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 - CONF AB - 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. AU - Alp, Enis Ceyhun AU - Kokoris Kogias, Eleftherios AU - Fragkouli, Georgia AU - Ford, Bryan ID - 8296 SN - 9781450367271 T2 - Proceedings of the Workshop on Hot Topics in Operating Systems TI - Rethinking general-purpose decentralized computing 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 -