@article{508, abstract = {The phagocyte NADPH oxidase catalyzes the reduction of O2 to reactive oxygen species with microbicidal activity. It is composed of two membrane-spanning subunits, gp91-phox and p22-phox (encoded by CYBB and CYBA, respectively), and three cytoplasmic subunits, p40-phox, p47-phox, and p67-phox (encoded by NCF4, NCF1, and NCF2, respectively). Mutations in any of these genes can result in chronic granulomatous disease, a primary immunodeficiency characterized by recurrent infections. Using evolutionary mapping, we determined that episodes of adaptive natural selection have shaped the extracellular portion of gp91-phox during the evolution of mammals, which suggests that this region may have a function in host-pathogen interactions. On the basis of a resequencing analysis of approximately 35 kb of CYBB, CYBA, NCF2, and NCF4 in 102 ethnically diverse individuals (24 of African ancestry, 31 of European ancestry, 24 of Asian/Oceanians, and 23 US Hispanics), we show that the pattern of CYBA diversity is compatible with balancing natural selection, perhaps mediated by catalase-positive pathogens. NCF2 in Asian populations shows a pattern of diversity characterized by a differentiated haplotype structure. Our study provides insight into the role of pathogen-driven natural selection in an innate immune pathway and sheds light on the role of CYBA in endothelial, nonphagocytic NADPH oxidases, which are relevant in the pathogenesis of cardiovascular and other complex diseases.}, author = {Tarazona Santos, Eduardo and Machado, Moara and Magalhães, Wagner and Chen, Renee and Lyon, Fernanda and Burdett, Laurie and Crenshaw, Andrew and Fabbri, Cristina and Pereira, Latife and Pinto, Laelia and Fernandes Redondo, Rodrigo A and Sestanovich, Ben and Yeager, Meredith and Chanock, Stephen}, journal = {Molecular Biology and Evolution}, number = {9}, pages = {2157 -- 2167}, publisher = {Oxford University Press}, title = {{Evolutionary dynamics of the human NADPH oxidase genes CYBB, CYBA, NCF2, and NCF4: Functional implications}}, doi = {10.1093/molbev/mst119}, volume = {30}, year = {2013}, } @article{509, abstract = {Clathrin-mediated endocytosis (CME) regulates many aspects of plant development, including hormone signaling and responses to environmental stresses. Despite the importance of this process, the machinery that regulates CME in plants is largely unknown. In mammals, the heterotetrameric ADAPTOR PROTEIN COMPLEX-2 (AP-2) is required for the formation of clathrin-coated vesicles at the plasma membrane (PM). Although the existence of AP-2 has been predicted in Arabidopsis thaliana, the biochemistry and functionality of the complex is still uncharacterized. Here, we identified all the subunits of the Arabidopsis AP-2 by tandem affinity purification and found that one of the large AP-2 subunits, AP2A1, localized at the PM and interacted with clathrin. Furthermore, endocytosis of the leucine-rich repeat receptor kinase, BRASSINOSTEROID INSENSITIVE1 (BRI1), was shown to depend on AP-2. Knockdown of the two Arabidopsis AP2A genes or overexpression of a dominant-negative version of the medium AP-2 subunit, AP2M, impaired BRI1 endocytosis and enhanced the brassinosteroid signaling. Our data reveal that the CME machinery in Arabidopsis is evolutionarily conserved and that AP-2 functions in receptormediated endocytosis. }, author = {Di Rubbo, Simone and Irani, Niloufer and Kim, Soo and Xu, Zheng and Gadeyne, Astrid and Dejonghe, Wim and Vanhoutte, Isabelle and Persiau, Geert and Eeckhout, Dominique and Simon, Sibu and Song, Kyungyoung and Kleine Vehn, Jürgen and Friml, Jirí and De Jaeger, Geert and Van Damme, Daniël and Hwang, Inhwan and Russinova, Eugenia}, journal = {Plant Cell}, number = {8}, pages = {2986 -- 2997}, publisher = {American Society of Plant Biologists}, title = {{The clathrin adaptor complex AP-2 mediates endocytosis of brassinosteroid INSENSITIVE1 in arabidopsis}}, doi = {10.1105/tpc.113.114058}, volume = {25}, year = {2013}, } @article{511, abstract = {The native auxin, indole-3-acetic acid (IAA), is a major regulator of plant growth and development. Its nonuniform distribution between cells and tissues underlies the spatiotemporal coordination of many developmental events and responses to environmental stimuli. The regulation of auxin gradients and the formation of auxin maxima/minima most likely involve the regulation of both metabolic and transport processes. In this article, we have demonstrated that 2-oxindole-3-acetic acid (oxIAA) is a major primary IAA catabolite formed in Arabidopsis thaliana root tissues. OxIAA had little biological activity and was formed rapidly and irreversibly in response to increases in auxin levels. We further showed that there is cell type-specific regulation of oxIAA levels in the Arabidopsis root apex. We propose that oxIAA is an important element in the regulation of output from auxin gradients and, therefore, in the regulation of auxin homeostasis and response mechanisms.}, author = {Pěnčík, Aleš and Simonovik, Biljana and Petersson, Sara and Henyková, Eva and Simon, Sibu and Greenham, Kathleen and Zhang, Yi and Kowalczyk, Mariusz and Estelle, Mark and Zažímalová, Eva and Novák, Ondřej and Sandberg, Göran and Ljung, Karin}, journal = {Plant Cell}, number = {10}, pages = {3858 -- 3870}, publisher = {American Society of Plant Biologists}, title = {{Regulation of auxin homeostasis and gradients in Arabidopsis roots through the formation of the indole-3-acetic acid catabolite 2-oxindole-3-acetic acid}}, doi = {10.1105/tpc.113.114421}, volume = {25}, year = {2013}, } @article{516, abstract = {In plants, changes in local auxin concentrations can trigger a range of developmental processes as distinct tissues respond differently to the same auxin stimulus. However, little is known about how auxin is interpreted by individual cell types. We performed a transcriptomic analysis of responses to auxin within four distinct tissues of the Arabidopsis thaliana root and demonstrate that different cell types show competence for discrete responses. The majority of auxin‐responsive genes displayed a spatial bias in their induction or repression. The novel data set was used to examine how auxin influences tissue‐specific transcriptional regulation of cell‐identity markers. Additionally, the data were used in combination with spatial expression maps of the root to plot a transcriptomic auxin‐response gradient across the apical and basal meristem. The readout revealed a strong correlation for thousands of genes between the relative response to auxin and expression along the longitudinal axis of the root. This data set and comparative analysis provide a transcriptome‐level spatial breakdown of the response to auxin within an organ where this hormone mediates many aspects of development.}, author = {Bargmann, Bastiaan and Vanneste, Steffen and Krouk, Gabriel and Nawy, Tal and Efroni, Idan and Shani, Eilon and Choe, Goh and Friml, Jirí and Bergmann, Dominique and Estelle, Mark and Birnbaum, Kenneth}, journal = {Molecular Systems Biology}, number = {1}, publisher = {Nature Publishing Group}, title = {{A map of cell type‐specific auxin responses}}, doi = {10.1038/msb.2013.40}, volume = {9}, year = {2013}, } @misc{5399, abstract = {In this work we present a flexible tool for tumor progression, which simulates the evolutionary dynamics of cancer. Tumor progression implements a multi-type branching process where the key parameters are the fitness landscape, the mutation rate, and the average time of cell division. The fitness of a cancer cell depends on the mutations it has accumulated. The input to our tool could be any fitness landscape, mutation rate, and cell division time, and the tool produces the growth dynamics and all relevant statistics.}, author = {Reiter, Johannes and Bozic, Ivana and Chatterjee, Krishnendu and Nowak, Martin}, issn = {2664-1690}, pages = {17}, publisher = {IST Austria}, title = {{TTP: Tool for Tumor Progression}}, doi = {10.15479/AT:IST-2013-104-v1-1}, year = {2013}, } @misc{5400, abstract = {We consider partially observable Markov decision processes (POMDPs) with ω-regular conditions specified as parity objectives. The class of ω-regular languages extends regular languages to infinite strings and provides a robust specification language to express all properties used in verification, and parity objectives are canonical forms to express ω-regular conditions. The qualitative analysis problem given a POMDP and a parity objective asks whether there is a strategy to ensure that the objective is satis- fied with probability 1 (resp. positive probability). While the qualitative analysis problems are known to be undecidable even for very special cases of parity objectives, we establish decidability (with optimal complexity) of the qualitative analysis problems for POMDPs with all parity objectives under finite- memory strategies. We establish asymptotically optimal (exponential) memory bounds and EXPTIME- completeness of the qualitative analysis problems under finite-memory strategies for POMDPs with parity objectives.}, author = {Chatterjee, Krishnendu and Chmelik, Martin and Tracol, Mathieu}, issn = {2664-1690}, pages = {41}, publisher = {IST Austria}, title = {{What is decidable about partially observable Markov decision processes with ω-regular objectives}}, doi = {10.15479/AT:IST-2013-109-v1-1}, year = {2013}, } @techreport{5401, abstract = {This document is created as a part of the project “Repository for Research Data at IST Austria”. It summarises the actual initiatives, projects and standards related to the project. It supports the preparation of standards and specifications for the project, which should be considered and followed to ensure interoperability and visibility of the uploaded data.}, author = {Porsche, Jana}, publisher = {IST Austria}, title = {{Initiatives and projects related to RD}}, year = {2013}, } @misc{5402, abstract = {Linearizability requires that the outcome of calls by competing threads to a concurrent data structure is the same as some sequential execution where each thread has exclusive access to the data structure. In an ordered data structure, such as a queue or a stack, linearizability is ensured by requiring threads commit in the order dictated by the sequential semantics of the data structure; e.g., in a concurrent queue implementation a dequeue can only remove the oldest element. In this paper, we investigate the impact of this strict ordering, by comparing what linearizability allows to what existing implementations do. We first give an operational definition for linearizability which allows us to build the most general linearizable implementation as a transition system for any given sequential specification. We then use this operational definition to categorize linearizable implementations based on whether they are bound or free. In a bound implementation, whenever all threads observe the same logical state, the updates to the logical state and the temporal order of commits coincide. All existing queue implementations we know of are bound. We then proceed to present, to the best of our knowledge, the first ever free queue implementation. Our experiments show that free implementations have the potential for better performance by suffering less from contention.}, author = {Henzinger, Thomas A and Sezgin, Ali}, issn = {2664-1690}, pages = {16}, publisher = {IST Austria}, title = {{How free is your linearizable concurrent data structure?}}, doi = {10.15479/AT:IST-2013-123-v1-1}, year = {2013}, } @misc{5403, abstract = {We consider concurrent games played by two-players on a finite state graph, where in every round the players simultaneously choose a move, and the current state along with the joint moves determine the successor state. We study the most fundamental objective for concurrent games, namely, mean-payoff or limit-average objective, where a reward is associated to every transition, and the goal of player 1 is to maximize the long-run average of the rewards, and the objective of player 2 is strictly the opposite (i.e., the games are zero-sum). The path constraint for player 1 could be qualitative, i.e., the mean-payoff is the maximal reward, or arbitrarily close to it; or quantitative, i.e., a given threshold between the minimal and maximal reward. We consider the computation of the almost-sure (resp. positive) winning sets, where player 1 can ensure that the path constraint is satisfied with probability 1 (resp. positive probability). Almost-sure winning with qualitative constraint exactly corresponds to the question whether there exists a strategy to ensure that the payoff is the maximal reward of the game. Our main results for qualitative path constraints are as follows: (1) we establish qualitative determinacy results that show for every state either player 1 has a strategy to ensure almost-sure (resp. positive) winning against all player-2 strategies or player 2 has a spoiling strategy to falsify almost-sure (resp. positive) winning against all player-1 strategies; (2) we present optimal strategy complexity results that precisely characterize the classes of strategies required for almost-sure and positive winning for both players; and (3) we present quadratic time algorithms to compute the almost-sure and the positive winning sets, matching the best known bound of the algorithms for much simpler problems (such as reachability objectives). For quantitative constraints we show that a polynomial time solution for the almost-sure or the positive winning set would imply a solution to a long-standing open problem (of solving the value problem of mean-payoff games) that is not known to be in polynomial time.}, author = {Chatterjee, Krishnendu and Ibsen-Jensen, Rasmus}, issn = {2664-1690}, pages = {33}, publisher = {IST Austria}, title = {{Qualitative analysis of concurrent mean-payoff games}}, doi = {10.15479/AT:IST-2013-126-v1-1}, year = {2013}, } @misc{5404, abstract = {We study finite-state two-player (zero-sum) concurrent mean-payoff games played on a graph. We focus on the important sub-class of ergodic games where all states are visited infinitely often with probability 1. The algorithmic study of ergodic games was initiated in a seminal work of Hoffman and Karp in 1966, but all basic complexity questions have remained unresolved. Our main results for ergodic games are as follows: We establish (1) an optimal exponential bound on the patience of stationary strategies (where patience of a distribution is the inverse of the smallest positive probability and represents a complexity measure of a stationary strategy); (2) the approximation problem lie in FNP; (3) the approximation problem is at least as hard as the decision problem for simple stochastic games (for which NP and coNP is the long-standing best known bound). We show that the exact value can be expressed in the existential theory of the reals, and also establish square-root sum hardness for a related class of games.}, author = {Chatterjee, Krishnendu and Ibsen-Jensen, Rasmus}, issn = {2664-1690}, pages = {29}, publisher = {IST Austria}, title = {{The complexity of ergodic games}}, doi = {10.15479/AT:IST-2013-127-v1-1}, year = {2013}, } @misc{5405, abstract = {The theory of graph games is the foundation for modeling and synthesizing reactive processes. In the synthesis of stochastic processes, we use 2-1/2-player games where some transitions of the game graph are controlled by two adversarial players, the System and the Environment, and the other transitions are determined probabilistically. We consider 2-1/2-player games where the objective of the System is the conjunction of a qualitative objective (specified as a parity condition) and a quantitative objective (specified as a mean-payoff condition). We establish that the problem of deciding whether the System can ensure that the probability to satisfy the mean-payoff parity objective is at least a given threshold is in NP ∩ coNP, matching the best known bound in the special case of 2-player games (where all transitions are deterministic) with only parity objectives, or with only mean-payoff objectives. We present an algorithm running in time O(d · n^{2d}·MeanGame) to compute the set of almost-sure winning states from which the objective can be ensured with probability 1, where n is the number of states of the game, d the number of priorities of the parity objective, and MeanGame is the complexity to compute the set of almost-sure winning states in 2-1/2-player mean-payoff games. Our results are useful in the synthesis of stochastic reactive systems with both functional requirement (given as a qualitative objective) and performance requirement (given as a quantitative objective).}, author = {Chatterjee, Krishnendu and Doyen, Laurent and Gimbert, Hugo and Oualhadj, Youssouf}, issn = {2664-1690}, pages = {22}, publisher = {IST Austria}, title = {{Perfect-information stochastic mean-payoff parity games}}, doi = {10.15479/AT:IST-2013-128-v1-1}, year = {2013}, } @misc{5406, abstract = {We consider the distributed synthesis problem fortemporal logic specifications. Traditionally, the problem has been studied for LTL, and the previous results show that the problem is decidable iff there is no information fork in the architecture. We consider the problem for fragments of LTLand our main results are as follows: (1) We show that the problem is undecidable for architectures with information forks even for the fragment of LTL with temporal operators restricted to next and eventually. (2) For specifications restricted to globally along with non-nested next operators, we establish decidability (in EXPSPACE) for star architectures where the processes receive disjoint inputs, whereas we establish undecidability for architectures containing an information fork-meet structure. (3)Finally, we consider LTL without the next operator, and establish decidability (NEXPTIME-complete) for all architectures for a fragment that consists of a set of safety assumptions, and a set of guarantees where each guarantee is a safety, reachability, or liveness condition.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan and Pavlogiannis, Andreas}, issn = {2664-1690}, pages = {11}, publisher = {IST Austria}, title = {{Distributed synthesis for LTL Fragments}}, doi = {10.15479/AT:IST-2013-130-v1-1}, year = {2013}, } @techreport{5407, abstract = {This document is created as a part of the project “Repository for Research Data at IST Austria”. It summarises the mandatory features, which need to be fulfilled to provide an institutional repository as a platform and also a service to the scientists at the institute. It also includes optional features, which would be of strong benefit for the scientists and would increase the usage of the repository, and hence the visibility of research at IST Austria.}, author = {Porsche, Jana}, publisher = {IST Austria}, title = {{Technical requirements and features}}, year = {2013}, } @misc{5408, abstract = {We consider two-player partial-observation stochastic games where player 1 has partial observation and player 2 has perfect observation. The winning condition we study are omega-regular conditions specified as parity objectives. The qualitative analysis problem given a partial-observation stochastic game and a parity objective asks whether there is a strategy to ensure that the objective is satisfied with probability 1 (resp. positive probability). While the qualitative analysis problems are known to be undecidable even for very special cases of parity objectives, they were shown to be decidable in 2EXPTIME under finite-memory strategies. We improve the complexity and show that the qualitative analysis problems for partial-observation stochastic parity games under finite-memory strategies are EXPTIME-complete; and also establish optimal (exponential) memory bounds for finite-memory strategies required for qualitative analysis. }, author = {Chatterjee, Krishnendu and Doyen, Laurent and Nain, Sumit and Vardi, Moshe}, issn = {2664-1690}, pages = {17}, publisher = {IST Austria}, title = {{The complexity of partial-observation stochastic parity games with finite-memory strategies}}, doi = {10.15479/AT:IST-2013-141-v1-1}, year = {2013}, } @misc{5409, abstract = {The edit distance between two (untimed) traces is the minimum cost of a sequence of edit operations (insertion, deletion, or substitution) needed to transform one trace to the other. Edit distances have been extensively studied in the untimed setting, and form the basis for approximate matching of sequences in different domains such as coding theory, parsing, and speech recognition. In this paper, we lift the study of edit distances from untimed languages to the timed setting. We define an edit distance between timed words which incorporates both the edit distance between the untimed words and the absolute difference in timestamps. Our edit distance between two timed words is computable in polynomial time. Further, we show that the edit distance between a timed word and a timed language generated by a timed automaton, defined as the edit distance between the word and the closest word in the language, is PSPACE-complete. While computing the edit distance between two timed automata is undecidable, we show that the approximate version, where we decide if the edit distance between two timed automata is either less than a given parameter or more than delta away from the parameter, for delta>0, can be solved in exponential space and is EXPSPACE-hard. Our definitions and techniques can be generalized to the setting of hybrid systems, and we show analogous decidability results for rectangular automata.}, author = {Chatterjee, Krishnendu and Ibsen-Jensen, Rasmus and Majumdar, Rupak}, issn = {2664-1690}, pages = {12}, publisher = {IST Austria}, title = {{Edit distance for timed automata}}, doi = {10.15479/AT:IST-2013-144-v1-1}, year = {2013}, } @misc{5410, abstract = {Board games, like Tic-Tac-Toe and CONNECT-4, play an important role not only in development of mathematical and logical skills, but also in emotional and social development. In this paper, we address the problem of generating targeted starting positions for such games. This can facilitate new approaches for bringing novice players to mastery, and also leads to discovery of interesting game variants. Our approach generates starting states of varying hardness levels for player 1 in a two-player board game, given rules of the board game, the desired number of steps required for player 1 to win, and the expertise levels of the two players. Our approach leverages symbolic methods and iterative simulation to efficiently search the extremely large state space. We present experimental results that include discovery of states of varying hardness levels for several simple grid-based board games. Also, the presence of such states for standard game variants like Tic-Tac-Toe on board size 4x4 opens up new games to be played that have not been played for ages since the default start state is heavily biased. }, author = {Ahmed, Umair and Chatterjee, Krishnendu and Gulwani, Sumit}, issn = {2664-1690}, pages = {13}, publisher = {IST Austria}, title = {{Automatic generation of alternative starting positions for traditional board games}}, doi = {10.15479/AT:IST-2013-146-v1-1}, year = {2013}, } @inbook{5747, author = {Dragoi, Cezara and Gupta, Ashutosh and Henzinger, Thomas A}, booktitle = {Computer Aided Verification}, isbn = {9783642397981}, issn = {1611-3349}, location = {Saint Petersburg, Russia}, pages = {174--190}, publisher = {Springer Berlin Heidelberg}, title = {{Automatic Linearizability Proofs of Concurrent Objects with Cooperating Updates}}, doi = {10.1007/978-3-642-39799-8_11}, volume = {8044}, year = {2013}, } @article{595, author = {Bernecky, Carrie A and Cramer, Patrick}, journal = {EMBO Journal}, number = {6}, pages = {771 -- 772}, publisher = {Wiley-Blackwell}, title = {{Struggling to let go: A non-coding RNA directs its own extension and destruction}}, doi = {10.1038/emboj.2013.36}, volume = {32}, year = {2013}, } @article{6128, abstract = {Different interoceptive systems must be integrated to ensure that multiple homeostatic insults evoke appropriate behavioral and physiological responses. Little is known about how this is achieved. Using C. elegans, we dissect cross-modulation between systems that monitor temperature, O2 and CO2. CO2 is less aversive to animals acclimated to 15°C than those grown at 22°C. This difference requires the AFD neurons, which respond to both temperature and CO2 changes. CO2 evokes distinct AFD Ca2+ responses in animals acclimated at 15°C or 22°C. Mutants defective in synaptic transmission can reprogram AFD CO2 responses according to temperature experience, suggesting reprogramming occurs cell autonomously. AFD is exquisitely sensitive to CO2. Surprisingly, gradients of 0.01% CO2/second evoke very different Ca2+ responses from gradients of 0.04% CO2/second. Ambient O2 provides further contextual modulation of CO2 avoidance. At 21% O2 tonic signalling from the O2-sensing neuron URX inhibits CO2 avoidance. This inhibition can be graded according to O2 levels. In a natural wild isolate, a switch from 21% to 19% O2 is sufficient to convert CO2 from a neutral to an aversive cue. This sharp tuning is conferred partly by the neuroglobin GLB-5. The modulatory effects of O2 on CO2 avoidance involve the RIA interneurons, which are post-synaptic to URX and exhibit CO2-evoked Ca2+ responses. Ambient O2 and acclimation temperature act combinatorially to modulate CO2 responsiveness. Our work highlights the integrated architecture of homeostatic responses in C. elegans.}, author = {Kodama-Namba, Eiji and Fenk, Lorenz A. and Bretscher, Andrew J. and Gross, Einav and Busch, K. Emanuel and de Bono, Mario}, issn = {1553-7404}, journal = {PLoS Genetics}, number = {12}, publisher = {Public Library of Science (PLoS)}, title = {{Cross-modulation of homeostatic responses to temperature, oxygen and carbon dioxide in C. elegans}}, doi = {10.1371/journal.pgen.1004011}, volume = {9}, year = {2013}, } @article{6130, abstract = {Cas9 is an RNA-guided double-stranded DNA nuclease that participates in clustered regularly interspaced short palindromic repeats (CRISPR)-mediated adaptive immunity in prokaryotes. CRISPR–Cas9 has recently been used to generate insertion and deletion mutations in Caenorhabditis elegans, but not to create tailored changes (knock-ins). We show that the CRISPR–CRISPR-associated (Cas) system can be adapted for efficient and precise editing of the C. elegans genome. The targeted double-strand breaks generated by CRISPR are substrates for transgene-instructed gene conversion. This allows customized changes in the C. elegans genome by homologous recombination: sequences contained in the repair template (the transgene) are copied by gene conversion into the genome. The possibility to edit the C. elegans genome at selected locations will facilitate the systematic study of gene function in this widely used model organism.}, author = {Chen, Changchun and Fenk, Lorenz A. and de Bono, Mario}, issn = {1362-4962}, journal = {Nucleic Acids Research}, number = {20}, publisher = {Oxford University Press}, title = {{Efficient genome editing in Caenorhabditis elegans by CRISPR-targeted homologous recombination}}, doi = {10.1093/nar/gkt805}, volume = {41}, year = {2013}, }