@phdthesis{1121, abstract = {Horizontal gene transfer (HGT), the lateral acquisition of genes across existing species boundaries, is a major evolutionary force shaping microbial genomes that facilitates adaptation to new environments as well as resistance to antimicrobial drugs. As such, understanding the mechanisms and constraints that determine the outcomes of HGT events is crucial to understand the dynamics of HGT and to design better strategies to overcome the challenges that originate from it. Following the insertion and expression of a newly transferred gene, the success of an HGT event will depend on the fitness effect it has on the recipient (host) cell. Therefore, predicting the impact of HGT on the genetic composition of a population critically depends on the distribution of fitness effects (DFE) of horizontally transferred genes. However, to date, we have little knowledge of the DFE of newly transferred genes, and hence little is known about the shape and scale of this distribution. It is particularly important to better understand the selective barriers that determine the fitness effects of newly transferred genes. In spite of substantial bioinformatics efforts to identify horizontally transferred genes and selective barriers, a systematic experimental approach to elucidate the roles of different selective barriers in defining the fate of a transfer event has largely been absent. Similarly, although the fact that environment might alter the fitness effect of a horizontally transferred gene may seem obvious, little attention has been given to it in a systematic experimental manner. In this study, we developed a systematic experimental approach that consists of transferring 44 arbitrarily selected Salmonella typhimurium orthologous genes into an Escherichia coli host, and estimating the fitness effects of these transferred genes at a constant expression level by performing competition assays against the wild type. In chapter 2, we performed one-to-one competition assays between a mutant strain carrying a transferred gene and the wild type strain. By using flow cytometry we estimated selection coefficients for the transferred genes with a precision level of 10-3,and obtained the DFE of horizontally transferred genes. We then investigated if these fitness effects could be predicted by any of the intrinsic properties of the genes, namely, functional category, degree of complexity (protein-protein interactions), GC content, codon usage and length. Our analyses revealed that the functional category and length of the genes act as potential selective barriers. Finally, using the same procedure with the endogenous E. coli orthologs of these 44 genes, we demonstrated that gene dosage is the most prominent selective barrier to HGT. In chapter 3, using the same set of genes we investigated the role of environment on the success of HGT events. Under six different environments with different levels of stress we performed more complex competition assays, where we mixed all 44 mutant strains carrying transferred genes with the wild type strain. To estimate the fitness effects of genes relative to wild type we used next generation sequencing. We found that the DFEs of horizontally transferred genes are highly dependent on the environment, with abundant gene–by-environment interactions. Furthermore, we demonstrated a relationship between average fitness effect of a gene across all environments and its environmental variance, and thus its predictability. Finally, in spite of the fitness effects of genes being highly environment-dependent, we still observed a common shape of DFEs across all tested environments.}, author = {Acar, Hande}, issn = {2663-337X}, pages = {75}, publisher = {Institute of Science and Technology Austria}, title = {{Selective barriers to horizontal gene transfer}}, year = {2016}, } @phdthesis{1122, abstract = {Computer graphics is an extremely exciting field for two reasons. On the one hand, there is a healthy injection of pragmatism coming from the visual effects industry that want robust algorithms that work so they can produce results at an increasingly frantic pace. On the other hand, they must always try to push the envelope and achieve the impossible to wow their audiences in the next blockbuster, which means that the industry has not succumb to conservatism, and there is plenty of room to try out new and crazy ideas if there is a chance that it will pan into something useful. Water simulation has been in visual effects for decades, however it still remains extremely challenging because of its high computational cost and difficult artdirectability. The work in this thesis tries to address some of these difficulties. Specifically, we make the following three novel contributions to the state-of-the-art in water simulation for visual effects. First, we develop the first algorithm that can convert any sequence of closed surfaces in time into a moving triangle mesh. State-of-the-art methods at the time could only handle surfaces with fixed connectivity, but we are the first to be able to handle surfaces that merge and split apart. This is important for water simulation practitioners, because it allows them to convert splashy water surfaces extracted from particles or simulated using grid-based level sets into triangle meshes that can be either textured and enhanced with extra surface dynamics as a post-process. We also apply our algorithm to other phenomena that merge and split apart, such as morphs and noisy reconstructions of human performances. Second, we formulate a surface-based energy that measures the deviation of a water surface froma physically valid state. Such discrepancies arise when there is a mismatch in the degrees of freedom between the water surface and the underlying physics solver. This commonly happens when practitioners use a moving triangle mesh with a grid-based physics solver, or when high-resolution grid-based surfaces are combined with low-resolution physics. Following the direction of steepest descent on our surface-based energy, we can either smooth these artifacts or turn them into high-resolution waves by interpreting the energy as a physical potential. Third, we extend state-of-the-art techniques in non-reflecting boundaries to handle spatially and time-varying background flows. This allows a novel new workflow where practitioners can re-simulate part of an existing simulation, such as removing a solid obstacle, adding a new splash or locally changing the resolution. Such changes can easily lead to new waves in the re-simulated region that would reflect off of the new simulation boundary, effectively ruining the illusion of a seamless simulation boundary between the existing and new simulations. Our non-reflecting boundaries makes sure that such waves are absorbed.}, author = {Bojsen-Hansen, Morten}, issn = {2663-337X}, pages = {114}, publisher = {Institute of Science and Technology Austria}, title = {{Tracking, correcting and absorbing water surface waves}}, doi = {10.15479/AT:ISTA:th_640}, year = {2016}, } @phdthesis{1123, abstract = {Motivated by topological Tverberg-type problems in topological combinatorics and by classical results about embeddings (maps without double points), we study the question whether a finite simplicial complex K can be mapped into Rd without triple, quadruple, or, more generally, r-fold points (image points with at least r distinct preimages), for a given multiplicity r ≤ 2. In particular, we are interested in maps f : K → Rd that have no global r -fold intersection points, i.e., no r -fold points with preimages in r pairwise disjoint simplices of K , and we seek necessary and sufficient conditions for the existence of such maps. We present higher-multiplicity analogues of several classical results for embeddings, in particular of the completeness of the Van Kampen obstruction for embeddability of k -dimensional complexes into R2k , k ≥ 3. Speciffically, we show that under suitable restrictions on the dimensions(viz., if dimK = (r ≥ 1)k and d = rk \ for some k ≥ 3), a well-known deleted product criterion (DPC ) is not only necessary but also sufficient for the existence of maps without global r -fold points. Our main technical tool is a higher-multiplicity version of the classical Whitney trick , by which pairs of isolated r -fold points of opposite sign can be eliminated by local modiffications of the map, assuming codimension d – dimK ≥ 3. An important guiding idea for our work was that suffciency of the DPC, together with an old result of Özaydin's on the existence of equivariant maps, might yield an approach to disproving the remaining open cases of the the long-standing topological Tverberg conjecture , i.e., to construct maps from the N -simplex σN to Rd without r-Tverberg points when r not a prime power and N = (d + 1)(r – 1). Unfortunately, our proof of the sufficiency of the DPC requires codimension d – dimK ≥ 3, which is not satisfied for K = σN . In 2015, Frick [16] found a very elegant way to overcome this \codimension 3 obstacle" and to construct the first counterexamples to the topological Tverberg conjecture for all parameters(d; r ) with d ≥ 3r + 1 and r not a prime power, by a reduction1 to a suitable lower-dimensional skeleton, for which the codimension 3 restriction is satisfied and maps without r -Tverberg points exist by Özaydin's result and sufficiency of the DPC. In this thesis, we present a different construction (which does not use the constraint method) that yields counterexamples for d ≥ 3r , r not a prime power. }, author = {Mabillard, Isaac}, issn = {2663-337X}, pages = {55}, publisher = {Institute of Science and Technology Austria}, title = {{Eliminating higher-multiplicity intersections: an r-fold Whitney trick for the topological Tverberg conjecture}}, year = {2016}, } @phdthesis{1124, author = {Morri, Maurizio}, issn = {2663-337X}, pages = {129}, publisher = {Institute of Science and Technology Austria}, title = {{Optical functionalization of human class A orphan G-protein coupled receptors}}, year = {2016}, } @phdthesis{1125, abstract = {Natural environments are never constant but subject to spatial and temporal change on all scales, increasingly so due to human activity. Hence, it is crucial to understand the impact of environmental variation on evolutionary processes. In this thesis, I present three topics that share the common theme of environmental variation, yet illustrate its effect from different perspectives. First, I show how a temporally fluctuating environment gives rise to second-order selection on a modifier for stress-induced mutagenesis. Without fluctuations, when populations are adapted to their environment, mutation rates are minimized. I argue that a stress-induced mutator mechanism may only be maintained if the population is repeatedly subjected to diverse environmental challenges, and I outline implications of the presented results to antibiotic treatment strategies. Second, I discuss my work on the evolution of dispersal. Besides reproducing known results about the effect of heterogeneous habitats on dispersal, it identifies spatial changes in dispersal type frequencies as a source for selection for increased propensities to disperse. This concept contains effects of relatedness that are known to promote dispersal, and I explain how it identifies other forces selecting for dispersal and puts them on a common scale. Third, I analyse genetic variances of phenotypic traits under multivariate stabilizing selection. For the case of constant environments, I generalize known formulae of equilibrium variances to multiple traits and discuss how the genetic variance of a focal trait is influenced by selection on background traits. I conclude by presenting ideas and preliminary work aiming at including environmental fluctuations in the form of moving trait optima into the model.}, author = {Novak, Sebastian}, issn = {2663-337X}, pages = {124}, publisher = {Institute of Science and Technology Austria}, title = {{Evolutionary proccesses in variable emvironments}}, year = {2016}, } @phdthesis{1126, abstract = {Traditionally machine learning has been focusing on the problem of solving a single task in isolation. While being quite well understood, this approach disregards an important aspect of human learning: when facing a new problem, humans are able to exploit knowledge acquired from previously learned tasks. Intuitively, access to several problems simultaneously or sequentially could also be advantageous for a machine learning system, especially if these tasks are closely related. Indeed, results of many empirical studies have provided justification for this intuition. However, theoretical justifications of this idea are rather limited. The focus of this thesis is to expand the understanding of potential benefits of information transfer between several related learning problems. We provide theoretical analysis for three scenarios of multi-task learning - multiple kernel learning, sequential learning and active task selection. We also provide a PAC-Bayesian perspective on lifelong learning and investigate how the task generation process influences the generalization guarantees in this scenario. In addition, we show how some of the obtained theoretical results can be used to derive principled multi-task and lifelong learning algorithms and illustrate their performance on various synthetic and real-world datasets.}, author = {Pentina, Anastasia}, issn = {2663-337X}, pages = {127}, publisher = {Institute of Science and Technology Austria}, title = {{Theoretical foundations of multi-task lifelong learning}}, doi = {10.15479/AT:ISTA:TH_776}, year = {2016}, } @phdthesis{1128, abstract = {The process of gene expression is central to the modern understanding of how cellular systems function. In this process, a special kind of regulatory proteins, called transcription factors, are important to determine how much protein is produced from a given gene. As biological information is transmitted from transcription factor concentration to mRNA levels to amounts of protein, various sources of noise arise and pose limits to the fidelity of intracellular signaling. This thesis concerns itself with several aspects of stochastic gene expression: (i) the mathematical description of complex promoters responsible for the stochastic production of biomolecules, (ii) fundamental limits to information processing the cell faces due to the interference from multiple fluctuating signals, (iii) how the presence of gene expression noise influences the evolution of regulatory sequences, (iv) and tools for the experimental study of origins and consequences of cell-cell heterogeneity, including an application to bacterial stress response systems.}, author = {Rieckh, Georg}, issn = {2663-337X}, pages = {114}, publisher = {Institute of Science and Technology Austria}, title = {{Studying the complexities of transcriptional regulation}}, year = {2016}, } @phdthesis{1129, abstract = {Directed cell migration is a hallmark feature, present in almost all multi-cellular organisms. Despite its importance, basic questions regarding force transduction or directional sensing are still heavily investigated. Directed migration of cells guided by immobilized guidance cues - haptotaxis - occurs in key-processes, such as embryonic development and immunity (Middleton et al., 1997; Nguyen et al., 2000; Thiery, 1984; Weber et al., 2013). Immobilized guidance cues comprise adhesive ligands, such as collagen and fibronectin (Barczyk et al., 2009), or chemokines - the main guidance cues for migratory leukocytes (Middleton et al., 1997; Weber et al., 2013). While adhesive ligands serve as attachment sites guiding cell migration (Carter, 1965), chemokines instruct haptotactic migration by inducing adhesion to adhesive ligands and directional guidance (Rot and Andrian, 2004; Schumann et al., 2010). Quantitative analysis of the cellular response to immobilized guidance cues requires in vitro assays that foster cell migration, offer accurate control of the immobilized cues on a subcellular scale and in the ideal case closely reproduce in vivo conditions. The exploration of haptotactic cell migration through design and employment of such assays represents the main focus of this work. Dendritic cells (DCs) are leukocytes, which after encountering danger signals such as pathogens in peripheral organs instruct naïve T-cells and consequently the adaptive immune response in the lymph node (Mellman and Steinman, 2001). To reach the lymph node from the periphery, DCs follow haptotactic gradients of the chemokine CCL21 towards lymphatic vessels (Weber et al., 2013). Questions about how DCs interpret haptotactic CCL21 gradients have not yet been addressed. The main reason for this is the lack of an assay that offers diverse haptotactic environments, hence allowing the study of DC migration as a response to different signals of immobilized guidance cue. In this work, we developed an in vitro assay that enables us to quantitatively assess DC haptotaxis, by combining precisely controllable chemokine photo-patterning with physically confining migration conditions. With this tool at hand, we studied the influence of CCL21 gradient properties and concentration on DC haptotaxis. We found that haptotactic gradient sensing depends on the absolute CCL21 concentration in combination with the local steepness of the gradient. Our analysis suggests that the directionality of migrating DCs is governed by the signal-to-noise ratio of CCL21 binding to its receptor CCR7. Moreover, the haptotactic CCL21 gradient formed in vivo provides an optimal shape for DCs to recognize haptotactic guidance cue. By reconstitution of the CCL21 gradient in vitro we were also able to study the influence of CCR7 signal termination on DC haptotaxis. To this end, we used DCs lacking the G-protein coupled receptor kinase GRK6, which is responsible for CCL21 induced CCR7 receptor phosphorylation and desensitization (Zidar et al., 2009). We found that CCR7 desensitization by GRK6 is crucial for maintenance of haptotactic CCL21 gradient sensing in vitro and confirm those observations in vivo. In the context of the organism, immobilized haptotactic guidance cues often coincide and compete with soluble chemotactic guidance cues. During wound healing, fibroblasts are exposed and influenced by adhesive cues and soluble factors at the same time (Wu et al., 2012; Wynn, 2008). Similarly, migrating DCs are exposed to both, soluble chemokines (CCL19 and truncated CCL21) inducing chemotactic behavior as well as the immobilized CCL21. To quantitatively assess these complex coinciding immobilized and soluble guidance cues, we implemented our chemokine photo-patterning technique in a microfluidic system allowing for chemotactic gradient generation. To validate the assay, we observed DC migration in competing CCL19/CCL21 environments. Adhesiveness guided haptotaxis has been studied intensively over the last century. However, quantitative studies leading to conceptual models are largely missing, again due to the lack of a precisely controllable in vitro assay. A requirement for such an in vitro assay is that it must prevent any uncontrolled cell adhesion. This can be accomplished by stable passivation of the surface. In addition, controlled adhesion must be sustainable, quantifiable and dose dependent in order to create homogenous gradients. Therefore, we developed a novel covalent photo-patterning technique satisfying all these needs. In combination with a sustainable poly-vinyl alcohol (PVA) surface coating we were able to generate gradients of adhesive cue to direct cell migration. This approach allowed us to characterize the haptotactic migratory behavior of zebrafish keratocytes in vitro. Furthermore, defined patterns of adhesive cue allowed us to control for cell shape and growth on a subcellular scale.}, author = {Schwarz, Jan}, issn = {2663-337X}, pages = {178}, publisher = {Institute of Science and Technology Austria}, title = {{Quantitative analysis of haptotactic cell migration}}, year = {2016}, } @phdthesis{1130, abstract = {In this thesis we present a computer-aided programming approach to concurrency. Our approach helps the programmer by automatically fixing concurrency-related bugs, i.e. bugs that occur when the program is executed using an aggressive preemptive scheduler, but not when using a non-preemptive (cooperative) scheduler. Bugs are program behaviours that are incorrect w.r.t. a specification. We consider both user-provided explicit specifications in the form of assertion statements in the code as well as an implicit specification. The implicit specification is inferred from the non-preemptive behaviour. Let us consider sequences of calls that the program makes to an external interface. The implicit specification requires that any such sequence produced under a preemptive scheduler should be included in the set of sequences produced under a non-preemptive scheduler. We consider several semantics-preserving fixes that go beyond atomic sections typically explored in the synchronisation synthesis literature. Our synthesis is able to place locks, barriers and wait-signal statements and last, but not least reorder independent statements. The latter may be useful if a thread is released to early, e.g., before some initialisation is completed. We guarantee that our synthesis does not introduce deadlocks and that the synchronisation inserted is optimal w.r.t. a given objective function. We dub our solution trace-based synchronisation synthesis and it is loosely based on counterexample-guided inductive synthesis (CEGIS). The synthesis works by discovering a trace that is incorrect w.r.t. the specification and identifying ordering constraints crucial to trigger the specification violation. Synchronisation may be placed immediately (greedy approach) or delayed until all incorrect traces are found (non-greedy approach). For the non-greedy approach we construct a set of global constraints over synchronisation placements. Each model of the global constraints set corresponds to a correctness-ensuring synchronisation placement. The placement that is optimal w.r.t. the given objective function is chosen as the synchronisation solution. We evaluate our approach on a number of realistic (albeit simplified) Linux device-driver benchmarks. The benchmarks are versions of the drivers with known concurrency-related bugs. For the experiments with an explicit specification we added assertions that would detect the bugs in the experiments. Device drivers lend themselves to implicit specification, where the device and the operating system are the external interfaces. Our experiments demonstrate that our synthesis method is precise and efficient. We implemented objective functions for coarse-grained and fine-grained locking and observed that different synchronisation placements are produced for our experiments, favouring e.g. a minimal number of synchronisation operations or maximum concurrency.}, author = {Tarrach, Thorsten}, issn = {2663-337X}, pages = {151}, publisher = {Institute of Science and Technology Austria}, title = {{Automatic synthesis of synchronisation primitives for concurrent programs}}, doi = {10.15479/at:ista:1130}, year = {2016}, } @phdthesis{1131, abstract = {Evolution of gene regulation is important for phenotypic evolution and diversity. Sequence-specific binding of regulatory proteins is one of the key regulatory mechanisms determining gene expression. Although there has been intense interest in evolution of regulatory binding sites in the last decades, a theoretical understanding is far from being complete. In this thesis, I aim at a better understanding of the evolution of transcriptional regulatory binding sequences by using biophysical and population genetic models. In the first part of the thesis, I discuss how to formulate the evolutionary dynamics of binding se- quences in a single isolated binding site and in promoter/enhancer regions. I develop a theoretical framework bridging between a thermodynamical model for transcription and a mutation-selection-drift model for monomorphic populations. I mainly address the typical evolutionary rates, and how they de- pend on biophysical parameters (e.g. binding length and specificity) and population genetic parameters (e.g. population size and selection strength). In the second part of the thesis, I analyse empirical data for a better evolutionary and biophysical understanding of sequence-specific binding of bacterial RNA polymerase. First, I infer selection on regulatory and non-regulatory binding sites of RNA polymerase in the E. coli K12 genome. Second, I infer the chemical potential of RNA polymerase, an important but unknown physical parameter defining the threshold energy for strong binding. Furthermore, I try to understand the relation between the lac promoter sequence diversity and the LacZ activity variation among 20 bacterial isolates by constructing a simple but biophysically motivated gene expression model. Lastly, I lay out a statistical framework to predict adaptive point mutations in de novo promoter evolution in a selection experiment.}, author = {Tugrul, Murat}, issn = {2663-337X}, pages = {89}, publisher = {Institute of Science and Technology Austria}, title = {{Evolution of transcriptional regulatory sequences}}, year = {2016}, } @inproceedings{1134, abstract = {Hybrid systems have both continuous and discrete dynamics and are useful for modeling a variety of control systems, from air traffic control protocols to robotic maneuvers and beyond. Recently, numerous powerful and scalable tools for analyzing hybrid systems have emerged. Several of these tools implement automated formal methods for mathematically proving a system meets a specification. This tutorial session will present three recent hybrid systems tools: C2E2, HyST, and TuLiP. C2E2 is a simulated-based verification tool for hybrid systems, and uses validated numerical solvers and bloating of simulation traces to verify systems meet specifications. HyST is a hybrid systems model transformation and translation tool, and uses a canonical intermediate representation to support most of the recent verification tools, as well as automated sound abstractions that simplify verification of a given hybrid system. TuLiP is a controller synthesis tool for hybrid systems, where given a temporal logic specification to be satisfied for a system (plant) model, TuLiP will find a controller that meets a given specification. © 2016 IEEE.}, author = {Duggirala, Parasara and Fan, Chuchu and Potok, Matthew and Qi, Bolun and Mitra, Sayan and Viswanathan, Mahesh and Bak, Stanley and Bogomolov, Sergiy and Johnson, Taylor and Nguyen, Luan and Schilling, Christian and Sogokon, Andrew and Tran, Hoang and Xiang, Weiming}, booktitle = {2016 IEEE Conference on Control Applications}, location = {Buenos Aires, Argentina }, publisher = {IEEE}, title = {{Tutorial: Software tools for hybrid systems verification transformation and synthesis C2E2 HyST and TuLiP}}, doi = {10.1109/CCA.2016.7587948}, year = {2016}, } @inproceedings{1135, abstract = {Time-triggered (TT) switched networks are a deterministic communication infrastructure used by real-time distributed embedded systems. These networks rely on the notion of globally discretized time (i.e. time slots) and a static TT schedule that prescribes which message is sent through which link at every time slot, such that all messages reach their destination before a global timeout. These schedules are generated offline, assuming a static network with fault-free links, and entrusting all error-handling functions to the end user. Assuming the network is static is an over-optimistic view, and indeed links tend to fail in practice. We study synthesis of TT schedules on a network in which links fail over time and we assume the switches run a very simple error-recovery protocol once they detect a crashed link. We address the problem of finding a pk; qresistant schedule; namely, one that, assuming the switches run a fixed error-recovery protocol, guarantees that the number of messages that arrive at their destination by the timeout is at least no matter what sequence of at most k links fail. Thus, we maintain the simplicity of the switches while giving a guarantee on the number of messages that meet the timeout. We show how a pk; q-resistant schedule can be obtained using a CEGAR-like approach: find a schedule, decide whether it is pk; q-resistant, and if it is not, use the witnessing fault sequence to generate a constraint that is added to the program. The newly added constraint disallows the schedule to be regenerated in a future iteration while also eliminating several other schedules that are not pk; q-resistant. We illustrate the applicability of our approach using an SMT-based implementation. © 2016 ACM.}, author = {Avni, Guy and Guha, Shibashis and Rodríguez Navas, Guillermo}, booktitle = {Proceedings of the 13th International Conference on Embedded Software }, location = {Pittsburgh, PA, USA}, publisher = {ACM}, title = {{Synthesizing time triggered schedules for switched networks with faulty links}}, doi = {10.1145/2968478.2968499}, year = {2016}, } @inproceedings{1136, abstract = {We propose an interactive sculpting system for seamlessly editing pre-computed animations of liquid, without the need for any resimulation. The input is a sequence of meshes without correspondences representing the liquid surface over time. Our method enables the efficient selection of consistent space-time parts of this animation, such as moving waves or droplets, which we call space-time features. Once selected, a feature can be copied, edited, or duplicated and then pasted back anywhere in space and time in the same or in another liquid animation sequence. Our method circumvents tedious user interactions by automatically computing the spatial and temporal ranges of the selected feature. We also provide space-time shape editing tools for non-uniform scaling, rotation, trajectory changes, and temporal editing to locally speed up or slow down motion. Using our tools, the user can edit and progressively refine any input simulation result, possibly using a library of precomputed space-time features extracted from other animations. In contrast to the trial-and-error loop usually required to edit animation results through the tuning of indirect simulation parameters, our method gives the user full control over the edited space-time behaviors. © 2016 Copyright held by the owner/author(s).}, author = {Manteaux, Pierre and Vimont, Ulysse and Wojtan, Christopher J and Rohmer, Damien and Cani, Marie}, booktitle = {Proceedings of the 9th International Conference on Motion in Games }, location = {San Francisco, CA, USA}, publisher = {ACM}, title = {{Space-time sculpting of liquid animation}}, doi = {10.1145/2994258.2994261}, year = {2016}, } @article{1137, abstract = {RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.}, author = {Salzer, Elisabeth and Çaǧdaş, Deniz and Hons, Miroslav and Mace, Emily and Garncarz, Wojciech and Petronczki, Oezlem and Platzer, René and Pfajfer, Laurène and Bilic, Ivan and Ban, Sol and Willmann, Katharina and Mukherjee, Malini and Supper, Verena and Hsu, Hsiangting and Banerjee, Pinaki and Sinha, Papiya and Mcclanahan, Fabienne and Zlabinger, Gerhard and Pickl, Winfried and Gribben, John and Stockinger, Hannes and Bennett, Keiryn and Huppa, Johannes and Dupré, Loï̈C and Sanal, Özden and Jäger, Ulrich and Sixt, Michael K and Tezcan, Ilhan and Orange, Jordan and Boztug, Kaan}, journal = {Nature Immunology}, number = {12}, pages = {1352 -- 1360}, publisher = {Nature Publishing Group}, title = {{RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics}}, doi = {10.1038/ni.3575}, volume = {17}, year = {2016}, } @inproceedings{1138, abstract = {Automata with monitor counters, where the transitions do not depend on counter values, and nested weighted automata are two expressive automata-theoretic frameworks for quantitative properties. For a well-studied and wide class of quantitative functions, we establish that automata with monitor counters and nested weighted automata are equivalent. We study for the first time such quantitative automata under probabilistic semantics. We show that several problems that are undecidable for the classical questions of emptiness and universality become decidable under the probabilistic semantics. We present a complete picture of decidability for such automata, and even an almost-complete picture of computational complexity, for the probabilistic questions we consider. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Henzinger, Thomas A and Otop, Jan}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium}, location = {New York, NY, USA}, pages = {76 -- 85}, publisher = {IEEE}, title = {{Quantitative automata under probabilistic semantics}}, doi = {10.1145/2933575.2933588}, year = {2016}, } @article{1139, abstract = {Microtubules switch stochastically between phases of growth and shrinkage. The molecular mechanism responsible for the end of a growth phase, an event called catastrophe, is still not understood. The probability for a catastrophe to occur increases with microtubule age, putting constraints on the possible molecular mechanism of catastrophe induction. Here we used microfluidics-Assisted fast tubulin washout experiments to induce microtubule depolymerization in a controlled manner at different times after the start of growth. We found that aging can also be observed in this assay, providing valuable new constraints against which theoretical models of catastrophe induction can be tested. We found that the data can be quantitatively well explained by a simple kinetic threshold model that assumes an age-dependent broadening of the protective cap at the microtubule end as a result of an evolving tapered end structure; this leads to a decrease of the cap density and its stability. This analysis suggests an intuitive picture of the role of morphological changes of the protective cap for the age dependence of microtubule stability.}, author = {Düllberg, Christian F and Cade, Nicholas and Surrey, Thomas}, journal = {Molecular Biology and Evolution}, number = {22}, pages = {3563 -- 3573}, publisher = {Oxford University Press}, title = {{Microtubule aging probed by microfluidics assisted tubulin washout}}, doi = {10.1091/mbc.E16-07-0548}, volume = {27}, year = {2016}, } @inproceedings{1140, abstract = {Given a model of a system and an objective, the model-checking question asks whether the model satisfies the objective. We study polynomial-time problems in two classical models, graphs and Markov Decision Processes (MDPs), with respect to several fundamental -regular objectives, e.g., Rabin and Streett objectives. For many of these problems the best-known upper bounds are quadratic or cubic, yet no super-linear lower bounds are known. In this work our contributions are two-fold: First, we present several improved algorithms, and second, we present the first conditional super-linear lower bounds based on widely believed assumptions about the complexity of CNF-SAT and combinatorial Boolean matrix multiplication. A separation result for two models with respect to an objective means a conditional lower bound for one model that is strictly higher than the existing upper bound for the other model, and similarly for two objectives with respect to a model. Our results establish the following separation results: (1) A separation of models (graphs and MDPs) for disjunctive queries of reachability and Büchi objectives. (2) Two kinds of separations of objectives, both for graphs and MDPs, namely, (2a) the separation of dual objectives such as Streett/Rabin objectives, and (2b) the separation of conjunction and disjunction of multiple objectives of the same type such as safety, Büchi, and coBüchi. In summary, our results establish the first model and objective separation results for graphs and MDPs for various classical -regular objectives. Quite strikingly, we establish conditional lower bounds for the disjunction of objectives that are strictly higher than the existing upper bounds for the conjunction of the same objectives. © 2016 ACM.}, author = {Chatterjee, Krishnendu and Dvoák, Wolfgang and Henzinger, Monika H and Loitzenbauer, Veronika}, booktitle = {Proceedings of the 31st Annual ACM/IEEE Symposium on Logic in Computer Science}, location = {New York, NY, USA}, pages = {197 -- 206}, publisher = {IEEE}, title = {{Model and objective separation with conditional lower bounds: disjunction is harder than conjunction}}, doi = {10.1145/2933575.2935304}, year = {2016}, } @article{1141, abstract = {In this paper we introduce the Multiobjective Optimization Hierarchic Genetic Strategy with maturing (MO-mHGS), a meta-algorithm that performs evolutionary optimization in a hierarchy of populations. The maturing mechanism improves growth and reduces redundancy. The performance of MO-mHGS with selected state-of-the-art multiobjective evolutionary algorithms as internal algorithms is analysed on benchmark problems and their modifications for which single fitness evaluation time depends on the solution accuracy. We compare the proposed algorithm with the Island Model Genetic Algorithm as well as with single-deme methods, and discuss the impact of internal algorithms on the MO-mHGS meta-algorithm. © 2016 Elsevier B.V.}, author = {Łazarz, Radosław and Idzik, Michał and Gądek, Konrad and Gajda-Zagorska, Ewa P}, journal = {Journal of Computational Science}, number = {1}, pages = {249 -- 260}, publisher = {Elsevier}, title = {{Hierarchic genetic strategy with maturing as a generic tool for multiobjective optimization}}, doi = {10.1016/j.jocs.2016.03.004}, volume = {17}, year = {2016}, } @article{1142, abstract = {Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.}, author = {Martins, Rui and Maier, Julia and Gorki, Anna and Huber, Kilian and Sharif, Omar and Starkl, Philipp and Saluzzo, Simona and Quattrone, Federica and Gawish, Riem and Lakovits, Karin and Aichinger, Michael and Radic Sarikas, Branka and Lardeau, Charles and Hladik, Anastasiya and Korosec, Ana and Brown, Markus and Vaahtomeri, Kari and Duggan, Michelle and Kerjaschki, Dontscho and Esterbauer, Harald and Colinge, Jacques and Eisenbarth, Stephanie and Decker, Thomas and Bennett, Keiryn and Kubicek, Stefan and Sixt, Michael K and Superti Furga, Giulio and Knapp, Sylvia}, journal = {Nature Immunology}, number = {12}, pages = {1361 -- 1372}, publisher = {Nature Publishing Group}, title = {{Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions}}, doi = {10.1038/ni.3590}, volume = {17}, year = {2016}, } @article{1143, abstract = {We study the ground state of a dilute Bose gas in a scaling limit where the Gross-Pitaevskii functional emerges. This is a repulsive nonlinear Schrödinger functional whose quartic term is proportional to the scattering length of the interparticle interaction potential. We propose a new derivation of this limit problem, with a method that bypasses some of the technical difficulties that previous derivations had to face. The new method is based on a combination of Dyson\'s lemma, the quantum de Finetti theorem and a second moment estimate for ground states of the effective Dyson Hamiltonian. It applies equally well to the case where magnetic fields or rotation are present.}, author = {Nam, Phan and Rougerie, Nicolas and Seiringer, Robert}, journal = {Analysis and PDE}, number = {2}, pages = {459 -- 485}, publisher = {Mathematical Sciences Publishers}, title = {{Ground states of large bosonic systems: The gross Pitaevskii limit revisited}}, doi = {10.2140/apde.2016.9.459}, volume = {9}, year = {2016}, }