TY - GEN
AB - Evolution occurs in populations of reproducing individuals. The structure of the population affects the outcome of the evolutionary process. Evolutionary graph theory is a powerful approach to study this phenomenon. There are two graphs. The interaction graph specifies who interacts with whom in the context of evolution.The replacement graph specifies who competes with whom for reproduction.
The vertices of the two graphs are the same, and each vertex corresponds to an individual of the population. A key quantity is the fixation probability of a new mutant. It is defined as the probability that a newly introduced mutant (on a single vertex) generates a lineage of offspring which eventually takes over the entire population of resident individuals. The basic computational questions are as follows: (i) the qualitative question asks whether the fixation probability is positive; and (ii) the quantitative approximation question asks for an approximation of the fixation probability.
Our main results are:
(1) We show that the qualitative question is NP-complete and the quantitative approximation question is #P-hard in the special case when the interaction and the replacement graphs coincide and even with the restriction that the resident individuals do not reproduce (which corresponds to an invading population taking over an empty structure).
(2) We show that in general the qualitative question is PSPACE-complete and the quantitative approximation question is PSPACE-hard and can be solved in exponential time.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Nowak, Martin
ID - 5432
SN - 2664-1690
TI - The complexity of evolutionary games on graphs
ER -
TY - GEN
AB - Evolution occurs in populations of reproducing individuals. The structure of the population affects the outcome of the evolutionary process. Evolutionary graph theory is a powerful approach to study this phenomenon. There are two graphs. The interaction graph specifies who interacts with whom for payoff in the context of evolution. The replacement graph specifies who competes with whom for reproduction. The vertices of the two graphs are the same, and each vertex corresponds to an individual of the population. The fitness (or the reproductive rate) is a non-negative number, and depends on the payoff. A key quantity is the fixation probability of a new mutant. It is defined as the probability that a newly introduced mutant (on a single vertex) generates a lineage of offspring which eventually takes over the entire population of resident individuals. The basic computational questions are as follows: (i) the qualitative question asks whether the fixation probability is positive; and (ii) the quantitative approximation question asks for an approximation of the fixation probability. Our main results are as follows: First, we consider a special case of the general problem, where the residents do not reproduce. We show that the qualitative question is NP-complete, and the quantitative approximation question is #P-complete, and the hardness results hold even in the special case where the interaction and the replacement graphs coincide. Second, we show that in general both the qualitative and the quantitative approximation questions are PSPACE-complete. The PSPACE-hardness result for quantitative approximation holds even when the fitness is always positive.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Nowak, Martin
ID - 5440
SN - 2664-1690
TI - The complexity of evolutionary games on graphs
ER -
TY - GEN
AB - POMDPs are standard models for probabilistic planning problems, where an agent interacts with an uncertain environment. We study the problem of almost-sure reachability, where given a set of target states, the question is to decide whether there is a policy to ensure that the target set is reached with probability 1 (almost-surely). While in general the problem is EXPTIME-complete, in many practical cases policies with a small amount of memory suffice. Moreover, the existing solution to the problem is explicit, which first requires to construct explicitly an exponential reduction to a belief-support MDP. In this work, we first study the existence of observation-stationary strategies, which is NP-complete, and then small-memory strategies. We present a symbolic algorithm by an efficient encoding to SAT and using a SAT solver for the problem. We report experimental results demonstrating the scalability of our symbolic (SAT-based) approach.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Davies, Jessica
ID - 5443
SN - 2664-1690
TI - A symbolic SAT-based algorithm for almost-sure reachability with small strategies in POMDPs
ER -
TY - GEN
AB - A comprehensive understanding of the clonal evolution of cancer is critical for understanding neoplasia. Genome-wide sequencing data enables evolutionary studies at unprecedented depth. However, classical phylogenetic methods often struggle with noisy sequencing data of impure DNA samples and fail to detect subclones that have different evolutionary trajectories. We have developed a tool, called Treeomics, that allows us to reconstruct the phylogeny of a cancer with commonly available sequencing technologies. Using Bayesian inference and Integer Linear Programming, robust phylogenies consistent with the biological processes underlying cancer evolution were obtained for pancreatic, ovarian, and prostate cancers. Furthermore, Treeomics correctly identified sequencing artifacts such as those resulting from low statistical power; nearly 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumor heterogeneity among distinct samples. Importantly, we show that the evolutionary trees generated with Treeomics are mathematically optimal.
AU - Reiter, Johannes
AU - Makohon-Moore, Alvin
AU - Gerold, Jeffrey
AU - Bozic, Ivana
AU - Chatterjee, Krishnendu
AU - Iacobuzio-Donahue, Christine
AU - Vogelstein, Bert
AU - Nowak, Martin
ID - 5444
SN - 2664-1690
TI - Reconstructing robust phylogenies of metastatic cancers
ER -
TY - DATA
AB - This repository contains the experimental part of the CAV 2015 publication Counterexample Explanation by Learning Small Strategies in Markov Decision Processes.
We extended the probabilistic model checker PRISM to represent strategies of Markov Decision Processes as Decision Trees.
The archive contains a java executable version of the extended tool (prism_dectree.jar) together with a few examples of the PRISM benchmark library.
To execute the program, please have a look at the README.txt, which provides instructions and further information on the archive.
The archive contains scripts that (if run often enough) reproduces the data presented in the publication.
AU - Fellner, Andreas
ID - 5549
KW - Markov Decision Process
KW - Decision Tree
KW - Probabilistic Verification
KW - Counterexample Explanation
TI - Experimental part of CAV 2015 publication: Counterexample Explanation by Learning Small Strategies in Markov Decision Processes
ER -
TY - CONF
AB - For deterministic systems, a counterexample to a property can simply be an error trace, whereas counterexamples in probabilistic systems are necessarily more complex. For instance, a set of erroneous traces with a sufficient cumulative probability mass can be used. Since these are too large objects to understand and manipulate, compact representations such as subchains have been considered. In the case of probabilistic systems with non-determinism, the situation is even more complex. While a subchain for a given strategy (or scheduler, resolving non-determinism) is a straightforward choice, we take a different approach. Instead, we focus on the strategy itself, and extract the most important decisions it makes, and present its succinct representation.
The key tools we employ to achieve this are (1) introducing a concept of importance of a state w.r.t. the strategy, and (2) learning using decision trees. There are three main consequent advantages of our approach. Firstly, it exploits the quantitative information on states, stressing the more important decisions. Secondly, it leads to a greater variability and degree of freedom in representing the strategies. Thirdly, the representation uses a self-explanatory data structure. In summary, our approach produces more succinct and more explainable strategies, as opposed to e.g. binary decision diagrams. Finally, our experimental results show that we can extract several rules describing the strategy even for very large systems that do not fit in memory, and based on the rules explain the erroneous behaviour.
AU - Brázdil, Tomáš
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Fellner, Andreas
AU - Kretinsky, Jan
ID - 1603
TI - Counterexample explanation by learning small strategies in Markov decision processes
VL - 9206
ER -
TY - JOUR
AB - Parasitism creates selection for resistance mechanisms in host populations and is hypothesized to promote increased host evolvability. However, the influence of these traits on host evolution when parasites are no longer present is unclear. We used experimental evolution and whole-genome sequencing of Escherichia coli to determine the effects of past and present exposure to parasitic viruses (phages) on the spread of mutator alleles, resistance, and bacterial competitive fitness. We found that mutator alleles spread rapidly during adaptation to any of four different phage species, and this pattern was even more pronounced with multiple phages present simultaneously. However, hypermutability did not detectably accelerate adaptation in the absence of phages and recovery of fitness costs associated with resistance. Several lineages evolved phage resistance through elevated mucoidy, and during subsequent evolution in phage-free conditions they rapidly reverted to nonmucoid, phage-susceptible phenotypes. Genome sequencing revealed that this phenotypic reversion was achieved by additional genetic changes rather than by genotypic reversion of the initial resistance mutations. Insertion sequence (IS) elements played a key role in both the acquisition of resistance and adaptation in the absence of parasites; unlike single nucleotide polymorphisms, IS insertions were not more frequent in mutator lineages. Our results provide a genetic explanation for rapid reversion of mucoidy, a phenotype observed in other bacterial species including human pathogens. Moreover, this demonstrates that the types of genetic change underlying adaptation to fitness costs, and consequently the impact of evolvability mechanisms such as increased point-mutation rates, depend critically on the mechanism of resistance.
AU - Wielgoss, Sébastien
AU - Bergmiller, Tobias
AU - Bischofberger, Anna M.
AU - Hall, Alex R.
ID - 5749
IS - 3
JF - Molecular Biology and Evolution
SN - 0737-4038
TI - Adaptation to Parasites and Costs of Parasite Resistance in Mutator and Nonmutator Bacteria
VL - 33
ER -
TY - JOUR
AB - We present here the first integer-based algorithm for constructing a well-defined lattice sphere specified by integer radius and integer center. The algorithm evolves from a unique correspondence between the lattice points comprising the sphere and the distribution of sum of three square numbers in integer intervals. We characterize these intervals to derive a useful set of recurrences, which, in turn, aids in efficient computation. Each point of the lattice sphere is determined by resorting to only a few primitive operations in the integer domain. The symmetry of its quadraginta octants provides an added advantage by confining the computation to its prima quadraginta octant. Detailed theoretical analysis and experimental results have been furnished to demonstrate its simplicity and elegance.
AU - Biswas, Ranita
AU - Bhowmick, Partha
ID - 5804
IS - 4
JF - Theoretical Computer Science
SN - 0304-3975
TI - From prima quadraginta octant to lattice sphere through primitive integer operations
VL - 624
ER -
TY - JOUR
AU - Biswas, Ranita
AU - Bhowmick, Partha
ID - 5807
IS - 11
JF - Theoretical Computer Science
SN - 0304-3975
TI - On different topological classes of spherical geodesic paths and circles inZ3
VL - 605
ER -
TY - JOUR
AU - Biswas, Ranita
AU - Bhowmick, Partha
ID - 5808
IS - 6-8
JF - The Visual Computer
SN - 0178-2789
TI - Layer the sphere
VL - 31
ER -
TY - JOUR
AU - Dereziński, Jan
AU - Napiórkowski, Marcin M
ID - 1939
IS - 7
JF - Annales Henri Poincare
TI - Erratum to: Excitation spectrum of interacting bosons in the Mean-Field Infinite-Volume limit
VL - 16
ER -
TY - JOUR
AB - Transcription of eukaryotic protein-coding genes commences with the assembly of a conserved initiation complex, which consists of RNA polymerase II (Pol II) and the general transcription factors, at promoter DNA. After two decades of research, the structural basis of transcription initiation is emerging. Crystal structures of many components of the initiation complex have been resolved, and structural information on Pol II complexes with general transcription factors has recently been obtained. Although mechanistic details await elucidation, available data outline how Pol II cooperates with the general transcription factors to bind to and open promoter DNA, and how Pol II directs RNA synthesis and escapes from the promoter.
AU - Sainsbury, Sarah
AU - Bernecky, Carrie A
AU - Cramer, Patrick
ID - 594
IS - 3
JF - Nature Reviews Molecular Cell Biology
TI - Structural basis of transcription initiation by RNA polymerase II
VL - 16
ER -
TY - GEN
AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural problems that arise in program analysis. We consider that each component of the concurrent system is a graph with constant treewidth, a property satisfied by the controlflow graphs of most programs. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis. The study of multiple queries allows us to consider the tradeoff between the resource usage of the one-time preprocessing and for each individual query. The traditional approach constructs the product graph of all components and applies the best-known graph algorithm on the product. In this approach, even the answer to a single query requires the transitive closure (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time. Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time, each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results showing that the worst-case running time of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (i.e., improving the worst-case bound for the shortest path problem in general graphs). Preliminary experimental results show that our algorithms perform favorably on several benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Goharshady, Amir
AU - Pavlogiannis, Andreas
ID - 5441
SN - 2664-1690
TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components
ER -
TY - GEN
AB - We study algorithmic questions for concurrent systems where the transitions are labeled from a complete, closed semiring, and path properties are algebraic with semiring operations. The algebraic path properties can model dataflow analysis problems, the shortest path problem, and many other natural properties that arise in program analysis.
We consider that each component of the concurrent system is a graph with constant treewidth, and it is known that the controlflow graphs of most programs have constant treewidth. We allow for multiple possible queries, which arise naturally in demand driven dataflow analysis problems (e.g., alias analysis). The study of multiple queries allows us to consider the tradeoff between the resource usage of the \emph{one-time} preprocessing and for \emph{each individual} query. The traditional approaches construct the product graph of all components and apply the best-known graph algorithm on the product. In the traditional approach, even the answer to a single query requires the transitive closure computation (i.e., the results of all possible queries), which provides no room for tradeoff between preprocessing and query time.
Our main contributions are algorithms that significantly improve the worst-case running time of the traditional approach, and provide various tradeoffs depending on the number of queries. For example, in a concurrent system of two components, the traditional approach requires hexic time in the worst case for answering one query as well as computing the transitive closure, whereas we show that with one-time preprocessing in almost cubic time,
each subsequent query can be answered in at most linear time, and even the transitive closure can be computed in almost quartic time. Furthermore, we establish conditional optimality results that show that the worst-case running times of our algorithms cannot be improved without achieving major breakthroughs in graph algorithms (such as improving
the worst-case bounds for the shortest path problem in general graphs whose current best-known bound has not been improved in five decades). Finally, we provide a prototype implementation of our algorithms which significantly outperforms the existing algorithmic methods on several benchmarks.
AU - Anonymous, 1
AU - Anonymous, 2
AU - Anonymous, 3
AU - Anonymous, 4
ID - 5442
SN - 2664-1690
TI - Algorithms for algebraic path properties in concurrent systems of constant treewidth components
ER -
TY - JOUR
AB - Carbon dioxide (CO2) gradients are ubiquitous and provide animals with information about their environment, such as the potential presence of prey or predators. The nematode Caenorhabditis elegans avoids elevated CO2, and previous work identified three neuron pairs called “BAG,” “AFD,” and “ASE” that respond to CO2 stimuli. Using in vivo Ca2+ imaging and behavioral analysis, we show that C. elegans can detect CO2 independently of these sensory pathways. Many of the C. elegans sensory neurons we examined, including the AWC olfactory neurons, the ASJ and ASK gustatory neurons, and the ASH and ADL nociceptors, respond to a rise in CO2 with a rise in Ca2+. In contrast, glial sheath cells harboring the sensory endings of C. elegans’ major chemosensory neurons exhibit strong and sustained decreases in Ca2+ in response to high CO2. Some of these CO2 responses appear to be cell intrinsic. Worms therefore may couple detection of CO2 to that of other cues at the earliest stages of sensory processing. We show that C. elegans persistently suppresses oviposition at high CO2. Hermaphrodite-specific neurons (HSNs), the executive neurons driving egg-laying, are tonically inhibited when CO2 is elevated. CO2 modulates the egg-laying system partly through the AWC olfactory neurons: High CO2 tonically activates AWC by a cGMP-dependent mechanism, and AWC output inhibits the HSNs. Our work shows that CO2 is a more complex sensory cue for C. elegans than previously thought, both in terms of behavior and neural circuitry.
AU - Fenk, Lorenz A.
AU - de Bono, Mario
ID - 6118
IS - 27
JF - Proceedings of the National Academy of Sciences
SN - 0027-8424
TI - Environmental CO2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity
VL - 112
ER -
TY - JOUR
AB - Brains organize behavior and physiology to optimize the response to threats or opportunities. We dissect how 21% O2, an indicator of surface exposure, reprograms C. elegans' global state, inducing sustained locomotory arousal and altering expression of neuropeptides, metabolic enzymes, and other non-neural genes. The URX O2-sensing neurons drive arousal at 21% O2 by tonically activating the RMG interneurons. Stimulating RMG is sufficient to switch behavioral state. Ablating the ASH, ADL, or ASK sensory neurons connected to RMG by gap junctions does not disrupt arousal. However, disrupting cation currents in these neurons curtails RMG neurosecretion and arousal. RMG signals high O2 by peptidergic secretion. Neuropeptide reporters reveal neural circuit state, as neurosecretion stimulates neuropeptide expression. Neural imaging in unrestrained animals shows that URX and RMG encode O2 concentration rather than behavior, while the activity of downstream interneurons such as AVB and AIY reflect both O2 levels and the behavior being executed.
AU - Laurent, Patrick
AU - Soltesz, Zoltan
AU - Nelson, Geoffrey M
AU - Chen, Changchun
AU - Arellano-Carbajal, Fausto
AU - Levy, Emmanuel
AU - de Bono, Mario
ID - 6120
JF - eLife
SN - 2050-084X
TI - Decoding a neural circuit controlling global animal state in C. elegans
VL - 4
ER -
TY - CONF
AB - The fact that the complete graph K_5 does not embed in the plane has been generalized in two independent directions. On the one hand, the solution of the classical Heawood problem for graphs on surfaces established that the complete graph K_n embeds in a closed surface M if and only if (n-3)(n-4) is at most 6b_1(M), where b_1(M) is the first Z_2-Betti number of M. On the other hand, Van Kampen and Flores proved that the k-skeleton of the n-dimensional simplex (the higher-dimensional analogue of K_{n+1}) embeds in R^{2k} if and only if n is less or equal to 2k+2. Two decades ago, Kuhnel conjectured that the k-skeleton of the n-simplex embeds in a compact, (k-1)-connected 2k-manifold with kth Z_2-Betti number b_k only if the following generalized Heawood inequality holds: binom{n-k-1}{k+1} is at most binom{2k+1}{k+1} b_k. This is a common generalization of the case of graphs on surfaces as well as the Van Kampen--Flores theorem. In the spirit of Kuhnel's conjecture, we prove that if the k-skeleton of the n-simplex embeds in a 2k-manifold with kth Z_2-Betti number b_k, then n is at most 2b_k binom{2k+2}{k} + 2k + 5. This bound is weaker than the generalized Heawood inequality, but does not require the assumption that M is (k-1)-connected. Our proof uses a result of Volovikov about maps that satisfy a certain homological triviality condition.
AU - Goaoc, Xavier
AU - Mabillard, Isaac
AU - Paták, Pavel
AU - Patakova, Zuzana
AU - Tancer, Martin
AU - Wagner, Uli
ID - 1511
TI - On generalized Heawood inequalities for manifolds: A Van Kampen–Flores-type nonembeddability result
VL - 34
ER -
TY - JOUR
AB - The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution.
AU - Chevereau, Guillaume
AU - Dravecka, Marta
AU - Batur, Tugce
AU - Guvenek, Aysegul
AU - Ayhan, Dilay
AU - Toprak, Erdal
AU - Bollenbach, Mark Tobias
ID - 1619
IS - 11
JF - PLoS Biology
TI - Quantifying the determinants of evolutionary dynamics leading to drug resistance
VL - 13
ER -
TY - CONF
AB - An instance of the Valued Constraint Satisfaction Problem (VCSP) is given by a finite set of variables, a finite domain of labels, and a sum of functions, each function depending on a subset of the variables. Each function can take finite values specifying costs of assignments of labels to its variables or the infinite value, which indicates an infeasible assignment. The goal is to find an assignment of labels to the variables that minimizes the sum. We study, assuming that P ≠ NP, how the complexity of this very general problem depends on the set of functions allowed in the instances, the so-called constraint language. The case when all allowed functions take values in {0, ∞} corresponds to ordinary CSPs, where one deals only with the feasibility issue and there is no optimization. This case is the subject of the Algebraic CSP Dichotomy Conjecture predicting for which constraint languages CSPs are tractable (i.e. solvable in polynomial time) and for which NP-hard. The case when all allowed functions take only finite values corresponds to finite-valued CSP, where the feasibility aspect is trivial and one deals only with the optimization issue. The complexity of finite-valued CSPs was fully classified by Thapper and Zivny. An algebraic necessary condition for tractability of a general-valued CSP with a fixed constraint language was recently given by Kozik and Ochremiak. As our main result, we prove that if a constraint language satisfies this algebraic necessary condition, and the feasibility CSP (i.e. the problem of deciding whether a given instance has a feasible solution) corresponding to the VCSP with this language is tractable, then the VCSP is tractable. The algorithm is a simple combination of the assumed algorithm for the feasibility CSP and the standard LP relaxation. As a corollary, we obtain that a dichotomy for ordinary CSPs would imply a dichotomy for general-valued CSPs.
AU - Kolmogorov, Vladimir
AU - Krokhin, Andrei
AU - Rolinek, Michal
ID - 1637
TI - The complexity of general-valued CSPs
ER -
TY - JOUR
AB - The osteoclast-associated receptor (OSCAR) is a collagen-binding immune receptor with important roles in dendritic cell maturation and activation of inflammatory monocytes as well as in osteoclastogenesis. The crystal structure of the OSCAR ectodomain is presented, both free and in complex with a consensus triple-helical peptide (THP). The structures revealed a collagen-binding site in each immunoglobulin-like domain (D1 and D2). The THP binds near a predicted collagen-binding groove in D1, but a more extensive interaction with D2 is facilitated by the unusually wide D1-D2 interdomain angle in OSCAR. Direct binding assays, combined with site-directed mutagenesis, confirm that the primary collagen-binding site in OSCAR resides in D2, in marked contrast to the related collagen receptors, glycoprotein VI (GPVI) and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). Monomeric OSCAR D1D2 binds to the consensus THP with a KD of 28 µM measured in solution, but shows a higher affinity (KD 1.5 μM) when binding to a solid-phase THP, most likely due to an avidity effect. These data suggest a 2-stage model for the interaction of OSCAR with a collagen fibril, with transient, low-affinity interactions initiated by the membrane-distal D1, followed by firm adhesion to the primary binding site in D2.
AU - Zhou, Long
AU - Hinerman, J. M.
AU - Blaszczyk, M.
AU - Miller, J. L. C.
AU - Conrady, D. G.
AU - Barrow, A. D.
AU - Chirgadze, D. Y.
AU - Bihan, D.
AU - Farndale, R. W.
AU - Herr, A. B.
ID - 6507
IS - 5
JF - Blood
SN - 0006-4971
TI - Structural basis for collagen recognition by the immune receptor OSCAR
VL - 127
ER -
TY - JOUR
AB - Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that noncognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here, we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibrium models of TF binding, and propose an alternative nonequilibrium scheme that implements kinetic proofreading to suppress erroneous initiation. This proposal is consistent with the observed covalent modifications of the transcriptional apparatus and predicts increased noise in gene expression as a trade-off for improved specificity. Using information theory, we quantify this trade-off to find when optimal proofreading architectures are favored over their equilibrium counterparts. Such architectures exhibit significant super-Poisson noise at low expression in steady state.
AU - Cepeda Humerez, Sarah A
AU - Rieckh, Georg
AU - Tkacik, Gasper
ID - 1576
IS - 24
JF - Physical Review Letters
TI - Stochastic proofreading mechanism alleviates crosstalk in transcriptional regulation
VL - 115
ER -
TY - JOUR
AB - Motivated by the significant performance gains which polar codes experience under successive cancellation list decoding, their scaling exponent is studied as a function of the list size. In particular, the error probability is fixed, and the tradeoff between the block length and back-off from capacity is analyzed. A lower bound is provided on the error probability under MAP decoding with list size L for any binary-input memoryless output-symmetric channel and for any class of linear codes such that their minimum distance is unbounded as the block length grows large. Then, it is shown that under MAP decoding, although the introduction of a list can significantly improve the involved constants, the scaling exponent itself, i.e., the speed at which capacity is approached, stays unaffected for any finite list size. In particular, this result applies to polar codes, since their minimum distance tends to infinity as the block length increases. A similar result is proved for genie-aided successive cancellation decoding when transmission takes place over the binary erasure channel, namely, the scaling exponent remains constant for any fixed number of helps from the genie. Note that since genie-aided successive cancellation decoding might be strictly worse than successive cancellation list decoding, the problem of establishing the scaling exponent of the latter remains open.
AU - Mondelli, Marco
AU - Hassani, Hamed
AU - Urbanke, Rudiger
ID - 6736
IS - 9
JF - IEEE Transactions on Information Theory
TI - Scaling exponent of list decoders with applications to polar codes
VL - 61
ER -
TY - JOUR
AB - This paper presents polar coding schemes for the two-user discrete memoryless broadcast channel (DM-BC) which achieve Marton's region with both common and private messages. This is the best achievable rate region known to date, and it is tight for all classes of two-user DM-BCs whose capacity regions are known. To accomplish this task, we first construct polar codes for both the superposition as well as binning strategy. By combining these two schemes, we obtain Marton's region with private messages only. Finally, we show how to handle the case of common information. The proposed coding schemes possess the usual advantages of polar codes, i.e., they have low encoding and decoding complexity and a superpolynomial decay rate of the error probability. We follow the lead of Goela, Abbe, and Gastpar, who recently introduced polar codes emulating the superposition and binning schemes. To align the polar indices, for both schemes, their solution involves some degradedness constraints that are assumed to hold between the auxiliary random variables and channel outputs. To remove these constraints, we consider the transmission of k blocks and employ a chaining construction that guarantees the proper alignment of the polarized indices. The techniques described in this paper are quite general, and they can be adopted to many other multiterminal scenarios whenever there polar indices need to be aligned.
AU - Mondelli, Marco
AU - Hassani, Hamed
AU - Sason, Igal
AU - Urbanke, Rudiger
ID - 6737
IS - 2
JF - IEEE Transactions on Information Theory
TI - Achieving Marton’s region for broadcast channels using polar codes
VL - 61
ER -
TY - JOUR
AB - Torque magnetization measurements on YBa2Cu3Oy (YBCO) at doping y=6.67 (p=0.12), in dc fields (B) up to 33 T and temperatures down to 4.5 K, show that weak diamagnetism persists above the extrapolated irreversibility field Hirr(T=0)≈24 T. The differential susceptibility dM/dB, however, is more rapidly suppressed for B≳16 T than expected from the properties of the low field superconducting state, and saturates at a low value for fields B≳24 T. In addition, torque measurements on a p=0.11 YBCO crystal in pulsed field up to 65 T and temperatures down to 8 K show similar behavior, with no additional features at higher fields. We offer two candidate scenarios to explain these observations: (a) superconductivity survives but is heavily suppressed at high field by competition with charge-density-wave (CDW) order; (b) static superconductivity disappears near 24 T and is followed by a region of fluctuating superconductivity, which causes dM/dB to saturate at high field. The diamagnetic signal observed above 50 T for the p=0.11 crystal at 40 K and below may be caused by changes in the normal state susceptibility rather than bulk or fluctuating superconductivity. There will be orbital (Landau) diamagnetism from electron pockets and possibly a reduction in spin susceptibility caused by the stronger three-dimensional ordered CDW.
AU - Yu, Jing Fei
AU - Ramshaw, B. J.
AU - Kokanović, I.
AU - Modic, Kimberly A
AU - Harrison, N.
AU - Day, James
AU - Liang, Ruixing
AU - Hardy, W. N.
AU - Bonn, D. A.
AU - McCollam, A.
AU - Julian, S. R.
AU - Cooper, J. R.
ID - 7070
IS - 18
JF - Physical Review B
SN - 1098-0121
TI - Magnetization of underdoped YBa2Cu3Oy above the irreversibility field
VL - 92
ER -
TY - JOUR
AB - Currently, there is much debate on the genetic architecture of quantitative traits in wild populations. Is trait variation influenced by many genes of small effect or by a few genes of major effect? Where is additive genetic variation located in the genome? Do the same loci cause similar phenotypic variation in different populations? Great tits (Parus major) have been studied extensively in long‐term studies across Europe and consequently are considered an ecological ‘model organism’. Recently, genomic resources have been developed for the great tit, including a custom SNP chip and genetic linkage map. In this study, we used a suite of approaches to investigate the genetic architecture of eight quantitative traits in two long‐term study populations of great tits—one in the Netherlands and the other in the United Kingdom. Overall, we found little evidence for the presence of genes of large effects in either population. Instead, traits appeared to be influenced by many genes of small effect, with conservative estimates of the number of contributing loci ranging from 31 to 310. Despite concordance between population‐specific heritabilities, we found no evidence for the presence of loci having similar effects in both populations. While population‐specific genetic architectures are possible, an undetected shared architecture cannot be rejected because of limited power to map loci of small and moderate effects. This study is one of few examples of genetic architecture analysis in replicated wild populations and highlights some of the challenges and limitations researchers will face when attempting similar molecular quantitative genetic studies in free‐living populations.
AU - Santure, Anna W.
AU - Poissant, Jocelyn
AU - De Cauwer, Isabelle
AU - van Oers, Kees
AU - Robinson, Matthew Richard
AU - Quinn, John L.
AU - Groenen, Martien A. M.
AU - Visser, Marcel E.
AU - Sheldon, Ben C.
AU - Slate, Jon
ID - 7739
JF - Molecular Ecology
SN - 0962-1083
TI - Replicated analysis of the genetic architecture of quantitative traits in two wild great tit populations
VL - 24
ER -
TY - JOUR
AB - Phenotypes expressed in a social context are not only a function of the individual, but can also be shaped by the phenotypes of social partners. These social effects may play a major role in the evolution of cooperative breeding if social partners differ in the quality of care they provide and if individual carers adjust their effort in relation to that of other carers. When applying social effects models to wild study systems, it is also important to explore sources of individual plasticity that could masquerade as social effects. We studied offspring provisioning rates of parents and helpers in a wild population of long-tailed tits Aegithalos caudatus using a quantitative genetic framework to identify these social effects and partition them into genetic, permanent environment and current environment components. Controlling for other effects, individuals were consistent in their provisioning effort at a given nest, but adjusted their effort based on who was in their social group, indicating the presence of social effects. However, these social effects differed between years and social contexts, indicating a current environment effect, rather than indicating a genetic or permanent environment effect. While this study reveals the importance of examining environmental and genetic sources of social effects, the framework we present is entirely general, enabling a greater understanding of potentially important social effects within any ecological population.
AU - Adams, Mark James
AU - Robinson, Matthew Richard
AU - Mannarelli, Maria-Elena
AU - Hatchwell, Ben J.
ID - 7741
IS - 1810
JF - Proceedings of the Royal Society B: Biological Sciences
SN - 0962-8452
TI - Social genetic and social environment effects on parental and helper care in a cooperatively breeding bird
VL - 282
ER -
TY - JOUR
AB - Across-nation differences in the mean values for complex traits are common1,2,3,4,5,6,7,8, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10−8; BMI, P < 5.95 × 10−4), and we find an among-population genetic correlation for tall and slender individuals (r = −0.80, 95% CI = −0.95, −0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).
AU - Robinson, Matthew Richard
AU - Hemani, Gibran
AU - Medina-Gomez, Carolina
AU - Mezzavilla, Massimo
AU - Esko, Tonu
AU - Shakhbazov, Konstantin
AU - Powell, Joseph E
AU - Vinkhuyzen, Anna
AU - Berndt, Sonja I
AU - Gustafsson, Stefan
AU - Justice, Anne E
AU - Kahali, Bratati
AU - Locke, Adam E
AU - Pers, Tune H
AU - Vedantam, Sailaja
AU - Wood, Andrew R
AU - van Rheenen, Wouter
AU - Andreassen, Ole A
AU - Gasparini, Paolo
AU - Metspalu, Andres
AU - Berg, Leonard H van den
AU - Veldink, Jan H
AU - Rivadeneira, Fernando
AU - Werge, Thomas M
AU - Abecasis, Goncalo R
AU - Boomsma, Dorret I
AU - Chasman, Daniel I
AU - de Geus, Eco J C
AU - Frayling, Timothy M
AU - Hirschhorn, Joel N
AU - Hottenga, Jouke Jan
AU - Ingelsson, Erik
AU - Loos, Ruth J F
AU - Magnusson, Patrik K E
AU - Martin, Nicholas G
AU - Montgomery, Grant W
AU - North, Kari E
AU - Pedersen, Nancy L
AU - Spector, Timothy D
AU - Speliotes, Elizabeth K
AU - Goddard, Michael E
AU - Yang, Jian
AU - Visscher, Peter M
ID - 7742
IS - 11
JF - Nature Genetics
SN - 1061-4036
TI - Population genetic differentiation of height and body mass index across Europe
VL - 47
ER -
TY - CONF
AB - High-performance concurrent priority queues are essential for applications such as task scheduling and discrete event simulation. Unfortunately, even the best performing implementations do not scale past a number of threads in the single digits. This is because of the sequential bottleneck in accessing the elements at the head of the queue in order to perform a DeleteMin operation. In this paper, we present the SprayList, a scalable priority queue with relaxed ordering semantics. Starting from a non-blocking SkipList, the main innovation behind our design is that the DeleteMin operations avoid a sequential bottleneck by "spraying" themselves onto the head of the SkipList list in a coordinated fashion. The spraying is implemented using a carefully designed random walk, so that DeleteMin returns an element among the first O(plog3p) in the list, with high probability, where p is the number of threads. We prove that the running time of a DeleteMin operation is O(log3p), with high probability, independent of the size of the list. Our experiments show that the relaxed semantics allow the data structure to scale for high thread counts, comparable to a classic unordered SkipList. Furthermore, we observe that, for reasonably parallel workloads, the scalability benefits of relaxation considerably outweigh the additional work due to out-of-order execution.
AU - Alistarh, Dan-Adrian
AU - Kopinsky, Justin
AU - Li, Jerry
AU - Shavit, Nir
ID - 776
TI - The SprayList: A scalable relaxed priority queue
VL - 2015-January
ER -
TY - JOUR
AB - We introduce a principle unique to disordered solids wherein the contribution of any bond to one global perturbation is uncorrelated with its contribution to another. Coupled with sufficient variability in the contributions of different bonds, this “independent bond-level response” paves the way for the design of real materials with unusual and exquisitely tuned properties. To illustrate this, we choose two global perturbations: compression and shear. By applying a bond removal procedure that is both simple and experimentally relevant to remove a very small fraction of bonds, we can drive disordered spring networks to both the incompressible and completely auxetic limits of mechanical behavior.
AU - Goodrich, Carl Peter
AU - Liu, Andrea J.
AU - Nagel, Sidney R.
ID - 7765
IS - 22
JF - Physical Review Letters
SN - 0031-9007
TI - The principle of independent bond-level response: Tuning by pruning to exploit disorder for global behavior
VL - 114
ER -
TY - JOUR
AB - We study the vibrational properties near a free surface of disordered spring networks derived from jammed sphere packings. In bulk systems, without surfaces, it is well understood that such systems have a plateau in the density of vibrational modes extending down to a frequency scale ω*. This frequency is controlled by ΔZ = 〈Z〉 − 2d, the difference between the average coordination of the spheres and twice the spatial dimension, d, of the system, which vanishes at the jamming transition. In the presence of a free surface we find that there is a density of disordered vibrational modes associated with the surface that extends far below ω*. The total number of these low-frequency surface modes is controlled by ΔZ, and the profile of their decay into the bulk has two characteristic length scales, which diverge as ΔZ−1/2 and ΔZ−1 as the jamming transition is approached.
AU - Sussman, Daniel M.
AU - Goodrich, Carl Peter
AU - Liu, Andrea J.
AU - Nagel, Sidney R.
ID - 7766
IS - 14
JF - Soft Matter
SN - 1744-683X
TI - Disordered surface vibrations in jammed sphere packings
VL - 11
ER -
TY - JOUR
AB - We present a model of soft active particles that leads to a rich array of collective behavior found also in dense biological swarms of bacteria and other unicellular organisms. Our model uses only local interactions, such as Vicsek-type nearest-neighbor alignment, short-range repulsion, and a local boundary term. Changing the relative strength of these interactions leads to migrating swarms, rotating swarms, and jammed swarms, as well as swarms that exhibit run-and-tumble motion, alternating between migration and either rotating or jammed states. Interestingly, although a migrating swarm moves slower than an individual particle, the diffusion constant can be up to three orders of magnitude larger, suggesting that collective motion can be highly advantageous, for example, when searching for food.
AU - van Drongelen, Ruben
AU - Pal, Anshuman
AU - Goodrich, Carl Peter
AU - Idema, Timon
ID - 7767
IS - 3
JF - Physical Review E
SN - 1539-3755
TI - Collective dynamics of soft active particles
VL - 91
ER -
TY - CONF
AB - In many applications, the data is of rich structure that can be represented by a hypergraph, where the data items are represented by vertices and the associations among items are represented by hyperedges. Equivalently, we are given an input bipartite graph with two types of vertices: items, and associations (which we refer to as topics). We consider the problem of partitioning the set of items into a given number of components such that the maximum number of topics covered by a component is minimized. This is a clustering problem with various applications, e.g. partitioning of a set of information objects such as documents, images, and videos, and load balancing in the context of modern computation platforms.Inthis paper, we focus on the streaming computation model for this problem, in which items arrive online one at a time and each item must be assigned irrevocably to a component at its arrival time. Motivated by scalability requirements, we focus on the class of streaming computation algorithms with memory limited to be at most linear in the number of components. We show that a greedy assignment strategy is able to recover a hidden co-clustering of items under a natural set of recovery conditions. We also report results of an extensive empirical evaluation, which demonstrate that this greedy strategy yields superior performance when compared with alternative approaches.
AU - Alistarh, Dan-Adrian
AU - Iglesias, Jennifer
AU - Vojnović, Milan
ID - 777
TI - Streaming min-max hypergraph partitioning
VL - 2015-January
ER -
TY - GEN
AB - The fact that a disordered material is not constrained in its properties in
the same way as a crystal presents significant and yet largely untapped
potential for novel material design. However, unlike their crystalline
counterparts, disordered solids are not well understood. One of the primary
obstacles is the lack of a theoretical framework for thinking about disorder
and its relation to mechanical properties. To this end, we study an idealized
system of frictionless athermal soft spheres that, when compressed, undergoes a
jamming phase transition with diverging length scales and clean power-law
signatures. This critical point is the cornerstone of a much larger "jamming
scenario" that has the potential to provide the essential theoretical
foundation necessary for a unified understanding of the mechanics of disordered
solids. We begin by showing that jammed sphere packings have a valid linear
regime despite the presence of "contact nonlinearities." We then investigate
the critical nature of the transition, focusing on diverging length scales and
finite-size effects. Next, we argue that jamming plays the same role for
disordered solids as the perfect crystal plays for crystalline solids. Not only
can it be considered an idealized starting point for understanding disordered
materials, but it can even influence systems that have a relatively high amount
of crystalline order. The behavior of solids can thus be thought of as existing
on a spectrum, with the perfect crystal and the jamming transition at opposing
ends. Finally, we introduce a new principle wherein the contribution of an
individual bond to one global property is independent of its contribution to
another. This principle allows the different global responses of a disordered
system to be manipulated independently and provides a great deal of flexibility
in designing materials with unique, textured and tunable properties.
AU - Goodrich, Carl Peter
ID - 7779
T2 - arXiv:1510.08820
TI - Unearthing the anticrystal: Criticality in the linear response of disordered solids
ER -
TY - CONF
AB - Several Hybrid Transactional Memory (HyTM) schemes have recently been proposed to complement the fast, but best-effort nature of Hardware Transactional Memory (HTM) with a slow, reliable software backup. However, the costs of providing concurrency between hardware and software transactions in HyTM are still not well understood. In this paper, we propose a general model for HyTM implementations, which captures the ability of hardware transactions to buffer memory accesses. The model allows us to formally quantify and analyze the amount of overhead (instrumentation) caused by the potential presence of software transactions.We prove that (1) it is impossible to build a strictly serializable HyTM implementation that has both uninstrumented reads and writes, even for very weak progress guarantees, and (2) the instrumentation cost incurred by a hardware transaction in any progressive opaque HyTM is linear in the size of the transaction’s data set.We further describe two implementations which exhibit optimal instrumentation costs for two different progress conditions. In sum, this paper proposes the first formal HyTM model and captures for the first time the trade-off between the degree of hardware-software TM concurrency and the amount of instrumentation overhead.
AU - Alistarh, Dan-Adrian
AU - Kopinsky, Justin
AU - Kuznetsov, Petr
AU - Ravi, Srivatsan
AU - Shavit, Nir
ID - 778
TI - Inherent limitations of hybrid transactional memory
VL - 9363
ER -
TY - CONF
AB - The concurrent memory reclamation problem is that of devising a way for a deallocating thread to verify that no other concurrent threads hold references to a memory block being deallocated. To date, in the absence of automatic garbage collection, there is no satisfactory solution to this problem; existing tracking methods like hazard pointers, reference counters, or epoch-based techniques like RCU, are either prohibitively expensive or require significant programming expertise, to the extent that implementing them efficiently can be worthy of a publication. None of the existing techniques are automatic or even semi-automated. In this paper, we take a new approach to concurrent memory reclamation: instead of manually tracking access to memory locations as done in techniques like hazard pointers, or restricting shared accesses to specific epoch boundaries as in RCU, our algorithm, called ThreadScan, leverages operating system signaling to automatically detect which memory locations are being accessed by concurrent threads. Initial empirical evidence shows that ThreadScan scales surprisingly well and requires negligible programming effort beyond the standard use of Malloc and Free.
AU - Alistarh, Dan-Adrian
AU - Matveev, Alexander
AU - Leiserson, William
AU - Shavit, Nir
ID - 779
TI - ThreadScan: Automatic and scalable memory reclamation
VL - 2015-June
ER -
TY - GEN
AB - We study conditions under which a finite simplicial complex $K$ can be mapped to $\mathbb R^d$ without higher-multiplicity intersections. An almost $r$-embedding is a map $f: K\to \mathbb R^d$ such that the images of any $r$
pairwise disjoint simplices of $K$ do not have a common point. We show that if $r$ is not a prime power and $d\geq 2r+1$, then there is a counterexample to the topological Tverberg conjecture, i.e., there is an almost $r$-embedding of
the $(d+1)(r-1)$-simplex in $\mathbb R^d$. This improves on previous constructions of counterexamples (for $d\geq 3r$) based on a series of papers by M. \"Ozaydin, M. Gromov, P. Blagojevi\'c, F. Frick, G. Ziegler, and the second and fourth present authors. The counterexamples are obtained by proving the following algebraic criterion in codimension 2: If $r\ge3$ and if $K$ is a finite $2(r-1)$-complex then there exists an almost $r$-embedding $K\to \mathbb R^{2r}$ if and only if there exists a general position PL map $f:K\to \mathbb R^{2r}$ such that the algebraic intersection number of the $f$-images of any $r$ pairwise disjoint simplices of $K$ is zero. This result can be restated in terms of cohomological obstructions or equivariant maps, and extends an analogous codimension 3 criterion by the second and fourth authors. As another application we classify ornaments $f:S^3 \sqcup S^3\sqcup S^3\to \mathbb R^5$ up to ornament
concordance. It follows from work of M. Freedman, V. Krushkal and P. Teichner that the analogous criterion for $r=2$ is false. We prove a lemma on singular higher-dimensional Borromean rings, yielding an elementary proof of the counterexample.
AU - Avvakumov, Sergey
AU - Mabillard, Isaac
AU - Skopenkov, A.
AU - Wagner, Uli
ID - 8183
T2 - arXiv
TI - Eliminating higher-multiplicity intersections, III. Codimension 2
ER -
TY - JOUR
AU - Einhorn, Lukas
AU - Fazekas, Judit
AU - Muhr, Martina
AU - Schoos, Alexandra
AU - Oida, Kumiko
AU - Singer, Josef
AU - Panakova, Lucia
AU - Manzano-Szalai, Krisztina
AU - Jensen-Jarolim, Erika
ID - 8242
IS - 2
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
TI - Generation of recombinant FcεRIα of dog, cat and horse for component-resolved allergy diagnosis in veterinary patients
VL - 135
ER -
TY - JOUR
AB - Interprocedural analysis is at the heart of numerous applications in programming languages, such as alias analysis, constant propagation, etc. Recursive state machines (RSMs) are standard models for interprocedural analysis. We consider a general framework with RSMs where the transitions are labeled from a semiring, and path properties are algebraic with semiring operations. RSMs with algebraic path properties can model interprocedural dataflow analysis problems, the shortest path problem, the most probable path problem, etc. The traditional algorithms for interprocedural analysis focus on path properties where the starting point is fixed as the entry point of a specific method. In this work, we consider possible multiple queries as required in many applications such as in alias analysis. The study of multiple queries allows us to bring in a very important algorithmic distinction between the resource usage of the one-time preprocessing vs for each individual query. The second aspect that we consider is that the control flow graphs for most programs have constant treewidth. Our main contributions are simple and implementable algorithms that supportmultiple queries for algebraic path properties for RSMs that have constant treewidth. Our theoretical results show that our algorithms have small additional one-time preprocessing, but can answer subsequent queries significantly faster as compared to the current best-known solutions for several important problems, such as interprocedural reachability and shortest path. We provide a prototype implementation for interprocedural reachability and intraprocedural shortest path that gives a significant speed-up on several benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
AU - Goyal, Prateesh
ID - 1602
IS - 1
JF - ACM SIGPLAN Notices
TI - Faster algorithms for algebraic path properties in recursive state machines with constant treewidth
VL - 50
ER -
TY - JOUR
AB - We consider the quantitative analysis problem for interprocedural control-flow graphs (ICFGs). The input consists of an ICFG, a positive weight function that assigns every transition a positive integer-valued number, and a labelling of the transitions (events) as good, bad, and neutral events. The weight function assigns to each transition a numerical value that represents ameasure of how good or bad an event is. The quantitative analysis problem asks whether there is a run of the ICFG where the ratio of the sum of the numerical weights of good events versus the sum of weights of bad events in the long-run is at least a given threshold (or equivalently, to compute the maximal ratio among all valid paths in the ICFG). The quantitative analysis problem for ICFGs can be solved in polynomial time, and we present an efficient and practical algorithm for the problem. We show that several problems relevant for static program analysis, such as estimating the worst-case execution time of a program or the average energy consumption of a mobile application, can be modeled in our framework. We have implemented our algorithm as a tool in the Java Soot framework. We demonstrate the effectiveness of our approach with two case studies. First, we show that our framework provides a sound approach (no false positives) for the analysis of inefficiently-used containers. Second, we show that our approach can also be used for static profiling of programs which reasons about methods that are frequently invoked. Our experimental results show that our tool scales to relatively large benchmarks, and discovers relevant and useful information that can be used to optimize performance of the programs.
AU - Chatterjee, Krishnendu
AU - Pavlogiannis, Andreas
AU - Velner, Yaron
ID - 1604
IS - 1
JF - Proceedings of the 42nd Annual ACM SIGPLAN-SIGACT
SN - 978-1-4503-3300-9
TI - Quantitative interprocedural analysis
VL - 50
ER -
TY - CONF
AB - We consider the core algorithmic problems related to verification of systems with respect to three classical quantitative properties, namely, the mean-payoff property, the ratio property, and the minimum initial credit for energy property. The algorithmic problem given a graph and a quantitative property asks to compute the optimal value (the infimum value over all traces) from every node of the graph. We consider graphs with constant treewidth, and it is well-known that the control-flow graphs of most programs have constant treewidth. Let n denote the number of nodes of a graph, m the number of edges (for constant treewidth graphs m=O(n)) and W the largest absolute value of the weights. Our main theoretical results are as follows. First, for constant treewidth graphs we present an algorithm that approximates the mean-payoff value within a multiplicative factor of ϵ in time O(n⋅log(n/ϵ)) and linear space, as compared to the classical algorithms that require quadratic time. Second, for the ratio property we present an algorithm that for constant treewidth graphs works in time O(n⋅log(|a⋅b|))=O(n⋅log(n⋅W)), when the output is ab, as compared to the previously best known algorithm with running time O(n2⋅log(n⋅W)). Third, for the minimum initial credit problem we show that (i) for general graphs the problem can be solved in O(n2⋅m) time and the associated decision problem can be solved in O(n⋅m) time, improving the previous known O(n3⋅m⋅log(n⋅W)) and O(n2⋅m) bounds, respectively; and (ii) for constant treewidth graphs we present an algorithm that requires O(n⋅logn) time, improving the previous known O(n4⋅log(n⋅W)) bound. We have implemented some of our algorithms and show that they present a significant speedup on standard benchmarks.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
AU - Pavlogiannis, Andreas
ID - 1607
TI - Faster algorithms for quantitative verification in constant treewidth graphs
VL - 9206
ER -
TY - CONF
AB - We present a flexible framework for the automated competitive analysis of on-line scheduling algorithms for firm-deadline real-time tasks based on multi-objective graphs: Given a task set and an on-line scheduling algorithm specified as a labeled transition system, along with some optional safety, liveness, and/or limit-average constraints for the adversary, we automatically compute the competitive ratio of the algorithm w.r.t. A clairvoyant scheduler. We demonstrate the flexibility and power of our approach by comparing the competitive ratio of several on-line algorithms, including Dover, that have been proposed in the past, for various task sets. Our experimental results reveal that none of these algorithms is universally optimal, in the sense that there are task sets where other schedulers provide better performance. Our framework is hence a very useful design tool for selecting optimal algorithms for a given application.
AU - Chatterjee, Krishnendu
AU - Pavlogiannis, Andreas
AU - Kößler, Alexander
AU - Schmid, Ulrich
ID - 1714
IS - January
T2 - Real-Time Systems Symposium
TI - A framework for automated competitive analysis of on-line scheduling of firm-deadline tasks
VL - 2015
ER -
TY - JOUR
AB - Plants maintain capacity to form new organs such as leaves, flowers, lateral shoots and roots throughout their postembryonic lifetime. Lateral roots (LRs) originate from a few pericycle cells that acquire attributes of founder cells (FCs), undergo series of anticlinal divisions, and give rise to a few short initial cells. After initiation, coordinated cell division and differentiation occur, giving rise to lateral root primordia (LRP). Primordia continue to grow, emerge through the cortex and epidermal layers of the primary root, and finally a new apical meristem is established taking over the responsibility for growth of mature lateral roots [for detailed description of the individual stages of lateral root organogenesis see Malamy and Benfey (1997)]. To examine this highly dynamic developmental process and to investigate a role of various hormonal, genetic and environmental factors in the regulation of lateral root organogenesis, the real time imaging based analyses represent extremely powerful tools (Laskowski et al., 2008; De Smet et al., 2012; Marhavy et al., 2013 and 2014). Herein, we describe a protocol for real time lateral root primordia (LRP) analysis, which enables the monitoring of an onset of the specific gene expression and subcellular protein localization during primordia organogenesis, as well as the evaluation of the impact of genetic and environmental perturbations on LRP organogenesis.
AU - Peter Marhavy
AU - Eva Benková
ID - 832
IS - 8
JF - Bio-protocol
TI - Real time analysis of lateral root organogenesis in arabidopsis
VL - 5
ER -
TY - JOUR
AB - The large majority of three-dimensional structures of biological macromolecules have been determined by X-ray diffraction of crystalline samples. High-resolution structure determination crucially depends on the homogeneity of the protein crystal. Overall ‘rocking’ motion of molecules in the crystal is expected to influence diffraction quality, and such motion may therefore affect the process of solving crystal structures. Yet, so far overall molecular motion has not directly been observed in protein crystals, and the timescale of such dynamics remains unclear. Here we use solid-state NMR, X-ray diffraction methods and μs-long molecular dynamics simulations to directly characterize the rigid-body motion of a protein in different crystal forms. For ubiquitin crystals investigated in this study we determine the range of possible correlation times of rocking motion, 0.1–100 μs. The amplitude of rocking varies from one crystal form to another and is correlated with the resolution obtainable in X-ray diffraction experiments.
AU - Ma, Peixiang
AU - Xue, Yi
AU - Coquelle, Nicolas
AU - Haller, Jens D.
AU - Yuwen, Tairan
AU - Ayala, Isabel
AU - Mikhailovskii, Oleg
AU - Willbold, Dieter
AU - Colletier, Jacques-Philippe
AU - Skrynnikov, Nikolai R.
AU - Schanda, Paul
ID - 8456
JF - Nature Communications
KW - General Biochemistry
KW - Genetics and Molecular Biology
KW - General Physics and Astronomy
KW - General Chemistry
SN - 2041-1723
TI - Observing the overall rocking motion of a protein in a crystal
VL - 6
ER -
TY - JOUR
AB - We review recent advances in methodologies to study microseconds‐to‐milliseconds exchange processes in biological molecules using magic‐angle spinning solid‐state nuclear magnetic resonance (MAS ssNMR) spectroscopy. The particularities of MAS ssNMR, as compared to solution‐state NMR, are elucidated using numerical simulations and experimental data. These simulations reveal the potential of MAS NMR to provide detailed insight into short‐lived conformations of biological molecules. Recent studies of conformational exchange dynamics in microcrystalline ubiquitin are discussed.
AU - Ma, Peixiang
AU - Schanda, Paul
ID - 8457
IS - 3
JF - eMagRes
SN - 9780470034590
TI - Conformational exchange processes in biological systems: Detection by solid-state NMR
VL - 4
ER -
TY - JOUR
AB - The nature of factors governing the tempo and mode of protein evolution is a fundamental issue in evolutionary biology. Specifically, whether or not interactions between different sites, or epistasis, are important in directing the course of evolution became one of the central questions. Several recent reports have scrutinized patterns of long-term protein evolution claiming them to be compatible only with an epistatic fitness landscape. However, these claims have not yet been substantiated with a formal model of protein evolution. Here, we formulate a simple covarion-like model of protein evolution focusing on the rate at which the fitness impact of amino acids at a site changes with time. We then apply the model to the data on convergent and divergent protein evolution to test whether or not the incorporation of epistatic interactions is necessary to explain the data. We find that convergent evolution cannot be explained without the incorporation of epistasis and the rate at which an amino acid state switches from being acceptable at a site to being deleterious is faster than the rate of amino acid substitution. Specifically, for proteins that have persisted in modern prokaryotic organisms since the last universal common ancestor for one amino acid substitution approximately ten amino acid states switch from being accessible to being deleterious, or vice versa. Thus, molecular evolution can only be perceived in the context of rapid turnover of which amino acids are available for evolution.
AU - Usmanova, Dinara
AU - Ferretti, Luca
AU - Povolotskaya, Inna
AU - Vlasov, Peter
AU - Kondrashov, Fyodor
ID - 848
IS - 2
JF - Molecular Biology and Evolution
TI - A model of substitution trajectories in sequence space and long-term protein evolution
VL - 32
ER -
TY - JOUR
AB - In this note, we consider the dynamics associated to a perturbation of an integrable Hamiltonian system in action-angle coordinates in any number of degrees of freedom and we prove the following result of ``micro-diffusion'': under generic assumptions on $ h$ and $ f$, there exists an orbit of the system for which the drift of its action variables is at least of order $ \sqrt {\varepsilon }$, after a time of order $ \sqrt {\varepsilon }^{-1}$. The assumptions, which are essentially minimal, are that there exists a resonant point for $ h$ and that the corresponding averaged perturbation is non-constant. The conclusions, although very weak when compared to usual instability phenomena, are also essentially optimal within this setting.
AU - Bounemoura, Abed
AU - Kaloshin, Vadim
ID - 8495
IS - 4
JF - Proceedings of the American Mathematical Society
SN - 0002-9939
TI - A note on micro-instability for Hamiltonian systems close to integrable
VL - 144
ER -
TY - JOUR
AB - In the present note we announce a proof of a strong form of Arnold diffusion for smooth convex Hamiltonian systems. Let ${\mathbb T}^2$ be a 2-dimensional torus and B2 be the unit ball around the origin in ${\mathbb R}^2$ . Fix ρ > 0. Our main result says that for a 'generic' time-periodic perturbation of an integrable system of two degrees of freedom $H_0(p)+\varepsilon H_1(\theta,p,t),\quad \ \theta\in {\mathbb T}^2,\ p\in B^2,\ t\in {\mathbb T}={\mathbb R}/{\mathbb Z}$ , with a strictly convex H0, there exists a ρ-dense orbit (θε, pε, t)(t) in ${\mathbb T}^2 \times B^2 \times {\mathbb T}$ , namely, a ρ-neighborhood of the orbit contains ${\mathbb T}^2 \times B^2 \times {\mathbb T}$ .
Our proof is a combination of geometric and variational methods. The fundamental elements of the construction are the usage of crumpled normally hyperbolic invariant cylinders from [9], flower and simple normally hyperbolic invariant manifolds from [36] as well as their kissing property at a strong double resonance. This allows us to build a 'connected' net of three-dimensional normally hyperbolic invariant manifolds. To construct diffusing orbits along this net we employ a version of the Mather variational method [41] equipped with weak KAM theory [28], proposed by Bernard in [7].
AU - Kaloshin, Vadim
AU - Zhang, K
ID - 8498
IS - 8
JF - Nonlinearity
KW - Mathematical Physics
KW - General Physics and Astronomy
KW - Applied Mathematics
KW - Statistical and Nonlinear Physics
SN - 0951-7715
TI - Arnold diffusion for smooth convex systems of two and a half degrees of freedom
VL - 28
ER -
TY - JOUR
AB - We consider the cubic defocusing nonlinear Schrödinger equation in the two dimensional torus. Fix s>1. Recently Colliander, Keel, Staffilani, Tao and Takaoka proved the existence of solutions with s-Sobolev norm growing in time.
We establish the existence of solutions with polynomial time estimates. More exactly, there is c>0 such that for any K≫1 we find a solution u and a time T such that ∥u(T)∥Hs≥K∥u(0)∥Hs. Moreover, the time T satisfies the polynomial bound 0