@unpublished{7950, abstract = {The input to the token swapping problem is a graph with vertices v1, v2, . . . , vn, and n tokens with labels 1,2, . . . , n, one on each vertex. The goal is to get token i to vertex vi for all i= 1, . . . , n using a minimum number of swaps, where a swap exchanges the tokens on the endpoints of an edge.Token swapping on a tree, also known as “sorting with a transposition tree,” is not known to be in P nor NP-complete. We present some partial results: 1. An optimum swap sequence may need to perform a swap on a leaf vertex that has the correct token (a “happy leaf”), disproving a conjecture of Vaughan. 2. Any algorithm that fixes happy leaves—as all known approximation algorithms for the problem do—has approximation factor at least 4/3. Furthermore, the two best-known 2-approximation algorithms have approximation factor exactly 2. 3. A generalized problem—weighted coloured token swapping—is NP-complete on trees, but solvable in polynomial time on paths and stars. In this version, tokens and vertices have colours, and colours have weights. The goal is to get every token to a vertex of the same colour, and the cost of a swap is the sum of the weights of the two tokens involved.}, author = {Biniaz, Ahmad and Jain, Kshitij and Lubiw, Anna and Masárová, Zuzana and Miltzow, Tillmann and Mondal, Debajyoti and Naredla, Anurag Murty and Tkadlec, Josef and Turcotte, Alexi}, booktitle = {arXiv}, title = {{Token swapping on trees}}, year = {2019}, } @article{6418, abstract = {Males and females of Artemia franciscana, a crustacean commonly used in the aquarium trade, are highly dimorphic. Sex is determined by a pair of ZW chromosomes, but the nature and extent of differentiation of these chromosomes is unknown. Here, we characterize the Z chromosome by detecting genomic regions that show lower genomic coverage in female than in male samples, and regions that harbor an excess of female-specific SNPs. We detect many Z-specific genes, which no longer have homologs on the W, but also Z-linked genes that appear to have diverged very recently from their existing W-linked homolog. We assess patterns of male and female expression in two tissues with extensive morphological dimorphism, gonads, and heads. In agreement with their morphology, sex-biased expression is common in both tissues. Interestingly, the Z chromosome is not enriched for sex-biased genes, and seems to in fact have a mechanism of dosage compensation that leads to equal expression in males and in females. Both of these patterns are contrary to most ZW systems studied so far, making A. franciscana an excellent model for investigating the interplay between the evolution of sexual dimorphism and dosage compensation, as well as Z chromosome evolution in general.}, author = {Huylmans, Ann K and Toups, Melissa A and Macon, Ariana and Gammerdinger, William J and Vicoso, Beatriz}, issn = {1759-6653}, journal = {Genome biology and evolution}, number = {4}, pages = {1033--1044}, publisher = {Oxford University Press}, title = {{Sex-biased gene expression and dosage compensation on the Artemia franciscana Z-chromosome}}, doi = {10.1093/gbe/evz053}, volume = {11}, year = {2019}, } @misc{7016, abstract = {Organisms cope with change by employing transcriptional regulators. However, when faced with rare environments, the evolution of transcriptional regulators and their promoters may be too slow. We ask whether the intrinsic instability of gene duplication and amplification provides a generic alternative to canonical gene regulation. By real-time monitoring of gene copy number mutations in E. coli, we show that gene duplications and amplifications enable adaptation to fluctuating environments by rapidly generating copy number, and hence expression level, polymorphism. This ‘amplification-mediated gene expression tuning’ occurs on timescales similar to canonical gene regulation and can deal with rapid environmental changes. Mathematical modeling shows that amplifications also tune gene expression in stochastic environments where transcription factor-based schemes are hard to evolve or maintain. The fleeting nature of gene amplifications gives rise to a generic population-level mechanism that relies on genetic heterogeneity to rapidly tune expression of any gene, without leaving any genomic signature.}, author = {Tomanek, Isabella}, keywords = {Escherichia coli, gene amplification, galactose, DOG, experimental evolution, Illumina sequence data, FACS data, microfluidics data}, publisher = {Institute of Science and Technology Austria}, title = {{Data for the paper "Gene amplification as a form of population-level gene expression regulation"}}, doi = {10.15479/AT:ISTA:7016}, year = {2019}, } @misc{7154, author = {Guseinov, Ruslan}, publisher = {Institute of Science and Technology Austria}, title = {{Supplementary data for "Programming temporal morphing of self-actuated shells"}}, doi = {10.15479/AT:ISTA:7154}, year = {2019}, } @misc{6060, author = {Vicoso, Beatriz}, publisher = {Institute of Science and Technology Austria}, title = {{Supplementary data for "Sex-biased gene expression and dosage compensation on the Artemia franciscana Z-chromosome" (Huylman, Toups et al., 2019). }}, doi = {10.15479/AT:ISTA:6060}, year = {2019}, } @misc{6074, abstract = {This dataset contains the supplementary data for the research paper "Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition". The contained files have the following content: 'Supplementary Figures.pdf' Additional figures (as referenced in the paper). 'Supplementary Table 1. Statistics.xlsx' Details on statistical tests performed in the paper. 'Supplementary Table 2. Differentially expressed gene analysis.xlsx' Results for the differential gene expression analysis for embryonic (E9.5; analysis with edgeR) and in vitro (ESCs, EBs, NPCs; analysis with DESeq2) samples. 'Supplementary Table 3. Gene Ontology (GO) term enrichment analysis.xlsx' Results for the GO term enrichment analysis for differentially expressed genes in embryonic (GO E9.5) and in vitro (GO ESC, GO EBs, GO NPCs) samples. Differentially expressed genes for in vitro samples were split into upregulated and downregulated genes (up/down) and the analysis was performed on each subset (e.g. GO ESC up / GO ESC down). 'Supplementary Table 4. Differentially expressed gene analysis for CFC samples.xlsx' Results for the differential gene expression analysis for samples from adult mice before (HC - Homecage) and 1h and 3h after contextual fear conditioning (1h and 3h, respectively). Each sheet shows the results for a different comparison. Sheets 1-3 show results for comparisons between timepoints for wild type (WT) samples only and sheets 4-6 for the same comparisons in mutant (Het) samples. Sheets 7-9 show results for comparisons between genotypes at each time point and sheet 10 contains the results for the analysis of differential expression trajectories between wild type and mutant. 'Supplementary Table 5. Cluster identification.xlsx' Results for k-means clustering of genes by expression. Sheet 1 shows clustering of just the genes with significantly different expression trajectories between genotypes. Sheet 2 shows clustering of all genes that are significantly differentially expressed in any of the comparisons (includes also genes with same trajectories). 'Supplementary Table 6. GO term cluster analysis.xlsx' Results for the GO term enrichment analysis and EWCE analysis for enrichment of cell type specific genes for each cluster identified by clustering genes with different expression trajectories (see Table S5, sheet 1). 'Supplementary Table 7. Setd5 mass spectrometry results.xlsx' Results showing proteins interacting with Setd5 as identified by mass spectrometry. Sheet 1 shows protein protein interaction data generated from these results (combined with data from the STRING database. Sheet 2 shows the results of the statistical analysis with limma. 'Supplementary Table 8. PolII ChIP-seq analysis.xlsx' Results for the Chip-Seq analysis for binding of RNA polymerase II (PolII). Sheet 1 shows results for differential binding of PolII at the transcription start site (TSS) between genotypes and sheets 2+3 show the corresponding GO enrichment analysis for these differentially bound genes. Sheet 4 shows RNAseq counts for genes with increased binding of PolII at the TSS.}, author = {Dotter, Christoph and Novarino, Gaia}, publisher = {Institute of Science and Technology Austria}, title = {{Supplementary data for the research paper "Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition"}}, doi = {10.15479/AT:ISTA:6074}, year = {2019}, } @misc{6062, abstract = {Open the files in Jupyter Notebook (reccomended https://www.anaconda.com/distribution/#download-section with Python 3.7).}, author = {Nardin, Michele}, publisher = {Institute of Science and Technology Austria}, title = {{Supplementary Code and Data for the paper "The Entorhinal Cognitive Map is Attracted to Goals"}}, doi = {10.15479/AT:ISTA:6062}, year = {2019}, } @article{6089, abstract = {Pleiotropy is the well-established idea that a single mutation affects multiple phenotypes. If a mutation has opposite effects on fitness when expressed in different contexts, then genetic conflict arises. Pleiotropic conflict is expected to reduce the efficacy of selection by limiting the fixation of beneficial mutations through adaptation, and the removal of deleterious mutations through purifying selection. Although this has been widely discussed, in particular in the context of a putative “gender load,” it has yet to be systematically quantified. In this work, we empirically estimate to which extent different pleiotropic regimes impede the efficacy of selection in Drosophila melanogaster. We use whole-genome polymorphism data from a single African population and divergence data from D. simulans to estimate the fraction of adaptive fixations (α), the rate of adaptation (ωA), and the direction of selection (DoS). After controlling for confounding covariates, we find that the different pleiotropic regimes have a relatively small, but significant, effect on selection efficacy. Specifically, our results suggest that pleiotropic sexual antagonism may restrict the efficacy of selection, but that this conflict can be resolved by limiting the expression of genes to the sex where they are beneficial. Intermediate levels of pleiotropy across tissues and life stages can also lead to maladaptation in D. melanogaster, due to inefficient purifying selection combined with low frequency of mutations that confer a selective advantage. Thus, our study highlights the need to consider the efficacy of selection in the context of antagonistic pleiotropy, and of genetic conflict in general.}, author = {Fraisse, Christelle and Puixeu Sala, Gemma and Vicoso, Beatriz}, issn = {1537-1719}, journal = {Molecular biology and evolution}, number = {3}, pages = {500--515}, publisher = {Oxford University Press}, title = {{Pleiotropy modulates the efficacy of selection in drosophila melanogaster}}, doi = {10.1093/molbev/msy246}, volume = {36}, year = {2019}, } @phdthesis{6179, abstract = {In the first part of this thesis we consider large random matrices with arbitrary expectation and a general slowly decaying correlation among its entries. We prove universality of the local eigenvalue statistics and optimal local laws for the resolvent in the bulk and edge regime. The main novel tool is a systematic diagrammatic control of a multivariate cumulant expansion. In the second part we consider Wigner-type matrices and show that at any cusp singularity of the limiting eigenvalue distribution the local eigenvalue statistics are uni- versal and form a Pearcey process. Since the density of states typically exhibits only square root or cubic root cusp singularities, our work complements previous results on the bulk and edge universality and it thus completes the resolution of the Wigner- Dyson-Mehta universality conjecture for the last remaining universality type. Our analysis holds not only for exact cusps, but approximate cusps as well, where an ex- tended Pearcey process emerges. As a main technical ingredient we prove an optimal local law at the cusp, and extend the fast relaxation to equilibrium of the Dyson Brow- nian motion to the cusp regime. In the third and final part we explore the entrywise linear statistics of Wigner ma- trices and identify the fluctuations for a large class of test functions with little regularity. This enables us to study the rectangular Young diagram obtained from the interlacing eigenvalues of the random matrix and its minor, and we find that, despite having the same limit, the fluctuations differ from those of the algebraic Young tableaux equipped with the Plancharel measure.}, author = {Schröder, Dominik J}, issn = {2663-337X}, pages = {375}, publisher = {Institute of Science and Technology Austria}, title = {{From Dyson to Pearcey: Universal statistics in random matrix theory}}, doi = {10.15479/AT:ISTA:th6179}, year = {2019}, } @inproceedings{6482, abstract = {Computer vision systems for automatic image categorization have become accurate and reliable enough that they can run continuously for days or even years as components of real-world commercial applications. A major open problem in this context, however, is quality control. Good classification performance can only be expected if systems run under the specific conditions, in particular data distributions, that they were trained for. Surprisingly, none of the currently used deep network architectures have a built-in functionality that could detect if a network operates on data from a distribution it was not trained for, such that potentially a warning to the human users could be triggered. In this work, we describe KS(conf), a procedure for detecting such outside of specifications (out-of-specs) operation, based on statistical testing of the network outputs. We show by extensive experiments using the ImageNet, AwA2 and DAVIS datasets on a variety of ConvNets architectures that KS(conf) reliably detects out-of-specs situations. It furthermore has a number of properties that make it a promising candidate for practical deployment: it is easy to implement, adds almost no overhead to the system, works with all networks, including pretrained ones, and requires no a priori knowledge of how the data distribution could change. }, author = {Sun, Rémy and Lampert, Christoph}, isbn = {9783030129385}, issn = {1611-3349}, location = {Stuttgart, Germany}, pages = {244--259}, publisher = {Springer Nature}, title = {{KS(conf): A light-weight test if a ConvNet operates outside of Its specifications}}, doi = {10.1007/978-3-030-12939-2_18}, volume = {11269}, year = {2019}, } @inproceedings{6642, abstract = {We present a thermodynamically based approach to the design of models for viscoelastic fluids with stress diffusion effect. In particular, we show how to add a stress diffusion term to some standard viscoelastic rate-type models (Giesekus, FENE-P, Johnson–Segalman, Phan-Thien–Tanner and Bautista–Manero–Puig) so that the resulting models with the added stress diffusion term are thermodynamically consistent in the sense that they obey the first and the second law of thermodynamics. We point out the potential applications of the provided thermodynamical background in the study of flows of fluids described by the proposed models.}, author = {Dostalík, Mark and Pruša, Vít and Skrivan, Tomas}, booktitle = {AIP Conference Proceedings}, location = {Zlin, Czech Republic}, publisher = {AIP Publishing}, title = {{On diffusive variants of some classical viscoelastic rate-type models}}, doi = {10.1063/1.5109493}, volume = {2107}, year = {2019}, } @article{7226, author = {Jaksic, Vojkan and Seiringer, Robert}, issn = {00222488}, journal = {Journal of Mathematical Physics}, number = {12}, publisher = {AIP Publishing}, title = {{Introduction to the Special Collection: International Congress on Mathematical Physics (ICMP) 2018}}, doi = {10.1063/1.5138135}, volume = {60}, year = {2019}, } @article{7190, abstract = {We investigate the ground-state energy of a one-dimensional Fermi gas with two bosonic impurities. We consider spinless fermions with no fermion-fermion interactions. The fermion-impurity and impurity-impurity interactions are modeled with Dirac delta functions. First, we study the case where impurity and fermion have equal masses, and the impurity-impurity two-body interaction is identical to the fermion-impurity interaction, such that the system is solvable with the Bethe ansatz. For attractive interactions, we find that the energy of the impurity-impurity subsystem is below the energy of the bound state that exists without the Fermi gas. We interpret this as a manifestation of attractive boson-boson interactions induced by the fermionic medium, and refer to the impurity-impurity subsystem as an in-medium bound state. For repulsive interactions, we find no in-medium bound states. Second, we construct an effective model to describe these interactions, and compare its predictions to the exact solution. We use this effective model to study nonintegrable systems with unequal masses and/or potentials. We discuss parameter regimes for which impurity-impurity attraction induced by the Fermi gas can lead to the formation of in-medium bound states made of bosons that repel each other in the absence of the Fermi gas.}, author = {Huber, D. and Hammer, H.-W. and Volosniev, Artem}, issn = {2643-1564}, journal = {Physical Review Research}, number = {3}, publisher = {American Physical Society}, title = {{In-medium bound states of two bosonic impurities in a one-dimensional Fermi gas}}, doi = {10.1103/physrevresearch.1.033177}, volume = {1}, year = {2019}, } @article{6575, abstract = {Motivated by recent experimental observations of coherent many-body revivals in a constrained Rydbergatom chain, we construct a weak quasilocal deformation of the Rydberg-blockaded Hamiltonian, whichmakes the revivals virtually perfect. Our analysis suggests the existence of an underlying nonintegrableHamiltonian which supports an emergent SU(2)-spin dynamics within a small subspace of the many-bodyHilbert space. We show that such perfect dynamics necessitates the existence of atypical, nonergodicenergy eigenstates—quantum many-body scars. Furthermore, using these insights, we construct a toymodel that hosts exact quantum many-body scars, providing an intuitive explanation of their origin. Ourresults offer specific routes to enhancing coherent many-body revivals and provide a step towardestablishing the stability of quantum many-body scars in the thermodynamic limit.}, author = {Choi, Soonwon and Turner, Christopher J. and Pichler, Hannes and Ho, Wen Wei and Michailidis, Alexios and Papić, Zlatko and Serbyn, Maksym and Lukin, Mikhail D. and Abanin, Dmitry A.}, issn = {10797114}, journal = {Physical Review Letters}, number = {22}, publisher = {American Physical Society}, title = {{Emergent SU(2) dynamics and perfect quantum many-body scars}}, doi = {10.1103/PhysRevLett.122.220603}, volume = {122}, year = {2019}, } @article{6092, abstract = {In 1915, Einstein and de Haas and Barnett demonstrated that changing the magnetization of a magnetic material results in mechanical rotation and vice versa. At the microscopic level, this effect governs the transfer between electron spin and orbital angular momentum, and lattice degrees of freedom, understanding which is key for molecular magnets, nano-magneto-mechanics, spintronics, and ultrafast magnetism. Until now, the timescales of electron-to-lattice angular momentum transfer remain unclear, since modeling this process on a microscopic level requires the addition of an infinite amount of quantum angular momenta. We show that this problem can be solved by reformulating it in terms of the recently discovered angulon quasiparticles, which results in a rotationally invariant quantum many-body theory. In particular, we demonstrate that nonperturbative effects take place even if the electron-phonon coupling is weak and give rise to angular momentum transfer on femtosecond timescales.}, author = {Mentink, Johann H and Katsnelson, Mikhail and Lemeshko, Mikhail}, journal = {Physical Review B}, number = {6}, publisher = {American Physical Society}, title = {{Quantum many-body dynamics of the Einstein-de Haas effect}}, doi = {10.1103/PhysRevB.99.064428}, volume = {99}, year = {2019}, } @article{6090, abstract = {Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems, leading to crosstalk between ligand-receptor pairs. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of noncognate ligands can interfere with the detection of the receptor's cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.}, author = {Carballo-Pacheco, Martín and Desponds, Jonathan and Gavrilchenko, Tatyana and Mayer, Andreas and Prizak, Roshan and Reddy, Gautam and Nemenman, Ilya and Mora, Thierry}, journal = {Physical Review E}, number = {2}, publisher = {American Physical Society}, title = {{Receptor crosstalk improves concentration sensing of multiple ligands}}, doi = {10.1103/PhysRevE.99.022423}, volume = {99}, year = {2019}, } @article{6786, abstract = {Dipolar coupling plays a fundamental role in the interaction between electrically or magnetically polarized species such as magnetic atoms and dipolar molecules in a gas or dipolar excitons in the solid state. Unlike Coulomb or contactlike interactions found in many atomic, molecular, and condensed-matter systems, this interaction is long-ranged and highly anisotropic, as it changes from repulsive to attractive depending on the relative positions and orientation of the dipoles. Because of this unique property, many exotic, symmetry-breaking collective states have been recently predicted for cold dipolar gases, but only a few have been experimentally detected and only in dilute atomic dipolar Bose-Einstein condensates. Here, we report on the first observation of attractive dipolar coupling between excitonic dipoles using a new design of stacked semiconductor bilayers. We show that the presence of a dipolar exciton fluid in one bilayer modifies the spatial distribution and increases the binding energy of excitonic dipoles in a vertically remote layer. The binding energy changes are explained using a many-body polaron model describing the deformation of the exciton cloud due to its interaction with a remote dipolar exciton. The surprising nonmonotonic dependence on the cloud density indicates the important role of dipolar correlations, which is unique to dense, strongly interacting dipolar solid-state systems. Our concept provides a route for the realization of dipolar lattices with strong anisotropic interactions in semiconductor systems, which open the way for the observation of theoretically predicted new and exotic collective phases, as well as for engineering and sensing their collective excitations.}, author = {Hubert, Colin and Baruchi, Yifat and Mazuz-Harpaz, Yotam and Cohen, Kobi and Biermann, Klaus and Lemeshko, Mikhail and West, Ken and Pfeiffer, Loren and Rapaport, Ronen and Santos, Paulo}, issn = {2160-3308}, journal = {Physical Review X}, number = {2}, publisher = {American Physical Society}, title = {{Attractive dipolar coupling between stacked exciton fluids}}, doi = {10.1103/PhysRevX.9.021026}, volume = {9}, year = {2019}, } @article{7013, abstract = {Chains of superconducting circuit devices provide a natural platform for studies of synthetic bosonic quantum matter. Motivated by the recent experimental progress in realizing disordered and interacting chains of superconducting transmon devices, we study the bosonic many-body localization phase transition using the methods of exact diagonalization as well as matrix product state dynamics. We estimate the location of transition separating the ergodic and the many-body localized phases as a function of the disorder strength and the many-body on-site interaction strength. The main difference between the bosonic model realized by superconducting circuits and similar fermionic model is that the effect of the on-site interaction is stronger due to the possibility of multiple excitations occupying the same site. The phase transition is found to be robust upon including longer-range hopping and interaction terms present in the experiments. Furthermore, we calculate experimentally relevant local observables and show that their temporal fluctuations can be used to distinguish between the dynamics of Anderson insulator, many-body localization, and delocalized phases. While we consider unitary dynamics, neglecting the effects of dissipation, decoherence, and measurement back action, the timescales on which the dynamics is unitary are sufficient for observation of characteristic dynamics in the many-body localized phase. Moreover, the experimentally available disorder strength and interactions allow for tuning the many-body localization phase transition, thus making the arrays of superconducting circuit devices a promising platform for exploring localization physics and phase transition.}, author = {Orell, Tuure and Michailidis, Alexios and Serbyn, Maksym and Silveri, Matti}, issn = {2469-9969}, journal = {Physical Review B}, number = {13}, publisher = {American Physical Society}, title = {{Probing the many-body localization phase transition with superconducting circuits}}, doi = {10.1103/physrevb.100.134504}, volume = {100}, year = {2019}, } @article{7200, abstract = {Recent scanning tunneling microscopy experiments in NbN thin disordered superconducting films found an emergent inhomogeneity at the scale of tens of nanometers. This inhomogeneity is mirrored by an apparent dimensional crossover in the paraconductivity measured in transport above the superconducting critical temperature Tc. This behavior was interpreted in terms of an anomalous diffusion of fluctuating Cooper pairs that display a quasiconfinement (i.e., a slowing down of their diffusive dynamics) on length scales shorter than the inhomogeneity identified by tunneling experiments. Here, we assume this anomalous diffusive behavior of fluctuating Cooper pairs and calculate the effect of these fluctuations on the electron density of states above Tc. We find that the density of states is substantially suppressed up to temperatures well above Tc. This behavior, which is closely reminiscent of a pseudogap, only arises from the anomalous diffusion of fluctuating Cooper pairs in the absence of stable preformed pairs, setting the stage for an intermediate behavior between the two common paradigms in the superconducting-insulator transition, namely, the localization of Cooper pairs (the so-called bosonic scenario) and the breaking of Cooper pairs into unpaired electrons due to strong disorder (the so-called fermionic scenario).}, author = {Brighi, Pietro and Grilli, Marco and Leridon, Brigitte and Caprara, Sergio}, issn = {2469-9969}, journal = {Physical Review B}, number = {17}, publisher = {American Physical Society}, title = {{Effect of anomalous diffusion of fluctuating Cooper pairs on the density of states of superconducting NbN thin films}}, doi = {10.1103/PhysRevB.100.174518}, volume = {100}, year = {2019}, } @article{6779, abstract = {Recent studies suggest that unstable recurrent solutions of the Navier-Stokes equation provide new insights into dynamics of turbulent flows. In this study, we compute an extensive network of dynamical connections between such solutions in a weakly turbulent quasi-two-dimensional Kolmogorov flow that lies in the inversion symmetric subspace. In particular, we find numerous isolated heteroclinic connections between different types of solutions—equilibria, periodic, and quasiperiodic orbits—as well as continua of connections forming higher-dimensional connecting manifolds. We also compute a homoclinic connection of a periodic orbit and provide strong evidence that the associated homoclinic tangle forms the chaotic repeller that underpins transient turbulence in the symmetric subspace.}, author = {Suri, Balachandra and Pallantla, Ravi Kumar and Schatz, Michael F. and Grigoriev, Roman O.}, issn = {2470-0053}, journal = {Physical Review E}, number = {1}, publisher = {American Physical Society}, title = {{Heteroclinic and homoclinic connections in a Kolmogorov-like flow}}, doi = {10.1103/physreve.100.013112}, volume = {100}, year = {2019}, } @article{7015, abstract = {We modify the "floating crystal" trial state for the classical homogeneous electron gas (also known as jellium), in order to suppress the boundary charge fluctuations that are known to lead to a macroscopic increase of the energy. The argument is to melt a thin layer of the crystal close to the boundary and consequently replace it by an incompressible fluid. With the aid of this trial state we show that three different definitions of the ground-state energy of jellium coincide. In the first point of view the electrons are placed in a neutralizing uniform background. In the second definition there is no background but the electrons are submitted to the constraint that their density is constant, as is appropriate in density functional theory. Finally, in the third system each electron interacts with a periodic image of itself; that is, periodic boundary conditions are imposed on the interaction potential.}, author = {Lewin, Mathieu and Lieb, Elliott H. and Seiringer, Robert}, issn = {2469-9969}, journal = {Physical Review B}, number = {3}, publisher = {American Physical Society}, title = {{Floating Wigner crystal with no boundary charge fluctuations}}, doi = {10.1103/physrevb.100.035127}, volume = {100}, year = {2019}, } @article{7145, abstract = {End-to-end correlated bound states are investigated in superconductor-semiconductor hybrid nanowires at zero magnetic field. Peaks in subgap conductance are independently identified from each wire end, and a cross-correlation function is computed that counts end-to-end coincidences, averaging over thousands of subgap features. Strong correlations in a short, 300-nm device are reduced by a factor of 4 in a long, 900-nm device. In addition, subgap conductance distributions are investigated, and correlations between the left and right distributions are identified based on their mutual information.}, author = {Anselmetti, G. L. R. and Martinez, E. A. and Ménard, G. C. and Puglia, D. and Malinowski, F. K. and Lee, J. S. and Choi, S. and Pendharkar, M. and Palmstrøm, C. J. and Marcus, C. M. and Casparis, L. and Higginbotham, Andrew P}, issn = {2469-9969}, journal = {Physical Review B}, number = {20}, publisher = {American Physical Society}, title = {{End-to-end correlated subgap states in hybrid nanowires}}, doi = {10.1103/physrevb.100.205412}, volume = {100}, year = {2019}, } @article{5906, abstract = {We introduce a simple, exactly solvable strong-randomness renormalization group (RG) model for the many-body localization (MBL) transition in one dimension. Our approach relies on a family of RG flows parametrized by the asymmetry between thermal and localized phases. We identify the physical MBL transition in the limit of maximal asymmetry, reflecting the instability of MBL against rare thermal inclusions. We find a critical point that is localized with power-law distributed thermal inclusions. The typical size of critical inclusions remains finite at the transition, while the average size is logarithmically diverging. We propose a two-parameter scaling theory for the many-body localization transition that falls into the Kosterlitz-Thouless universality class, with the MBL phase corresponding to a stable line of fixed points with multifractal behavior.}, author = {Goremykina, Anna and Vasseur, Romain and Serbyn, Maksym}, issn = {1079-7114}, journal = {Physical Review Letters}, number = {4}, publisher = {American Physical Society}, title = {{Analytically solvable renormalization group for the many-body localization transition}}, doi = {10.1103/physrevlett.122.040601}, volume = {122}, year = {2019}, } @article{6632, abstract = {We consider a two-component Bose gas in two dimensions at a low temperature with short-range repulsive interaction. In the coexistence phase where both components are superfluid, interspecies interactions induce a nondissipative drag between the two superfluid flows (Andreev-Bashkin effect). We show that this behavior leads to a modification of the usual Berezinskii-Kosterlitz-Thouless (BKT) transition in two dimensions. We extend the renormalization of the superfluid densities at finite temperature using the renormalization-group approach and find that the vortices of one component have a large influence on the superfluid properties of the other, mediated by the nondissipative drag. The extended BKT flow equations indicate that the occurrence of the vortex unbinding transition in one of the components can induce the breakdown of superfluidity also in the other, leading to a locking phenomenon for the critical temperatures of the two gases.}, author = {Karle, Volker and Defenu, Nicolò and Enss, Tilman}, issn = {24699934}, journal = {Physical Review A}, number = {6}, publisher = {American Physical Society}, title = {{Coupled superfluidity of binary Bose mixtures in two dimensions}}, doi = {10.1103/PhysRevA.99.063627}, volume = {99}, year = {2019}, } @article{7396, abstract = {The angular momentum of molecules, or, equivalently, their rotation in three-dimensional space, is ideally suited for quantum control. Molecular angular momentum is naturally quantized, time evolution is governed by a well-known Hamiltonian with only a few accurately known parameters, and transitions between rotational levels can be driven by external fields from various parts of the electromagnetic spectrum. Control over the rotational motion can be exerted in one-, two-, and many-body scenarios, thereby allowing one to probe Anderson localization, target stereoselectivity of bimolecular reactions, or encode quantum information to name just a few examples. The corresponding approaches to quantum control are pursued within separate, and typically disjoint, subfields of physics, including ultrafast science, cold collisions, ultracold gases, quantum information science, and condensed-matter physics. It is the purpose of this review to present the various control phenomena, which all rely on the same underlying physics, within a unified framework. To this end, recall the Hamiltonian for free rotations, assuming the rigid rotor approximation to be valid, and summarize the different ways for a rotor to interact with external electromagnetic fields. These interactions can be exploited for control—from achieving alignment, orientation, or laser cooling in a one-body framework, steering bimolecular collisions, or realizing a quantum computer or quantum simulator in the many-body setting.}, author = {Koch, Christiane P. and Lemeshko, Mikhail and Sugny, Dominique}, issn = {1539-0756}, journal = {Reviews of Modern Physics}, number = {3}, publisher = {American Physical Society}, title = {{Quantum control of molecular rotation}}, doi = {10.1103/revmodphys.91.035005}, volume = {91}, year = {2019}, } @inproceedings{7606, abstract = {We derive a tight lower bound on equivocation (conditional entropy), or equivalently a tight upper bound on mutual information between a signal variable and channel outputs. The bound is in terms of the joint distribution of the signals and maximum a posteriori decodes (most probable signals given channel output). As part of our derivation, we describe the key properties of the distribution of signals, channel outputs and decodes, that minimizes equivocation and maximizes mutual information. This work addresses a problem in data analysis, where mutual information between signals and decodes is sometimes used to lower bound the mutual information between signals and channel outputs. Our result provides a corresponding upper bound.}, author = {Hledik, Michal and Sokolowski, Thomas R and Tkačik, Gašper}, booktitle = {IEEE Information Theory Workshop, ITW 2019}, isbn = {9781538669006}, location = {Visby, Sweden}, publisher = {IEEE}, title = {{A tight upper bound on mutual information}}, doi = {10.1109/ITW44776.2019.8989292}, year = {2019}, } @inproceedings{6933, abstract = {We design fast deterministic algorithms for distance computation in the CONGESTED CLIQUE model. Our key contributions include: - A (2+ε)-approximation for all-pairs shortest paths problem in O(log²n / ε) rounds on unweighted undirected graphs. With a small additional additive factor, this also applies for weighted graphs. This is the first sub-polynomial constant-factor approximation for APSP in this model. - A (1+ε)-approximation for multi-source shortest paths problem from O(√n) sources in O(log² n / ε) rounds on weighted undirected graphs. This is the first sub-polynomial algorithm obtaining this approximation for a set of sources of polynomial size. Our main techniques are new distance tools that are obtained via improved algorithms for sparse matrix multiplication, which we leverage to construct efficient hopsets and shortest paths. Furthermore, our techniques extend to additional distance problems for which we improve upon the state-of-the-art, including diameter approximation, and an exact single-source shortest paths algorithm for weighted undirected graphs in Õ(n^{1/6}) rounds.}, author = {Censor-Hillel, Keren and Dory, Michal and Korhonen, Janne and Leitersdorf, Dean}, booktitle = {Proceedings of the 2019 ACM Symposium on Principles of Distributed Computin}, isbn = {9781450362177}, location = {Toronto, ON, Canada}, pages = {74--83}, publisher = {ACM}, title = {{Fast approximate shortest paths in the congested clique}}, doi = {10.1145/3293611.3331633}, year = {2019}, } @phdthesis{6435, abstract = {Social insect colonies tend to have numerous members which function together like a single organism in such harmony that the term ``super-organism'' is often used. In this analogy the reproductive caste is analogous to the primordial germ cells of a metazoan, while the sterile worker caste corresponds to somatic cells. The worker castes, like tissues, are in charge of all functions of a living being, besides reproduction. The establishment of new super-organismal units (i.e. new colonies) is accomplished by the co-dependent castes. The term oftentimes goes beyond a metaphor. We invoke it when we speak about the metabolic rate, thermoregulation, nutrient regulation and gas exchange of a social insect colony. Furthermore, we assert that the super-organism has an immune system, and benefits from ``social immunity''. Social immunity was first summoned by evolutionary biologists to resolve the apparent discrepancy between the expected high frequency of disease outbreak amongst numerous, closely related tightly-interacting hosts, living in stable and microbially-rich environments, against the exceptionally scarce epidemic accounts in natural populations. Social immunity comprises a multi-layer assembly of behaviours which have evolved to effectively keep the pathogenic enemies of a colony at bay. The field of social immunity has drawn interest, as it becomes increasingly urgent to stop the collapse of pollinator species and curb the growth of invasive pests. In the past decade, several mechanisms of social immune responses have been dissected, but many more questions remain open. I present my work in two experimental chapters. In the first, I use invasive garden ants (*Lasius neglectus*) to study how pathogen load and its distribution among nestmates affect the grooming response of the group. Any given group of ants will carry out the same total grooming work, but will direct their grooming effort towards individuals carrying a relatively higher spore load. Contrary to expectation, the highest risk of transmission does not stem from grooming highly contaminated ants, but instead, we suggest that the grooming response likely minimizes spore loss to the environment, reducing contamination from inadvertent pickup from the substrate. The second is a comparative developmental approach. I follow black garden ant queens (*Lasius niger*) and their colonies from mating flight, through hibernation for a year. Colonies which grow fast from the start, have a lower chance of survival through hibernation, and those which survive grow at a lower pace later. This is true for colonies of naive and challenged queens. Early pathogen exposure of the queens changes colony dynamics in an unexpected way: colonies from exposed queens are more likely to grow slowly and recover in numbers only after they survive hibernation. In addition to the two experimental chapters, this thesis includes a co-authored published review on organisational immunity, where we enlist the experimental evidence and theoretical framework on which this hypothesis is built, identify the caveats and underline how the field is ripe to overcome them. In a final chapter, I describe my part in two collaborative efforts, one to develop an image-based tracker, and the second to develop a classifier for ant behaviour.}, author = {Casillas Perez, Barbara E}, issn = {2663-337X}, keywords = {Social Immunity, Sanitary care, Social Insects, Organisational Immunity, Colony development, Multi-target tracking}, pages = {183}, publisher = {Institute of Science and Technology Austria}, title = {{Collective defenses of garden ants against a fungal pathogen}}, doi = {10.15479/AT:ISTA:6435}, year = {2019}, } @phdthesis{6269, abstract = {Clathrin-Mediated Endocytosis (CME) is an aspect of cellular trafficking that is constantly regulated for mediating developmental and physiological responses. The main aim of my thesis is to decipher the basic mechanisms of CME and post-endocytic trafficking in the whole multicellular organ systems of Arabidopsis. The first chapter of my thesis describes the search for new components involved in CME. Tandem affinity purification was conducted using CLC and its interacting partners were identified. Amongst the identified proteins were the Auxilin-likes1 and 2 (Axl1/2), putative uncoating factors, for which we made a full functional analysis. Over-expression of Axl1/2 causes extreme modifications in the dynamics of the machinery proteins and inhibition of endocytosis altogether. However the loss of function of the axl1/2 did not present any cellular or physiological phenotype, meaning Auxilin-likes do not form the major uncoating machinery. The second chapter of my thesis describes the establishment/utilisation of techniques to capture the dynamicity and the complexity of CME and post-endocytic trafficking. We have studied the development of endocytic pits at the PM – specifically, the mode of membrane remodeling during pit development and the role of actin in it, given plant cells possess high turgor pressure. Utilizing the improved z-resolution of TIRF and VAEM techniques, we captured the time-lapse of the endocytic events at the plasma membrane; and using particle detection software, we quantitatively analysed all the endocytic trajectories in an unbiased way to obtain the endocytic rate of the system. This together with the direct analysis of cargo internalisation from the PM provided an estimate on the endocytic potential of the cell. We also developed a methodology for ultrastructural analysis of different populations of Clathrin-Coated Structures (CCSs) in both PM and endomembranes in unroofed protoplasts. Structural analysis, together with the intensity profile of CCSs at the PM show that the mode of CCP development at the PM follows ‘Constant curvature model’; meaning that clathrin polymerisation energy is a major contributing factor of membrane remodeling. In addition, other analyses clearly show that actin is not required for membrane remodeling during invagination or any other step of CCP development, despite the prevalent high turgor pressure. However, actin is essential in orchestrating the post-endocytic trafficking of CCVs facilitating the EE formation. We also observed that the uncoating process post-endocytosis is not immediate; an alternative mechanism of uncoating – Sequential multi-step process – functions in the cell. Finally we also looked at one of the important physiological stimuli modulating the process – hormone, auxin. auxin has been known to influence CME before. We have made a detailed study on the concentration-time based effect of auxin on the machinery proteins, CCP development, and the specificity of cargoes endocytosed. To this end, we saw no general effect of auxin on CME at earlier time points. However, very low concentration of IAA, such as 50nM, accelerates endocytosis of specifically PIN2 through CME. Such a tight regulatory control with high specificity to PIN2 could be essential in modulating its polarity. }, author = {Narasimhan, Madhumitha}, issn = {2663-337X}, pages = {138}, publisher = {Institute of Science and Technology Austria}, title = {{Clathrin-Mediated endocytosis, post-endocytic trafficking and their regulatory controls in plants }}, doi = {10.15479/at:ista:th1075}, year = {2019}, } @inproceedings{11222, author = {Kim, Olena and Borges Merjane, Carolina and Jonas, Peter M}, booktitle = {Intrinsic Activity}, issn = {2309-8503}, keywords = {hippocampus, mossy fibers, readily releasable pool, electron microscopy}, location = {Innsbruck, Austria}, number = {Suppl. 1}, publisher = {Austrian Pharmacological Society}, title = {{Functional analysis of the docked vesicle pool in hippocampal mossy fiber terminals by electron microscopy}}, doi = {10.25006/ia.7.s1-a3.27}, volume = {7}, year = {2019}, } @phdthesis{6947, abstract = {Lymph nodes are es s ential organs of the immune s ys tem where adaptive immune responses originate, and consist of various leukocyte populations and a stromal backbone. Fibroblastic reticular cells (FRCs) are the main stromal cells and form a sponge-like extracellular matrix network, called conduits , which they thems elves enwrap and contract. Lymph, containing s oluble antigens , arrive in lymph nodes via afferent lymphatic vessels that connect to the s ubcaps ular s inus and conduit network. According to the current paradigm, the conduit network dis tributes afferent lymph through lymph nodes and thus provides acces s for immune cells to lymph-borne antigens. An elas tic caps ule s urrounds the organ and confines the immune cells and FRC network. Lymph nodes are completely packed with lymphocytes and lymphocyte numbers directly dictates the size of the organ. Although lymphocytes cons tantly enter and leave the lymph node, its s ize remains remarkedly s table under homeostatic conditions. It is only partly known how the cellularity and s ize of the lymph node is regulated and how the lymph node is able to swell in inflammation. The role of the FRC network in lymph node s welling and trans fer of fluids are inves tigated in this thes is. Furthermore, we s tudied what trafficking routes are us ed by cancer cells in lymph nodes to form distal metastases.We examined the role of a mechanical feedback in regulation of lymph node swelling. Using parallel plate compression and UV-las er cutting experiments we dis s ected the mechanical force dynamics of the whole lymph node, and individually for FRCs and the caps ule. Physical forces generated by packed lymphocytes directly affect the tens ion on the FRC network and capsule, which increases its resistance to swelling. This implies a feedback mechanism between tis s ue pres s ure and ability of lymphocytes to enter the organ. Following inflammation, the lymph node swells ∼10 fold in two weeks . Yet, what is the role for tens ion on the FRC network and caps ule, and how are lymphocytes able to enter in conditions that resist swelling remain open ques tions . We s how that tens ion on the FRC network is important to limit the swelling rate of the organ so that the FRC network can grow in a coordinated fashion. This is illustrated by interfering with FRC contractility, which leads to faster swelling rates and a dis organized FRC network in the inflamed lymph node. Growth of the FRC network in turn is expected to releas e tens ion on thes e s tructures and lowers the res is tance to swelling, thereby allowing more lymphocytes to enter the organ and drive more swelling. Halt of swelling coincides with a thickening of the caps ule, which forms a thick res is tant band around the organ and lowers tens ion on the FRC network to form a new force equilibrium.The FRC and conduit network are further believed to be a privileged s ite of s oluble information within the lymph node, although many details remain uns olved. We s how by 3D ultra-recons truction that FRCs and antigen pres enting cells cover the s urface of conduit s ys tem for more than 99% and we dis cus s the implications for s oluble information exchangeat the conduit level.Finally, there is an ongoing debate in the cancer field whether and how cancer cells in lymph nodes s eed dis tal metas tas es . We s how that cancer cells infus ed into the lymph node can utilize trafficking routes of immune cells and rapidly migrate to blood vessels. Once in the blood circulation, these cells are able to form metastases in distal tissues.}, author = {Assen, Frank P}, issn = {2663-337X}, pages = {142}, publisher = {Institute of Science and Technology Austria}, title = {{Lymph node mechanics: Deciphering the interplay between stroma contractility, morphology and lymphocyte trafficking}}, doi = {10.15479/AT:ISTA:6947}, year = {2019}, } @phdthesis{6849, abstract = {Brain function is mediated by complex dynamical interactions between excitatory and inhibitory cell types. The Cholecystokinin-expressing inhibitory cells (CCK-interneurons) are one of the least studied types, despite being suspected to play important roles in cognitive processes. We studied the network effects of optogenetic silencing of CCK-interneurons in the CA1 hippocampal area during exploration and sleep states. The cell firing pattern in response to light pulses allowed us to classify the recorded neurons in 5 classes, including disinhibited and non-responsive pyramidal cell and interneurons, and the inhibited interneurons corresponding to the CCK group. The light application, which inhibited the activity of CCK interneurons triggered wider changes in the firing dynamics of cells. We observed rate changes (i.e. remapping) of pyramidal cells during the exploration session in which the light was applied relative to the previous control session that was not restricted neither in time nor space to the light delivery. Also, the disinhibited pyramidal cells had higher increase in bursting than in single spike firing rate as a result of CCK silencing. In addition, the firing activity patterns during exploratory periods were more weakly reactivated in sleep for those periods in which CCK-interneuron were silenced than in the unaffected periods. Furthermore, light pulses during sleep disrupted the reactivation of recent waking patterns. Hence, silencing CCK neurons during exploration suppressed the reactivation of waking firing patterns in sleep and CCK interneuron activity was also required during sleep for the normal reactivation of waking patterns. These findings demonstrate the involvement of CCK cells in reactivation-related memory consolidation. An important part of our analysis was to test the relationship of the identified CCKinterneurons to brain oscillations. Our findings showed that these cells exhibited different oscillatory behaviour during anaesthesia and natural waking and sleep conditions. We showed that: 1) Contrary to the past studies performed under anaesthesia, the identified CCKinterneurons fired on the descending portion of the theta phase in waking exploration. 2) CCKinterneuron preferred phases around the trough of gamma oscillations. 3) Contrary to anaesthesia conditions, the average firing rate of the CCK-interneurons increased around the peak activity of the sharp-wave ripple (SWR) events in natural sleep, which is congruent with new reports about their functional connectivity. We also found that light driven CCK-interneuron silencing altered the dynamics on the CA1 network oscillatory activity: 1) Pyramidal cells negatively shifted their preferred theta phases when the light was applied, while interneurons responses were less consistent. 2) As a population, pyramidal cells negatively shifted their preferred activity during gamma oscillations, albeit we did not find gamma modulation differences related to the light application when pyramidal cells were subdivided into the disinhibited and unaffected groups. 3) During the peak of SWR events, all but the CCK-interneurons had a reduction in their relative firing rate change during the light application as compared to the change observed at SWR initiation. Finally, regarding to the place field activity of the recorded pyramidal neurons, we showed that the disinhibited pyramidal cells had reduced place field similarity, coherence and spatial information, but only during the light application. The mechanisms behind such observed behaviours might involve eCB signalling and plastic changes in CCK-interneuron synapses. In conclusion, the observed changes related to the light-mediated silencing of CCKinterneurons have unravelled characteristics of this interneuron subpopulation that might change the understanding not only of their particular network interactions, but also of the current theories about the emergence of certain cognitive processes such as place coding needed for navigation or hippocampus-dependent memory consolidation. }, author = {Rangel Guerrero, Dámaris K}, isbn = {9783990780039}, issn = {2663-337X}, pages = {97}, publisher = {Institute of Science and Technology Austria}, title = {{The role of CCK-interneurons in regulating hippocampal network dynamics}}, doi = {10.15479/AT:ISTA:6849}, year = {2019}, } @article{6351, abstract = {A process of restorative patterning in plant roots correctly replaces eliminated cells to heal local injuries despite the absence of cell migration, which underpins wound healing in animals. Patterning in plants relies on oriented cell divisions and acquisition of specific cell identities. Plants regularly endure wounds caused by abiotic or biotic environmental stimuli and have developed extraordinary abilities to restore their tissues after injuries. Here, we provide insight into a mechanism of restorative patterning that repairs tissues after wounding. Laser-assisted elimination of different cells in Arabidopsis root combined with live-imaging tracking during vertical growth allowed analysis of the regeneration processes in vivo. Specifically, the cells adjacent to the inner side of the injury re-activated their stem cell transcriptional programs. They accelerated their progression through cell cycle, coordinately changed the cell division orientation, and ultimately acquired de novo the correct cell fates to replace missing cells. These observations highlight existence of unknown intercellular positional signaling and demonstrate the capability of specified cells to re-acquire stem cell programs as a crucial part of the plant-specific mechanism of wound healing.}, author = {Marhavá, Petra and Hörmayer, Lukas and Yoshida, Saiko and Marhavy, Peter and Benková, Eva and Friml, Jiří}, issn = {10974172}, journal = {Cell}, number = {4}, pages = {957--969.e13}, publisher = {Elsevier}, title = {{Re-activation of stem cell pathways for pattern restoration in plant wound healing}}, doi = {10.1016/j.cell.2019.04.015}, volume = {177}, year = {2019}, } @article{6943, abstract = {Plants as sessile organisms are constantly under attack by herbivores, rough environmental situations, or mechanical pressure. These challenges often lead to the induction of wounds or destruction of already specified and developed tissues. Additionally, wounding makes plants vulnerable to invasion by pathogens, which is why wound signalling often triggers specific defence responses. To stay competitive or, eventually, survive under these circumstances, plants need to regenerate efficiently, which in rigid, tissue migration-incompatible plant tissues requires post-embryonic patterning and organogenesis. Now, several studies used laser-assisted single cell ablation in the Arabidopsis root tip as a minimal wounding proxy. Here, we discuss their findings and put them into context of a broader spectrum of wound signalling, pathogen responses and tissue as well as organ regeneration.}, author = {Hörmayer, Lukas and Friml, Jiří}, issn = {1369-5266}, journal = {Current Opinion in Plant Biology}, pages = {124--130}, publisher = {Elsevier}, title = {{Targeted cell ablation-based insights into wound healing and restorative patterning}}, doi = {10.1016/j.pbi.2019.08.006}, volume = {52}, year = {2019}, } @article{7391, abstract = {Electron microscopy (EM) is a technology that enables visualization of single proteins at a nanometer resolution. However, current protein analysis by EM mainly relies on immunolabeling with gold-particle-conjugated antibodies, which is compromised by large size of antibody, precluding precise detection of protein location in biological samples. Here, we develop a specific chemical labeling method for EM detection of proteins at single-molecular level. Rational design of α-helical peptide tag and probe structure provided a complementary reaction pair that enabled specific cysteine conjugation of the tag. The developed chemical labeling with gold-nanoparticle-conjugated probe showed significantly higher labeling efficiency and detectability of high-density clusters of tag-fused G protein-coupled receptors in freeze-fracture replicas compared with immunogold labeling. Furthermore, in ultrathin sections, the spatial resolution of the chemical labeling was significantly higher than that of antibody-mediated labeling. These results demonstrate substantial advantages of the chemical labeling approach for single protein visualization by EM.}, author = {Tabata, Shigekazu and Jevtic, Marijo and Kurashige, Nobutaka and Fuchida, Hirokazu and Kido, Munetsugu and Tani, Kazushi and Zenmyo, Naoki and Uchinomiya, Shohei and Harada, Harumi and Itakura, Makoto and Hamachi, Itaru and Shigemoto, Ryuichi and Ojida, Akio}, issn = {2589-0042}, journal = {iScience}, number = {12}, pages = {256--268}, publisher = {Elsevier}, title = {{Electron microscopic detection of single membrane proteins by a specific chemical labeling}}, doi = {10.1016/j.isci.2019.11.025}, volume = {22}, year = {2019}, } @article{6848, abstract = {Proton-translocating transhydrogenase (also known as nicotinamide nucleotide transhydrogenase (NNT)) is found in the plasma membranes of bacteria and the inner mitochondrial membranes of eukaryotes. NNT catalyses the transfer of a hydride between NADH and NADP+, coupled to the translocation of one proton across the membrane. Its main physiological function is the generation of NADPH, which is a substrate in anabolic reactions and a regulator of oxidative status; however, NNT may also fine-tune the Krebs cycle1,2. NNT deficiency causes familial glucocorticoid deficiency in humans and metabolic abnormalities in mice, similar to those observed in type II diabetes3,4. The catalytic mechanism of NNT has been proposed to involve a rotation of around 180° of the entire NADP(H)-binding domain that alternately participates in hydride transfer and proton-channel gating. However, owing to the lack of high-resolution structures of intact NNT, the details of this process remain unclear5,6. Here we present the cryo-electron microscopy structure of intact mammalian NNT in different conformational states. We show how the NADP(H)-binding domain opens the proton channel to the opposite sides of the membrane, and we provide structures of these two states. We also describe the catalytically important interfaces and linkers between the membrane and the soluble domains and their roles in nucleotide exchange. These structures enable us to propose a revised mechanism for a coupling process in NNT that is consistent with a large body of previous biochemical work. Our results are relevant to the development of currently unavailable NNT inhibitors, which may have therapeutic potential in ischaemia reperfusion injury, metabolic syndrome and some cancers7,8,9.}, author = {Kampjut, Domen and Sazanov, Leonid A}, issn = {1476-4687}, journal = {Nature}, number = {7773}, pages = {291–295}, publisher = {Springer Nature}, title = {{Structure and mechanism of mitochondrial proton-translocating transhydrogenase}}, doi = {10.1038/s41586-019-1519-2}, volume = {573}, year = {2019}, } @article{6194, abstract = {Grid cells with their rigid hexagonal firing fields are thought to provide an invariant metric to the hippocampal cognitive map, yet environmental geometrical features have recently been shown to distort the grid structure. Given that the hippocampal role goes beyond space, we tested the influence of nonspatial information on the grid organization. We trained rats to daily learn three new reward locations on a cheeseboard maze while recording from the medial entorhinal cortex and the hippocampal CA1 region. Many grid fields moved toward goal location, leading to long-lasting deformations of the entorhinal map. Therefore, distortions in the grid structure contribute to goal representation during both learning and recall, which demonstrates that grid cells participate in mnemonic coding and do not merely provide a simple metric of space.}, author = {Boccara, Charlotte N. and Nardin, Michele and Stella, Federico and O'Neill, Joseph and Csicsvari, Jozsef L}, issn = {1095-9203}, journal = {Science}, number = {6434}, pages = {1443--1447}, publisher = {American Association for the Advancement of Science}, title = {{The entorhinal cognitive map is attracted to goals}}, doi = {10.1126/science.aav4837}, volume = {363}, year = {2019}, } @phdthesis{7132, abstract = {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.}, author = {Mckenzie, Catherine}, issn = {2663-337X}, pages = {95}, publisher = {Institute of Science and Technology Austria}, title = {{Design and characterization of methods and biological components to realize synthetic neurotransmission}}, doi = {10.15479/at:ista:7132}, year = {2019}, } @article{5949, abstract = {Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single-unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted-in-Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention-related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed-modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location-independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty-induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms.}, author = {Käfer, Karola and Malagon-Vina, Hugo and Dickerson, Desiree and O'Neill, Joseph and Trossbach, Svenja V. and Korth, Carsten and Csicsvari, Jozsef L}, journal = {Hippocampus}, number = {9}, pages = {802--816}, publisher = {Wiley}, title = {{Disrupted-in-schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization}}, doi = {10.1002/hipo.23076}, volume = {29}, year = {2019}, } @phdthesis{6825, abstract = {The solving of complex tasks requires the functions of more than one brain area and their interaction. Whilst spatial navigation and memory is dependent on the hippocampus, flexible behavior relies on the medial prefrontal cortex (mPFC). To further examine the roles of the hippocampus and mPFC, we recorded their neural activity during a task that depends on both of these brain regions. With tetrodes, we recorded the extracellular activity of dorsal hippocampal CA1 (HPC) and mPFC neurons in Long-Evans rats performing a rule-switching task on the plus-maze. The plus-maze task had a spatial component since it required navigation along one of the two start arms and at the maze center a choice between one of the two goal arms. Which goal contained a reward depended on the rule currently in place. After an uncued rule change the animal had to abandon the old strategy and switch to the new rule, testing cognitive flexibility. Investigating the coordination of activity between the HPC and mPFC allows determination during which task stages their interaction is required. Additionally, comparing neural activity patterns in these two brain regions allows delineation of the specialized functions of the HPC and mPFC in this task. We analyzed neural activity in the HPC and mPFC in terms of oscillatory interactions, rule coding and replay. We found that theta coherence between the HPC and mPFC is increased at the center and goals of the maze, both when the rule was stable or has changed. Similar results were found for locking of HPC and mPFC neurons to HPC theta oscillations. However, no differences in HPC-mPFC theta coordination were observed between the spatially- and cue-guided rule. Phase locking of HPC and mPFC neurons to HPC gamma oscillations was not modulated by maze position or rule type. We found that the HPC coded for the two different rules with cofiring relationships between cell pairs. However, we could not find conclusive evidence for rule coding in the mPFC. Spatially-selective firing in the mPFC generalized between the two start and two goal arms. With Bayesian positional decoding, we found that the mPFC reactivated non-local positions during awake immobility periods. Replay of these non-local positions could represent entire behavioral trajectories resembling trajectory replay of the HPC. Furthermore, mPFC trajectory-replay at the goal positively correlated with rule-switching performance. Finally, HPC and mPFC trajectory replay occurred independently of each other. These results show that the mPFC can replay ordered patterns of activity during awake immobility, possibly underlying its role in flexible behavior. }, author = {Käfer, Karola}, issn = {2663-337X}, pages = {89}, publisher = {Institute of Science and Technology Austria}, title = {{The hippocampus and medial prefrontal cortex during flexible behavior}}, doi = {10.15479/AT:ISTA:6825}, year = {2019}, } @article{6713, abstract = {Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response.}, author = {Castro, João Pl and Yancoskie, Michelle N. and Marchini, Marta and Belohlavy, Stefanie and Hiramatsu, Layla and Kučka, Marek and Beluch, William H. and Naumann, Ronald and Skuplik, Isabella and Cobb, John and Barton, Nicholas H and Rolian, Campbell and Chan, Yingguang Frank}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice}}, doi = {10.7554/eLife.42014}, volume = {8}, year = {2019}, } @unpublished{10065, abstract = {We study double quantum dots in a Ge/SiGe heterostructure and test their maturity towards singlet-triplet ($S-T_0$) qubits. We demonstrate a large range of tunability, from two single quantum dots to a double quantum dot. We measure Pauli spin blockade and study the anisotropy of the $g$-factor. We use an adjacent quantum dot for sensing charge transitions in the double quantum dot at interest. In conclusion, Ge/SiGe possesses all ingredients necessary for building a singlet-triplet qubit.}, author = {Hofmann, Andrea C and Jirovec, Daniel and Borovkov, Maxim and Prieto Gonzalez, Ivan and Ballabio, Andrea and Frigerio, Jacopo and Chrastina, Daniel and Isella, Giovanni and Katsaros, Georgios}, booktitle = {arXiv}, title = {{Assessing the potential of Ge/SiGe quantum dots as hosts for singlet-triplet qubits}}, doi = {10.48550/arXiv.1910.05841}, year = {2019}, } @article{6187, abstract = {Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis.}, author = {Valosková, Katarina and Biebl, Julia and Roblek, Marko and Emtenani, Shamsi and György, Attila and Misova, Michaela and Ratheesh, Aparna and Rodrigues, Patricia and Shkarina, Katerina and Larsen, Ida Signe Bohse and Vakhrushev, Sergey Y and Clausen, Henrik and Siekhaus, Daria E}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion}}, doi = {10.7554/elife.41801}, volume = {8}, year = {2019}, } @phdthesis{6546, abstract = {Invasive migration plays a crucial role not only during development and homeostasis but also in pathological states, such as tumor metastasis. Drosophila macrophage migration into the extended germband is an interesting system to study invasive migration. It carries similarities to immune cell transmigration and cancer cell invasion, therefore studying this process could also bring new understanding of invasion in higher organisms. In our work, we uncover a highly conserved member of the major facilitator family that plays a role in tissue invasion through regulation of glycosylation on a subgroup of proteins and/or by aiding the precise timing of DN-Cadherin downregulation. Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis. }, author = {Valosková, Katarina}, issn = {2663-337X}, pages = {141}, publisher = {Institute of Science and Technology Austria}, title = {{The role of a highly conserved major facilitator superfamily member in Drosophila embryonic macrophage migration}}, doi = {10.15479/AT:ISTA:6546}, year = {2019}, } @phdthesis{6363, abstract = {Distinguishing between similar experiences is achieved by the brain in a process called pattern separation. In the hippocampus, pattern separation reduces the interference of memories and increases the storage capacity by decorrelating similar inputs patterns of neuronal activity into non-overlapping output firing patterns. Winners-take-all (WTA) mechanism is a theoretical model for pattern separation in which a "winner" cell suppresses the activity of the neighboring neurons through feedback inhibition. However, if the network properties of the dentate gyrus support WTA as a biologically conceivable model remains unknown. Here, we showed that the connectivity rules of PV+interneurons and their synaptic properties are optimizedfor efficient pattern separation. We found using multiple whole-cell in vitrorecordings that PV+interneurons mainly connect to granule cells (GC) through lateral inhibition, a form of feedback inhibition in which a GC inhibits other GCs but not itself through the activation of PV+interneurons. Thus, lateral inhibition between GC–PV+interneurons was ~10 times more abundant than recurrent connections. Furthermore, the GC–PV+interneuron connectivity was more spatially confined but less abundant than PV+interneurons–GC connectivity, leading to an asymmetrical distribution of excitatory and inhibitory connectivity. Our network model of the dentate gyrus with incorporated real connectivity rules efficiently decorrelates neuronal activity patterns using WTA as the primary mechanism. This process relied on lateral inhibition, fast-signaling properties of PV+interneurons and the asymmetrical distribution of excitatory and inhibitory connectivity. Finally, we found that silencing the activity of PV+interneurons in vivoleads to acute deficits in discrimination between similar environments, suggesting that PV+interneuron networks are necessary for behavioral relevant computations. Our results demonstrate that PV+interneurons possess unique connectivity and fast signaling properties that confer to the dentate gyrus network properties that allow the emergence of pattern separation. Thus, our results contribute to the knowledge of how specific forms of network organization underlie sophisticated types of information processing. }, author = {Espinoza Martinez, Claudia }, isbn = {978-3-99078-000-8}, issn = {2663-337X}, pages = {140}, publisher = {Institute of Science and Technology Austria}, title = {{Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits}}, doi = {10.15479/AT:ISTA:6363}, year = {2019}, } @inproceedings{6780, abstract = {In this work, we consider the almost-sure termination problem for probabilistic programs that asks whether a given probabilistic program terminates with probability 1. Scalable approaches for program analysis often rely on modularity as their theoretical basis. In non-probabilistic programs, the classical variant rule (V-rule) of Floyd-Hoare logic provides the foundation for modular analysis. Extension of this rule to almost-sure termination of probabilistic programs is quite tricky, and a probabilistic variant was proposed in [16]. While the proposed probabilistic variant cautiously addresses the key issue of integrability, we show that the proposed modular rule is still not sound for almost-sure termination of probabilistic programs. Besides establishing unsoundness of the previous rule, our contributions are as follows: First, we present a sound modular rule for almost-sure termination of probabilistic programs. Our approach is based on a novel notion of descent supermartingales. Second, for algorithmic approaches, we consider descent supermartingales that are linear and show that they can be synthesized in polynomial time. Finally, we present experimental results on a variety of benchmarks and several natural examples that model various types of nested while loops in probabilistic programs and demonstrate that our approach is able to efficiently prove their almost-sure termination property}, author = {Huang, Mingzhang and Fu, Hongfei and Chatterjee, Krishnendu and Goharshady, Amir Kafshdar}, booktitle = {Proceedings of the 34th ACM International Conference on Object-Oriented Programming, Systems, Languages, and Applications }, location = {Athens, Greece}, publisher = {ACM}, title = {{Modular verification for almost-sure termination of probabilistic programs}}, doi = {10.1145/3360555}, volume = {3}, year = {2019}, } @article{6380, abstract = {There is a huge gap between the speeds of modern caches and main memories, and therefore cache misses account for a considerable loss of efficiency in programs. The predominant technique to address this issue has been Data Packing: data elements that are frequently accessed within time proximity are packed into the same cache block, thereby minimizing accesses to the main memory. We consider the algorithmic problem of Data Packing on a two-level memory system. Given a reference sequence R of accesses to data elements, the task is to partition the elements into cache blocks such that the number of cache misses on R is minimized. The problem is notoriously difficult: it is NP-hard even when the cache has size 1, and is hard to approximate for any cache size larger than 4. Therefore, all existing techniques for Data Packing are based on heuristics and lack theoretical guarantees. In this work, we present the first positive theoretical results for Data Packing, along with new and stronger negative results. We consider the problem under the lens of the underlying access hypergraphs, which are hypergraphs of affinities between the data elements, where the order of an access hypergraph corresponds to the size of the affinity group. We study the problem parameterized by the treewidth of access hypergraphs, which is a standard notion in graph theory to measure the closeness of a graph to a tree. Our main results are as follows: We show there is a number q* depending on the cache parameters such that (a) if the access hypergraph of order q* has constant treewidth, then there is a linear-time algorithm for Data Packing; (b)the Data Packing problem remains NP-hard even if the access hypergraph of order q*-1 has constant treewidth. Thus, we establish a fine-grained dichotomy depending on a single parameter, namely, the highest order among access hypegraphs that have constant treewidth; and establish the optimal value q* of this parameter. Finally, we present an experimental evaluation of a prototype implementation of our algorithm. Our results demonstrate that, in practice, access hypergraphs of many commonly-used algorithms have small treewidth. We compare our approach with several state-of-the-art heuristic-based algorithms and show that our algorithm leads to significantly fewer cache-misses. }, author = {Chatterjee, Krishnendu and Goharshady, Amir Kafshdar and Okati, Nastaran and Pavlogiannis, Andreas}, issn = {2475-1421}, journal = {Proceedings of the ACM on Programming Languages}, number = {POPL}, publisher = {ACM}, title = {{Efficient parameterized algorithms for data packing}}, doi = {10.1145/3290366}, volume = {3}, year = {2019}, } @inproceedings{6056, abstract = {In today's programmable blockchains, smart contracts are limited to being deterministic and non-probabilistic. This lack of randomness is a consequential limitation, given that a wide variety of real-world financial contracts, such as casino games and lotteries, depend entirely on randomness. As a result, several ad-hoc random number generation approaches have been developed to be used in smart contracts. These include ideas such as using an oracle or relying on the block hash. However, these approaches are manipulatable, i.e. their output can be tampered with by parties who might not be neutral, such as the owner of the oracle or the miners.We propose a novel game-theoretic approach for generating provably unmanipulatable pseudorandom numbers on the blockchain. Our approach allows smart contracts to access a trustworthy source of randomness that does not rely on potentially compromised miners or oracles, hence enabling the creation of a new generation of smart contracts that are not limited to being non-probabilistic and can be drawn from the much more general class of probabilistic programs.}, author = {Chatterjee, Krishnendu and Goharshady, Amir Kafshdar and Pourdamghani, Arash}, booktitle = {IEEE International Conference on Blockchain and Cryptocurrency}, location = {Seoul, Korea}, publisher = {IEEE}, title = {{Probabilistic smart contracts: Secure randomness on the blockchain}}, doi = {10.1109/BLOC.2019.8751326}, year = {2019}, } @inproceedings{6378, abstract = {In today's cryptocurrencies, Hashcash proof of work is the most commonly-adopted approach to mining. In Hashcash, when a miner decides to add a block to the chain, she has to solve the difficult computational puzzle of inverting a hash function. While Hashcash has been successfully adopted in both Bitcoin and Ethereum, it has attracted significant and harsh criticism due to its massive waste of electricity, its carbon footprint and environmental effects, and the inherent lack of usefulness in inverting a hash function. Various other mining protocols have been suggested, including proof of stake, in which a miner's chance of adding the next block is proportional to her current balance. However, such protocols lead to a higher entry cost for new miners who might not still have any stake in the cryptocurrency, and can in the worst case lead to an oligopoly, where the rich have complete control over mining. In this paper, we propose Hybrid Mining: a new mining protocol that combines solving real-world useful problems with Hashcash. Our protocol allows new miners to join the network by taking part in Hashcash mining without having to own an initial stake. It also allows nodes of the network to submit hard computational problems whose solutions are of interest in the real world, e.g.~protein folding problems. Then, miners can choose to compete in solving these problems, in lieu of Hashcash, for adding a new block. Hence, Hybrid Mining incentivizes miners to solve useful problems, such as hard computational problems arising in biology, in a distributed manner. It also gives researchers in other areas an easy-to-use tool to outsource their hard computations to the blockchain network, which has enormous computational power, by paying a reward to the miner who solves the problem for them. Moreover, our protocol provides strong security guarantees and is at least as resilient to double spending as Bitcoin.}, author = {Chatterjee, Krishnendu and Goharshady, Amir Kafshdar and Pourdamghani, Arash}, booktitle = {Proceedings of the 34th ACM Symposium on Applied Computing}, isbn = {9781450359337}, location = {Limassol, Cyprus}, pages = {374--381}, publisher = {ACM}, title = {{Hybrid Mining: Exploiting blockchain’s computational power for distributed problem solving}}, doi = {10.1145/3297280.3297319}, volume = {Part F147772}, year = {2019}, } @inproceedings{6175, abstract = {We consider the problem of expected cost analysis over nondeterministic probabilistic programs, which aims at automated methods for analyzing the resource-usage of such programs. Previous approaches for this problem could only handle nonnegative bounded costs. However, in many scenarios, such as queuing networks or analysis of cryptocurrency protocols, both positive and negative costs are necessary and the costs are unbounded as well. In this work, we present a sound and efficient approach to obtain polynomial bounds on the expected accumulated cost of nondeterministic probabilistic programs. Our approach can handle (a) general positive and negative costs with bounded updates in variables; and (b) nonnegative costs with general updates to variables. We show that several natural examples which could not be handled by previous approaches are captured in our framework. Moreover, our approach leads to an efficient polynomial-time algorithm, while no previous approach for cost analysis of probabilistic programs could guarantee polynomial runtime. Finally, we show the effectiveness of our approach using experimental results on a variety of programs for which we efficiently synthesize tight resource-usage bounds.}, author = {Wang, Peixin and Fu, Hongfei and Goharshady, Amir Kafshdar and Chatterjee, Krishnendu and Qin, Xudong and Shi, Wenjun}, booktitle = {PLDI 2019: Proceedings of the 40th ACM SIGPLAN Conference on Programming Language Design and Implementation}, keywords = {Program Cost Analysis, Program Termination, Probabilistic Programs, Martingales}, location = {Phoenix, AZ, United States}, pages = {204--220}, publisher = {Association for Computing Machinery}, title = {{Cost analysis of nondeterministic probabilistic programs}}, doi = {10.1145/3314221.3314581}, year = {2019}, }