@article{7128, abstract = {Loss of functional cardiomyocytes is a major determinant of heart failure after myocardial infarction. Previous high throughput screening studies have identified a few microRNAs (miRNAs) that can induce cardiomyocyte proliferation and stimulate cardiac regeneration in mice. Here, we show that all of the most effective of these miRNAs activate nuclear localization of the master transcriptional cofactor Yes-associated protein (YAP) and induce expression of YAP-responsive genes. In particular, miR-199a-3p directly targets two mRNAs coding for proteins impinging on the Hippo pathway, the upstream YAP inhibitory kinase TAOK1, and the E3 ubiquitin ligase β-TrCP, which leads to YAP degradation. Several of the pro-proliferative miRNAs (including miR-199a-3p) also inhibit filamentous actin depolymerization by targeting Cofilin2, a process that by itself activates YAP nuclear translocation. Thus, activation of YAP and modulation of the actin cytoskeleton are major components of the pro-proliferative action of miR-199a-3p and other miRNAs that induce cardiomyocyte proliferation.}, author = {Torrini, Consuelo and Cubero, Ryan J and Dirkx, Ellen and Braga, Luca and Ali, Hashim and Prosdocimo, Giulia and Gutierrez, Maria Ines and Collesi, Chiara and Licastro, Danilo and Zentilin, Lorena and Mano, Miguel and Zacchigna, Serena and Vendruscolo, Michele and Marsili, Matteo and Samal, Areejit and Giacca, Mauro}, issn = {2211-1247}, journal = {Cell Reports}, keywords = {cardiomyocyte, cell cycle, Cofilin2, cytoskeleton, Hippo, microRNA, regeneration, YAP}, number = {9}, pages = {2759--2771.e5}, publisher = {Elsevier}, title = {{Common regulatory pathways mediate activity of microRNAs inducing cardiomyocyte proliferation}}, doi = {10.1016/j.celrep.2019.05.005}, volume = {27}, year = {2019}, } @article{7130, abstract = {We show that statistical criticality, i.e. the occurrence of power law frequency distributions, arises in samples that are maximally informative about the underlying generating process. In order to reach this conclusion, we first identify the frequency with which different outcomes occur in a sample, as the variable carrying useful information on the generative process. The entropy of the frequency, that we call relevance, provides an upper bound to the number of informative bits. This differs from the entropy of the data, that we take as a measure of resolution. Samples that maximise relevance at a given resolution—that we call maximally informative samples—exhibit statistical criticality. In particular, Zipf's law arises at the optimal trade-off between resolution (i.e. compression) and relevance. As a byproduct, we derive a bound of the maximal number of parameters that can be estimated from a dataset, in the absence of prior knowledge on the generative model. Furthermore, we relate criticality to the statistical properties of the representation of the data generating process. We show that, as a consequence of the concentration property of the asymptotic equipartition property, representations that are maximally informative about the data generating process are characterised by an exponential distribution of energy levels. This arises from a principle of minimal entropy, that is conjugate of the maximum entropy principle in statistical mechanics. This explains why statistical criticality requires no parameter fine tuning in maximally informative samples.}, author = {Cubero, Ryan J and Jo, Junghyo and Marsili, Matteo and Roudi, Yasser and Song, Juyong}, issn = {1742-5468}, journal = {Journal of Statistical Mechanics: Theory and Experiment}, keywords = {optimization under uncertainty, source coding, large deviation}, number = {6}, publisher = {IOP Publishing}, title = {{Statistical criticality arises in most informative representations}}, doi = {10.1088/1742-5468/ab16c8}, volume = {2019}, year = {2019}, } @article{7150, abstract = {In this work, we use algebraic methods for studying distance computation and subgraph detection tasks in the congested clique model. Specifically, we adapt parallel matrix multiplication implementations to the congested clique, obtaining an O(n1−2/ω) round matrix multiplication algorithm, where ω<2.3728639 is the exponent of matrix multiplication. In conjunction with known techniques from centralised algorithmics, this gives significant improvements over previous best upper bounds in the congested clique model. The highlight results include: 1. triangle and 4-cycle counting in O(n0.158) rounds, improving upon the O(n1/3) algorithm of Dolev et al. [DISC 2012], 2. a (1+o(1))-approximation of all-pairs shortest paths in O(n0.158) rounds, improving upon the O~(n1/2)-round (2+o(1))-approximation algorithm given by Nanongkai [STOC 2014], and 3. computing the girth in O(n0.158) rounds, which is the first non-trivial solution in this model. In addition, we present a novel constant-round combinatorial algorithm for detecting 4-cycles.}, author = {Censor-Hillel, Keren and Kaski, Petteri and Korhonen, Janne and Lenzen, Christoph and Paz, Ami and Suomela, Jukka}, issn = {0178-2770}, journal = {Distributed Computing}, number = {6}, pages = {461--478}, publisher = {Springer Nature}, title = {{Algebraic methods in the congested clique}}, doi = {10.1007/s00446-016-0270-2}, volume = {32}, year = {2019}, } @book{7171, abstract = {Wissen Sie, was sich hinter künstlicher Intelligenz und maschinellem Lernen verbirgt? Dieses Sachbuch erklärt Ihnen leicht verständlich und ohne komplizierte Formeln die grundlegenden Methoden und Vorgehensweisen des maschinellen Lernens. Mathematisches Vorwissen ist dafür nicht nötig. Kurzweilig und informativ illustriert Lisa, die Protagonistin des Buches, diese anhand von Alltagssituationen. Ein Buch für alle, die in Diskussionen über Chancen und Risiken der aktuellen Entwicklung der künstlichen Intelligenz und des maschinellen Lernens mit Faktenwissen punkten möchten. Auch für Schülerinnen und Schüler geeignet!}, editor = {Kersting, Kristian and Lampert, Christoph and Rothkopf, Constantin}, isbn = {978-3-658-26762-9}, pages = {XIV, 245}, publisher = {Springer Nature}, title = {{Wie Maschinen Lernen: Künstliche Intelligenz Verständlich Erklärt}}, doi = {10.1007/978-3-658-26763-6}, year = {2019}, } @article{7275, abstract = {Aprotic alkali metal–oxygen batteries require reversible formation of metal superoxide or peroxide on cycling. Severe parasitic reactions cause poor rechargeability, efficiency, and cycle life and have been shown to be caused by singlet oxygen (1O2) that forms at all stages of cycling. However, its formation mechanism remains unclear. We show that disproportionation of superoxide, the product or intermediate on discharge and charge, to peroxide and oxygen is responsible for 1O2 formation. While the overall reaction is driven by the stability of peroxide and thus favored by stronger Lewis acidic cations such as Li+, the 1O2 fraction is enhanced by weak Lewis acids such as organic cations. Concurrently, the metal peroxide yield drops with increasing 1O2. The results explain a major parasitic pathway during cell cycling and the growing severity in K–, Na–, and Li–O2 cells based on the growing propensity for disproportionation. High capacities and rates with peroxides are now realized to require solution processes, which form peroxide or release O2via disproportionation. The results therefore establish the central dilemma that disproportionation is required for high capacity but also responsible for irreversible reactions. Highly reversible cell operation requires hence finding reaction routes that avoid disproportionation.}, author = {Mourad, Eléonore and Petit, Yann K. and Spezia, Riccardo and Samojlov, Aleksej and Summa, Francesco F. and Prehal, Christian and Leypold, Christian and Mahne, Nika and Slugovc, Christian and Fontaine, Olivier and Brutti, Sergio and Freunberger, Stefan Alexander}, issn = {1754-5692}, journal = {Energy & Environmental Science}, number = {8}, pages = {2559--2568}, publisher = {RSC}, title = {{Singlet oxygen from cation driven superoxide disproportionation and consequences for aprotic metal–O2 batteries}}, doi = {10.1039/c9ee01453e}, volume = {12}, year = {2019}, } @article{7280, abstract = {Non-aqueous lithium-oxygen batteries cycle by forming lithium peroxide during discharge and oxidizing it during recharge. The significant problem of oxidizing the solid insulating lithium peroxide can greatly be facilitated by incorporating redox mediators that shuttle electron-holes between the porous substrate and lithium peroxide. Redox mediator stability is thus key for energy efficiency, reversibility, and cycle life. However, the gradual deactivation of redox mediators during repeated cycling has not conclusively been explained. Here, we show that organic redox mediators are predominantly decomposed by singlet oxygen that forms during cycling. Their reaction with superoxide, previously assumed to mainly trigger their degradation, peroxide, and dioxygen, is orders of magnitude slower in comparison. The reduced form of the mediator is markedly more reactive towards singlet oxygen than the oxidized form, from which we derive reaction mechanisms supported by density functional theory calculations. Redox mediators must thus be designed for stability against singlet oxygen.}, author = {Kwak, Won-Jin and Kim, Hun and Petit, Yann K. and Leypold, Christian and Nguyen, Trung Thien and Mahne, Nika and Redfern, Paul and Curtiss, Larry A. and Jung, Hun-Gi and Borisov, Sergey M. and Freunberger, Stefan Alexander and Sun, Yang-Kook}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Deactivation of redox mediators in lithium-oxygen batteries by singlet oxygen}}, doi = {10.1038/s41467-019-09399-0}, volume = {10}, year = {2019}, } @article{7276, abstract = {Singlet oxygen (1O2) causes a major fraction of the parasitic chemistry during the cycling of non‐aqueous alkali metal‐O2 batteries and also contributes to interfacial reactivity of transition‐metal oxide intercalation compounds. We introduce DABCOnium, the mono alkylated form of 1,4‐diazabicyclo[2.2.2]octane (DABCO), as an efficient 1O2 quencher with an unusually high oxidative stability of ca. 4.2 V vs. Li/Li+. Previous quenchers are strongly Lewis basic amines with too low oxidative stability. DABCOnium is an ionic liquid, non‐volatile, highly soluble in the electrolyte, stable against superoxide and peroxide, and compatible with lithium metal. The electrochemical stability covers the required range for metal–O2 batteries and greatly reduces 1O2 related parasitic chemistry as demonstrated for the Li–O2 cell.}, author = {Petit, Yann K. and Leypold, Christian and Mahne, Nika and Mourad, Eléonore and Schafzahl, Lukas and Slugovc, Christian and Borisov, Sergey M. and Freunberger, Stefan Alexander}, issn = {1433-7851}, journal = {Angewandte Chemie International Edition}, number = {20}, pages = {6535--6539}, publisher = {Wiley}, title = {{DABCOnium: An efficient and high-voltage stable singlet oxygen quencher for metal-O2 cells}}, doi = {10.1002/anie.201901869}, volume = {58}, year = {2019}, } @article{7281, abstract = {Li–O2 batteries are plagued by side reactions that cause poor rechargeability and efficiency. These reactions were recently revealed to be predominantly caused by singlet oxygen, which can be neutralized by chemical traps or physical quenchers. However, traps are irreversibly consumed and thus only active for a limited time, and so far identified quenchers lack oxidative stability to be suitable for typically required recharge potentials. Thus, reducing the charge potential within the stability limit of the quencher and/or finding more stable quenchers is required. Here, we show that dimethylphenazine as a redox mediator decreases the charge potential well within the stability limit of the quencher 1,4-diazabicyclo[2.2.2]octane. The quencher can thus mitigate the parasitic reactions without being oxidatively decomposed. At the same time the quencher protects the redox mediator from singlet oxygen attack. The mutual conservation of the redox mediator and the quencher is rational for stable and effective Li–O2 batteries.}, author = {Kwak, Won-Jin and Freunberger, Stefan Alexander and Kim, Hun and Park, Jiwon and Nguyen, Trung Thien and Jung, Hun-Gi and Byon, Hye Ryung and Sun, Yang-Kook}, issn = {2155-5435}, journal = {ACS Catalysis}, number = {11}, pages = {9914--9922}, publisher = {ACS}, title = {{Mutual conservation of redox mediator and singlet oxygen quencher in Lithium–Oxygen batteries}}, doi = {10.1021/acscatal.9b01337}, volume = {9}, year = {2019}, } @article{7282, abstract = {Interphases that form on the anode surface of lithium-ion batteries are critical for performance and lifetime, but are poorly understood. Now, a decade-old misconception regarding a main component of the interphase has been revealed, which could potentially lead to improved devices.}, author = {Freunberger, Stefan Alexander}, issn = {1755-4330}, journal = {Nature Chemistry}, number = {9}, pages = {761--763}, publisher = {Springer Nature}, title = {{Interphase identity crisis}}, doi = {10.1038/s41557-019-0311-0}, volume = {11}, year = {2019}, } @article{7283, abstract = {Potassium–air batteries, which suffer from oxygen cathode and potassium metal anode degradation, can be cycled thousands of times when an organic anode replaces the metal.}, author = {Petit, Yann K. and Freunberger, Stefan Alexander}, issn = {1476-1122}, journal = {Nature Materials}, number = {4}, pages = {301--302}, publisher = {Springer Nature}, title = {{Thousands of cycles}}, doi = {10.1038/s41563-019-0313-8}, volume = {18}, year = {2019}, } @article{7284, abstract = {In this issue of Joule, Dongmin Im and coworkers from Samsung in South Korea describe a prototype lithium-O2 battery that reaches ∼700 Wh kg–1 and ∼600 Wh L–1 on the cell level. They cut all components to the minimum to reach this value. Difficulties filling the pores with discharge product and inhomogeneous cell utilization turn out to limit the achievable energy. Their work underlines the importance of reporting performance with respect to full cell weight and volume.}, author = {Prehal, Christian and Freunberger, Stefan Alexander}, issn = {2542-4351}, journal = {Joule}, number = {2}, pages = {321--323}, publisher = {Elsevier}, title = {{Li-O2 cell-scale energy densities}}, doi = {10.1016/j.joule.2019.01.020}, volume = {3}, year = {2019}, } @unpublished{7358, abstract = {Telencephalic organoids generated from human pluripotent stem cells (hPSCs) are emerging as an effective system to study the distinct features of the developing human brain and the underlying causes of many neurological disorders. While progress in organoid technology has been steadily advancing, many challenges remain including rampant batch-to-batch and cell line-to-cell line variability and irreproducibility. Here, we demonstrate that a major contributor to successful cortical organoid production is the manner in which hPSCs are maintained prior to differentiation. Optimal results were achieved using fibroblast-feeder-supported hPSCs compared to feeder-independent cells, related to differences in their transcriptomic states. Feeder-supported hPSCs display elevated activation of diverse TGFβ superfamily signaling pathways and increased expression of genes associated with naïve pluripotency. We further identify combinations of TGFβ-related growth factors that are necessary and together sufficient to impart broad telencephalic organoid competency to feeder-free hPSCs and enable reproducible formation of brain structures suitable for disease modeling.}, author = {Watanabe, Momoko and Haney, Jillian R. and Vishlaghi, Neda and Turcios, Felix and Buth, Jessie E. and Gu, Wen and Collier, Amanda J. and Miranda, Osvaldo and Chen, Di and Sabri, Shan and Clark, Amander T. and Plath, Kathrin and Christofk, Heather R. and Gandal, Michael J. and Novitch, Bennett G.}, booktitle = {bioRxiv}, pages = {75}, publisher = {Cold Spring Harbor Laboratory}, title = {{TGFβ superfamily signaling regulates the state of human stem cell pluripotency and competency to create telencephalic organoids}}, doi = {10.1101/2019.12.13.875773}, year = {2019}, } @inproceedings{7401, abstract = {The genus g(G) of a graph G is the minimum g such that G has an embedding on the orientable surface M_g of genus g. A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The Z_2-genus of a graph G, denoted by g_0(G), is the minimum g such that G has an independently even drawing on M_g. By a result of Battle, Harary, Kodama and Youngs from 1962, the graph genus is additive over 2-connected blocks. In 2013, Schaefer and Stefankovic proved that the Z_2-genus of a graph is additive over 2-connected blocks as well, and asked whether this result can be extended to so-called 2-amalgamations, as an analogue of results by Decker, Glover, Huneke, and Stahl for the genus. We give the following partial answer. If G=G_1 cup G_2, G_1 and G_2 intersect in two vertices u and v, and G-u-v has k connected components (among which we count the edge uv if present), then |g_0(G)-(g_0(G_1)+g_0(G_2))|<=k+1. For complete bipartite graphs K_{m,n}, with n >= m >= 3, we prove that g_0(K_{m,n})/g(K_{m,n})=1-O(1/n). Similar results are proved also for the Euler Z_2-genus. We express the Z_2-genus of a graph using the minimum rank of partial symmetric matrices over Z_2; a problem that might be of independent interest. }, author = {Fulek, Radoslav and Kyncl, Jan}, booktitle = {35th International Symposium on Computational Geometry (SoCG 2019)}, isbn = {978-3-95977-104-7}, issn = {1868-8969}, location = {Portland, OR, United States}, publisher = {Schloss Dagstuhl - Leibniz-Zentrum für Informatik}, title = {{Z_2-Genus of graphs and minimum rank of partial symmetric matrices}}, doi = {10.4230/LIPICS.SOCG.2019.39}, volume = {129}, year = {2019}, } @inbook{7453, abstract = {We illustrate the ingredients of the state-of-the-art of model-based approach for the formal design and verification of cyber-physical systems. To capture the interaction between a discrete controller and its continuously evolving environment, we use the formal models of timed and hybrid automata. We explain the steps of modeling and verification in the tools Uppaal and SpaceEx using a case study based on a dual-chamber implantable pacemaker monitoring a human heart. We show how to design a model as a composition of components, how to construct models at varying levels of detail, how to establish that one model is an abstraction of another, how to specify correctness requirements using temporal logic, and how to verify that a model satisfies a logical requirement.}, author = {Alur, Rajeev and Giacobbe, Mirco and Henzinger, Thomas A and Larsen, Kim G. and Mikučionis, Marius}, booktitle = {Computing and Software Science}, editor = {Steffen, Bernhard and Woeginger, Gerhard}, isbn = {9783319919072}, issn = {0302-9743}, pages = {452--477}, publisher = {Springer Nature}, title = {{Continuous-time models for system design and analysis}}, doi = {10.1007/978-3-319-91908-9_22}, volume = {10000}, year = {2019}, } @article{7459, abstract = {We report the fabrication of BaTiO3-Ni magnetoelectric nanocomposites comprising of BaTiO3 nanotubes surrounded by Ni matrix. BaTiO3 nanotubes obtained from the hydrothermal transformation of TiO2 have both inner and outer surfaces, which facilitates greater magnetoelectric coupling with the surrounding Ni matrix. The magnetoelectric coupling was studied by measuring the piezoelectric behavior in the presence of an in-plane direct magnetic field. A higher magnetoelectric voltage coefficient of 110 mV/cm·Oe was obtained, because of better coupling between Ni and BaTiO3 through the walls of the nanotubes. Such nanocomposite developed directly on Ti substrate may lead to efficient fabrication of magnetoelectric devices.}, author = {Vadla, Samba Siva and Costanzo, Tommaso and John, Subish and Caruntu, Gabriel and Roy, Somnath C.}, issn = {1359-6462}, journal = {Scripta Materialia}, pages = {33--36}, publisher = {Elsevier}, title = {{Local probing of magnetoelectric coupling in BaTiO3-Ni 1–3 composites}}, doi = {10.1016/j.scriptamat.2018.09.003}, volume = {159}, year = {2019}, } @article{7476, abstract = {The sebaceous gland (SG) is an essential component of the skin, and SG dysfunction is debilitating1,2. Yet, the cellular bases for its origin, development and subsequent maintenance remain poorly understood. Here, we apply large-scale quantitative fate mapping to define the patterns of cell fate behaviour during SG development and maintenance. We show that the SG develops from a defined number of lineage-restricted progenitors that undergo a programme of independent and stochastic cell fate decisions. Following an expansion phase, equipotent progenitors transition into a phase of homeostatic turnover, which is correlated with changes in the mechanical properties of the stroma and spatial restrictions on gland size. Expression of the oncogene KrasG12D results in a release from these constraints and unbridled gland expansion. Quantitative clonal fate analysis reveals that, during this phase, the primary effect of the Kras oncogene is to drive a constant fate bias with little effect on cell division rates. These findings provide insight into the developmental programme of the SG, as well as the mechanisms that drive tumour progression and gland dysfunction.}, author = {Andersen, Marianne Stemann and Hannezo, Edouard B and Ulyanchenko, Svetlana and Estrach, Soline and Antoku, Yasuko and Pisano, Sabrina and Boonekamp, Kim E. and Sendrup, Sarah and Maimets, Martti and Pedersen, Marianne Terndrup and Johansen, Jens V. and Clement, Ditte L. and Feral, Chloe C. and Simons, Benjamin D. and Jensen, Kim B.}, issn = {1465-7392}, journal = {Nature Cell Biology}, number = {8}, pages = {924--932}, publisher = {Springer Nature}, title = {{Tracing the cellular dynamics of sebaceous gland development in normal and perturbed states}}, doi = {10.1038/s41556-019-0362-x}, volume = {21}, year = {2019}, } @article{7548, abstract = {Although the aggregation of the amyloid-β peptide (Aβ) into amyloid fibrils is a well-established hallmark of Alzheimer’s disease, the complex mechanisms linking this process to neurodegeneration are still incompletely understood. The nematode worm C. elegans is a valuable model organism through which to study these mechanisms because of its simple nervous system and its relatively short lifespan. Standard Aβ-based C. elegans models of Alzheimer’s disease are designed to study the toxic effects of the overexpression of Aβ in the muscle or nervous systems. However, the wide variety of effects associated with the tissue-level overexpression of Aβ makes it difficult to single out and study specific cellular mechanisms related to the onset of Alzheimer’s disease. Here, to better understand how to investigate the early events affecting neuronal signalling, we created a C. elegans model expressing Aβ42, the 42-residue form of Aβ, from a single-copy gene insertion in just one pair of glutamatergic sensory neurons, the BAG neurons. In behavioural assays, we found that the Aβ42-expressing animals displayed a subtle modulation of the response to CO2, compared to controls. Ca2+ imaging revealed that the BAG neurons in young Aβ42-expressing nematodes were activated more strongly than in control animals, and that neuronal activation remained intact until old age. Taken together, our results suggest that Aβ42-expression in this very subtle model of AD is sufficient to modulate the behavioural response but not strong enough to generate significant neurotoxicity, suggesting that slightly more aggressive perturbations will enable effectively studies of the links between the modulation of a physiological response and its associated neurotoxicity.}, author = {Sinnige, Tessa and Ciryam, Prashanth and Casford, Samuel and Dobson, Christopher M. and de Bono, Mario and Vendruscolo, Michele}, issn = {1932-6203}, journal = {PLOS ONE}, number = {5}, publisher = {Public Library of Science}, title = {{Expression of the amyloid-β peptide in a single pair of C. elegans sensory neurons modulates the associated behavioural response}}, doi = {10.1371/journal.pone.0217746}, volume = {14}, year = {2019}, } @article{7547, abstract = {The BH3-only family of proteins is key for initiating apoptosis in a variety of contexts, and may also contribute to non-apoptotic cellular processes. Historically, the nematode Caenorhabditis elegans has provided a powerful system for studying and identifying conserved regulators of BH3-only proteins. In C. elegans, the BH3-only protein egl-1 is expressed during development to cell-autonomously trigger most developmental cell deaths. Here we provide evidence that egl-1 is also transcribed after development in the sensory neuron pair URX without inducing apoptosis. We used genetic screening and epistasis analysis to determine that its transcription is regulated in URX by neuronal activity and/or in parallel by orthologs of Protein Kinase G and the Salt-Inducible Kinase family. Because several BH3-only family proteins are also expressed in the adult nervous system of mammals, we suggest that studying egl-1 expression in URX may shed light on mechanisms that regulate conserved family members in higher organisms.}, author = {Cohn, Jesse and Dwivedi, Vivek and Valperga, Giulio and Zarate, Nicole and de Bono, Mario and Horvitz, H. Robert and Pierce, Jonathan T.}, issn = {2160-1836}, journal = {G3: Genes, Genomes, Genetics}, number = {11}, pages = {3703--3714}, publisher = {Genetics Society of America}, title = {{Activity-dependent regulation of the proapoptotic BH3-only gene egl-1 in a living neuron pair in Caenorhabditis elegans}}, doi = {10.1534/g3.119.400654}, volume = {9}, year = {2019}, } @article{7550, abstract = {We consider an optimal control problem for an abstract nonlinear dissipative evolution equation. The differential constraint is penalized by augmenting the target functional by a nonnegative global-in-time functional which is null-minimized in the evolution equation is satisfied. Different variational settings are presented, leading to the convergence of the penalization method for gradient flows, noncyclic and semimonotone flows, doubly nonlinear evolutions, and GENERIC systems. }, author = {Portinale, Lorenzo and Stefanelli, Ulisse}, issn = {1343-4373}, journal = {Advances in Mathematical Sciences and Applications}, number = {2}, pages = {425--447}, publisher = {Gakko Tosho}, title = {{Penalization via global functionals of optimal-control problems for dissipative evolution}}, volume = {28}, year = {2019}, } @unpublished{7552, abstract = {There is increasing evidence that protein binding to specific sites along DNA can activate the reading out of genetic information without coming into direct physical contact with the gene. There also is evidence that these distant but interacting sites are embedded in a liquid droplet of proteins which condenses out of the surrounding solution. We argue that droplet-mediated interactions can account for crucial features of gene regulation only if the droplet is poised at a non-generic point in its phase diagram. We explore a minimal model that embodies this idea, show that this model has a natural mechanism for self-tuning, and suggest direct experimental tests. }, author = {Bialek, William and Gregor, Thomas and Tkačik, Gašper}, booktitle = {arXiv:1912.08579}, pages = {5}, publisher = {ArXiv}, title = {{Action at a distance in transcriptional regulation}}, year = {2019}, } @inproceedings{7576, abstract = {We present the results of a friendly competition for formal verification of continuous and hybrid systems with nonlinear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In this year, 6 tools Ariadne, CORA, DynIbex, Flow*, Isabelle/HOL, and JuliaReach (in alphabetic order) participated. They are applied to solve reachability analysis problems on four benchmark problems, one of them with hybrid dynamics. We do not rank the tools based on the results, but show the current status and discover the potential advantages of different tools.}, author = {Immler, Fabian and Althoff, Matthias and Benet, Luis and Chapoutot, Alexandre and Chen, Xin and Forets, Marcelo and Geretti, Luca and Kochdumper, Niklas and Sanders, David P. and Schilling, Christian}, booktitle = {EPiC Series in Computing}, issn = {23987340}, location = {Montreal, Canada}, pages = {41--61}, publisher = {EasyChair Publications}, title = {{ARCH-COMP19 Category Report: Continuous and hybrid systems with nonlinear dynamics}}, doi = {10.29007/m75b}, volume = {61}, year = {2019}, } @unpublished{7627, abstract = {Electrodepositing insulating and insoluble Li2O2 is the key process during discharge of aprotic Li-O2 batteries and determines rate, capacity, and reversibility. Current understanding states that the partition between surface adsorbed and solvated LiO2 governs whether Li2O2 grows as surface film, leading to low capacity even at low rates, or in solution, leading to particles and high capacities. Here we show that Li2O2 forms to the widest extent as particles via solution mediated LiO2 disproportionation. We describe a unified Li2O2 growth model that conclusively explains capacity limitations across the whole range of electrolytes. Deciding for particle morphology, achievable rate and capacities are species mobilities, electrode specific surface area (determining true areal rate) and the concentration distribution of associated LiO2 in solution. Provided that species mobilities and surface are high, high, capacities are possible even with low-donor-number electrolytes, previously considered prototypical for low capacity via surface growth. The tools for these insights are microscopy, hydrodynamic voltammetry, a numerical reaction model, and in situ small/wide angle X-ray scattering (SAXS/WAXS). Combined with sophisticated data analysis, SAXS allows retrieving rich quantitative information from complex multi-phase systems. On a wider perspective, this SAXS method is a powerful in situ metrology with atomic to sub-micron resolution to study mechanisms in complex electrochemical systems and beyond. }, author = {Prehal, Christian and Samojlov, Aleksej and Nachtnebel, Manfred and Kriechbaum, Manfred and Amenitsch, Heinz and Freunberger, Stefan Alexander}, pages = {50}, publisher = {ChemRxiv}, title = {{A revised O2 reduction model in Li-O2 batteries as revealed by in situ small angle X-ray scattering}}, year = {2019}, } @article{7710, abstract = {The number of human genomes being genotyped or sequenced increases exponentially and efficient haplotype estimation methods able to handle this amount of data are now required. Here we present a method, SHAPEIT4, which substantially improves upon other methods to process large genotype and high coverage sequencing datasets. It notably exhibits sub-linear running times with sample size, provides highly accurate haplotypes and allows integrating external phasing information such as large reference panels of haplotypes, collections of pre-phased variants and long sequencing reads. We provide SHAPEIT4 in an open source format and demonstrate its performance in terms of accuracy and running times on two gold standard datasets: the UK Biobank data and the Genome In A Bottle.}, author = {Delaneau, Olivier and Zagury, Jean-François and Robinson, Matthew Richard and Marchini, Jonathan L. and Dermitzakis, Emmanouil T.}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Accurate, scalable and integrative haplotype estimation}}, doi = {10.1038/s41467-019-13225-y}, volume = {10}, year = {2019}, } @article{7711, abstract = {The nature and extent of mitochondrial DNA variation in a population and how it affects traits is poorly understood. Here we resequence the mitochondrial genomes of 169 Drosophila Genetic Reference Panel lines, identifying 231 variants that stratify along 12 mitochondrial haplotypes. We identify 1,845 cases of mitonuclear allelic imbalances, thus implying that mitochondrial haplotypes are reflected in the nuclear genome. However, no major fitness effects are associated with mitonuclear imbalance, suggesting that such imbalances reflect population structure at the mitochondrial level rather than genomic incompatibilities. Although mitochondrial haplotypes have no direct impact on mitochondrial respiration, some haplotypes are associated with stress- and metabolism-related phenotypes, including food intake in males. Finally, through reciprocal swapping of mitochondrial genomes, we demonstrate that a mitochondrial haplotype associated with high food intake can rescue a low food intake phenotype. Together, our findings provide new insight into population structure at the mitochondrial level and point to the importance of incorporating mitochondrial haplotypes in genotype–phenotype relationship studies.}, author = {Bevers, Roel P. J. and Litovchenko, Maria and Kapopoulou, Adamandia and Braman, Virginie S. and Robinson, Matthew Richard and Auwerx, Johan and Hollis, Brian and Deplancke, Bart}, issn = {2522-5812}, journal = {Nature Metabolism}, number = {12}, pages = {1226--1242}, publisher = {Springer Nature}, title = {{Mitochondrial haplotypes affect metabolic phenotypes in the Drosophila Genetic Reference Panel}}, doi = {10.1038/s42255-019-0147-3}, volume = {1}, year = {2019}, } @unpublished{7782, abstract = {As genome-wide association studies (GWAS) increased in size, numerous gene-environment interactions (GxE) have been discovered, many of which however explore only one environment at a time and may suffer from statistical artefacts leading to biased interaction estimates. Here we propose a maximum likelihood method to estimate the contribution of GxE to complex traits taking into account all interacting environmental variables at the same time, without the need to measure any. This is possible because GxE induces fluctuations in the conditional trait variance, the extent of which depends on the strength of GxE. The approach can be applied to continuous outcomes and for single SNPs or genetic risk scores (GRS). Extensive simulations demonstrated that our method yields unbiased interaction estimates and excellent confidence interval coverage. We also offer a strategy to distinguish specific GxE from general heteroscedasticity (scale effects). Applying our method to 32 complex traits in the UK Biobank reveals that for body mass index (BMI) the GRSxE explains an additional 1.9% variance on top of the 5.2% GRS contribution. However, this interaction is not specific to the GRS and holds for any variable similarly correlated with BMI. On the contrary, the GRSxE interaction effect for leg impedance Embedded Image is significantly (P < 10−56) larger than it would be expected for a similarly correlated variable Embedded Image. We showed that our method could robustly detect the global contribution of GxE to complex traits, which turned out to be substantial for certain obesity measures.}, author = {Sulc, Jonathan and Mounier, Ninon and Günther, Felix and Winkler, Thomas and Wood, Andrew R. and Frayling, Timothy M. and Heid, Iris M. and Robinson, Matthew Richard and Kutalik, Zoltán}, booktitle = {bioRxiv}, pages = {20}, publisher = {Cold Spring Harbor Laboratory}, title = {{Maximum likelihood method quantifies the overall contribution of gene-environment interaction to continuous traits: An application to complex traits in the UK Biobank}}, year = {2019}, } @article{8013, author = {Currin, Christopher B. and Khoza, Phumlani N. and Antrobus, Alexander D. and Latham, Peter E. and Vogels, Tim P and Raimondo, Joseph V.}, issn = {1553-7358}, journal = {PLOS Computational Biology}, number = {7}, publisher = {Public Library of Science}, title = {{Think: Theory for Africa}}, doi = {10.1371/journal.pcbi.1007049}, volume = {15}, year = {2019}, } @article{8014, abstract = {Working memory, the ability to keep recently accessed information available for immediate manipulation, has been proposed to rely on two mechanisms that appear difficult to reconcile: self-sustained neural firing, or the opposite—activity-silent synaptic traces. Here we review and contrast models of these two mechanisms, and then show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or “focused” state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diversity of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework.}, author = {Manohar, Sanjay G. and Zokaei, Nahid and Fallon, Sean J. and Vogels, Tim P and Husain, Masud}, issn = {0149-7634}, journal = {Neuroscience and Biobehavioral Reviews}, pages = {1--12}, publisher = {Elsevier }, title = {{Neural mechanisms of attending to items in working memory}}, doi = {10.1016/j.neubiorev.2019.03.017}, volume = {101}, year = {2019}, } @inproceedings{8175, abstract = {We study edge asymptotics of poissonized Plancherel-type measures on skew Young diagrams (integer partitions). These measures can be seen as generalizations of those studied by Baik--Deift--Johansson and Baik--Rains in resolving Ulam's problem on longest increasing subsequences of random permutations and the last passage percolation (corner growth) discrete versions thereof. Moreover they interpolate between said measures and the uniform measure on partitions. In the new KPZ-like 1/3 exponent edge scaling limit with logarithmic corrections, we find new probability distributions generalizing the classical Tracy--Widom GUE, GOE and GSE distributions from the theory of random matrices.}, author = {Betea, Dan and Bouttier, Jérémie and Nejjar, Peter and Vuletíc, Mirjana}, booktitle = {Proceedings on the 31st International Conference on Formal Power Series and Algebraic Combinatorics}, location = {Ljubljana, Slovenia}, publisher = {Formal Power Series and Algebraic Combinatorics}, title = {{New edge asymptotics of skew Young diagrams via free boundaries}}, year = {2019}, } @article{8228, abstract = {Background: Atopics have a lower risk for malignancies, and IgE targeted to tumors is superior to IgG in fighting cancer. Whether IgE-mediated innate or adaptive immune surveillance can confer protection against tumors remains unclear. Objective: We aimed to investigate the effects of active and passive immunotherapy to the tumor-associated antigen HER-2 in three murine models differing in Epsilon-B-cell-receptor expression affecting the levels of expressed IgE. Methods: We compared the levels of several serum specific anti-HER-2 antibodies (IgE, IgG1, IgG2a, IgG2b, IgA) and the survival rates in low-IgE ΔM1M2 mice lacking the transmembrane/cytoplasmic domain of Epsilon-B-cell-receptors expressing reduced IgE levels, high-IgE KN1 mice expressing chimeric Epsilon-Gamma1-B-cell receptors with 4-6-fold elevated serum IgE levels, and wild type (WT) BALB/c. Prior engrafting mice with D2F2/E2 mammary tumors overexpressing HER-2, mice were vaccinated with HER-2 or vehicle control PBS using the Th2-adjuvant Al(OH)3 (active immunotherapy), or treated with the murine anti-HER-2 IgG1 antibody 4D5 (passive immunotherapy). Results: Overall, among the three strains of mice, HER-2 vaccination induced significantly higher levels of HER-2 specific IgE and IgG1 in high-IgE KN1, while low-IgE ΔM1M2 mice had higher IgG2a levels. HER-2 vaccination and passive immunotherapy prolonged the survival in tumor-grafted WT and low-IgE ΔM1M2 strains compared with treatment controls; active vaccination provided the highest benefit. Notably, untreated high-IgE KN1 mice displayed the longest survival of all strains, which could not be further extended by active or passive immunotherapy. Conclusion: Active and passive immunotherapies prolong survival in wild type and low-IgE ΔM1M2 mice engrafted with mammary tumors. High-IgE KN1 mice have an innate survival benefit following tumor challenge.}, author = {Singer, Josef and Achatz-Straussberger, Gertrude and Bentley-Lukschal, Anna and Fazekas-Singer, Judit and Achatz, Gernot and Karagiannis, Sophia N. and Jensen-Jarolim, Erika}, issn = {1939-4551}, journal = {World Allergy Organization Journal}, number = {7}, publisher = {Elsevier}, title = {{AllergoOncology: High innate IgE levels are decisive for the survival of cancer-bearing mice}}, doi = {10.1016/j.waojou.2019.100044}, volume = {12}, year = {2019}, } @article{8229, abstract = {Food proteins may get nitrated by various exogenous or endogenous mechanisms. As individuals might get recurrently exposed to nitrated proteins via daily diet, we aimed to investigate the effect of repeatedly ingested nitrated food proteins on the subsequent immune response in non-allergic and allergic mice using the milk allergen beta-lactoglobulin (BLG) as model food protein in a mouse model. Evaluating the presence of nitrated proteins in food, we could detect 3-nitrotyrosine (3-NT) in extracts of different foods and in stomach content extracts of non-allergic mice under physiological conditions. Chemically nitrated BLG (BLGn) exhibited enhanced susceptibility to degradation in simulated gastric fluid experiments compared to untreated BLG (BLGu). Gavage of BLGn to non-allergic animals increased interferon-γ and interleukin-10 release of stimulated spleen cells and led to the formation of BLG-specific serum IgA. Allergic mice receiving three oral gavages of BLGn had higher levels of mouse mast cell protease-1 (mMCP-1) compared to allergic mice receiving BLGu. Regardless of the preceding immune status, non-allergic or allergic, repeatedly ingested nitrated food proteins seem to considerably influence the subsequent immune response.}, author = {Ondracek, Anna S. and Heiden, Denise and Oostingh, Gertie J. and Fuerst, Elisabeth and Fazekas-Singer, Judit and Bergmayr, Cornelia and Rohrhofer, Johanna and Jensen-Jarolim, Erika and Duschl, Albert and Untersmayr, Eva}, issn = {2072-6643}, journal = {Nutrients}, number = {10}, publisher = {MDPI}, title = {{Immune effects of the nitrated food allergen beta-lactoglobulin in an experimental food allergy model}}, doi = {10.3390/nu11102463}, volume = {11}, year = {2019}, } @article{8227, author = {Ilieva, Kristina M. and Fazekas-Singer, Judit and Bax, Heather J. and Crescioli, Silvia and Montero‐Morales, Laura and Mele, Silvia and Sow, Heng Sheng and Stavraka, Chara and Josephs, Debra H. and Spicer, James F. and Steinkellner, Herta and Jensen‐Jarolim, Erika and Tutt, Andrew N. J. and Karagiannis, Sophia N.}, issn = {0105-4538}, journal = {Allergy}, number = {10}, pages = {1985--1989}, publisher = {Wiley}, title = {{AllergoOncology: Expression platform development and functional profiling of an anti‐HER2 IgE antibody}}, doi = {10.1111/all.13818}, volume = {74}, year = {2019}, } @article{8263, abstract = {Background: The genus Streptococcus comprises pathogens that strongly influence the health of humans and animals. Genome sequencing of multiple Streptococcus strains demonstrated high variability in gene content and order even in closely related strains of the same species and created a newly emerged object for genomic analysis, the pan-genome. Here we analysed the genome evolution of 25 strains of Streptococcus suis, 50 strains of Streptococcus pyogenes and 28 strains of Streptococcus pneumoniae. Results: Fractions of the pan-genome, unique, periphery, and universal genes differ in size, functional composition, the level of nucleotide substitutions, and predisposition to horizontal gene transfer and genomic rearrangements. The density of substitutions in intergenic regions appears to be correlated with selection acting on adjacent genes, implying that more conserved genes tend to have more conserved regulatory regions. The total pan-genome of the genus is open, but only due to strain-specific genes, whereas other pan-genome fractions reach saturation. We have identified the set of genes with phylogenies inconsistent with species and non-conserved location in the chromosome; these genes are rare in at least one species and have likely experienced recent horizontal transfer between species. The strain-specific fraction is enriched with mobile elements and hypothetical proteins, but also contains a number of candidate virulence-related genes, so it may have a strong impact on adaptability and pathogenicity. Mapping the rearrangements to the phylogenetic tree revealed large parallel inversions in all species. A parallel inversion of length 15 kB with breakpoints formed by genes encoding surface antigen proteins PhtD and PhtB in S. pneumoniae leads to replacement of gene fragments that likely indicates the action of an antigen variation mechanism. Conclusions: Members of genus Streptococcus have a highly dynamic, open pan-genome, that potentially confers them with the ability to adapt to changing environmental conditions, i.e. antibiotic resistance or transmission between different hosts. Hence, integrated analysis of all aspects of genome evolution is important for the identification of potential pathogens and design of drugs and vaccines.}, author = {Shelyakin, Pavel V. and Bochkareva, Olga and Karan, Anna A. and Gelfand, Mikhail S.}, issn = {1471-2148}, journal = {BMC Evolutionary Biology}, publisher = {Springer Nature}, title = {{Micro-evolution of three Streptococcus species: Selection, antigenic variation, and horizontal gene inflow}}, doi = {10.1186/s12862-019-1403-6}, volume = {19}, year = {2019}, } @inproceedings{8296, abstract = {While showing great promise, smart contracts are difficult to program correctly, as they need a deep understanding of cryptography and distributed algorithms, and offer limited functionality, as they have to be deterministic and cannot operate on secret data. In this paper we present Protean, a general-purpose decentralized computing platform that addresses these limitations by moving from a monolithic execution model, where all participating nodes store all the state and execute every computation, to a modular execution-model. Protean employs secure specialized modules, called functional units, for building decentralized applications that are currently insecure or impossible to implement with smart contracts. Each functional unit is a distributed system that provides a special-purpose functionality by exposing atomic transactions to the smart-contract developer. Combining these transactions into arbitrarily-defined workflows, developers can build a larger class of decentralized applications, such as provably-secure and fair lotteries or e-voting.}, author = {Alp, Enis Ceyhun and Kokoris Kogias, Eleftherios and Fragkouli, Georgia and Ford, Bryan}, booktitle = {Proceedings of the Workshop on Hot Topics in Operating Systems}, isbn = {9781450367271}, location = {Bertinoro, Italy}, pages = {105--112}, publisher = {ACM}, title = {{Rethinking general-purpose decentralized computing}}, doi = {10.1145/3317550.3321448}, year = {2019}, } @unpublished{8304, abstract = {Enabling secure communication across distributed systems is usually studied under the assumption of trust between the different systems and an external adversary trying to compromise the messages. With the appearance of distributed ledgers or blockchains, numerous protocols have emerged, which attempt to achieve trustless communication between distrusting ledgers and participants. Cross-chain communication (CCC) thereby plays a fundamental role in cryptocurrency exchanges, sharding, bootstrapping of new and feature-extension of existing distributed ledgers. Unfortunately, existing proposals are designed ad-hoc for specific use-cases, making it hard to gain confidence on their correctness and composability. We provide the first systematic exposition of protocols for CCC. First, we formalize the underlying research problem and show that CCC is impossible without a trusted third party, contrary to common beliefs in the blockchain community. We then develop a framework to evaluate existing and to design new cross-chain protocols. The framework is based on the use case, the trust model, and the security assumptions of interlinked blockchains. Finally, we identify security and privacy challenges faced by protocols in the cross-chain setting. This Systematization of Knowledge (SoK) offers a comprehensive guide for designing protocols bridging the numerous distributed ledgers available today. It aims to facilitate clearer communication between academia and industry in the field.}, author = {Zamyatin, Alexei and Al-Bassam, Mustafa and Zindros, Dionysis and Kokoris Kogias, Eleftherios and Moreno-Sanchez, Pedro and Kiayias, Aggelos and Knottenbelt, William J.}, booktitle = {Cryptology ePrint Archive}, title = {{SoK: Communication across distributed ledgers}}, year = {2019}, } @unpublished{8303, abstract = {ByzCoin, a promising alternative of Bitcoin, is a scalable consensus protocol used as a building block of many research and enterprise-level decentralized systems. In this paper, we show that ByzCoin is unsuitable for deployment in an anopen, adversarial network and instead introduceMOTOR. MOTORis designed as a secure, robust, and scalable consensus suitable for permissionless sharded blockchains. MOTORachieves these properties by making four key design choices: (a) it prioritizes robustness in adversarial environments while maintaining adequate scalability, (b) it employees provably correct cryptography that resists DoS attacks from individual nodes, (c) it deploys unpredictable rotating leaders to defend against mildly-adaptive adversaries and prevents censorship, and (d) it creates an incentive compatible reward mechanism. These choices are materialized as (a) a “rotating subleader” communication pattern that balances the scalability needs with the robustness requirements under failures, (b) deployment of provable secure BLS multi-signatures, (c) use of deterministic thresh-old signatures as a source of randomness and (d) careful design of the reward allocation mechanism. We have implemented MOTORand compare it withByzCoin. We show that MOTORcan scale similar to ByzCoin with an at most2xoverhead whereas it maintains good performance even under high-percentage of faults, unlike ByzCoin.}, author = {Kokoris Kogias, Eleftherios}, booktitle = {Cryptology ePrint Archive}, title = {{Robust and scalable consensus for sharded distributed ledgers}}, year = {2019}, } @phdthesis{8311, abstract = {One of the core promises of blockchain technology is that of enabling trustworthy data dissemination in a trustless environment. What current blockchain systems deliver, however, is slow dissemination of public data, rendering blockchain technology unusable in settings where latency, transaction capacity, or data confidentiality are important. In this thesis we focus on providing solutions on two of the most pressing problems blockchain technology currently faces: scalability and data confidentiality. To address the scalability issue, we present OMNILEDGER, a novel scale-out distributed ledger that preserves long-term security under permissionless operation. It ensures security and correctness by using a bias-resistant public-randomness protocol for choosing large, statistically representative shards that process transactions, and by introducing an efficient cross-shard commit protocol that atomically handles transactions affecting multiple shards. To enable secure sharing of confidential data we present CALYPSO, the first fully decentralized, auditable access-control framework for secure blockchain-based data sharing which builds upon two abstractions. First, on-chain secrets enable collective management of (verifiably shared) secrets under a Byzantine adversary where an access-control blockchain enforces user-specific access rules and a secret-management cothority administers encrypted data. Second, skipchain-based identity and access management enables efficient administration of dynamic, sovereign identities and access policies and, in particular, permits clients to maintain long-term relationships with respect to evolving user identities thanks to the trust-delegating forward links of skipchains. In order to build OMNILEDGER and CALYPSO, we first build a set of tools for efficient decentralization, which are presented in Part II of this dissertation. These tools can be used in decentralized and distributed systems to achieve (1) scalable consensus (BYZCOIN), (2) bias- resistant distributed randomness creations (RANDHOUND), and (3) relationship-keeping between independently updating communication endpoints (SKIPCHAINIAC). Although we use this tools in the scope off this thesis, they can be (and already have been) used in a far wider scope.}, author = {Kokoris Kogias, Eleftherios}, pages = {244}, publisher = {École Polytechnique Fédérale de Lausanne}, title = {{Secure, confidential blockchains providing high throughput and low latency}}, doi = {10.5075/epfl-thesis-7101}, year = {2019}, } @unpublished{8314, abstract = {Off-chain protocols (channels) are a promising solution to the scalability and privacy challenges of blockchain payments. Current proposals, however, require synchrony assumptions to preserve the safety of a channel, leaking to an adversary the exact amount of time needed to control the network for a successful attack. In this paper, we introduce Brick, the first payment channel that remains secure under network asynchrony and concurrently provides correct incentives. The core idea is to incorporate the conflict resolution process within the channel by introducing a rational committee of external parties, called Wardens. Hence, if a party wants to close a channel unilaterally, it can only get the committee's approval for the last valid state. Brick provides sub-second latency because it does not employ heavy-weight consensus. Instead, Brick uses consistent broadcast to announce updates and close the channel, a light-weight abstraction that is powerful enough to preserve safety and liveness to any rational parties. Furthermore, we consider permissioned blockchains, where the additional property of auditability might be desired for regulatory purposes. We introduce Brick+, an off-chain construction that provides auditability on top of Brick without conflicting with its privacy guarantees. We formally define the properties our payment channel construction should fulfill, and prove that both Brick and Brick+ satisfy them. We also design incentives for Brick such that honest and rational behavior aligns. Finally, we provide a reference implementation of the smart contracts in Solidity.}, author = {Avarikioti, Georgia and Kokoris Kogias, Eleftherios and Wattenhofer, Roger and Zindros, Dionysis}, booktitle = {arXiv}, title = {{Brick: Asynchronous payment channels}}, year = {2019}, } @unpublished{8315, abstract = {Sharding distributed ledgers is the most promising on-chain solution for scaling blockchain technology. In this work, we define and analyze the properties a sharded distributed ledger should fulfill. More specifically, we show that a sharded blockchain cannot be scalable under a fully adaptive adversary, but it can scale up to $O(n/\log n)$ under an epoch-adaptive adversary. This is possible only if the distributed ledger creates succinct proofs of the valid state updates at the end of each epoch. Our model builds upon and extends the Bitcoin backbone protocol by defining consistency and scalability. Consistency encompasses the need for atomic execution of cross-shard transactions to preserve safety, whereas scalability encapsulates the speedup a sharded system can gain in comparison to a non-sharded system. In order to show the power of our framework, we analyze the most prominent sharded blockchains and either prove their correctness (OmniLedger, RapidChain) under our model or pinpoint where they fail to balance the consistency and scalability requirements (Elastico, Monoxide). }, author = {Avarikioti, Georgia and Kokoris Kogias, Eleftherios and Wattenhofer, Roger}, booktitle = {arXiv}, title = {{Divide and scale: Formalization of distributed ledger sharding protocols}}, year = {2019}, } @misc{8313, abstract = {The present invention concerns a computer-implemented method for secure data exchange between a sender (A) and a recipient (B), wherein the method is performed by the sender (A) and comprises encrypting data using a symmetric key k, creating a write transaction T W , wherein the write transaction T W comprises information usable to derive the symmetric key k and an access policy identifying the recipient (B) as being allowed to decrypt the encrypted data, providing the recipient (B) access to the encrypted data, and sending the write transaction T W to a first group of servers (AC) for being stored in a blockchain data structure maintained by the first group of servers (AC).}, author = {Ford, Bryan and Gasser, Linus and Kokoris Kogias, Eleftherios and Janovic, Philipp}, title = {{Methods and systems for secure data exchange}}, year = {2019}, } @article{8405, abstract = {Atomic-resolution structure determination is crucial for understanding protein function. Cryo-EM and NMR spectroscopy both provide structural information, but currently cryo-EM does not routinely give access to atomic-level structural data, and, generally, NMR structure determination is restricted to small (<30 kDa) proteins. We introduce an integrated structure determination approach that simultaneously uses NMR and EM data to overcome the limits of each of these methods. The approach enables structure determination of the 468 kDa large dodecameric aminopeptidase TET2 to a precision and accuracy below 1 Å by combining secondary-structure information obtained from near-complete magic-angle-spinning NMR assignments of the 39 kDa-large subunits, distance restraints from backbone amides and ILV methyl groups, and a 4.1 Å resolution EM map. The resulting structure exceeds current standards of NMR and EM structure determination in terms of molecular weight and precision. Importantly, the approach is successful even in cases where only medium-resolution cryo-EM data are available.}, author = {Gauto, Diego F. and Estrozi, Leandro F. and Schwieters, Charles D. and Effantin, Gregory and Macek, Pavel and Sounier, Remy and Sivertsen, Astrid C. and Schmidt, Elena and Kerfah, Rime and Mas, Guillaume and Colletier, Jacques-Philippe and Güntert, Peter and Favier, Adrien and Schoehn, Guy and Schanda, Paul and Boisbouvier, Jerome}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry}, publisher = {Springer Nature}, title = {{Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex}}, doi = {10.1038/s41467-019-10490-9}, volume = {10}, year = {2019}, } @article{8406, abstract = {Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.}, author = {Felix, Jan and Weinhäupl, Katharina and Chipot, Christophe and Dehez, François and Hessel, Audrey and Gauto, Diego F. and Morlot, Cecile and Abian, Olga and Gutsche, Irina and Velazquez-Campoy, Adrian and Schanda, Paul and Fraga, Hugo}, issn = {2375-2548}, journal = {Science Advances}, number = {9}, publisher = {American Association for the Advancement of Science}, title = {{Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors}}, doi = {10.1126/sciadv.aaw3818}, volume = {5}, year = {2019}, } @article{8413, abstract = {NMR relaxation dispersion methods provide a holistic way to observe microsecond time-scale protein backbone motion both in solution and in the solid state. Different nuclei (1H and 15N) and different relaxation dispersion techniques (Bloch–McConnell and near-rotary-resonance) give complementary information about the amplitudes and time scales of the conformational dynamics and provide comprehensive insights into the mechanistic details of the structural rearrangements. In this paper, we exemplify the benefits of the combination of various solution- and solid-state relaxation dispersion methods on a microcrystalline protein (α-spectrin SH3 domain), for which we are able to identify and model the functionally relevant conformational rearrangements around the ligand recognition loop occurring on multiple microsecond time scales. The observed loop motions suggest that the SH3 domain exists in a binding-competent conformation in dynamic equilibrium with a sterically impaired ground-state conformation both in solution and in crystalline form. This inherent plasticity between the interconverting macrostates is compatible with a conformational-preselection model and provides new insights into the recognition mechanisms of SH3 domains.}, author = {Rovó, Petra and Smith, Colin A. and Gauto, Diego and de Groot, Bert L. and Schanda, Paul and Linser, Rasmus}, issn = {0002-7863}, journal = {Journal of the American Chemical Society}, keywords = {Colloid and Surface Chemistry, Biochemistry, General Chemistry, Catalysis}, number = {2}, pages = {858--869}, publisher = {American Chemical Society}, title = {{Mechanistic insights into microsecond time-scale motion of solid proteins using complementary 15N and 1H relaxation dispersion techniques}}, doi = {10.1021/jacs.8b09258}, volume = {141}, year = {2019}, } @article{8412, abstract = {Microsecond to millisecond timescale backbone dynamics of the amyloid core residues in Y145Stop human prion protein (PrP) fibrils were investigated by using 15N rotating frame (R1ρ) relaxation dispersion solid‐state nuclear magnetic resonance spectroscopy over a wide range of spin‐lock fields. Numerical simulations enabled the experimental relaxation dispersion profiles for most of the fibril core residues to be modelled by using a two‐state exchange process with a common exchange rate of 1000 s−1, corresponding to protein backbone motion on the timescale of 1 ms, and an excited‐state population of 2 %. We also found that the relaxation dispersion profiles for several amino acids positioned near the edges of the most structured regions of the amyloid core were better modelled by assuming somewhat higher excited‐state populations (∼5–15 %) and faster exchange rate constants, corresponding to protein backbone motions on the timescale of ∼100–300 μs. The slow backbone dynamics of the core residues were evaluated in the context of the structural model of human Y145Stop PrP amyloid.}, author = {Shannon, Matthew D. and Theint, Theint and Mukhopadhyay, Dwaipayan and Surewicz, Krystyna and Surewicz, Witold K. and Marion, Dominique and Schanda, Paul and Jaroniec, Christopher P.}, issn = {1439-4235}, journal = {ChemPhysChem}, keywords = {Physical and Theoretical Chemistry, Atomic and Molecular Physics, and Optics}, number = {2}, pages = {311--317}, publisher = {Wiley}, title = {{Conformational dynamics in the core of human Y145Stop prion protein amyloid probed by relaxation dispersion NMR}}, doi = {10.1002/cphc.201800779}, volume = {20}, year = {2019}, } @article{8411, abstract = {Studying protein dynamics on microsecond‐to‐millisecond (μs‐ms) time scales can provide important insight into protein function. In magic‐angle‐spinning (MAS) NMR, μs dynamics can be visualized by R1p rotating‐frame relaxation dispersion experiments in different regimes of radio‐frequency field strengths: at low RF field strength, isotropic‐chemical‐shift fluctuation leads to “Bloch‐McConnell‐type” relaxation dispersion, while when the RF field approaches rotary resonance conditions bond angle fluctuations manifest as increased R1p rate constants (“Near‐Rotary‐Resonance Relaxation Dispersion”, NERRD). Here we explore the joint analysis of both regimes to gain comprehensive insight into motion in terms of geometric amplitudes, chemical‐shift changes, populations and exchange kinetics. We use a numerical simulation procedure to illustrate these effects and the potential of extracting exchange parameters, and apply the methodology to the study of a previously described conformational exchange process in microcrystalline ubiquitin.}, author = {Marion, Dominique and Gauto, Diego F. and Ayala, Isabel and Giandoreggio-Barranco, Karine and Schanda, Paul}, issn = {1439-4235}, journal = {ChemPhysChem}, keywords = {Physical and Theoretical Chemistry, Atomic and Molecular Physics, and Optics}, number = {2}, pages = {276--284}, publisher = {Wiley}, title = {{Microsecond protein dynamics from combined Bloch-McConnell and Near-Rotary-Resonance R1p relaxation-dispersion MAS NMR}}, doi = {10.1002/cphc.201800935}, volume = {20}, year = {2019}, } @article{8415, abstract = {We consider billiards obtained by removing three strictly convex obstacles satisfying the non-eclipse condition on the plane. The restriction of the dynamics to the set of non-escaping orbits is conjugated to a subshift on three symbols that provides a natural labeling of all periodic orbits. We study the following inverse problem: does the Marked Length Spectrum (i.e., the set of lengths of periodic orbits together with their labeling), determine the geometry of the billiard table? We show that from the Marked Length Spectrum it is possible to recover the curvature at periodic points of period two, as well as the Lyapunov exponent of each periodic orbit.}, author = {Bálint, Péter and De Simoi, Jacopo and Kaloshin, Vadim and Leguil, Martin}, issn = {0010-3616}, journal = {Communications in Mathematical Physics}, keywords = {Mathematical Physics, Statistical and Nonlinear Physics}, number = {3}, pages = {1531--1575}, publisher = {Springer Nature}, title = {{Marked length spectrum, homoclinic orbits and the geometry of open dispersing billiards}}, doi = {10.1007/s00220-019-03448-x}, volume = {374}, year = {2019}, } @article{8409, abstract = {The bacterial cell wall is composed of the peptidoglycan (PG), a large polymer that maintains the integrity of the bacterial cell. Due to its multi-gigadalton size, heterogeneity, and dynamics, atomic-resolution studies are inherently complex. Solid-state NMR is an important technique to gain insight into its structure, dynamics and interactions. Here, we explore the possibilities to study the PG with ultra-fast (100 kHz) magic-angle spinning NMR. We demonstrate that highly resolved spectra can be obtained, and show strategies to obtain site-specific resonance assignments and distance information. We also explore the use of proton-proton correlation experiments, thus opening the way for NMR studies of intact cell walls without the need for isotope labeling.}, author = {Bougault, Catherine and Ayala, Isabel and Vollmer, Waldemar and Simorre, Jean-Pierre and Schanda, Paul}, issn = {1047-8477}, journal = {Journal of Structural Biology}, keywords = {Structural Biology}, number = {1}, pages = {66--72}, publisher = {Elsevier}, title = {{Studying intact bacterial peptidoglycan by proton-detected NMR spectroscopy at 100 kHz MAS frequency}}, doi = {10.1016/j.jsb.2018.07.009}, volume = {206}, year = {2019}, } @article{8407, author = {Schanda, Paul}, issn = {1090-7807}, journal = {Journal of Magnetic Resonance}, keywords = {Nuclear and High Energy Physics, Biophysics, Biochemistry, Condensed Matter Physics}, pages = {180--186}, publisher = {Elsevier}, title = {{Relaxing with liquids and solids – A perspective on biomolecular dynamics}}, doi = {10.1016/j.jmr.2019.07.025}, volume = {306}, year = {2019}, } @article{8410, author = {Schanda, Paul and Chekmenev, Eduard Y.}, issn = {1439-4235}, journal = {ChemPhysChem}, number = {2}, pages = {177--177}, publisher = {Wiley}, title = {{NMR for Biological Systems}}, doi = {10.1002/cphc.201801100}, volume = {20}, year = {2019}, } @inproceedings{8570, abstract = {This report presents the results of a friendly competition for formal verification of continuous and hybrid systems with linear continuous dynamics. The friendly competition took place as part of the workshop Applied Verification for Continuous and Hybrid Systems (ARCH) in 2019. In its third edition, seven tools have been applied to solve six different benchmark problems in the category for linear continuous dynamics (in alphabetical order): CORA, CORA/SX, HyDRA, Hylaa, JuliaReach, SpaceEx, and XSpeed. This report is a snapshot of the current landscape of tools and the types of benchmarks they are particularly suited for. Due to the diversity of problems, we are not ranking tools, yet the presented results provide one of the most complete assessments of tools for the safety verification of continuous and hybrid systems with linear continuous dynamics up to this date.}, author = {Althoff, Matthias and Bak, Stanley and Forets, Marcelo and Frehse, Goran and Kochdumper, Niklas and Ray, Rajarshi and Schilling, Christian and Schupp, Stefan}, booktitle = {EPiC Series in Computing}, issn = {23987340}, location = {Montreal, Canada}, pages = {14--40}, publisher = {EasyChair}, title = {{ARCH-COMP19 Category Report: Continuous and hybrid systems with linear continuous dynamics}}, doi = {10.29007/bj1w}, volume = {61}, year = {2019}, } @article{9016, abstract = {Inhibiting the histone H3–ASF1 (anti‐silencing function 1) protein–protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α‐helix‐mediated PPI, constraining the key histone H3 helix (residues 118–135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3118–135 peptides bearing pentenylglycine residues at the i and i+4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy–entropy compensation occurs.}, author = {Bakail, May M and Rodriguez‐Marin, Silvia and Hegedüs, Zsófia and Perrin, Marie E. and Ochsenbein, Françoise and Wilson, Andrew J.}, issn = {1439-4227}, journal = {ChemBioChem}, number = {7}, pages = {891--895}, publisher = {Wiley}, title = {{Recognition of ASF1 by using hydrocarbon‐constrained peptides}}, doi = {10.1002/cbic.201800633}, volume = {20}, year = {2019}, }