. These sources have luminosities LLy α ≈ 3 × 1043 erg s−1, very high rest-frame equivalent widths of EW0 ≳ 200 Å and narrow Ly α lines (200–340 km s−1). VR7 is the most UV-luminous LAE at z > 6.5, with M1500 = −22.5, even brighter in the UV than CR7. Besides Ly α, we do not detect any other rest-frame UV lines in the spectra of SR6 and VR7, and argue that rest-frame UV lines are easier to observe in bright galaxies with low Ly α equivalent widths. We confirm that Ly α line widths increase with Ly α luminosity at z = 5.7, while there are indications that Ly α lines of faint LAEs become broader at z = 6.6, potentially due to reionization. We find a large spread of up to 3 dex in UV luminosity for >L⋆ LAEs, but find that the Ly α luminosity of the brightest LAEs is strongly related to UV luminosity at z = 6.6. Under basic assumptions, we find that several LAEs at z ≈ 6–7 have Ly α escape fractions ≳ 100  per cent, indicating bursty star formation histories, alternative Ly α production mechanisms, or dust attenuating Ly α emission differently than UV emission. Finally, we present a method to compute ξion, the production efficiency of ionizing photons, and find that LAEs at z ≈ 6–7 have high values of log10(ξion/Hz erg−1) ≈ 25.51 ± 0.09 that may alleviate the need for high Lyman-Continuum escape fractions required for reionization. AU - Matthee, Jorryt J AU - Sobral, David AU - Darvish, Behnam AU - Santos, Sérgio AU - Mobasher, Bahram AU - Paulino-Afonso, Ana AU - Röttgering, Huub AU - Alegre, Lara ID - 11572 IS - 1 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution – galaxies: high-redshift KW - dark ages KW - reionization KW - first stars KW - cosmology: observations SN - 0035-8711 TI - Spectroscopic properties of luminous Ly α emitters at z ≈ 6–7 and comparison to the Lyman-break population VL - 472 ER - TY - JOUR AB - We present dynamical measurements from the KMOS (K-band multi-object spectrograph) Deep Survey (KDS), which comprises 77 typical star-forming galaxies at z ≃ 3.5 in the mass range 9.0 < log (M⋆/M⊙) < 10.5. These measurements constrain the internal dynamics, the intrinsic velocity dispersions (σint) and rotation velocities (VC) of galaxies in the high-redshift Universe. The mean velocity dispersion of the galaxies in our sample is σint=70.8+3.3−3.1kms−1⁠, revealing that the increasing average σint with increasing redshift, reported for z ≲ 2, continues out to z ≃ 3.5. Only 36 ± 8 per cent of our galaxies are rotation-dominated (VC/σint > 1), with the sample average VC/σint value much smaller than at lower redshift. After carefully selecting comparable star-forming samples at multiple epochs, we find that the rotation-dominated fraction evolves with redshift with a z−0.2 dependence. The rotation-dominated KDS galaxies show no clear offset from the local rotation velocity–stellar mass (i.e. VC–M⋆) relation, although a smaller fraction of the galaxies are on the relation due to the increase in the dispersion-dominated fraction. These observations are consistent with a simple equilibrium model picture, in which random motions are boosted in high-redshift galaxies by a combination of the increasing gas fractions, accretion efficiency, specific star formation rate and stellar feedback and which may provide significant pressure support against gravity on the galactic disc scale. AU - Turner, O. J. AU - Cirasuolo, M. AU - Harrison, C. M. AU - McLure, R. J. AU - Dunlop, J. S. AU - Swinbank, A. M. AU - Johnson, H. L. AU - Sobral, D. AU - Matthee, Jorryt J AU - Sharples, R. M. ID - 11573 IS - 2 JF - Monthly Notices of the Royal Astronomical Society KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - galaxies: evolution KW - galaxies: high-redshift KW - galaxies: kinematics and dynamics SN - 0035-8711 TI - The KMOS Deep Survey (KDS) – I. Dynamical measurements of typical star-forming galaxies at z ≃ 3.5 VL - 471 ER - TY - GEN AB - Our understanding of stars through asteroseismic data analysis is limited by our ability to take advantage of the huge amount of observed stars provided by space missions such as CoRoT, Kepler , K2, and soon TESS and PLATO. Global seismic pipelines provide global stellar parameters such as mass and radius using the mean seismic parameters, as well as the effective temperature. These pipelines are commonly used automatically on thousands of stars observed by K2 for 3 months (and soon TESS for at least ∼ 1 month). However, pipelines are not immune from misidentifying noise peaks and stellar oscillations. Therefore, new validation techniques are required to assess the quality of these results. We present a new metric called FliPer (Flicker in Power), which takes into account the average variability at all measured time scales. The proper calibration of FliPer enables us to obtain good estimations of global stellar parameters such as surface gravity that are robust against the influence of noise peaks and hence are an excellent way to find faults in asteroseismic pipelines. AU - Bugnet, Lisa Annabelle AU - Garcia, R. A. AU - Davies, G. R. AU - Mathur, S. AU - Corsaro, E. ID - 11633 KW - asteroseismology - methods KW - data analysis - stars KW - oscillations T2 - arXiv TI - FliPer: Checking the reliability of global seismic parameters from automatic pipelines ER - TY - CONF AB - Diffusions and related random walk procedures are of central importance in many areas of machine learning, data analysis, and applied mathematics. Because they spread mass agnostically at each step in an iterative manner, they can sometimes spread mass “too aggressively,” thereby failing to find the “right” clusters. We introduce a novel Capacity Releasing Diffusion (CRD) Process, which is both faster and stays more local than the classical spectral diffusion process. As an application, we use our CRD Process to develop an improved local algorithm for graph clustering. Our local graph clustering method can find local clusters in a model of clustering where one begins the CRD Process in a cluster whose vertices are connected better internally than externally by an O(log2n) factor, where n is the number of nodes in the cluster. Thus, our CRD Process is the first local graph clustering algorithm that is not subject to the well-known quadratic Cheeger barrier. Our result requires a certain smoothness condition, which we expect to be an artifact of our analysis. Our empirical evaluation demonstrates improved results, in particular for realistic social graphs where there are moderately good—but not very good—clusters. AU - Wang, Di AU - Fountoulakis, Kimon AU - Henzinger, Monika H AU - Mahoney, Michael W. AU - Rao , Satish ID - 11651 T2 - Proceedings of the 34th International Conference on Machine Learning TI - Capacity releasing diffusion for speed and locality VL - 70 ER - TY - JOUR AB - We study the problem of maintaining a breadth-first spanning tree (BFS tree) in partially dynamic distributed networks modeling a sequence of either failures or additions of communication links (but not both). We present deterministic (1+ϵ)-approximation algorithms whose amortized time (over some number of link changes) is sublinear in D, the maximum diameter of the network. Our technique also leads to a deterministic (1+ϵ)-approximate incremental algorithm for single-source shortest paths in the sequential (usual RAM) model. Prior to our work, the state of the art was the classic exact algorithm of Even and Shiloach (1981), which is optimal under some assumptions (Roditty and Zwick 2011; Henzinger et al. 2015). Our result is the first to show that, in the incremental setting, this bound can be beaten in certain cases if some approximation is allowed. AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 11665 IS - 4 JF - ACM Transactions on Algorithms SN - 1549-6325 TI - Sublinear-time maintenance of breadth-first spanning trees in partially dynamic networks VL - 13 ER - TY - JOUR AB - We study the problem of maximizing a monotone submodular function with viability constraints. This problem originates from computational biology, where we are given a phylogenetic tree over a set of species and a directed graph, the so-called food web, encoding viability constraints between these species. These food webs usually have constant depth. The goal is to select a subset of k species that satisfies the viability constraints and has maximal phylogenetic diversity. As this problem is known to be NP-hard, we investigate approximation algorithms. We present the first constant factor approximation algorithm if the depth is constant. Its approximation ratio is (1−1e√). This algorithm not only applies to phylogenetic trees with viability constraints but for arbitrary monotone submodular set functions with viability constraints. Second, we show that there is no (1−1/e+ϵ)-approximation algorithm for our problem setting (even for additive functions) and that there is no approximation algorithm for a slight extension of this setting. AU - Dvořák, Wolfgang AU - Henzinger, Monika H AU - Williamson, David P. ID - 11676 IS - 1 JF - Algorithmica KW - Approximation algorithms KW - Submodular functions KW - Phylogenetic diversity KW - Viability constraints SN - 0178-4617 TI - Maximizing a submodular function with viability constraints VL - 77 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 - CONF AB - In recent years it has become popular to study dynamic problems in a sensitivity setting: Instead of allowing for an arbitrary sequence of updates, the sensitivity model only allows to apply batch updates of small size to the original input data. The sensitivity model is particularly appealing since recent strong conditional lower bounds ruled out fast algorithms for many dynamic problems, such as shortest paths, reachability, or subgraph connectivity. In this paper we prove conditional lower bounds for these and additional problems in a sensitivity setting. For example, we show that under the Boolean Matrix Multiplication (BMM) conjecture combinatorial algorithms cannot compute the (4/3-\varepsilon)-approximate diameter of an undirected unweighted dense graph with truly subcubic preprocessing time and truly subquadratic update/query time. This result is surprising since in the static setting it is not clear whether a reduction from BMM to diameter is possible. We further show under the BMM conjecture that many problems, such as reachability or approximate shortest paths, cannot be solved faster than by recomputation from scratch even after only one or two edge insertions. We extend our reduction from BMM to Diameter to give a reduction from All Pairs Shortest Paths to Diameter under one deletion in weighted graphs. This is intriguing, as in the static setting it is a big open problem whether Diameter is as hard as APSP. We further get a nearly tight lower bound for shortest paths after two edge deletions based on the APSP conjecture. We give more lower bounds under the Strong Exponential Time Hypothesis. Many of our lower bounds also hold for static oracle data structures where no sensitivity is required. Finally, we give the first algorithm for the (1+\varepsilon)-approximate radius, diameter, and eccentricity problems in directed or undirected unweighted graphs in case of single edges failures. The algorithm has a truly subcubic running time for graphs with a truly subquadratic number of edges; it is tight w.r.t. the conditional lower bounds we obtain. AU - Henzinger, Monika H AU - Lincoln, Andrea AU - Neumann, Stefan AU - Vassilevska Williams, Virginia ID - 11829 SN - 1868-8969 T2 - 8th Innovations in Theoretical Computer Science Conference TI - Conditional hardness for sensitivity problems VL - 67 ER - TY - CONF AB - We introduce a new algorithmic framework for designing dynamic graph algorithms in minor-free graphs, by exploiting the structure of such graphs and a tool called vertex sparsification, which is a way to compress large graphs into small ones that well preserve relevant properties among a subset of vertices and has previously mainly been used in the design of approximation algorithms. Using this framework, we obtain a Monte Carlo randomized fully dynamic algorithm for (1 + epsilon)-approximating the energy of electrical flows in n-vertex planar graphs with tilde{O}(r epsilon^{-2}) worst-case update time and tilde{O}((r + n / sqrt{r}) epsilon^{-2}) worst-case query time, for any r larger than some constant. For r=n^{2/3}, this gives tilde{O}(n^{2/3} epsilon^{-2}) update time and tilde{O}(n^{2/3} epsilon^{-2}) query time. We also extend this algorithm to work for minor-free graphs with similar approximation and running time guarantees. Furthermore, we illustrate our framework on the all-pairs max flow and shortest path problems by giving corresponding dynamic algorithms in minor-free graphs with both sublinear update and query times. To the best of our knowledge, our results are the first to systematically establish such a connection between dynamic graph algorithms and vertex sparsification. We also present both upper bound and lower bound for maintaining the energy of electrical flows in the incremental subgraph model, where updates consist of only vertex activations, which might be of independent interest. AU - Goranci, Gramoz AU - Henzinger, Monika H AU - Peng, Pan ID - 11833 SN - 1868-8969 T2 - 25th Annual European Symposium on Algorithms TI - The power of vertex sparsifiers in dynamic graph algorithms VL - 87 ER - TY - CONF AB - In this paper, we study the problem of opening centers to cluster a set of clients in a metric space so as to minimize the sum of the costs of the centers and of the cluster radii, in a dynamic environment where clients arrive and depart, and the solution must be updated efficiently while remaining competitive with respect to the current optimal solution. We call this dynamic sum-of-radii clustering problem. We present a data structure that maintains a solution whose cost is within a constant factor of the cost of an optimal solution in metric spaces with bounded doubling dimension and whose worst-case update time is logarithmic in the parameters of the problem. AU - Henzinger, Monika H AU - Leniowski, Dariusz AU - Mathieu, Claire ID - 11832 SN - 1868-8969 T2 - 25th Annual European Symposium on Algorithms TI - Dynamic clustering to minimize the sum of radii VL - 87 ER - TY - CONF AB - We consider the problem of maintaining an approximately maximum (fractional) matching and an approximately minimum vertex cover in a dynamic graph. Starting with the seminal paper by Onak and Rubinfeld [STOC 2010], this problem has received significant attention in recent years. There remains, however, a polynomial gap between the best known worst case update time and the best known amortised update time for this problem, even after allowing for randomisation. Specifically, Bernstein and Stein [ICALP 2015, SODA 2016] have the best known worst case update time. They present a deterministic data structure with approximation ratio (3/2 + ∊) and worst case update time O(m1/4/ ∊2), where m is the number of edges in the graph. In recent past, Gupta and Peng [FOCS 2013] gave a deterministic data structure with approximation ratio (1+ ∊) and worst case update time No known randomised data structure beats the worst case update times of these two results. In contrast, the paper by Onak and Rubinfeld [STOC 2010] gave a randomised data structure with approximation ratio O(1) and amortised update time O(log2 n), where n is the number of nodes in the graph. This was later improved by Baswana, Gupta and Sen [FOCS 2011] and Solomon [FOCS 2016], leading to a randomised date structure with approximation ratio 2 and amortised update time O(1). We bridge the polynomial gap between the worst case and amortised update times for this problem, without using any randomisation. We present a deterministic data structure with approximation ratio (2 + ∊) and worst case update time O(log3 n), for all sufficiently small constants ∊. AU - Bhattacharya, Sayan AU - Henzinger, Monika H AU - Nanongkai, Danupon ID - 11874 T2 - 28th Annual ACM-SIAM Symposium on Discrete Algorithms TI - Fully dynamic approximate maximum matching and minimum vertex cover in o(log3 n) worst case update time ER - TY - CONF AB - We study the problem of computing a minimum cut in a simple, undirected graph and give a deterministic O(m log2 n log log2 n) time algorithm. This improves both on the best previously known deterministic running time of O(m log12 n) (Kawarabayashi and Thorup [12]) and the best previously known randomized running time of O(mlog3n) (Karger [11]) for this problem, though Karger's algorithm can be further applied to weighted graphs. Our approach is using the Kawarabayashi and Tho- rup graph compression technique, which repeatedly finds low-conductance cuts. To find these cuts they use a diffusion-based local algorithm. We use instead a flow- based local algorithm and suitably adjust their framework to work with our flow-based subroutine. Both flow and diffusion based methods have a long history of being applied to finding low conductance cuts. Diffusion algorithms have several variants that are naturally local while it is more complicated to make flow methods local. Some prior work has proven nice properties for local flow based algorithms with respect to improving or cleaning up low conductance cuts. Our flow subroutine, however, is the first that is both local and produces low conductance cuts. Thus, it may be of independent interest. AU - Henzinger, Monika H AU - Rao, Satish AU - Wang, Di ID - 11873 T2 - 28th Annual ACM-SIAM Symposium on Discrete Algorithms TI - Local flow partitioning for faster edge connectivity ER - TY - CONF AB - Graph Sparsification aims at compressing large graphs into smaller ones while (approximately) preserving important characteristics of the input graph. In this work we study Vertex Sparsifiers, i.e., sparsifiers whose goal is to reduce the number of vertices. Given a weighted graph G=(V,E), and a terminal set K with |K|=k, a quality-q vertex cut sparsifier of G is a graph H with K contained in V_H that preserves the value of minimum cuts separating any bipartition of K, up to a factor of q. We show that planar graphs with all the k terminals lying on the same face admit quality-1 vertex cut sparsifier of size O(k^2) that are also planar. Our result extends to vertex flow and distance sparsifiers. It improves the previous best known bound of O(k^2 2^(2k)) for cut and flow sparsifiers by an exponential factor, and matches an Omega(k^2) lower-bound for this class of graphs. We also study vertex reachability sparsifiers for directed graphs. Given a digraph G=(V,E) and a terminal set K, a vertex reachability sparsifier of G is a digraph H=(V_H,E_H), K contained in V_H that preserves all reachability information among terminal pairs. We introduce the notion of reachability-preserving minors, i.e., we require H to be a minor of G. Among others, for general planar digraphs, we construct reachability-preserving minors of size O(k^2 log^2 k). We complement our upper-bound by showing that there exists an infinite family of acyclic planar digraphs such that any reachability-preserving minor must have Omega(k^2) vertices. AU - Goranci, Gramoz AU - Henzinger, Monika H AU - Peng, Pan ID - 11831 SN - 1868-8969 T2 - 25th Annual European Symposium on Algorithms TI - Improved guarantees for vertex sparsification in planar graphs VL - 87 ER - TY - JOUR AB - Online social networks allow the collection of large amounts of data about the influence between users connected by a friendship-like relationship. When distributing items among agents forming a social network, this information allows us to exploit network externalities that each agent receives from his neighbors that get the same item. In this paper we consider Friends-of-Friends (2-hop) network externalities, i.e., externalities that not only depend on the neighbors that get the same item but also on neighbors of neighbors. For these externalities we study a setting where multiple different items are assigned to unit-demand agents. Specifically, we study the problem of welfare maximization under different types of externality functions. Let n be the number of agents and m be the number of items. Our contributions are the following: (1) We show that welfare maximization is APX-hard; we show that even for step functions with 2-hop (and also with 1-hop) externalities it is NP-hard to approximate social welfare better than (1−1/e). (2) On the positive side we present (i) an 𝑂(𝑛√)-approximation algorithm for general concave externality functions, (ii) an O(log m)-approximation algorithm for linear externality functions, and (iii) a 518(1−1/𝑒)-approximation algorithm for 2-hop step function externalities. We also improve the result from [7] for 1-hop step function externalities by giving a 12(1−1/𝑒)-approximation algorithm. AU - Bhattacharya, Sayan AU - Dvořák, Wolfgang AU - Henzinger, Monika H AU - Starnberger, Martin ID - 11903 IS - 4 JF - Theory of Computing Systems SN - 1432-4350 TI - Welfare maximization with friends-of-friends network externalities VL - 61 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 - The way organic multistep synthesis is performed is changing due to the adoption of flow chemical techniques, which has enabled the development of improved methods to make complex molecules. The modular nature of the technique provides not only access to target molecules via linear flow approaches but also for the targeting of structural cores with single systems. This perspective article summarizes the state of the art of continuous multistep synthesis and discusses the main challenges and opportunities in this area. AU - Pieber, Bartholomäus AU - Gilmore, Kerry AU - Seeberger, Peter H. ID - 11976 IS - 3-4 JF - Journal of Flow Chemistry SN - 2062-249X TI - Integrated flow processing - challenges in continuous multistep synthesis VL - 7 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 - The Leidenfrost effect occurs when an object near a hot surface vaporizes rapidly enough to lift itself up and hover. Although well understood for liquids and stiff sublimable solids, nothing is known about the effect with materials whose stiffness lies between these extremes. Here we introduce a new phenomenon that occurs with vaporizable soft solids - the elastic Leidenfrost effect. By dropping hydrogel spheres onto hot surfaces we find that, rather than hovering, they energetically bounce several times their diameter for minutes at a time. With high-speed video during a single impact, we uncover high-frequency microscopic gap dynamics at the sphere/substrate interface. We show how these otherwise-hidden agitations constitute work cycles that harvest mechanical energy from the vapour and sustain the bouncing. Our findings suggest a new strategy for injecting mechanical energy into a widely used class of soft materials, with potential relevance to fields such as active matter, soft robotics and microfluidics. AU - Waitukaitis, Scott R AU - Zuiderwijk, Antal AU - Souslov, Anton AU - Coulais, Corentin AU - Van Hecke, Martin ID - 123 IS - 11 JF - Nature Physics TI - Coupling the Leidenfrost effect and elastic deformations to power sustained bouncing VL - 13 ER - TY - CONF AB - We consider the problems of maintaining approximate maximum matching and minimum vertex cover in a dynamic graph. Starting with the seminal work of Onak and Rubinfeld [STOC 2010], this problem has received significant attention in recent years. Very recently, extending the framework of Baswana, Gupta and Sen [FOCS 2011], Solomon [FOCS 2016] gave a randomized 2-approximation dynamic algorithm for this problem that has amortized update time of O(1) with high probability. We consider the natural open question of derandomizing this result. We present a new deterministic fully dynamic algorithm that maintains a O(1)-approximate minimum vertex cover and maximum fractional matching, with an amortized update time of O(1). Previously, the best deterministic algorithm for this problem was due to Bhattacharya, Henzinger and Italiano [SODA 2015]; it had an approximation ratio of (2+ϵ) and an amortized update time of O(logn/ϵ2). Our result can be generalized to give a fully dynamic O(f3)-approximation algorithm with O(f2) amortized update time for the hypergraph vertex cover and fractional matching problems, where every hyperedge has at most f vertices. AU - Bhattacharya, Sayan AU - Chakrabarty, Deeparnab AU - Henzinger, Monika H ID - 12571 SN - 0302-9743 T2 - 19th International Conference on Integer Programming and Combinatorial Optimization TI - Deterministic fully dynamic approximate vertex cover and fractional matching in O(1) amortized update time VL - 10328 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 - JOUR AB - We show that a twisted variant of Linnik’s conjecture on sums of Kloosterman sums leads to an optimal covering exponent for S3. AU - Browning, Timothy D AU - Kumaraswamy, Vinay AU - Steiner, Rapael ID - 169 JF - International Mathematics Research Notices TI - Twisted Linnik implies optimal covering exponent for S3 ER - TY - JOUR AB - We study strong approximation for some algebraic varieties over ℚ which are defined using norm forms. This allows us to confirm a special case of a conjecture due to Harpaz and Wittenberg. AU - Browning, Timothy D AU - Schindler, Damaris ID - 172 JF - International Mathematics Research Notices TI - Strong approximation and a conjecture of Harpaz and Wittenberg ER - TY - JOUR AB - We use a three-pulse ultrafast optical spectroscopy to study the relaxation processes in a frustrated Mott insulator Na2IrO3. By being able to independently produce the out-of-equilibrium bound states (excitons) of doublons and holons with the first pulse and suppress the underlying antiferromagnetic order with the second one, we were able to elucidate the relaxation mechanism of quasiparticles in this system. By observing the difference in the exciton dynamics in the magnetically ordered and disordered phases we found that the mass of this quasiparticle is mostly determined by its interaction with the surrounding spins. AU - Alpichshev, Zhanybek AU - Sie, Edbert AU - Mahmood, Fahad AU - Cao, Gang AU - Gedik, Nuh ID - 393 IS - 23 JF - Physical Review B TI - Origin of the exciton mass in the frustrated Mott insulator Na2IrO3 VL - 96 ER - TY - JOUR AB - We used femtosecond optical pump-probe spectroscopy to study the photoinduced change in reflectivity of thin films of the electron-doped cuprate La2-xCexCuO4 (LCCO) with dopings of x=0.08 (underdoped) and x=0.11 (optimally doped). Above Tc, we observe fluence-dependent relaxation rates that begin at a temperature similar to the one where transport measurements first show signatures of antiferromagnetic correlations. Upon suppressing superconductivity with a magnetic field, it is found that the fluence and temperature dependence of relaxation rates are consistent with bimolecular recombination of electrons and holes across a gap (2ΔAF) originating from antiferromagnetic correlations which comprise the pseudogap in electron-doped cuprates. This can be used to learn about coupling between electrons and high-energy (ω>2ΔAF) excitations in these compounds and set limits on the time scales on which antiferromagnetic correlations are static. AU - Vishik, Inna AU - Mahmood, Fahad AU - Alpichshev, Zhanybek AU - Gedik, Nuh AU - Higgins, Joshu AU - Greene, Richard ID - 392 IS - 11 JF - Physical Review B TI - Ultrafast dynamics in the presence of antiferromagnetic correlations in electron doped cuprate La2 xCexCuO4±δ VL - 95 ER - TY - JOUR AB - Pancreatic cancer has a five-year survival rate of ~8%, with characteristic molecular heterogeneity and restricted treatment options. Targeting metabolism has emerged as a potentially effective therapeutic strategy for cancers such as pancreatic cancer, which are driven by genetic alterations that are not tractable drug targets. Although somatic mitochondrial genome (mtDNA) mutations have been observed in various tumors types, understanding of metabolic genotype-phenotype relationships is limited. AU - Hardie, Rae AU - Van Dam, Ellen AU - Cowley, Mark AU - Han, Ting AU - Balaban, Seher AU - Pajic, Marina AU - Pinese, Mark AU - Iconomou, Mary AU - Shearer, Robert AU - Mckenna, Jessie AU - Miller, David AU - Waddell, Nicola AU - Pearson, John AU - Grimmond, Sean AU - Sazanov, Leonid A AU - Biankin, Andrew AU - Villas Boas, Silas AU - Hoy, Andrew AU - Turner, Nigel AU - Saunders, Darren ID - 443 IS - 2 JF - Cancer & Metabolism TI - Mitochondrial mutations and metabolic adaptation in pancreatic cancer VL - 5 ER - TY - JOUR AB - The Loschmidt echo, defined as the overlap between quantum wave function evolved with different Hamiltonians, quantifies the sensitivity of quantum dynamics to perturbations and is often used as a probe of quantum chaos. In this work we consider the behavior of the Loschmidt echo in the many-body localized phase, which is characterized by emergent local integrals of motion and provides a generic example of nonergodic dynamics. We demonstrate that the fluctuations of the Loschmidt echo decay as a power law in time in the many-body localized phase, in contrast to the exponential decay in few-body ergodic systems. We consider the spin-echo generalization of the Loschmidt echo and argue that the corresponding correlation function saturates to a finite value in localized systems. Slow, power-law decay of fluctuations of such spin-echo-type overlap is related to the operator spreading and is present only in the many-body localized phase, but not in a noninteracting Anderson insulator. While most of the previously considered probes of dephasing dynamics could be understood by approximating physical spin operators with local integrals of motion, the Loschmidt echo and its generalizations crucially depend on the full expansion of the physical operators via local integrals of motion operators, as well as operators which flip local integrals of motion. Hence these probes allow one to get insights into the relation between physical operators and local integrals of motion and access the operator spreading in the many-body localized phase. AU - Maksym Serbyn AU - Abanin, Dimitry A ID - 445 IS - 1 JF - Physical Review B - Condensed Matter and Materials Physics TI - Loschmidt echo in many body localized phases VL - 96 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 -