TY - GEN AB - 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. AU - Prehal, Christian AU - Samojlov, Aleksej AU - Nachtnebel, Manfred AU - Kriechbaum, Manfred AU - Amenitsch, Heinz AU - Freunberger, Stefan Alexander ID - 7627 TI - A revised O2 reduction model in Li-O2 batteries as revealed by in situ small angle X-ray scattering ER - TY - JOUR AB - 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. AU - Delaneau, Olivier AU - Zagury, Jean-François AU - Robinson, Matthew Richard AU - Marchini, Jonathan L. AU - Dermitzakis, Emmanouil T. ID - 7710 JF - Nature Communications SN - 2041-1723 TI - Accurate, scalable and integrative haplotype estimation VL - 10 ER - TY - GEN AB - 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. AU - Sulc, Jonathan AU - Mounier, Ninon AU - Günther, Felix AU - Winkler, Thomas AU - Wood, Andrew R. AU - Frayling, Timothy M. AU - Heid, Iris M. AU - Robinson, Matthew Richard AU - Kutalik, Zoltán ID - 7782 T2 - bioRxiv TI - Maximum likelihood method quantifies the overall contribution of gene-environment interaction to continuous traits: An application to complex traits in the UK Biobank ER - TY - JOUR AU - Currin, Christopher B. AU - Khoza, Phumlani N. AU - Antrobus, Alexander D. AU - Latham, Peter E. AU - Vogels, Tim P AU - Raimondo, Joseph V. ID - 8013 IS - 7 JF - PLOS Computational Biology SN - 1553-7358 TI - Think: Theory for Africa VL - 15 ER - TY - JOUR AB - 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. AU - Manohar, Sanjay G. AU - Zokaei, Nahid AU - Fallon, Sean J. AU - Vogels, Tim P AU - Husain, Masud ID - 8014 JF - Neuroscience and Biobehavioral Reviews SN - 0149-7634 TI - Neural mechanisms of attending to items in working memory VL - 101 ER - TY - CONF AB - 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. AU - Betea, Dan AU - Bouttier, Jérémie AU - Nejjar, Peter AU - Vuletíc, Mirjana ID - 8175 T2 - Proceedings on the 31st International Conference on Formal Power Series and Algebraic Combinatorics TI - New edge asymptotics of skew Young diagrams via free boundaries ER - TY - JOUR AB - 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. AU - Singer, Josef AU - Achatz-Straussberger, Gertrude AU - Bentley-Lukschal, Anna AU - Fazekas-Singer, Judit AU - Achatz, Gernot AU - Karagiannis, Sophia N. AU - Jensen-Jarolim, Erika ID - 8228 IS - 7 JF - World Allergy Organization Journal SN - 1939-4551 TI - AllergoOncology: High innate IgE levels are decisive for the survival of cancer-bearing mice VL - 12 ER - TY - JOUR AB - 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. AU - Ondracek, Anna S. AU - Heiden, Denise AU - Oostingh, Gertie J. AU - Fuerst, Elisabeth AU - Fazekas-Singer, Judit AU - Bergmayr, Cornelia AU - Rohrhofer, Johanna AU - Jensen-Jarolim, Erika AU - Duschl, Albert AU - Untersmayr, Eva ID - 8229 IS - 10 JF - Nutrients SN - 2072-6643 TI - Immune effects of the nitrated food allergen beta-lactoglobulin in an experimental food allergy model VL - 11 ER - TY - JOUR AU - Ilieva, Kristina M. AU - Fazekas-Singer, Judit AU - Bax, Heather J. AU - Crescioli, Silvia AU - Montero‐Morales, Laura AU - Mele, Silvia AU - Sow, Heng Sheng AU - Stavraka, Chara AU - Josephs, Debra H. AU - Spicer, James F. AU - Steinkellner, Herta AU - Jensen‐Jarolim, Erika AU - Tutt, Andrew N. J. AU - Karagiannis, Sophia N. ID - 8227 IS - 10 JF - Allergy SN - 0105-4538 TI - AllergoOncology: Expression platform development and functional profiling of an anti‐HER2 IgE antibody VL - 74 ER - TY - JOUR AB - 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. AU - Shelyakin, Pavel V. AU - Bochkareva, Olga AU - Karan, Anna A. AU - Gelfand, Mikhail S. ID - 8263 JF - BMC Evolutionary Biology SN - 1471-2148 TI - Micro-evolution of three Streptococcus species: Selection, antigenic variation, and horizontal gene inflow VL - 19 ER - TY - GEN AB - 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. AU - Zamyatin, Alexei AU - Al-Bassam, Mustafa AU - Zindros, Dionysis AU - Kokoris Kogias, Eleftherios AU - Moreno-Sanchez, Pedro AU - Kiayias, Aggelos AU - Knottenbelt, William J. ID - 8304 T2 - Cryptology ePrint Archive TI - SoK: Communication across distributed ledgers ER - TY - GEN AB - 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. AU - Kokoris Kogias, Eleftherios ID - 8303 T2 - Cryptology ePrint Archive TI - Robust and scalable consensus for sharded distributed ledgers ER - TY - THES AB - 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. AU - Kokoris Kogias, Eleftherios ID - 8311 TI - Secure, confidential blockchains providing high throughput and low latency ER - TY - GEN AB - 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. AU - Avarikioti, Georgia AU - Kokoris Kogias, Eleftherios AU - Wattenhofer, Roger AU - Zindros, Dionysis ID - 8314 T2 - arXiv TI - Brick: Asynchronous payment channels ER - TY - GEN AB - 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). AU - Avarikioti, Georgia AU - Kokoris Kogias, Eleftherios AU - Wattenhofer, Roger ID - 8315 T2 - arXiv TI - Divide and scale: Formalization of distributed ledger sharding protocols ER - TY - GEN AB - 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). AU - Ford, Bryan AU - Gasser, Linus AU - Kokoris Kogias, Eleftherios AU - Janovic, Philipp ID - 8313 TI - Methods and systems for secure data exchange ER - TY - JOUR AB - 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. AU - Gauto, Diego F. AU - Estrozi, Leandro F. AU - Schwieters, Charles D. AU - Effantin, Gregory AU - Macek, Pavel AU - Sounier, Remy AU - Sivertsen, Astrid C. AU - Schmidt, Elena AU - Kerfah, Rime AU - Mas, Guillaume AU - Colletier, Jacques-Philippe AU - Güntert, Peter AU - Favier, Adrien AU - Schoehn, Guy AU - Schanda, Paul AU - Boisbouvier, Jerome ID - 8405 JF - Nature Communications KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Physics and Astronomy KW - General Chemistry SN - 2041-1723 TI - Integrated NMR and cryo-EM atomic-resolution structure determination of a half-megadalton enzyme complex VL - 10 ER - TY - JOUR AB - 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. AU - Felix, Jan AU - Weinhäupl, Katharina AU - Chipot, Christophe AU - Dehez, François AU - Hessel, Audrey AU - Gauto, Diego F. AU - Morlot, Cecile AU - Abian, Olga AU - Gutsche, Irina AU - Velazquez-Campoy, Adrian AU - Schanda, Paul AU - Fraga, Hugo ID - 8406 IS - 9 JF - Science Advances SN - 2375-2548 TI - Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors VL - 5 ER - TY - JOUR AB - 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. AU - Bálint, Péter AU - De Simoi, Jacopo AU - Kaloshin, Vadim AU - Leguil, Martin ID - 8415 IS - 3 JF - Communications in Mathematical Physics KW - Mathematical Physics KW - Statistical and Nonlinear Physics SN - 0010-3616 TI - Marked length spectrum, homoclinic orbits and the geometry of open dispersing billiards VL - 374 ER - TY - JOUR AU - Schanda, Paul AU - Chekmenev, Eduard Y. ID - 8410 IS - 2 JF - ChemPhysChem SN - 1439-4235 TI - NMR for Biological Systems VL - 20 ER - TY - CONF AB - 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. AU - Althoff, Matthias AU - Bak, Stanley AU - Forets, Marcelo AU - Frehse, Goran AU - Kochdumper, Niklas AU - Ray, Rajarshi AU - Schilling, Christian AU - Schupp, Stefan ID - 8570 T2 - EPiC Series in Computing TI - ARCH-COMP19 Category Report: Continuous and hybrid systems with linear continuous dynamics VL - 61 ER - TY - JOUR AB - 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. AU - Bakail, May M AU - Rodriguez‐Marin, Silvia AU - Hegedüs, Zsófia AU - Perrin, Marie E. AU - Ochsenbein, Françoise AU - Wilson, Andrew J. ID - 9016 IS - 7 JF - ChemBioChem SN - 1439-4227 TI - Recognition of ASF1 by using hydrocarbon‐constrained peptides VL - 20 ER - TY - JOUR AB - Molecular motors are essential to the living, generating fluctuations that boost transport and assist assembly. Active colloids, that consume energy to move, hold similar potential for man-made materials controlled by forces generated from within. Yet, their use as a powerhouse in materials science lacks. Here we show a massive acceleration of the annealing of a monolayer of passive beads by moderate addition of self-propelled microparticles. We rationalize our observations with a model of collisions that drive active fluctuations and activate the annealing. The experiment is quantitatively compared with Brownian dynamic simulations that further unveil a dynamical transition in the mechanism of annealing. Active dopants travel uniformly in the system or co-localize at the grain boundaries as a result of the persistence of their motion. Our findings uncover the potential of internal activity to control materials and lay the groundwork for the rise of materials science beyond equilibrium. AU - Ramananarivo, Sophie AU - Ducrot, Etienne AU - Palacci, Jérémie A ID - 9060 IS - 1 JF - Nature Communications KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Physics and Astronomy KW - General Chemistry SN - 2041-1723 TI - Activity-controlled annealing of colloidal monolayers VL - 10 ER - TY - JOUR AB - Epigenetic reprogramming is required for proper regulation of gene expression in eukaryotic organisms. In Arabidopsis, active DNA demethylation is crucial for seed viability, pollen function, and successful reproduction. The DEMETER (DME) DNA glycosylase initiates localized DNA demethylation in vegetative and central cells, so-called companion cells that are adjacent to sperm and egg gametes, respectively. In rice, the central cell genome displays local DNA hypomethylation, suggesting that active DNA demethylation also occurs in rice; however, the enzyme responsible for this process is unknown. One candidate is the rice REPRESSOR OF SILENCING 1a (ROS1a) gene, which is related to DME and is essential for rice seed viability and pollen function. Here, we report genome-wide analyses of DNA methylation in wild-type and ros1a mutant sperm and vegetative cells. We find that the rice vegetative cell genome is locally hypomethylated compared with sperm by a process that requires ROS1a activity. We show that many ROS1a target sequences in the vegetative cell are hypomethylated in the rice central cell, suggesting that ROS1a also demethylates the central cell genome. Similar to Arabidopsis, we show that sperm non-CG methylation is indirectly promoted by DNA demethylation in the vegetative cell. These results reveal that DNA glycosylase-mediated DNA demethylation processes are conserved in Arabidopsis and rice, plant species that diverged 150 million years ago. Finally, although global non-CG methylation levels of sperm and egg differ, the maternal and paternal embryo genomes show similar non-CG methylation levels, suggesting that rice gamete genomes undergo dynamic DNA methylation reprogramming after cell fusion. AU - Kim, M. Yvonne AU - Ono, Akemi AU - Scholten, Stefan AU - Kinoshita, Tetsu AU - Zilberman, Daniel AU - Okamoto, Takashi AU - Fischer, Robert L. ID - 9460 IS - 19 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - DNA demethylation by ROS1a in rice vegetative cells promotes methylation in sperm VL - 116 ER - TY - JOUR AB - A central goal of computational physics and chemistry is to predict material properties by using first-principles methods based on the fundamental laws of quantum mechanics. However, the high computational costs of these methods typically prevent rigorous predictions of macroscopic quantities at finite temperatures, such as heat capacity, density, and chemical potential. Here, we enable such predictions by marrying advanced free-energy methods with data-driven machine-learning interatomic potentials. We show that, for the ubiquitous and technologically essential system of water, a first-principles thermodynamic description not only leads to excellent agreement with experiments, but also reveals the crucial role of nuclear quantum fluctuations in modulating the thermodynamic stabilities of different phases of water. AU - Cheng, Bingqing AU - Engel, Edgar A. AU - Behler, Jörg AU - Dellago, Christoph AU - Ceriotti, Michele ID - 9689 IS - 4 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Ab initio thermodynamics of liquid and solid water VL - 116 ER - TY - JOUR AB - Glyphosate (N-phosphonomethyl glycine) and its commercial herbicide formulations have been shown to exert toxicity via various mechanisms. It has been asserted that glyphosate substitutes for glycine in polypeptide chains leading to protein misfolding and toxicity. However, as no direct evidence exists for glycine to glyphosate substitution in proteins, including in mammalian organisms, we tested this claim by conducting a proteomics analysis of MDA-MB-231 human breast cancer cells grown in the presence of 100 mg/L glyphosate for 6 days. Protein extracts from three treated and three untreated cell cultures were analysed as one TMT-6plex labelled sample, to highlight a specific pattern (+/+/+/−/−/−) of reporter intensities for peptides bearing true glyphosate treatment induced-post translational modifications as well as allowing an investigation of the total proteome. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 6819 JF - BMC Research Notes TI - Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells VL - 12 ER - TY - GEN AB - Additional file 1: Table S1. Kinetics of MDA-MB-231 cell growth in either the presence or absence of 100Â mg/L glyphosate. Cell counts are given at day-1 of seeding flasks and following 6-days of continuous culture. Note: no differences in cell numbers were observed between negative control and glyphosate treated cultures. AU - Antoniou, Michael N. AU - Nicolas, Armel AU - Mesnage, Robin AU - Biserni, Martina AU - Rao, Francesco V. AU - Martin, Cristina Vazquez ID - 9784 TI - MOESM1 of Glyphosate does not substitute for glycine in proteins of actively dividing mammalian cells ER - TY - GEN AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 9839 TI - Data from: Is the sky the limit? On the expansion threshold of a species' range ER - TY - JOUR AB - For the Restricted Circular Planar 3 Body Problem, we show that there exists an open set U in phase space of fixed measure, where the set of initial points which lead to collision is O(μ120) dense as μ→0. AU - Guardia, Marcel AU - Kaloshin, Vadim AU - Zhang, Jianlu ID - 8418 IS - 2 JF - Archive for Rational Mechanics and Analysis KW - Mechanical Engineering KW - Mathematics (miscellaneous) KW - Analysis SN - 0003-9527 TI - Asymptotic density of collision orbits in the Restricted Circular Planar 3 Body Problem VL - 233 ER - TY - JOUR AB - In this paper, we show that any smooth one-parameter deformations of a strictly convex integrable billiard table Ω0 preserving the integrability near the boundary have to be tangent to a finite dimensional space passing through Ω0. AU - Huang, Guan AU - Kaloshin, Vadim ID - 8416 IS - 2 JF - Moscow Mathematical Journal SN - 1609-4514 TI - On the finite dimensionality of integrable deformations of strictly convex integrable billiard tables VL - 19 ER - TY - JOUR AB - We review V. I. Arnold’s 1963 celebrated paper [1] Proof of A. N. Kolmogorov’s Theorem on the Conservation of Conditionally Periodic Motions with a Small Variation in the Hamiltonian, and prove that, optimising Arnold’s scheme, one can get “sharp” asymptotic quantitative conditions (as ε → 0, ε being the strength of the perturbation). All constants involved are explicitly computed. AU - Chierchia, Luigi AU - Koudjinan, Edmond ID - 8693 JF - Regular and Chaotic Dynamics TI - V. I. Arnold’s “pointwise” KAM theorem VL - 24 ER - TY - JOUR AB - Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design peptides that inhibit the ASF1-histone interaction. Starting from the structure of the human ASF1-histone complex, we developed a rational design strategy combining epitope tethering and optimization of interface contacts to identify a potent peptide inhibitor with a dissociation constant of 3 nM. When introduced into cultured cells, the inhibitors impair cell proliferation, perturb cell-cycle progression, and reduce cell migration and invasion in a manner commensurate with their affinity for ASF1. Finally, we find that direct injection of the most potent ASF1 peptide inhibitor in mouse allografts reduces tumor growth. Our results open new avenues to use ASF1 inhibitors as promising leads for cancer therapy. AU - Bakail, May M AU - Gaubert, Albane AU - Andreani, Jessica AU - Moal, Gwenaëlle AU - Pinna, Guillaume AU - Boyarchuk, Ekaterina AU - Gaillard, Marie-Cécile AU - Courbeyrette, Regis AU - Mann, Carl AU - Thuret, Jean-Yves AU - Guichard, Bérengère AU - Murciano, Brice AU - Richet, Nicolas AU - Poitou, Adeline AU - Frederic, Claire AU - Le Du, Marie-Hélène AU - Agez, Morgane AU - Roelants, Caroline AU - Gurard-Levin, Zachary A. AU - Almouzni, Geneviève AU - Cherradi, Nadia AU - Guerois, Raphael AU - Ochsenbein, Françoise ID - 9018 IS - 11 JF - Cell Chemical Biology KW - Clinical Biochemistry KW - Molecular Medicine KW - Biochemistry KW - Molecular Biology KW - Pharmacology KW - Drug Discovery SN - 2451-9456 TI - Design on a rational basis of high-affinity peptides inhibiting the histone chaperone ASF1 VL - 26 ER - TY - JOUR AB - Background DNA methylation of active genes, also known as gene body methylation, is found in many animal and plant genomes. Despite this, the transcriptional and developmental role of such methylation remains poorly understood. Here, we explore the dynamic range of DNA methylation in honey bee, a model organism for gene body methylation. Results Our data show that CG methylation in gene bodies globally fluctuates during honey bee development. However, these changes cause no gene expression alterations. Intriguingly, despite the global alterations, tissue-specific CG methylation patterns of complete genes or exons are rare, implying robust maintenance of genic methylation during development. Additionally, we show that CG methylation maintenance fluctuates in somatic cells, while reaching maximum fidelity in sperm cells. Finally, unlike universally present CG methylation, we discovered non-CG methylation specifically in bee heads that resembles such methylation in mammalian brain tissue. Conclusions Based on these results, we propose that gene body CG methylation can oscillate during development if it is kept to a level adequate to preserve function. Additionally, our data suggest that heightened non-CG methylation is a conserved regulator of animal nervous systems. AU - Harris, Keith D. AU - Lloyd, James P. B. AU - Domb, Katherine AU - Zilberman, Daniel AU - Zemach, Assaf ID - 9530 JF - Epigenetics and Chromatin TI - DNA methylation is maintained with high fidelity in the honey bee germline and exhibits global non-functional fluctuations during somatic development VL - 12 ER - TY - JOUR AB - Consider integers 𝑘,ℓ such that 0⩽ℓ⩽(𝑘2) . Given a large graph 𝐺 , what is the fraction of 𝑘 -vertex subsets of 𝐺 which span exactly ℓ edges? When 𝐺 is empty or complete, and ℓ is zero or (𝑘2) , this fraction can be exactly 1. On the other hand, if ℓ is far from these extreme values, one might expect that this fraction is substantially smaller than 1. This was recently proved by Alon, Hefetz, Krivelevich, and Tyomkyn who initiated the systematic study of this question and proposed several natural conjectures. Let ℓ∗=min{ℓ,(𝑘2)−ℓ} . Our main result is that for any 𝑘 and ℓ , the fraction of 𝑘 -vertex subsets that span ℓ edges is at most log𝑂(1)(ℓ∗/𝑘)√ 𝑘/ℓ∗, which is best-possible up to the logarithmic factor. This improves on multiple results of Alon, Hefetz, Krivelevich, and Tyomkyn, and resolves one of their conjectures. In addition, we also make some first steps towards some analogous questions for hypergraphs. Our proofs involve some Ramsey-type arguments, and a number of different probabilistic tools, such as polynomial anticoncentration inequalities, hypercontractivity, and a coupling trick for random variables defined on a ‘slice’ of the Boolean hypercube. AU - Kwan, Matthew Alan AU - Sudakov, Benny AU - Tran, Tuan ID - 9586 IS - 3 JF - Journal of the London Mathematical Society SN - 0024-6107 TI - Anticoncentration for subgraph statistics VL - 99 ER - TY - JOUR AB - An r-cut of a k-uniform hypergraph H is a partition of the vertex set of H into r parts and the size of the cut is the number of edges which have a vertex in each part. A classical result of Edwards says that every m-edge graph has a 2-cut of size m/2+Ω)(m−−√) and this is best possible. That is, there exist cuts which exceed the expected size of a random cut by some multiple of the standard deviation. We study analogues of this and related results in hypergraphs. First, we observe that similarly to graphs, every m-edge k-uniform hypergraph has an r-cut whose size is Ω(m−−√) larger than the expected size of a random r-cut. Moreover, in the case where k = 3 and r = 2 this bound is best possible and is attained by Steiner triple systems. Surprisingly, for all other cases (that is, if k ≥ 4 or r ≥ 3), we show that every m-edge k-uniform hypergraph has an r-cut whose size is Ω(m5/9) larger than the expected size of a random r-cut. This is a significant difference in behaviour, since the amount by which the size of the largest cut exceeds the expected size of a random cut is now considerably larger than the standard deviation. AU - Conlon, David AU - Fox, Jacob AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9580 IS - 1 JF - Israel Journal of Mathematics SN - 0021-2172 TI - Hypergraph cuts above the average VL - 233 ER - TY - JOUR AB - An n-vertex graph is called C-Ramsey if it has no clique or independent set of size C log n. All known constructions of Ramsey graphs involve randomness in an essential way, and there is an ongoing line of research towards showing that in fact all Ramsey graphs must obey certain “richness” properties characteristic of random graphs. More than 25 years ago, Erdős, Faudree and Sós conjectured that in any C-Ramsey graph there are Ω(n^5/2) induced subgraphs, no pair of which have the same numbers of vertices and edges. Improving on earlier results of Alon, Balogh, Kostochka and Samotij, in this paper we prove this conjecture. AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9585 IS - 8 JF - Transactions of the American Mathematical Society SN - 0002-9947 TI - Proof of a conjecture on induced subgraphs of Ramsey graphs VL - 372 ER - TY - JOUR AB - Progress in the atomic-scale modeling of matter over the past decade has been tremendous. This progress has been brought about by improvements in methods for evaluating interatomic forces that work by either solving the electronic structure problem explicitly, or by computing accurate approximations of the solution and by the development of techniques that use the Born–Oppenheimer (BO) forces to move the atoms on the BO potential energy surface. As a consequence of these developments it is now possible to identify stable or metastable states, to sample configurations consistent with the appropriate thermodynamic ensemble, and to estimate the kinetics of reactions and phase transitions. All too often, however, progress is slowed down by the bottleneck associated with implementing new optimization algorithms and/or sampling techniques into the many existing electronic-structure and empirical-potential codes. To address this problem, we are thus releasing a new version of the i-PI software. This piece of software is an easily extensible framework for implementing advanced atomistic simulation techniques using interatomic potentials and forces calculated by an external driver code. While the original version of the code (Ceriotti et al., 2014) was developed with a focus on path integral molecular dynamics techniques, this second release of i-PI not only includes several new advanced path integral methods, but also offers other classes of algorithms. In other words, i-PI is moving towards becoming a universal force engine that is both modular and tightly coupled to the driver codes that evaluate the potential energy surface and its derivatives. AU - Kapil, Venkat AU - Rossi, Mariana AU - Marsalek, Ondrej AU - Petraglia, Riccardo AU - Litman, Yair AU - Spura, Thomas AU - Cheng, Bingqing AU - Cuzzocrea, Alice AU - Meißner, Robert H. AU - Wilkins, David M. AU - Helfrecht, Benjamin A. AU - Juda, Przemysław AU - Bienvenue, Sébastien P. AU - Fang, Wei AU - Kessler, Jan AU - Poltavsky, Igor AU - Vandenbrande, Steven AU - Wieme, Jelle AU - Corminboeuf, Clemence AU - Kühne, Thomas D. AU - Manolopoulos, David E. AU - Markland, Thomas E. AU - Richardson, Jeremy O. AU - Tkatchenko, Alexandre AU - Tribello, Gareth A. AU - Van Speybroeck, Veronique AU - Ceriotti, Michele ID - 9677 JF - Computer Physics Communications SN - 0010-4655 TI - i-PI 2.0: A universal force engine for advanced molecular simulations VL - 236 ER - TY - JOUR AB - Atomistic modeling of phase transitions, chemical reactions, or other rare events that involve overcoming high free energy barriers usually entails prohibitively long simulation times. Introducing a bias potential as a function of an appropriately chosen set of collective variables can significantly accelerate the exploration of phase space, albeit at the price of distorting the distribution of microstates. Efficient reweighting to recover the unbiased distribution can be nontrivial when employing adaptive sampling techniques such as metadynamics, variationally enhanced sampling, or parallel bias metadynamics, in which the system evolves in a quasi-equilibrium manner under a time-dependent bias. We introduce an iterative unbiasing scheme that makes efficient use of all the trajectory data and that does not require the distribution to be evaluated on a grid. The method can thus be used even when the bias has a high dimensionality. We benchmark this approach against some of the existing schemes on model systems with different complexity and dimensionality. AU - Giberti, F. AU - Cheng, Bingqing AU - Tribello, G. A. AU - Ceriotti, M. ID - 9680 IS - 1 JF - Journal of Chemical Theory and Computation SN - 1549-9618 TI - Iterative unbiasing of quasi-equilibrium sampling VL - 16 ER - TY - JOUR AB - The snow cover dynamics of High Mountain Asia are usually assessed at spatial resolutions of 250 m or greater, but this scale is too coarse to clearly represent the rugged topography common to the region. Higher-resolution measurement of snow-covered area often results in biased sampling due to cloud cover and deep shadows. We therefore develop a Normalized Difference Snow Index-based workflow to delineate snow lines from Landsat Thematic Mapper/Enhanced Thematic Mapper+ imagery and apply it to the upper Langtang Valley in Nepal, processing 194 scenes spanning 1999 to 2013. For each scene, we determine the spatial distribution of snow line altitudes (SLAs) with respect to aspect and across six subcatchments. Our results show that the mean SLA exhibits distinct seasonal behavior based on aspect and subcatchment position. We find that SLA dynamics respond to spatial and seasonal trade-offs in precipitation, temperature, and solar radiation, which act as primary controls. We identify two SLA spatial gradients, which we attribute to the effect of spatially variable precipitation. Our results also reveal that aspect-related SLA differences vary seasonally and are influenced by solar radiation. In terms of seasonal dominant controls, we demonstrate that the snow line is controlled by snow precipitation in winter, melt in premonsoon, a combination of both in postmonsoon, and temperature in monsoon, explaining to a large extent the spatial and seasonal variability of the SLA in the upper Langtang Valley. We conclude that while SLA and snow-covered area are complementary metrics, the SLA has a strong potential for understanding local-scale snow cover dynamics and their controlling mechanisms. AU - Girona‐Mata, Marc AU - Miles, Evan S. AU - Ragettli, Silvan AU - Pellicciotti, Francesca ID - 12600 IS - 8 JF - Water Resources Research KW - Water Science and Technology SN - 0043-1397 TI - High‐resolution snowline delineation from Landsat imagery to infer snow cover controls in a Himalayan catchment VL - 55 ER - TY - JOUR AB - This study aims at developing and applying a spatially-distributed coupled glacier mass balance and ice-flow model to attribute the response of glaciers to natural and anthropogenic climate change. We focus on two glaciers with contrasting surface characteristics: a debris-covered glacier (Langtang Glacier in Nepal) and a clean-ice glacier (Hintereisferner in Austria). The model is applied from the end of the Little Ice Age (1850) to the present-day (2016) and is forced with four bias-corrected General Circulation Models (GCMs) from the historical experiment of the CMIP5 archive. The selected GCMs represent region-specific warm-dry, warm-wet, cold-dry, and cold-wet climate conditions. To isolate the effects of anthropogenic climate change on glacier mass balance and flow runs from these GCMs with and without further anthropogenic forcing after 1970 until 2016 are selected. The outcomes indicate that both glaciers experience the largest reduction in area and volume under warm climate conditions, whereas area and volume reductions are smaller under cold climate conditions. Simultaneously with changes in glacier area and volume, surface velocities generally decrease over time. Without further anthropogenic forcing the results reveal a 3% (9%) smaller decline in glacier area (volume) for the debris-covered glacier and a 18% (39%) smaller decline in glacier area (volume) for the clean-ice glacier. The difference in the magnitude between the two glaciers can mainly be attributed to differences in the response time of the glaciers, where the clean-ice glacier shows a much faster response to climate change. We conclude that the response of the two glaciers can mainly be attributed to anthropogenic climate change and that the impact is larger on the clean-ice glacier. The outcomes show that the model performs well under different climate conditions and that the developed approach can be used for regional-scale glacio-hydrological modeling. AU - Wijngaard, René R. AU - Steiner, Jakob F. AU - Kraaijenbrink, Philip D. A. AU - Klug, Christoph AU - Adhikari, Surendra AU - Banerjee, Argha AU - Pellicciotti, Francesca AU - van Beek, Ludovicus P. H. AU - Bierkens, Marc F. P. AU - Lutz, Arthur F. AU - Immerzeel, Walter W. ID - 12602 JF - Frontiers in Earth Science SN - 2296-6463 TI - Modeling the response of the Langtang Glacier and the Hintereisferner to a changing climate since the Little Ice Age VL - 7 ER - TY - JOUR AB - Ice cliffs and ponds on debris-covered glaciers have received increased attention due to their role in amplifying local melt. However, very few studies have looked at these features on the catchment scale to determine their patterns and changes in space and time. We have compiled a detailed inventory of cliffs and ponds in the Langtang catchment, central Himalaya, from six high-resolution satellite orthoimages and DEMs between 2006 and 2015, and a historic orthophoto from 1974. Cliffs cover between 1.4% (± 0.4%) in the dry and 3.4% (± 0.9%) in the wet seasons and ponds between 0.6% (± 0.1%) and 1.6% (± 0.3%) of the total debris-covered tongues. We find large variations between seasons, as cliffs and ponds tend to grow in the wetter monsoon period, but there is no obvious trend in total area over the study period. The inventory further shows that cliffs are predominately north-facing irrespective of the glacier flow direction. Both cliffs and ponds appear in higher densities several hundred metres from the terminus in areas where tributaries reach the main glacier tongue. On the largest glacier in the catchment ~10% of all cliffs and ponds persisted over nearly a decade. AU - STEINER, JAKOB F. AU - BURI, PASCAL AU - MILES, EVAN S. AU - RAGETTLI, SILVAN AU - Pellicciotti, Francesca ID - 12601 IS - 252 JF - Journal of Glaciology SN - 0022-1430 TI - Supraglacial ice cliffs and ponds on debris-covered glaciers: Spatio-temporal distribution and characteristics VL - 65 ER - TY - JOUR AB - Transposable elements (TEs), the movement of which can damage the genome, are epigenetically silenced in eukaryotes. Intriguingly, TEs are activated in the sperm companion cell – vegetative cell (VC) – of the flowering plant Arabidopsis thaliana. However, the extent and mechanism of this activation are unknown. Here we show that about 100 heterochromatic TEs are activated in VCs, mostly by DEMETER-catalyzed DNA demethylation. We further demonstrate that DEMETER access to some of these TEs is permitted by the natural depletion of linker histone H1 in VCs. Ectopically expressed H1 suppresses TEs in VCs by reducing DNA demethylation and via a methylation-independent mechanism. We demonstrate that H1 is required for heterochromatin condensation in plant cells and show that H1 overexpression creates heterochromatic foci in the VC progenitor cell. Taken together, our results demonstrate that the natural depletion of H1 during male gametogenesis facilitates DEMETER-directed DNA demethylation, heterochromatin relaxation, and TE activation. AU - He, Shengbo AU - Vickers, Martin AU - Zhang, Jingyi AU - Feng, Xiaoqi ID - 12192 JF - eLife KW - General Immunology and Microbiology KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Medicine KW - General Neuroscience SN - 2050-084X TI - Natural depletion of histone H1 in sex cells causes DNA demethylation, heterochromatin decondensation and transposon activation VL - 8 ER - TY - GEN AB - In this paper, we present the first fully asynchronous distributed key generation (ADKG) algorithm as well as the first distributed key generation algorithm that can create keys with a dual (f,2f+1)−threshold that are necessary for scalable consensus (which so far needs a trusted dealer assumption). In order to create a DKG with a dual (f,2f+1)− threshold we first answer in the affirmative the open question posed by Cachin et al. how to create an AVSS protocol with recovery thresholds f+1