TY - JOUR AB - Proton-translocating transhydrogenase (also known as nicotinamide nucleotide transhydrogenase (NNT)) is found in the plasma membranes of bacteria and the inner mitochondrial membranes of eukaryotes. NNT catalyses the transfer of a hydride between NADH and NADP+, coupled to the translocation of one proton across the membrane. Its main physiological function is the generation of NADPH, which is a substrate in anabolic reactions and a regulator of oxidative status; however, NNT may also fine-tune the Krebs cycle1,2. NNT deficiency causes familial glucocorticoid deficiency in humans and metabolic abnormalities in mice, similar to those observed in type II diabetes3,4. The catalytic mechanism of NNT has been proposed to involve a rotation of around 180° of the entire NADP(H)-binding domain that alternately participates in hydride transfer and proton-channel gating. However, owing to the lack of high-resolution structures of intact NNT, the details of this process remain unclear5,6. Here we present the cryo-electron microscopy structure of intact mammalian NNT in different conformational states. We show how the NADP(H)-binding domain opens the proton channel to the opposite sides of the membrane, and we provide structures of these two states. We also describe the catalytically important interfaces and linkers between the membrane and the soluble domains and their roles in nucleotide exchange. These structures enable us to propose a revised mechanism for a coupling process in NNT that is consistent with a large body of previous biochemical work. Our results are relevant to the development of currently unavailable NNT inhibitors, which may have therapeutic potential in ischaemia reperfusion injury, metabolic syndrome and some cancers7,8,9. AU - Kampjut, Domen AU - Sazanov, Leonid A ID - 6848 IS - 7773 JF - Nature SN - 0028-0836 TI - Structure and mechanism of mitochondrial proton-translocating transhydrogenase VL - 573 ER - TY - JOUR AB - Grid cells with their rigid hexagonal firing fields are thought to provide an invariant metric to the hippocampal cognitive map, yet environmental geometrical features have recently been shown to distort the grid structure. Given that the hippocampal role goes beyond space, we tested the influence of nonspatial information on the grid organization. We trained rats to daily learn three new reward locations on a cheeseboard maze while recording from the medial entorhinal cortex and the hippocampal CA1 region. Many grid fields moved toward goal location, leading to long-lasting deformations of the entorhinal map. Therefore, distortions in the grid structure contribute to goal representation during both learning and recall, which demonstrates that grid cells participate in mnemonic coding and do not merely provide a simple metric of space. AU - Boccara, Charlotte N. AU - Nardin, Michele AU - Stella, Federico AU - O'Neill, Joseph AU - Csicsvari, Jozsef L ID - 6194 IS - 6434 JF - Science SN - 0036-8075 TI - The entorhinal cognitive map is attracted to goals VL - 363 ER - TY - THES AB - A major challenge in neuroscience research is to dissect the circuits that orchestrate behavior in health and disease. Proteins from a wide range of non-mammalian species, such as microbial opsins, have been successfully transplanted to specific neuronal targets to override their natural communication patterns. The goal of our work is to manipulate synaptic communication in a manner that closely incorporates the functional intricacies of synapses by preserving temporal encoding (i.e. the firing pattern of the presynaptic neuron) and connectivity (i.e. target specific synapses rather than specific neurons). Our strategy to achieve this goal builds on the use of non-mammalian transplants to create a synthetic synapse. The mode of modulation comes from pre-synaptic uptake of a synthetic neurotransmitter (SN) into synaptic vesicles by means of a genetically targeted transporter selective for the SN. Upon natural vesicular release, exposure of the SN to the synaptic cleft will modify the post-synaptic potential through an orthogonal ligand gated ion channel. To achieve this goal we have functionally characterized a mixed cationic methionine-gated ion channel from Arabidopsis thaliana, designed a method to functionally characterize a synthetic transporter in isolated synaptic vesicles without the need for transgenic animals, identified and extracted multiple prokaryotic uptake systems that are substrate specific for methionine (Met), and established a primary/cell line co-culture system that would allow future combinatorial testing of this orthogonal transmitter-transporter-channel trifecta. Synthetic synapses will provide a unique opportunity to manipulate synaptic communication while maintaining the electrophysiological integrity of the pre-synaptic cell. In this way, information may be preserved that was generated in upstream circuits and that could be essential for concerted function and information processing. AU - Mckenzie, Catherine ID - 7132 SN - 2663-337X TI - Design and characterization of methods and biological components to realize synthetic neurotransmission ER - TY - JOUR AB - Aberrant proteostasis of protein aggregation may lead to behavior disorders including chronic mental illnesses (CMI). Furthermore, the neuronal activity alterations that underlie CMI are not well understood. We recorded the local field potential and single-unit activity of the hippocampal CA1 region in vivo in rats transgenically overexpressing the Disrupted-in-Schizophrenia 1 (DISC1) gene (tgDISC1), modeling sporadic CMI. These tgDISC1 rats have previously been shown to exhibit DISC1 protein aggregation, disturbances in the dopaminergic system and attention-related deficits. Recordings were performed during exploration of familiar and novel open field environments and during sleep, allowing investigation of neuronal abnormalities in unconstrained behavior. Compared to controls, tgDISC1 place cells exhibited smaller place fields and decreased speed-modulation of their firing rates, demonstrating altered spatial coding and deficits in encoding location-independent sensory inputs. Oscillation analyses showed that tgDISC1 pyramidal neurons had higher theta phase locking strength during novelty, limiting their phase coding ability. However, their mean theta phases were more variable at the population level, reducing oscillatory network synchronization. Finally, tgDISC1 pyramidal neurons showed a lack of novelty-induced shift in their preferred theta and gamma firing phases, indicating deficits in coding of novel environments with oscillatory firing. By combining single cell and neuronal population analyses, we link DISC1 protein pathology with abnormal hippocampal neural coding and network synchrony, and thereby gain a more comprehensive understanding of CMI mechanisms. AU - Käfer, Karola AU - Malagon-Vina, Hugo AU - Dickerson, Desiree AU - O'Neill, Joseph AU - Trossbach, Svenja V. AU - Korth, Carsten AU - Csicsvari, Jozsef L ID - 5949 IS - 9 JF - Hippocampus TI - Disrupted-in-schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization VL - 29 ER - TY - THES AB - The solving of complex tasks requires the functions of more than one brain area and their interaction. Whilst spatial navigation and memory is dependent on the hippocampus, flexible behavior relies on the medial prefrontal cortex (mPFC). To further examine the roles of the hippocampus and mPFC, we recorded their neural activity during a task that depends on both of these brain regions. With tetrodes, we recorded the extracellular activity of dorsal hippocampal CA1 (HPC) and mPFC neurons in Long-Evans rats performing a rule-switching task on the plus-maze. The plus-maze task had a spatial component since it required navigation along one of the two start arms and at the maze center a choice between one of the two goal arms. Which goal contained a reward depended on the rule currently in place. After an uncued rule change the animal had to abandon the old strategy and switch to the new rule, testing cognitive flexibility. Investigating the coordination of activity between the HPC and mPFC allows determination during which task stages their interaction is required. Additionally, comparing neural activity patterns in these two brain regions allows delineation of the specialized functions of the HPC and mPFC in this task. We analyzed neural activity in the HPC and mPFC in terms of oscillatory interactions, rule coding and replay. We found that theta coherence between the HPC and mPFC is increased at the center and goals of the maze, both when the rule was stable or has changed. Similar results were found for locking of HPC and mPFC neurons to HPC theta oscillations. However, no differences in HPC-mPFC theta coordination were observed between the spatially- and cue-guided rule. Phase locking of HPC and mPFC neurons to HPC gamma oscillations was not modulated by maze position or rule type. We found that the HPC coded for the two different rules with cofiring relationships between cell pairs. However, we could not find conclusive evidence for rule coding in the mPFC. Spatially-selective firing in the mPFC generalized between the two start and two goal arms. With Bayesian positional decoding, we found that the mPFC reactivated non-local positions during awake immobility periods. Replay of these non-local positions could represent entire behavioral trajectories resembling trajectory replay of the HPC. Furthermore, mPFC trajectory-replay at the goal positively correlated with rule-switching performance. Finally, HPC and mPFC trajectory replay occurred independently of each other. These results show that the mPFC can replay ordered patterns of activity during awake immobility, possibly underlying its role in flexible behavior. AU - Käfer, Karola ID - 6825 SN - 2663-337X TI - The hippocampus and medial prefrontal cortex during flexible behavior ER - TY - JOUR AB - Evolutionary studies are often limited by missing data that are critical to understanding the history of selection. Selection experiments, which reproduce rapid evolution under controlled conditions, are excellent tools to study how genomes evolve under selection. Here we present a genomic dissection of the Longshanks selection experiment, in which mice were selectively bred over 20 generations for longer tibiae relative to body mass, resulting in 13% longer tibiae in two replicates. We synthesized evolutionary theory, genome sequences and molecular genetics to understand the selection response and found that it involved both polygenic adaptation and discrete loci of major effect, with the strongest loci tending to be selected in parallel between replicates. We show that selection may favor de-repression of bone growth through inactivating two limb enhancers of an inhibitor, Nkx3-2. Our integrative genomic analyses thus show that it is possible to connect individual base-pair changes to the overall selection response. AU - Castro, João Pl AU - Yancoskie, Michelle N. AU - Marchini, Marta AU - Belohlavy, Stefanie AU - Hiramatsu, Layla AU - Kučka, Marek AU - Beluch, William H. AU - Naumann, Ronald AU - Skuplik, Isabella AU - Cobb, John AU - Barton, Nicholas H AU - Rolian, Campbell AU - Chan, Yingguang Frank ID - 6713 JF - eLife TI - An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice VL - 8 ER - TY - GEN AB - We study double quantum dots in a Ge/SiGe heterostructure and test their maturity towards singlet-triplet ($S-T_0$) qubits. We demonstrate a large range of tunability, from two single quantum dots to a double quantum dot. We measure Pauli spin blockade and study the anisotropy of the $g$-factor. We use an adjacent quantum dot for sensing charge transitions in the double quantum dot at interest. In conclusion, Ge/SiGe possesses all ingredients necessary for building a singlet-triplet qubit. AU - Hofmann, Andrea C AU - Jirovec, Daniel AU - Borovkov, Maxim AU - Prieto Gonzalez, Ivan AU - Ballabio, Andrea AU - Frigerio, Jacopo AU - Chrastina, Daniel AU - Isella, Giovanni AU - Katsaros, Georgios ID - 10065 T2 - arXiv TI - Assessing the potential of Ge/SiGe quantum dots as hosts for singlet-triplet qubits ER - TY - JOUR AB - Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis. AU - Valosková, Katarina AU - Biebl, Julia AU - Roblek, Marko AU - Emtenani, Shamsi AU - György, Attila AU - Misova, Michaela AU - Ratheesh, Aparna AU - Rodrigues, Patricia AU - Shkarina, Katerina AU - Larsen, Ida Signe Bohse AU - Vakhrushev, Sergey Y AU - Clausen, Henrik AU - Siekhaus, Daria E ID - 6187 JF - eLife SN - 2050-084X TI - A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion VL - 8 ER - TY - THES AB - Invasive migration plays a crucial role not only during development and homeostasis but also in pathological states, such as tumor metastasis. Drosophila macrophage migration into the extended germband is an interesting system to study invasive migration. It carries similarities to immune cell transmigration and cancer cell invasion, therefore studying this process could also bring new understanding of invasion in higher organisms. In our work, we uncover a highly conserved member of the major facilitator family that plays a role in tissue invasion through regulation of glycosylation on a subgroup of proteins and/or by aiding the precise timing of DN-Cadherin downregulation. Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis. AU - Valosková, Katarina ID - 6546 SN - 2663-337X TI - The role of a highly conserved major facilitator superfamily member in Drosophila embryonic macrophage migration ER - TY - THES AB - Distinguishing between similar experiences is achieved by the brain in a process called pattern separation. In the hippocampus, pattern separation reduces the interference of memories and increases the storage capacity by decorrelating similar inputs patterns of neuronal activity into non-overlapping output firing patterns. Winners-take-all (WTA) mechanism is a theoretical model for pattern separation in which a "winner" cell suppresses the activity of the neighboring neurons through feedback inhibition. However, if the network properties of the dentate gyrus support WTA as a biologically conceivable model remains unknown. Here, we showed that the connectivity rules of PV+interneurons and their synaptic properties are optimizedfor efficient pattern separation. We found using multiple whole-cell in vitrorecordings that PV+interneurons mainly connect to granule cells (GC) through lateral inhibition, a form of feedback inhibition in which a GC inhibits other GCs but not itself through the activation of PV+interneurons. Thus, lateral inhibition between GC–PV+interneurons was ~10 times more abundant than recurrent connections. Furthermore, the GC–PV+interneuron connectivity was more spatially confined but less abundant than PV+interneurons–GC connectivity, leading to an asymmetrical distribution of excitatory and inhibitory connectivity. Our network model of the dentate gyrus with incorporated real connectivity rules efficiently decorrelates neuronal activity patterns using WTA as the primary mechanism. This process relied on lateral inhibition, fast-signaling properties of PV+interneurons and the asymmetrical distribution of excitatory and inhibitory connectivity. Finally, we found that silencing the activity of PV+interneurons in vivoleads to acute deficits in discrimination between similar environments, suggesting that PV+interneuron networks are necessary for behavioral relevant computations. Our results demonstrate that PV+interneurons possess unique connectivity and fast signaling properties that confer to the dentate gyrus network properties that allow the emergence of pattern separation. Thus, our results contribute to the knowledge of how specific forms of network organization underlie sophisticated types of information processing. AU - Espinoza Martinez, Claudia ID - 6363 SN - 2663-337X TI - Parvalbumin+ interneurons enable efficient pattern separation in hippocampal microcircuits ER - TY - CONF AB - In this work, we consider the almost-sure termination problem for probabilistic programs that asks whether a given probabilistic program terminates with probability 1. Scalable approaches for program analysis often rely on modularity as their theoretical basis. In non-probabilistic programs, the classical variant rule (V-rule) of Floyd-Hoare logic provides the foundation for modular analysis. Extension of this rule to almost-sure termination of probabilistic programs is quite tricky, and a probabilistic variant was proposed in [16]. While the proposed probabilistic variant cautiously addresses the key issue of integrability, we show that the proposed modular rule is still not sound for almost-sure termination of probabilistic programs. Besides establishing unsoundness of the previous rule, our contributions are as follows: First, we present a sound modular rule for almost-sure termination of probabilistic programs. Our approach is based on a novel notion of descent supermartingales. Second, for algorithmic approaches, we consider descent supermartingales that are linear and show that they can be synthesized in polynomial time. Finally, we present experimental results on a variety of benchmarks and several natural examples that model various types of nested while loops in probabilistic programs and demonstrate that our approach is able to efficiently prove their almost-sure termination property AU - Huang, Mingzhang AU - Fu, Hongfei AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar ID - 6780 T2 - Proceedings of the 34th ACM International Conference on Object-Oriented Programming, Systems, Languages, and Applications TI - Modular verification for almost-sure termination of probabilistic programs VL - 3 ER - TY - JOUR AB - There is a huge gap between the speeds of modern caches and main memories, and therefore cache misses account for a considerable loss of efficiency in programs. The predominant technique to address this issue has been Data Packing: data elements that are frequently accessed within time proximity are packed into the same cache block, thereby minimizing accesses to the main memory. We consider the algorithmic problem of Data Packing on a two-level memory system. Given a reference sequence R of accesses to data elements, the task is to partition the elements into cache blocks such that the number of cache misses on R is minimized. The problem is notoriously difficult: it is NP-hard even when the cache has size 1, and is hard to approximate for any cache size larger than 4. Therefore, all existing techniques for Data Packing are based on heuristics and lack theoretical guarantees. In this work, we present the first positive theoretical results for Data Packing, along with new and stronger negative results. We consider the problem under the lens of the underlying access hypergraphs, which are hypergraphs of affinities between the data elements, where the order of an access hypergraph corresponds to the size of the affinity group. We study the problem parameterized by the treewidth of access hypergraphs, which is a standard notion in graph theory to measure the closeness of a graph to a tree. Our main results are as follows: We show there is a number q* depending on the cache parameters such that (a) if the access hypergraph of order q* has constant treewidth, then there is a linear-time algorithm for Data Packing; (b)the Data Packing problem remains NP-hard even if the access hypergraph of order q*-1 has constant treewidth. Thus, we establish a fine-grained dichotomy depending on a single parameter, namely, the highest order among access hypegraphs that have constant treewidth; and establish the optimal value q* of this parameter. Finally, we present an experimental evaluation of a prototype implementation of our algorithm. Our results demonstrate that, in practice, access hypergraphs of many commonly-used algorithms have small treewidth. We compare our approach with several state-of-the-art heuristic-based algorithms and show that our algorithm leads to significantly fewer cache-misses. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Okati, Nastaran AU - Pavlogiannis, Andreas ID - 6380 IS - POPL JF - Proceedings of the ACM on Programming Languages SN - 2475-1421 TI - Efficient parameterized algorithms for data packing VL - 3 ER - TY - CONF AB - In today's programmable blockchains, smart contracts are limited to being deterministic and non-probabilistic. This lack of randomness is a consequential limitation, given that a wide variety of real-world financial contracts, such as casino games and lotteries, depend entirely on randomness. As a result, several ad-hoc random number generation approaches have been developed to be used in smart contracts. These include ideas such as using an oracle or relying on the block hash. However, these approaches are manipulatable, i.e. their output can be tampered with by parties who might not be neutral, such as the owner of the oracle or the miners.We propose a novel game-theoretic approach for generating provably unmanipulatable pseudorandom numbers on the blockchain. Our approach allows smart contracts to access a trustworthy source of randomness that does not rely on potentially compromised miners or oracles, hence enabling the creation of a new generation of smart contracts that are not limited to being non-probabilistic and can be drawn from the much more general class of probabilistic programs. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Pourdamghani, Arash ID - 6056 T2 - IEEE International Conference on Blockchain and Cryptocurrency TI - Probabilistic smart contracts: Secure randomness on the blockchain ER - TY - CONF AB - In today's cryptocurrencies, Hashcash proof of work is the most commonly-adopted approach to mining. In Hashcash, when a miner decides to add a block to the chain, she has to solve the difficult computational puzzle of inverting a hash function. While Hashcash has been successfully adopted in both Bitcoin and Ethereum, it has attracted significant and harsh criticism due to its massive waste of electricity, its carbon footprint and environmental effects, and the inherent lack of usefulness in inverting a hash function. Various other mining protocols have been suggested, including proof of stake, in which a miner's chance of adding the next block is proportional to her current balance. However, such protocols lead to a higher entry cost for new miners who might not still have any stake in the cryptocurrency, and can in the worst case lead to an oligopoly, where the rich have complete control over mining. In this paper, we propose Hybrid Mining: a new mining protocol that combines solving real-world useful problems with Hashcash. Our protocol allows new miners to join the network by taking part in Hashcash mining without having to own an initial stake. It also allows nodes of the network to submit hard computational problems whose solutions are of interest in the real world, e.g.~protein folding problems. Then, miners can choose to compete in solving these problems, in lieu of Hashcash, for adding a new block. Hence, Hybrid Mining incentivizes miners to solve useful problems, such as hard computational problems arising in biology, in a distributed manner. It also gives researchers in other areas an easy-to-use tool to outsource their hard computations to the blockchain network, which has enormous computational power, by paying a reward to the miner who solves the problem for them. Moreover, our protocol provides strong security guarantees and is at least as resilient to double spending as Bitcoin. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Pourdamghani, Arash ID - 6378 SN - 9781450359337 T2 - Proceedings of the 34th ACM Symposium on Applied Computing TI - Hybrid Mining: Exploiting blockchain’s computational power for distributed problem solving VL - Part F147772 ER - TY - CONF AB - We consider the problem of expected cost analysis over nondeterministic probabilistic programs, which aims at automated methods for analyzing the resource-usage of such programs. Previous approaches for this problem could only handle nonnegative bounded costs. However, in many scenarios, such as queuing networks or analysis of cryptocurrency protocols, both positive and negative costs are necessary and the costs are unbounded as well. In this work, we present a sound and efficient approach to obtain polynomial bounds on the expected accumulated cost of nondeterministic probabilistic programs. Our approach can handle (a) general positive and negative costs with bounded updates in variables; and (b) nonnegative costs with general updates to variables. We show that several natural examples which could not be handled by previous approaches are captured in our framework. Moreover, our approach leads to an efficient polynomial-time algorithm, while no previous approach for cost analysis of probabilistic programs could guarantee polynomial runtime. Finally, we show the effectiveness of our approach using experimental results on a variety of programs for which we efficiently synthesize tight resource-usage bounds. AU - Wang, Peixin AU - Fu, Hongfei AU - Goharshady, Amir Kafshdar AU - Chatterjee, Krishnendu AU - Qin, Xudong AU - Shi, Wenjun ID - 6175 KW - Program Cost Analysis KW - Program Termination KW - Probabilistic Programs KW - Martingales T2 - PLDI 2019: Proceedings of the 40th ACM SIGPLAN Conference on Programming Language Design and Implementation TI - Cost analysis of nondeterministic probabilistic programs ER - TY - CONF AB - Smart contracts are programs that are stored and executed on the Blockchain and can receive, manage and transfer money (cryptocurrency units). Two important problems regarding smart contracts are formal analysis and compiler optimization. Formal analysis is extremely important, because smart contracts hold funds worth billions of dollars and their code is immutable after deployment. Hence, an undetected bug can cause significant financial losses. Compiler optimization is also crucial, because every action of a smart contract has to be executed by every node in the Blockchain network. Therefore, optimizations in compiling smart contracts can lead to significant savings in computation, time and energy. Two classical approaches in program analysis and compiler optimization are intraprocedural and interprocedural analysis. In intraprocedural analysis, each function is analyzed separately, while interprocedural analysis considers the entire program. In both cases, the analyses are usually reduced to graph problems over the control flow graph (CFG) of the program. These graph problems are often computationally expensive. Hence, there has been ample research on exploiting structural properties of CFGs for efficient algorithms. One such well-studied property is the treewidth, which is a measure of tree-likeness of graphs. It is known that intraprocedural CFGs of structured programs have treewidth at most 6, whereas the interprocedural treewidth cannot be bounded. This result has been used as a basis for many efficient intraprocedural analyses. In this paper, we explore the idea of exploiting the treewidth of smart contracts for formal analysis and compiler optimization. First, similar to classical programs, we show that the intraprocedural treewidth of structured Solidity and Vyper smart contracts is at most 9. Second, for global analysis, we prove that the interprocedural treewidth of structured smart contracts is bounded by 10 and, in sharp contrast with classical programs, treewidth-based algorithms can be easily applied for interprocedural analysis. Finally, we supplement our theoretical results with experiments using a tool we implemented for computing treewidth of smart contracts and show that the treewidth is much lower in practice. We use 36,764 real-world Ethereum smart contracts as benchmarks and find that they have an average treewidth of at most 3.35 for the intraprocedural case and 3.65 for the interprocedural case. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Goharshady, Ehsan Kafshdar ID - 6490 SN - 9781450359337 T2 - Proceedings of the 34th ACM Symposium on Applied Computing TI - The treewidth of smart contracts VL - Part F147772 ER - TY - JOUR AB - Interprocedural analysis is at the heart of numerous applications in programming languages, such as alias analysis, constant propagation, and so on. 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, and so on. 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 an important algorithmic distinction between the resource usage of the one-time preprocessing vs for each individual query. The second aspect we consider is that the control flow graphs for most programs have constant treewidth. Our main contributions are simple and implementable algorithms that support multiple 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 algorithmic solutions for interprocedural dataflow analysis. We have also implemented our algorithms and evaluated their performance for performing on-demand interprocedural dataflow analysis on various domains, such as for live variable analysis and reaching definitions, on a standard benchmark set. Our experimental results align with our theoretical statements and show that after a lightweight preprocessing, on-demand queries are answered much faster than the standard existing algorithmic approaches. AU - Chatterjee, Krishnendu AU - Goharshady, Amir Kafshdar AU - Goyal, Prateesh AU - Ibsen-Jensen, Rasmus AU - Pavlogiannis, Andreas ID - 7158 IS - 4 JF - ACM Transactions on Programming Languages and Systems SN - 0164-0925 TI - Faster algorithms for dynamic algebraic queries in basic RSMs with constant treewidth VL - 41 ER - TY - JOUR AB - We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of nonrecursive programs. First, we apply ranking functions to recursion, resulting in measure functions. We show that measure functions provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in nonpolynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas' Lemma, and Handelman's Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form $\mathcal{O}(n\log n)$ as well as $\mathcal{O}(n^r)$ where $r$ is not an integer. We present experimental results to demonstrate that our approach can obtain efficiently worst-case bounds of classical recursive algorithms such as (i) Merge-Sort, the divide-and-conquer algorithm for the Closest-Pair problem, where we obtain $\mathcal{O}(n \log n)$ worst-case bound, and (ii) Karatsuba's algorithm for polynomial multiplication and Strassen's algorithm for matrix multiplication, where we obtain $\mathcal{O}(n^r)$ bound such that $r$ is not an integer and close to the best-known bounds for the respective algorithms. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Goharshady, Amir Kafshdar ID - 7014 IS - 4 JF - ACM Transactions on Programming Languages and Systems TI - Non-polynomial worst-case analysis of recursive programs VL - 41 ER - TY - JOUR AB - Based on a novel control scheme, where a steady modification of the streamwise velocity profile leads to complete relaminarization of initially fully turbulent pipe flow, we investigate the applicability and usefulness of custom-shaped honeycombs for such control. The custom-shaped honeycombs are used as stationary flow management devices which generate specific modifications of the streamwise velocity profile. Stereoscopic particle image velocimetry and pressure drop measurements are used to investigate and capture the development of the relaminarizing flow downstream these devices. We compare the performance of straight (constant length across the radius of the pipe) honeycombs with custom-shaped ones (variable length across the radius) and try to determine the optimal shape for maximal relaminarization at minimal pressure loss. The optimally modified streamwise velocity profile is found to be M-shaped, and the maximum attainable Reynolds number for total relaminarization is found to be of the order of 10,000. Consequently, the respective reduction in skin friction downstream of the device is almost by a factor of 5. The break-even point, where the additional pressure drop caused by the device is balanced by the savings due to relaminarization and a net gain is obtained, corresponds to a downstream stretch of distances as low as approximately 100 pipe diameters of laminar flow. AU - Kühnen, Jakob AU - Scarselli, Davide AU - Hof, Björn ID - 6486 IS - 11 JF - Journal of Fluids Engineering SN - 00982202 TI - Relaminarization of pipe flow by means of 3D-printed shaped honeycombs VL - 141 ER - TY - JOUR AB - Following the recent observation that turbulent pipe flow can be relaminarised bya relatively simple modification of the mean velocity profile, we here carry out aquantitative experimental investigation of this phenomenon. Our study confirms thata flat velocity profile leads to a collapse of turbulence and in order to achieve theblunted profile shape, we employ a moving pipe segment that is briefly and rapidlyshifted in the streamwise direction. The relaminarisation threshold and the minimumshift length and speeds are determined as a function of Reynolds number. Althoughturbulence is still active after the acceleration phase, the modulated profile possessesa severely decreased lift-up potential as measured by transient growth. As shown,this results in an exponential decay of fluctuations and the flow relaminarises. Whilethis method can be easily applied at low to moderate flow speeds, the minimumstreamwise length over which the acceleration needs to act increases linearly with theReynolds number. AU - Scarselli, Davide AU - Kühnen, Jakob AU - Hof, Björn ID - 6228 JF - Journal of Fluid Mechanics SN - 00221120 TI - Relaminarising pipe flow by wall movement VL - 867 ER - TY - JOUR AB - Polar auxin transport plays a pivotal role in plant growth and development. PIN auxin efflux carriers regulate directional auxin movement by establishing local auxin maxima, minima, and gradients that drive multiple developmental processes and responses to environmental signals. Auxin has been proposed to modulate its own transport by regulating subcellular PIN trafficking via processes such as clathrin-mediated PIN endocytosis and constitutive recycling. Here, we further investigated the mechanisms by which auxin affects PIN trafficking by screening auxin analogs and identified pinstatic acid (PISA) as a positive modulator of polar auxin transport in Arabidopsis thaliana. PISA had an auxin-like effect on hypocotyl elongation and adventitious root formation via positive regulation of auxin transport. PISA did not activate SCFTIR1/AFB signaling and yet induced PIN accumulation at the cell surface by inhibiting PIN internalization from the plasma membrane. This work demonstrates PISA to be a promising chemical tool to dissect the regulatory mechanisms behind subcellular PIN trafficking and auxin transport. AU - Oochi, A AU - Hajny, Jakub AU - Fukui, K AU - Nakao, Y AU - Gallei, Michelle C AU - Quareshy, M AU - Takahashi, K AU - Kinoshita, T AU - Harborough, SR AU - Kepinski, S AU - Kasahara, H AU - Napier, RM AU - Friml, Jiří AU - Hayashi, KI ID - 6260 IS - 2 JF - Plant Physiology SN - 0032-0889 TI - Pinstatic acid promotes auxin transport by inhibiting PIN internalization VL - 180 ER - TY - JOUR AB - Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation. AU - Shamipour, Shayan AU - Kardos, Roland AU - Xue, Shi-lei AU - Hof, Björn AU - Hannezo, Edouard B AU - Heisenberg, Carl-Philipp J ID - 6508 IS - 6 JF - Cell SN - 00928674 TI - Bulk actin dynamics drive phase segregation in zebrafish oocytes VL - 177 ER - TY - JOUR AU - Schwayer, Cornelia AU - Shamipour, Shayan AU - Pranjic-Ferscha, Kornelija AU - Schauer, Alexandra AU - Balda, M AU - Tada, M AU - Matter, K AU - Heisenberg, Carl-Philipp J ID - 7001 IS - 4 JF - Cell SN - 0092-8674 TI - Mechanosensation of tight junctions depends on ZO-1 phase separation and flow VL - 179 ER - TY - THES AB - While cells of mesenchymal or epithelial origin perform their effector functions in a purely anchorage dependent manner, cells derived from the hematopoietic lineage are not committed to operate only within a specific niche. Instead, these cells are able to function autonomously of the molecular composition in a broad range of tissue compartments. By this means, cells of the hematopoietic lineage retain the capacity to disseminate into connective tissue and recirculate between organs, building the foundation for essential processes such as tissue regeneration or immune surveillance. Cells of the immune system, specifically leukocytes, are extraordinarily good at performing this task. These cells are able to flexibly shift their mode of migration between an adhesion-mediated and an adhesion-independent manner, instantaneously accommodating for any changes in molecular composition of the external scaffold. The key component driving directed leukocyte migration is the chemokine receptor 7, which guides the cell along gradients of chemokine ligand. Therefore, the physical destination of migrating leukocytes is purely deterministic, i.e. given by global directional cues such as chemokine gradients. Nevertheless, these cells typically reside in three-dimensional scaffolds of inhomogeneous complexity, raising the question whether cells are able to locally discriminate between multiple optional migration routes. Current literature provides evidence that leukocytes, specifically dendritic cells, do indeed probe their surrounding by virtue of multiple explorative protrusions. However, it remains enigmatic how these cells decide which one is the more favorable route to follow and what are the key players involved in performing this task. Due to the heterogeneous environment of most tissues, and the vast adaptability of migrating leukocytes, at this time it is not clear to what extent leukocytes are able to optimize their migratory strategy by adapting their level of adhesiveness. And, given the fact that leukocyte migration is characterized by branched cell shapes in combination with high migration velocities, it is reasonable to assume that these cells require fine tuned shape maintenance mechanisms that tightly coordinate protrusion and adhesion dynamics in a spatiotemporal manner. Therefore, this study aimed to elucidate how rapidly migrating leukocytes opt for an ideal migratory path while maintaining a continuous cell shape and balancing adhesive forces to efficiently navigate through complex microenvironments. The results of this study unraveled a role for the microtubule cytoskeleton in promoting the decision making process during path finding and for the first time point towards a microtubule-mediated function in cell shape maintenance of highly ramified cells such as dendritic cells. Furthermore, we found that migrating low-adhesive leukocytes are able to instantaneously adapt to increased tensile load by engaging adhesion receptors. This response was only occurring tangential to the substrate while adhesive properties in the vertical direction were not increased. As leukocytes are primed for rapid migration velocities, these results demonstrate that leukocyte integrins are able to confer a high level of traction forces parallel to the cell membrane along the direction of migration without wasting energy in gluing the cell to the substrate. Thus, the data in the here presented thesis provide new insights into the pivotal role of cytoskeletal dynamics and the mechanisms of force transduction during leukocyte migration. Thereby the here presented results help to further define fundamental principles underlying leukocyte migration and open up potential therapeutic avenues of clinical relevance. AU - Kopf, Aglaja ID - 6891 KW - cell biology KW - immunology KW - leukocyte KW - migration KW - microfluidics SN - 978-3-99078-002-2 TI - The implication of cytoskeletal dynamics on leukocyte migration ER - TY - JOUR AB - During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments1,2,3. These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell4,5. Most mesenchymal and epithelial cells and some—but not all—cancer cells actively generate their migratory path using pericellular tissue proteolysis6. By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion7, raising the question how these extremely fast cells navigate through dense tissues. Here we reveal that leukocytes sample their immediate vicinity for large pore sizes, and are thereby able to choose the path of least resistance. This allows them to circumnavigate local obstacles while effectively following global directional cues such as chemotactic gradients. Pore-size discrimination is facilitated by frontward positioning of the nucleus, which enables the cells to use their bulkiest compartment as a mechanical gauge. Once the nucleus and the closely associated microtubule organizing centre pass the largest pore, cytoplasmic protrusions still lingering in smaller pores are retracted. These retractions are coordinated by dynamic microtubules; when microtubules are disrupted, migrating cells lose coherence and frequently fragment into migratory cytoplasmic pieces. As nuclear positioning in front of the microtubule organizing centre is a typical feature of amoeboid migration, our findings link the fundamental organization of cellular polarity to the strategy of locomotion. AU - Renkawitz, Jörg AU - Kopf, Aglaja AU - Stopp, Julian A AU - de Vries, Ingrid AU - Driscoll, Meghan K. AU - Merrin, Jack AU - Hauschild, Robert AU - Welf, Erik S. AU - Danuser, Gaudenz AU - Fiolka, Reto AU - Sixt, Michael K ID - 6328 JF - Nature TI - Nuclear positioning facilitates amoeboid migration along the path of least resistance VL - 568 ER - TY - JOUR AU - Kopf, Aglaja AU - Sixt, Michael K ID - 6877 IS - 1 JF - Cell SN - 0092-8674 TI - The neural crest pitches in to remove apoptotic debris VL - 179 ER - TY - JOUR AU - Contreras, Ximena AU - Hippenmeyer, Simon ID - 6830 IS - 5 JF - Neuron SN - 08966273 TI - Memo1 tiles the radial glial cell grid VL - 103 ER - TY - JOUR AB - Cortical microtubule arrays in elongating epidermal cells in both the root and stem of plants have the propensity of dynamic reorientations that are correlated with the activation or inhibition of growth. Factors regulating plant growth, among them the hormone auxin, have been recognized as regulators of microtubule array orientations. Some previous work in the field has aimed at elucidating the causal relationship between cell growth, the signaling of auxin or other growth-regulating factors, and microtubule array reorientations, with various conclusions. Here, we revisit this problem of causality with a comprehensive set of experiments in Arabidopsis thaliana, using the now available pharmacological and genetic tools. We use isolated, auxin-depleted hypocotyls, an experimental system allowing for full control of both growth and auxin signaling. We demonstrate that reorientation of microtubules is not directly triggered by an auxin signal during growth activation. Instead, reorientation is triggered by the activation of the growth process itself and is auxin-independent in its nature. We discuss these findings in the context of previous relevant work, including that on the mechanical regulation of microtubule array orientation. AU - Adamowski, Maciek AU - Li, Lanxin AU - Friml, Jiří ID - 6627 IS - 13 JF - International Journal of Molecular Sciences TI - Reorientation of cortical microtubule arrays in the hypocotyl of arabidopsis thaliana is induced by the cell growth process and independent of auxin signaling VL - 20 ER - TY - JOUR AB - We propose a novel generic shape optimization method for CAD models based on the eXtended Finite Element Method (XFEM). Our method works directly on the intersection between the model and a regular simulation grid, without the need to mesh or remesh, thus removing a bottleneck of classical shape optimization strategies. This is made possible by a novel hierarchical integration scheme that accurately integrates finite element quantities with sub-element precision. For optimization, we efficiently compute analytical shape derivatives of the entire framework, from model intersection to integration rule generation and XFEM simulation. Moreover, we describe a differentiable projection of shape parameters onto a constraint manifold spanned by user-specified shape preservation, consistency, and manufacturability constraints. We demonstrate the utility of our approach by optimizing mass distribution, strength-to-weight ratio, and inverse elastic shape design objectives directly on parameterized 3D CAD models. AU - Hafner, Christian AU - Schumacher, Christian AU - Knoop, Espen AU - Auzinger, Thomas AU - Bickel, Bernd AU - Bächer, Moritz ID - 7117 IS - 6 JF - ACM Transactions on Graphics SN - 0730-0301 TI - X-CAD: Optimizing CAD Models with Extended Finite Elements VL - 38 ER - TY - JOUR AB - Suspended particles can alter the properties of fluids and in particular also affect the transition fromlaminar to turbulent flow. An earlier study [Mataset al.,Phys. Rev. Lett.90, 014501 (2003)] reported howthe subcritical (i.e., hysteretic) transition to turbulent puffs is affected by the addition of particles. Here weshow that in addition to this known transition, with increasing concentration a supercritical (i.e.,continuous) transition to a globally fluctuating state is found. At the same time the Newtonian-typetransition to puffs is delayed to larger Reynolds numbers. At even higher concentration only the globallyfluctuating state is found. The dynamics of particle laden flows are hence determined by two competinginstabilities that give rise to three flow regimes: Newtonian-type turbulence at low, a particle inducedglobally fluctuating state at high, and a coexistence state at intermediate concentrations. AU - Agrawal, Nishchal AU - Choueiri, George H AU - Hof, Björn ID - 6189 IS - 11 JF - Physical Review Letters SN - 00319007 TI - Transition to turbulence in particle laden flows VL - 122 ER - TY - THES AB - Decades of studies have revealed the mechanisms of gene regulation in molecular detail. We make use of such well-described regulatory systems to explore how the molecular mechanisms of protein-protein and protein-DNA interactions shape the dynamics and evolution of gene regulation. i) We uncover how the biophysics of protein-DNA binding determines the potential of regulatory networks to evolve and adapt, which can be captured using a simple mathematical model. ii) The evolution of regulatory connections can lead to a significant amount of crosstalk between binding proteins. We explore the effect of crosstalk on gene expression from a target promoter, which seems to be modulated through binding competition at non-specific DNA sites. iii) We investigate how the very same biophysical characteristics as in i) can generate significant fitness costs for cells through global crosstalk, meaning non-specific DNA binding across the genomic background. iv) Binding competition between proteins at a target promoter is a prevailing regulatory feature due to the prevalence of co-regulation at bacterial promoters. However, the dynamics of these systems are not always straightforward to determine even if the molecular mechanisms of regulation are known. A detailed model of the biophysical interactions reveals that interference between the regulatory proteins can constitute a new, generic form of system memory that records the history of the input signals at the promoter. We demonstrate how the biophysics of protein-DNA binding can be harnessed to investigate the principles that shape and ultimately limit cellular gene regulation. These results provide a basis for studies of higher-level functionality, which arises from the underlying regulation. AU - Igler, Claudia ID - 6371 KW - gene regulation KW - biophysics KW - transcription factor binding KW - bacteria SN - 2663-337X TI - On the nature of gene regulatory design - The biophysics of transcription factor binding shapes gene regulation ER - TY - JOUR AB - In this paper, we evaluate clock signals generated in ring oscillators and self-timed rings and the way their jitter can be transformed into random numbers. We show that counting the periods of the jittery clock signal produces random numbers of significantly better quality than the methods in which the jittery signal is simply sampled (the case in almost all current methods). Moreover, we use the counter values to characterize and continuously monitor the source of randomness. However, instead of using the widely used statistical variance, we propose to use Allan variance to do so. There are two main advantages: Allan variance is insensitive to low frequency noises such as flicker noise that are known to be autocorrelated and significantly less circuitry is required for its computation than that used to compute commonly used variance. We also show that it is essential to use a differential principle of randomness extraction from the jitter based on the use of two identical oscillators to avoid autocorrelations originating from external and internal global jitter sources and that this fact is valid for both kinds of rings. Last but not least, we propose a method of statistical testing based on high order Markov model to show the reduced dependencies when the proposed randomness extraction is applied. AU - Allini, Elie Noumon AU - Skórski, Maciej AU - Petura, Oto AU - Bernard, Florent AU - Laban, Marek AU - Fischer, Viktor ID - 10286 IS - 3 JF - IACR Transactions on Cryptographic Hardware and Embedded Systems TI - Evaluation and monitoring of free running oscillators serving as source of randomness VL - 2018 ER - TY - CONF AB - Solving parity games, which are equivalent to modal μ-calculus model checking, is a central algorithmic problem in formal methods, with applications in reactive synthesis, program repair, verification of branching-time properties, etc. Besides the standard compu- tation model with the explicit representation of games, another important theoretical model of computation is that of set-based symbolic algorithms. Set-based symbolic algorithms use basic set operations and one-step predecessor operations on the implicit description of games, rather than the explicit representation. The significance of symbolic algorithms is that they provide scalable algorithms for large finite-state systems, as well as for infinite-state systems with finite quotient. Consider parity games on graphs with n vertices and parity conditions with d priorities. While there is a rich literature of explicit algorithms for parity games, the main results for set-based symbolic algorithms are as follows: (a) the basic algorithm that requires O(nd) symbolic operations and O(d) symbolic space; and (b) an improved algorithm that requires O(nd/3+1) symbolic operations and O(n) symbolic space. In this work, our contributions are as follows: (1) We present a black-box set-based symbolic algorithm based on the explicit progress measure algorithm. Two important consequences of our algorithm are as follows: (a) a set-based symbolic algorithm for parity games that requires quasi-polynomially many symbolic operations and O(n) symbolic space; and (b) any future improvement in progress measure based explicit algorithms immediately imply an efficiency improvement in our set-based symbolic algorithm for parity games. (2) We present a set-based symbolic algorithm that requires quasi-polynomially many symbolic operations and O(d · log n) symbolic space. Moreover, for the important special case of d ≤ log n, our algorithm requires only polynomially many symbolic operations and poly-logarithmic symbolic space. AU - Chatterjee, Krishnendu AU - Dvořák, Wolfgang AU - Henzinger, Monika H AU - Svozil, Alexander ID - 10883 SN - 2398-7340 T2 - 22nd International Conference on Logic for Programming, Artificial Intelligence and Reasoning TI - Quasipolynomial set-based symbolic algorithms for parity games VL - 57 ER - TY - CONF AB - We report on a novel strategy to derive mean-field limits of quantum mechanical systems in which a large number of particles weakly couple to a second-quantized radiation field. The technique combines the method of counting and the coherent state approach to study the growth of the correlations among the particles and in the radiation field. As an instructional example, we derive the Schrödinger–Klein–Gordon system of equations from the Nelson model with ultraviolet cutoff and possibly massless scalar field. In particular, we prove the convergence of the reduced density matrices (of the nonrelativistic particles and the field bosons) associated with the exact time evolution to the projectors onto the solutions of the Schrödinger–Klein–Gordon equations in trace norm. Furthermore, we derive explicit bounds on the rate of convergence of the one-particle reduced density matrix of the nonrelativistic particles in Sobolev norm. AU - Leopold, Nikolai K AU - Pickl, Peter ID - 11 TI - Mean-field limits of particles in interaction with quantised radiation fields VL - 270 ER - TY - JOUR AB - Two generalizations of Itô formula to infinite-dimensional spaces are given. The first one, in Hilbert spaces, extends the classical one by taking advantage of cancellations when they occur in examples and it is applied to the case of a group generator. The second one, based on the previous one and a limit procedure, is an Itô formula in a special class of Banach spaces having a product structure with the noise in a Hilbert component; again the key point is the extension due to a cancellation. This extension to Banach spaces and in particular the specific cancellation are motivated by path-dependent Itô calculus. AU - Flandoli, Franco AU - Russo, Francesco AU - Zanco, Giovanni A ID - 1215 IS - 2 JF - Journal of Theoretical Probability TI - Infinite-dimensional calculus under weak spatial regularity of the processes VL - 31 ER - TY - CONF AB - We resolve in the affirmative conjectures of A. Skopenkov and Repovš (1998), and M. Skopenkov (2003) generalizing the classical Hanani-Tutte theorem to the setting of approximating maps of graphs on 2-dimensional surfaces by embeddings. Our proof of this result is constructive and almost immediately implies an efficient algorithm for testing whether a given piecewise linear map of a graph in a surface is approximable by an embedding. More precisely, an instance of this problem consists of (i) a graph G whose vertices are partitioned into clusters and whose inter-cluster edges are partitioned into bundles, and (ii) a region R of a 2-dimensional compact surface M given as the union of a set of pairwise disjoint discs corresponding to the clusters and a set of pairwise disjoint "pipes" corresponding to the bundles, connecting certain pairs of these discs. We are to decide whether G can be embedded inside M so that the vertices in every cluster are drawn in the corresponding disc, the edges in every bundle pass only through its corresponding pipe, and every edge crosses the boundary of each disc at most once. AU - Fulek, Radoslav AU - Kynčl, Jan ID - 185 SN - 978-3-95977-066-8 TI - Hanani-Tutte for approximating maps of graphs VL - 99 ER - TY - CONF AB - Smallest enclosing spheres of finite point sets are central to methods in topological data analysis. Focusing on Bregman divergences to measure dissimilarity, we prove bounds on the location of the center of a smallest enclosing sphere. These bounds depend on the range of radii for which Bregman balls are convex. AU - Edelsbrunner, Herbert AU - Virk, Ziga AU - Wagner, Hubert ID - 188 TI - Smallest enclosing spheres and Chernoff points in Bregman geometry VL - 99 ER - TY - JOUR AB - A cornerstone of statistical inference, the maximum entropy framework is being increasingly applied to construct descriptive and predictive models of biological systems, especially complex biological networks, from large experimental data sets. Both its broad applicability and the success it obtained in different contexts hinge upon its conceptual simplicity and mathematical soundness. Here we try to concisely review the basic elements of the maximum entropy principle, starting from the notion of ‘entropy’, and describe its usefulness for the analysis of biological systems. As examples, we focus specifically on the problem of reconstructing gene interaction networks from expression data and on recent work attempting to expand our system-level understanding of bacterial metabolism. Finally, we highlight some extensions and potential limitations of the maximum entropy approach, and point to more recent developments that are likely to play a key role in the upcoming challenges of extracting structures and information from increasingly rich, high-throughput biological data. AU - De Martino, Andrea AU - De Martino, Daniele ID - 306 IS - 4 JF - Heliyon TI - An introduction to the maximum entropy approach and its application to inference problems in biology VL - 4 ER - TY - BOOK AB - This book first explores the origins of this idea, grounded in theoretical work on temporal logic and automata. The editors and authors are among the world's leading researchers in this domain, and they contributed 32 chapters representing a thorough view of the development and application of the technique. Topics covered include binary decision diagrams, symbolic model checking, satisfiability modulo theories, partial-order reduction, abstraction, interpolation, concurrency, security protocols, games, probabilistic model checking, and process algebra, and chapters on the transfer of theory to industrial practice, property specification languages for hardware, and verification of real-time systems and hybrid systems. The book will be valuable for researchers and graduate students engaged with the development of formal methods and verification tools. AU - Clarke, Edmund M. AU - Henzinger, Thomas A AU - Veith, Helmut AU - Bloem, Roderick ID - 3300 SN - 978-3-319-10574-1 TI - Handbook of Model Checking ER - TY - CHAP AB - Developmental processes are inherently dynamic and understanding them requires quantitative measurements of gene and protein expression levels in space and time. While live imaging is a powerful approach for obtaining such data, it is still a challenge to apply it over long periods of time to large tissues, such as the embryonic spinal cord in mouse and chick. Nevertheless, dynamics of gene expression and signaling activity patterns in this organ can be studied by collecting tissue sections at different developmental stages. In combination with immunohistochemistry, this allows for measuring the levels of multiple developmental regulators in a quantitative manner with high spatiotemporal resolution. The mean protein expression levels over time, as well as embryo-to-embryo variability can be analyzed. A key aspect of the approach is the ability to compare protein levels across different samples. This requires a number of considerations in sample preparation, imaging and data analysis. Here we present a protocol for obtaining time course data of dorsoventral expression patterns from mouse and chick neural tube in the first 3 days of neural tube development. The described workflow starts from embryo dissection and ends with a processed dataset. Software scripts for data analysis are included. The protocol is adaptable and instructions that allow the user to modify different steps are provided. Thus, the procedure can be altered for analysis of time-lapse images and applied to systems other than the neural tube. AU - Zagórski, Marcin P AU - Kicheva, Anna ID - 37 SN - 1064-3745 T2 - Morphogen Gradients TI - Measuring dorsoventral pattern and morphogen signaling profiles in the growing neural tube VL - 1863 ER - TY - JOUR AB - The hanging-drop network (HDN) is a technology platform based on a completely open microfluidic network at the bottom of an inverted, surface-patterned substrate. The platform is predominantly used for the formation, culturing, and interaction of self-assembled spherical microtissues (spheroids) under precisely controlled flow conditions. Here, we describe design, fabrication, and operation of microfluidic hanging-drop networks. AU - Misun, Patrick AU - Birchler, Axel AU - Lang, Moritz AU - Hierlemann, Andreas AU - Frey, Olivier ID - 305 JF - Methods in Molecular Biology TI - Fabrication and operation of microfluidic hanging drop networks VL - 1771 ER - TY - CONF AB - Probabilistic programs extend classical imperative programs with real-valued random variables and random branching. The most basic liveness property for such programs is the termination property. The qualitative (aka almost-sure) termination problem asks whether a given program program terminates with probability 1. While ranking functions provide a sound and complete method for non-probabilistic programs, the extension of them to probabilistic programs is achieved via ranking supermartingales (RSMs). Although deep theoretical results have been established about RSMs, their application to probabilistic programs with nondeterminism has been limited only to programs of restricted control-flow structure. For non-probabilistic programs, lexicographic ranking functions provide a compositional and practical approach for termination analysis of real-world programs. In this work we introduce lexicographic RSMs and show that they present a sound method for almost-sure termination of probabilistic programs with nondeterminism. We show that lexicographic RSMs provide a tool for compositional reasoning about almost-sure termination, and for probabilistic programs with linear arithmetic they can be synthesized efficiently (in polynomial time). We also show that with additional restrictions even asymptotic bounds on expected termination time can be obtained through lexicographic RSMs. Finally, we present experimental results on benchmarks adapted from previous work to demonstrate the effectiveness of our approach. AU - Agrawal, Sheshansh AU - Chatterjee, Krishnendu AU - Novotny, Petr ID - 325 IS - POPL TI - Lexicographic ranking supermartingales: an efficient approach to termination of probabilistic programs VL - 2 ER - TY - CHAP AB - Adventitious roots (AR) are de novo formed roots that emerge from any part of the plant or from callus in tissue culture, except root tissue. The plant tissue origin and the method by which they are induced determine the physiological properties of emerged ARs. Hence, a standard method encompassing all types of AR does not exist. Here we describe a method for the induction and analysis of AR that emerge from the etiolated hypocotyl of dicot plants. The hypocotyl is formed during embryogenesis and shows a determined developmental pattern which usually does not involve AR formation. However, the hypocotyl shows propensity to form de novo roots under specific circumstances such as removal of the root system, high humidity or flooding, or during de-etiolation. The hypocotyl AR emerge from a pericycle-like cell layer surrounding the vascular tissue of the central cylinder, which is reminiscent to the developmental program of lateral roots. Here we propose an easy protocol for in vitro hypocotyl AR induction from etiolated Arabidopsis seedlings. AU - Trinh, Hoang AU - Verstraeten, Inge AU - Geelen, Danny ID - 408 SN - 1064-3745 T2 - Root Development TI - In vitro assay for induction of adventitious rooting on intact arabidopsis hypocotyls VL - 1761 ER - TY - CHAP AB - Immunolocalization is a valuable tool for cell biology research that allows to rapidly determine the localization and expression levels of endogenous proteins. In plants, whole-mount in situ immunolocalization remains a challenging method, especially in tissues protected by waxy layers and complex cell wall carbohydrates. Here, we present a robust method for whole-mount in situ immunolocalization in primary root meristems and lateral root primordia in Arabidopsis thaliana. For good epitope preservation, fixation is done in an alkaline paraformaldehyde/glutaraldehyde mixture. This fixative is suitable for detecting a wide range of proteins, including integral transmembrane proteins and proteins peripherally attached to the plasma membrane. From initiation until emergence from the primary root, lateral root primordia are surrounded by several layers of differentiated tissues with a complex cell wall composition that interferes with the efficient penetration of all buffers. Therefore, immunolocalization in early lateral root primordia requires a modified method, including a strong solvent treatment for removal of hydrophobic barriers and a specific cocktail of cell wall-degrading enzymes. The presented method allows for easy, reliable, and high-quality in situ detection of the subcellular localization of endogenous proteins in primary and lateral root meristems without the need of time-consuming crosses or making translational fusions to fluorescent proteins. AU - Karampelias, Michael AU - Tejos, Ricardo AU - Friml, Jirí AU - Vanneste, Steffen ED - Ristova, Daniela ED - Barbez, Elke ID - 411 T2 - Root Development. Methods and Protocols TI - Optimized whole mount in situ immunolocalization for Arabidopsis thaliana root meristems and lateral root primordia VL - 1761 ER - TY - JOUR AB - Inhibition of the endoplasmic reticulum stress pathway may hold the key to Zika virus-associated microcephaly treatment. AU - Novarino, Gaia ID - 456 IS - 423 JF - Science Translational Medicine TI - Zika-associated microcephaly: Reduce the stress and race for the treatment VL - 10 ER - TY - JOUR AB - We consider the problem of consensus in the challenging classic model. In this model, the adversary is adaptive; it can choose which processors crash at any point during the course of the algorithm. Further, communication is via asynchronous message passing: there is no known upper bound on the time to send a message from one processor to another, and all messages and coin flips are seen by the adversary. We describe a new randomized consensus protocol with expected message complexity O(n2log2n) when fewer than n / 2 processes may fail by crashing. This is an almost-linear improvement over the best previously known protocol, and within logarithmic factors of a known Ω(n2) message lower bound. The protocol further ensures that no process sends more than O(nlog3n) messages in expectation, which is again within logarithmic factors of optimal. We also present a generalization of the algorithm to an arbitrary number of failures t, which uses expected O(nt+t2log2t) total messages. Our approach is to build a message-efficient, resilient mechanism for aggregating individual processor votes, implementing the message-passing equivalent of a weak shared coin. Roughly, in our protocol, a processor first announces its votes to small groups, then propagates them to increasingly larger groups as it generates more and more votes. To bound the number of messages that an individual process might have to send or receive, the protocol progressively increases the weight of generated votes. The main technical challenge is bounding the impact of votes that are still “in flight” (generated, but not fully propagated) on the final outcome of the shared coin, especially since such votes might have different weights. We achieve this by leveraging the structure of the algorithm, and a technical argument based on martingale concentration bounds. Overall, we show that it is possible to build an efficient message-passing implementation of a shared coin, and in the process (almost-optimally) solve the classic consensus problem in the asynchronous message-passing model. AU - Alistarh, Dan-Adrian AU - Aspnes, James AU - King, Valerie AU - Saia, Jared ID - 536 IS - 6 JF - Distributed Computing SN - 01782770 TI - Communication-efficient randomized consensus VL - 31 ER - TY - JOUR AB - We analyse the canonical Bogoliubov free energy functional in three dimensions at low temperatures in the dilute limit. We prove existence of a first-order phase transition and, in the limit (Formula presented.), we determine the critical temperature to be (Formula presented.) to leading order. Here, (Formula presented.) is the critical temperature of the free Bose gas, ρ is the density of the gas and a is the scattering length of the pair-interaction potential V. We also prove asymptotic expansions for the free energy. In particular, we recover the Lee–Huang–Yang formula in the limit (Formula presented.). AU - Napiórkowski, Marcin M AU - Reuvers, Robin AU - Solovej, Jan ID - 554 IS - 1 JF - Communications in Mathematical Physics SN - 00103616 TI - The Bogoliubov free energy functional II: The dilute Limit VL - 360 ER - TY - CHAP AB - Primary neuronal cell culture preparations are widely used to investigate synaptic functions. This chapter describes a detailed protocol for the preparation of a neuronal cell culture in which giant calyx-type synaptic terminals are formed. This chapter also presents detailed protocols for utilizing the main technical advantages provided by such a preparation, namely, labeling and imaging of synaptic organelles and electrophysiological recordings directly from presynaptic terminals. AU - Dimitrov, Dimitar AU - Guillaud, Laurent AU - Eguchi, Kohgaku AU - Takahashi, Tomoyuki ED - Skaper, Stephen D. ID - 562 T2 - Neurotrophic Factors TI - Culture of mouse giant central nervous system synapses and application for imaging and electrophysiological analyses VL - 1727 ER - TY - CHAP AB - Graph-based games are an important tool in computer science. They have applications in synthesis, verification, refinement, and far beyond. We review graphbased games with objectives on infinite plays. We give definitions and algorithms to solve the games and to give a winning strategy. The objectives we consider are mostly Boolean, but we also look at quantitative graph-based games and their objectives. Synthesis aims to turn temporal logic specifications into correct reactive systems. We explain the reduction of synthesis to graph-based games (or equivalently tree automata) using synthesis of LTL specifications as an example. We treat the classical approach that uses determinization of parity automata and more modern approaches. AU - Bloem, Roderick AU - Chatterjee, Krishnendu AU - Jobstmann, Barbara ED - Henzinger, Thomas A ED - Clarke, Edmund M. ED - Veith, Helmut ED - Bloem, Roderick ID - 59 SN - 978-3-319-10574-1 T2 - Handbook of Model Checking TI - Graph games and reactive synthesis ER - TY - CHAP AB - Model checking is a computer-assisted method for the analysis of dynamical systems that can be modeled by state-transition systems. Drawing from research traditions in mathematical logic, programming languages, hardware design, and theoretical computer science, model checking is now widely used for the verification of hardware and software in industry. This chapter is an introduction and short survey of model checking. The chapter aims to motivate and link the individual chapters of the handbook, and to provide context for readers who are not familiar with model checking. AU - Clarke, Edmund AU - Henzinger, Thomas A AU - Veith, Helmut ED - Henzinger, Thomas A ID - 60 T2 - Handbook of Model Checking TI - Introduction to model checking ER - TY - CHAP AB - We prove that there is no strongly regular graph (SRG) with parameters (460; 153; 32; 60). The proof is based on a recent lower bound on the number of 4-cliques in a SRG and some applications of Euclidean representation of SRGs. AU - Bondarenko, Andriy AU - Mellit, Anton AU - Prymak, Andriy AU - Radchenko, Danylo AU - Viazovska, Maryna ID - 61 T2 - Contemporary Computational Mathematics TI - There is no strongly regular graph with parameters (460; 153; 32; 60) ER - TY - JOUR AB - Blood platelets are critical for hemostasis and thrombosis, but also play diverse roles during immune responses. We have recently reported that platelets migrate at sites of infection in vitro and in vivo. Importantly, platelets use their ability to migrate to collect and bundle fibrin (ogen)-bound bacteria accomplishing efficient intravascular bacterial trapping. Here, we describe a method that allows analyzing platelet migration in vitro, focusing on their ability to collect bacteria and trap bacteria under flow. AU - Fan, Shuxia AU - Lorenz, Michael AU - Massberg, Steffen AU - Gärtner, Florian R ID - 6354 IS - 18 JF - Bio-Protocol KW - Platelets KW - Cell migration KW - Bacteria KW - Shear flow KW - Fibrinogen KW - E. coli SN - 2331-8325 TI - Platelet migration and bacterial trapping assay under flow VL - 8 ER - TY - CHAP AB - This chapter finds an agreement of equivariant indices of semi-classical homomorphisms between pairwise mirror branes in the GL2 Higgs moduli space on a Riemann surface. On one side of the agreement, components of the Lagrangian brane of U(1,1) Higgs bundles, whose mirror was proposed by Hitchin to be certain even exterior powers of the hyperholomorphic Dirac bundle on the SL2 Higgs moduli space, are present. The agreement arises from a mysterious functional equation. This gives strong computational evidence for Hitchin’s proposal. AU - Hausel, Tamás AU - Mellit, Anton AU - Pei, Du ID - 6525 SN - 9780198802013 T2 - Geometry and Physics: Volume I TI - Mirror symmetry with branes by equivariant verlinde formulas ER - TY - JOUR AB - We consider spectral properties and the edge universality of sparse random matrices, the class of random matrices that includes the adjacency matrices of the Erdős–Rényi graph model G(N, p). We prove a local law for the eigenvalue density up to the spectral edges. Under a suitable condition on the sparsity, we also prove that the rescaled extremal eigenvalues exhibit GOE Tracy–Widom fluctuations if a deterministic shift of the spectral edge due to the sparsity is included. For the adjacency matrix of the Erdős–Rényi graph this establishes the Tracy–Widom fluctuations of the second largest eigenvalue when p is much larger than N−2/3 with a deterministic shift of order (Np)−1. AU - Lee, Jii AU - Schnelli, Kevin ID - 690 IS - 1-2 JF - Probability Theory and Related Fields TI - Local law and Tracy–Widom limit for sparse random matrices VL - 171 ER - TY - JOUR AB - We consider the NP-hard problem of MAP-inference for undirected discrete graphical models. We propose a polynomial time and practically efficient algorithm for finding a part of its optimal solution. Specifically, our algorithm marks some labels of the considered graphical model either as (i) optimal, meaning that they belong to all optimal solutions of the inference problem; (ii) non-optimal if they provably do not belong to any solution. With access to an exact solver of a linear programming relaxation to the MAP-inference problem, our algorithm marks the maximal possible (in a specified sense) number of labels. We also present a version of the algorithm, which has access to a suboptimal dual solver only and still can ensure the (non-)optimality for the marked labels, although the overall number of the marked labels may decrease. We propose an efficient implementation, which runs in time comparable to a single run of a suboptimal dual solver. Our method is well-scalable and shows state-of-the-art results on computational benchmarks from machine learning and computer vision. AU - Shekhovtsov, Alexander AU - Swoboda, Paul AU - Savchynskyy, Bogdan ID - 703 IS - 7 JF - IEEE Transactions on Pattern Analysis and Machine Intelligence SN - 01628828 TI - Maximum persistency via iterative relaxed inference with graphical models VL - 40 ER - TY - CONF AB - Training deep learning models has received tremendous research interest recently. In particular, there has been intensive research on reducing the communication cost of training when using multiple computational devices, through reducing the precision of the underlying data representation. Naturally, such methods induce system trade-offs—lowering communication precision could de-crease communication overheads and improve scalability; but, on the other hand, it can also reduce the accuracy of training. In this paper, we study this trade-off space, and ask:Can low-precision communication consistently improve the end-to-end performance of training modern neural networks, with no accuracy loss?From the performance point of view, the answer to this question may appear deceptively easy: compressing communication through low precision should help when the ratio between communication and computation is high. However, this answer is less straightforward when we try to generalize this principle across various neural network architectures (e.g., AlexNet vs. ResNet),number of GPUs (e.g., 2 vs. 8 GPUs), machine configurations(e.g., EC2 instances vs. NVIDIA DGX-1), communication primitives (e.g., MPI vs. NCCL), and even different GPU architectures(e.g., Kepler vs. Pascal). Currently, it is not clear how a realistic realization of all these factors maps to the speed up provided by low-precision communication. In this paper, we conduct an empirical study to answer this question and report the insights. AU - Grubic, Demjan AU - Tam, Leo AU - Alistarh, Dan-Adrian AU - Zhang, Ce ID - 7116 SN - 2367-2005 T2 - Proceedings of the 21st International Conference on Extending Database Technology TI - Synchronous multi-GPU training for deep learning with low-precision communications: An empirical study ER - TY - CONF AB - Proofs of space (PoS) [Dziembowski et al., CRYPTO'15] are proof systems where a prover can convince a verifier that he "wastes" disk space. PoS were introduced as a more ecological and economical replacement for proofs of work which are currently used to secure blockchains like Bitcoin. In this work we investigate extensions of PoS which allow the prover to embed useful data into the dedicated space, which later can be recovered. Our first contribution is a security proof for the original PoS from CRYPTO'15 in the random oracle model (the original proof only applied to a restricted class of adversaries which can store a subset of the data an honest prover would store). When this PoS is instantiated with recent constructions of maximally depth robust graphs, our proof implies basically optimal security. As a second contribution we show three different extensions of this PoS where useful data can be embedded into the space required by the prover. Our security proof for the PoS extends (non-trivially) to these constructions. We discuss how some of these variants can be used as proofs of catalytic space (PoCS), a notion we put forward in this work, and which basically is a PoS where most of the space required by the prover can be used to backup useful data. Finally we discuss how one of the extensions is a candidate construction for a proof of replication (PoR), a proof system recently suggested in the Filecoin whitepaper. AU - Pietrzak, Krzysztof Z ID - 7407 SN - 1868-8969 T2 - 10th Innovations in Theoretical Computer Science Conference (ITCS 2019) TI - Proofs of catalytic space VL - 124 ER - TY - JOUR 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 article, 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 - Leiserson, William AU - Matveev, Alexander AU - Shavit, Nir ID - 6001 IS - 4 JF - ACM Transactions on Parallel Computing SN - 2329-4949 TI - ThreadScan: Automatic and scalable memory reclamation VL - 4 ER - TY - CONF AB - Deep neural networks (DNNs) continue to make significant advances, solving tasks from image classification to translation or reinforcement learning. One aspect of the field receiving considerable attention is efficiently executing deep models in resource-constrained environments, such as mobile or embedded devices. This paper focuses on this problem, and proposes two new compression methods, which jointly leverage weight quantization and distillation of larger teacher networks into smaller student networks. The first method we propose is called quantized distillation and leverages distillation during the training process, by incorporating distillation loss, expressed with respect to the teacher, into the training of a student network whose weights are quantized to a limited set of levels. The second method, differentiable quantization, optimizes the location of quantization points through stochastic gradient descent, to better fit the behavior of the teacher model. We validate both methods through experiments on convolutional and recurrent architectures. We show that quantized shallow students can reach similar accuracy levels to full-precision teacher models, while providing order of magnitude compression, and inference speedup that is linear in the depth reduction. In sum, our results enable DNNs for resource-constrained environments to leverage architecture and accuracy advances developed on more powerful devices. AU - Polino, Antonio AU - Pascanu, Razvan AU - Alistarh, Dan-Adrian ID - 7812 T2 - 6th International Conference on Learning Representations TI - Model compression via distillation and quantization ER - TY - GEN AB - The cerebral cortex contains multiple hierarchically organized areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have quantitatively investigated the neuronal output of individual progenitor cells in the ventricular zone of the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. We found that individual cortical progenitor cells show a high degree of stochasticity and generate pyramidal cell lineages that adopt a wide range of laminar configurations. Mathematical modelling these lineage data suggests that a small number of progenitor cell populations, each generating pyramidal cells following different stochastic developmental programs, suffice to generate the heterogenous complement of pyramidal cell lineages that collectively build the complex cytoarchitecture of the neocortex. AU - Llorca, Alfredo AU - Ciceri, Gabriele AU - Beattie, Robert J AU - Wong, Fong K. AU - Diana, Giovanni AU - Serafeimidou, Eleni AU - Fernández-Otero, Marian AU - Streicher, Carmen AU - Arnold, Sebastian J. AU - Meyer, Martin AU - Hippenmeyer, Simon AU - Maravall, Miguel AU - Marín, Oscar ID - 8547 T2 - bioRxiv TI - Heterogeneous progenitor cell behaviors underlie the assembly of neocortical cytoarchitecture ER - TY - CHAP AB - Responsiveness—the requirement that every request to a system be eventually handled—is one of the fundamental liveness properties of a reactive system. Average response time is a quantitative measure for the responsiveness requirement used commonly in performance evaluation. We show how average response time can be computed on state-transition graphs, on Markov chains, and on game graphs. In all three cases, we give polynomial-time algorithms. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan ED - Lohstroh, Marten ED - Derler, Patricia ED - Sirjani, Marjan ID - 86 T2 - Principles of Modeling TI - Computing average response time VL - 10760 ER - TY - JOUR AU - Danzl, Johann G ID - 9229 IS - S1 JF - Opera Medica et Physiologica SN - 2500-2287 TI - Diffraction-unlimited optical imaging for synaptic physiology VL - 4 ER - TY - CONF AB - Network games are widely used as a model for selfish resource-allocation problems. In the classicalmodel, each player selects a path connecting her source and target vertices. The cost of traversingan edge depends on theload; namely, number of players that traverse it. Thus, it abstracts the factthat different users may use a resource at different times and for different durations, which playsan important role in determining the costs of the users in reality. For example, when transmittingpackets in a communication network, routing traffic in a road network, or processing a task in aproduction system, actual sharing and congestion of resources crucially depends on time.In [13], we introducedtimed network games, which add a time component to network games.Each vertexvin the network is associated with a cost function, mapping the load onvto theprice that a player pays for staying invfor one time unit with this load. Each edge in thenetwork is guarded by the time intervals in which it can be traversed, which forces the players tospend time in the vertices. In this work we significantly extend the way time can be referred toin timed network games. In the model we study, the network is equipped withclocks, and, as intimed automata, edges are guarded by constraints on the values of the clocks, and their traversalmay involve a reset of some clocks. We argue that the stronger model captures many realisticnetworks. The addition of clocks breaks the techniques we developed in [13] and we developnew techniques in order to show that positive results on classic network games carry over to thestronger timed setting. AU - Avni, Guy AU - Guha, Shibashis AU - Kupferman, Orna ID - 6005 SN - 1868-8969 TI - Timed network games with clocks VL - 117 ER - TY - JOUR AB - More than 100 years after Grigg’s influential analysis of species’ borders, the causes of limits to species’ ranges still represent a puzzle that has never been understood with clarity. The topic has become especially important recently as many scientists have become interested in the potential for species’ ranges to shift in response to climate change—and yet nearly all of those studies fail to recognise or incorporate evolutionary genetics in a way that relates to theoretical developments. I show that range margins can be understood based on just two measurable parameters: (i) the fitness cost of dispersal—a measure of environmental heterogeneity—and (ii) the strength of genetic drift, which reduces genetic diversity. Together, these two parameters define an ‘expansion threshold’: adaptation fails when genetic drift reduces genetic diversity below that required for adaptation to a heterogeneous environment. When the key parameters drop below this expansion threshold locally, a sharp range margin forms. When they drop below this threshold throughout the species’ range, adaptation collapses everywhere, resulting in either extinction or formation of a fragmented metapopulation. Because the effects of dispersal differ fundamentally with dimension, the second parameter—the strength of genetic drift—is qualitatively different compared to a linear habitat. In two-dimensional habitats, genetic drift becomes effectively independent of selection. It decreases with ‘neighbourhood size’—the number of individuals accessible by dispersal within one generation. Moreover, in contrast to earlier predictions, which neglected evolution of genetic variance and/or stochasticity in two dimensions, dispersal into small marginal populations aids adaptation. This is because the reduction of both genetic and demographic stochasticity has a stronger effect than the cost of dispersal through increased maladaptation. The expansion threshold thus provides a novel, theoretically justified, and testable prediction for formation of the range margin and collapse of the species’ range. AU - Polechova, Jitka ID - 315 IS - 6 JF - PLoS Biology SN - 15449173 TI - Is the sky the limit? On the expansion threshold of a species’ range VL - 16 ER - TY - JOUR AB - The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis. We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin. AU - Frost, Jennifer M. AU - Kim, M. Yvonne AU - Park, Guen Tae AU - Hsieh, Ping-Hung AU - Nakamura, Miyuki AU - Lin, Samuel J. H. AU - Yoo, Hyunjin AU - Choi, Jaemyung AU - Ikeda, Yoko AU - Kinoshita, Tetsu AU - Choi, Yeonhee AU - Zilberman, Daniel AU - Fischer, Robert L. ID - 9471 IS - 20 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis VL - 115 ER - TY - CONF AB - A drawing of a graph on a surface is independently even if every pair of nonadjacent edges in the drawing crosses an even number of times. The ℤ2-genus of a graph G is the minimum g such that G has an independently even drawing on the orientable surface of genus g. An unpublished result by Robertson and Seymour implies that for every t, every graph of sufficiently large genus contains as a minor a projective t × t grid or one of the following so-called t-Kuratowski graphs: K3, t, or t copies of K5 or K3,3 sharing at most 2 common vertices. We show that the ℤ2-genus of graphs in these families is unbounded in t; in fact, equal to their genus. Together, this implies that the genus of a graph is bounded from above by a function of its ℤ2-genus, solving a problem posed by Schaefer and Štefankovič, and giving an approximate version of the Hanani-Tutte theorem on orientable surfaces. AU - Fulek, Radoslav AU - Kynčl, Jan ID - 186 TI - The ℤ2-Genus of Kuratowski minors VL - 99 ER - TY - CONF AB - A thrackle is a graph drawn in the plane so that every pair of its edges meet exactly once: either at a common end vertex or in a proper crossing. We prove that any thrackle of n vertices has at most 1.3984n edges. Quasi-thrackles are defined similarly, except that every pair of edges that do not share a vertex are allowed to cross an odd number of times. It is also shown that the maximum number of edges of a quasi-thrackle on n vertices is 3/2(n-1), and that this bound is best possible for infinitely many values of n. AU - Fulek, Radoslav AU - Pach, János ID - 433 TI - Thrackles: An improved upper bound VL - 10692 ER - TY - GEN AB - Both classical and recent studies suggest that chromosomal inversion polymorphisms are important in adaptation and speciation. However, biases in discovery and reporting of inversions make it difficult to assess their prevalence and biological importance. Here, we use an approach based on linkage disequilibrium among markers genotyped for samples collected across a transect between contrasting habitats to detect chromosomal rearrangements de novo. We report 17 polymorphic rearrangements in a single locality for the coastal marine snail, Littorina saxatilis. Patterns of diversity in the field and of recombination in controlled crosses provide strong evidence that at least the majority of these rearrangements are inversions. Most show clinal changes in frequency between habitats, suggestive of divergent selection, but only one appears to be fixed for different arrangements in the two habitats. Consistent with widespread evidence for balancing selection on inversion polymorphisms, we argue that a combination of heterosis and divergent selection can explain the observed patterns and should be considered in other systems spanning environmental gradients. AU - Faria, Rui AU - Chaube, Pragya AU - Morales, Hernán E. AU - Larsson, Tomas AU - Lemmon, Alan R. AU - Lemmon, Emily M. AU - Rafajlović, Marina AU - Panova, Marina AU - Ravinet, Mark AU - Johannesson, Kerstin AU - Westram, Anja M AU - Butlin, Roger K. ID - 9837 TI - Data from: Multiple chromosomal rearrangements in a hybrid zone between Littorina saxatilis ecotypes ER - TY - CHAP AB - We prove that every congruence distributive variety has directed Jónsson terms, and every congruence modular variety has directed Gumm terms. The directed terms we construct witness every case of absorption witnessed by the original Jónsson or Gumm terms. This result is equivalent to a pair of claims about absorption for admissible preorders in congruence distributive and congruence modular varieties, respectively. For finite algebras, these absorption theorems have already seen significant applications, but until now, it was not clear if the theorems hold for general algebras as well. Our method also yields a novel proof of a result by P. Lipparini about the existence of a chain of terms (which we call Pixley terms) in varieties that are at the same time congruence distributive and k-permutable for some k. AU - Kazda, Alexandr AU - Kozik, Marcin AU - McKenzie, Ralph AU - Moore, Matthew ED - Czelakowski, J ID - 10864 SN - 2211-2758 T2 - Don Pigozzi on Abstract Algebraic Logic, Universal Algebra, and Computer Science TI - Absorption and directed Jónsson terms VL - 16 ER - TY - CONF AB - We prove that for every d ≥ 2, deciding if a pure, d-dimensional, simplicial complex is shellable is NP-hard, hence NP-complete. This resolves a question raised, e.g., by Danaraj and Klee in 1978. Our reduction also yields that for every d ≥ 2 and k ≥ 0, deciding if a pure, d-dimensional, simplicial complex is k-decomposable is NP-hard. For d ≥ 3, both problems remain NP-hard when restricted to contractible pure d-dimensional complexes. AU - Goaoc, Xavier AU - Paták, Pavel AU - Patakova, Zuzana AU - Tancer, Martin AU - Wagner, Uli ID - 184 TI - Shellability is NP-complete VL - 99 ER - TY - CONF AB - In graph theory, as well as in 3-manifold topology, there exist several width-type parameters to describe how "simple" or "thin" a given graph or 3-manifold is. These parameters, such as pathwidth or treewidth for graphs, or the concept of thin position for 3-manifolds, play an important role when studying algorithmic problems; in particular, there is a variety of problems in computational 3-manifold topology - some of them known to be computationally hard in general - that become solvable in polynomial time as soon as the dual graph of the input triangulation has bounded treewidth. In view of these algorithmic results, it is natural to ask whether every 3-manifold admits a triangulation of bounded treewidth. We show that this is not the case, i.e., that there exists an infinite family of closed 3-manifolds not admitting triangulations of bounded pathwidth or treewidth (the latter implies the former, but we present two separate proofs). We derive these results from work of Agol and of Scharlemann and Thompson, by exhibiting explicit connections between the topology of a 3-manifold M on the one hand and width-type parameters of the dual graphs of triangulations of M on the other hand, answering a question that had been raised repeatedly by researchers in computational 3-manifold topology. In particular, we show that if a closed, orientable, irreducible, non-Haken 3-manifold M has a triangulation of treewidth (resp. pathwidth) k then the Heegaard genus of M is at most 48(k+1) (resp. 4(3k+1)). AU - Huszár, Kristóf AU - Spreer, Jonathan AU - Wagner, Uli ID - 285 SN - 18688969 TI - On the treewidth of triangulated 3-manifolds VL - 99 ER - TY - GEN AB - This dataset contains a GitHub repository containing all the data, analysis, Nextflow workflows and Jupyter notebooks to replicate the manuscript titled "Fast and accurate large multiple sequence alignments with a root-to-leaf regressive method". It also contains the Multiple Sequence Alignments (MSAs) generated and well as the main figures and tables from the manuscript. The repository is also available at GitHub (https://github.com/cbcrg/dpa-analysis) release `v1.2`. For details on how to use the regressive alignment algorithm, see the T-Coffee software suite (https://github.com/cbcrg/tcoffee). AU - Garriga, Edgar AU - di Tommaso, Paolo AU - Magis, Cedrik AU - Erb, Ionas AU - Mansouri, Leila AU - Baltzis, Athanasios AU - Laayouni, Hafid AU - Kondrashov, Fyodor AU - Floden, Evan AU - Notredame, Cedric ID - 13059 TI - Fast and accurate large multiple sequence alignments with a root-to-leaf regressive method ER - TY - THES AB - Nowadays, quantum computation is receiving more and more attention as an alternative to the classical way of computing. For realizing a quantum computer, different devices are investigated as potential quantum bits. In this thesis, the focus is on Ge hut wires, which turned out to be promising candidates for implementing hole spin quantum bits. The advantages of Ge as a material system are the low hyperfine interaction for holes and the strong spin orbit coupling, as well as the compatibility with the highly developed CMOS processes in industry. In addition, Ge can also be isotopically purified which is expected to boost the spin coherence times. The strong spin orbit interaction for holes in Ge on the one hand enables the full electrical control of the quantum bit and on the other hand should allow short spin manipulation times. Starting with a bare Si wafer, this work covers the entire process reaching from growth over the fabrication and characterization of hut wire devices up to the demonstration of hole spin resonance. From experiments with single quantum dots, a large g-factor anisotropy between the in-plane and the out-of-plane direction was found. A comparison to a theoretical model unveiled the heavy-hole character of the lowest energy states. The second part of the thesis addresses double quantum dot devices, which were realized by adding two gate electrodes to a hut wire. In such devices, Pauli spin blockade was observed, which can serve as a read-out mechanism for spin quantum bits. Applying oscillating electric fields in spin blockade allowed the demonstration of continuous spin rotations and the extraction of a lower bound for the spin dephasing time. Despite the strong spin orbit coupling in Ge, the obtained value for the dephasing time is comparable to what has been recently reported for holes in Si. All in all, the presented results point out the high potential of Ge hut wires as a platform for long-lived, fast and fully electrically tunable hole spin quantum bits. AU - Watzinger, Hannes ID - 49 SN - 2663-337X TI - Ge hut wires - from growth to hole spin resonance ER - TY - THES AB - We describe arrangements of three-dimensional spheres from a geometrical and topological point of view. Real data (fitting this setup) often consist of soft spheres which show certain degree of deformation while strongly packing against each other. In this context, we answer the following questions: If we model a soft packing of spheres by hard spheres that are allowed to overlap, can we measure the volume in the overlapped areas? Can we be more specific about the overlap volume, i.e. quantify how much volume is there covered exactly twice, three times, or k times? What would be a good optimization criteria that rule the arrangement of soft spheres while making a good use of the available space? Fixing a particular criterion, what would be the optimal sphere configuration? The first result of this thesis are short formulas for the computation of volumes covered by at least k of the balls. The formulas exploit information contained in the order-k Voronoi diagrams and its closely related Level-k complex. The used complexes lead to a natural generalization into poset diagrams, a theoretical formalism that contains the order-k and degree-k diagrams as special cases. In parallel, we define different criteria to determine what could be considered an optimal arrangement from a geometrical point of view. Fixing a criterion, we find optimal soft packing configurations in 2D and 3D where the ball centers lie on a lattice. As a last step, we use tools from computational topology on real physical data, to show the potentials of higher-order diagrams in the description of melting crystals. The results of the experiments leaves us with an open window to apply the theories developed in this thesis in real applications. AU - Iglesias Ham, Mabel ID - 201 SN - 2663-337X TI - Multiple covers with balls ER - TY - THES AB - The most common assumption made in statistical learning theory is the assumption of the independent and identically distributed (i.i.d.) data. While being very convenient mathematically, it is often very clearly violated in practice. This disparity between the machine learning theory and applications underlies a growing demand in the development of algorithms that learn from dependent data and theory that can provide generalization guarantees similar to the independent situations. This thesis is dedicated to two variants of dependencies that can arise in practice. One is a dependence on the level of samples in a single learning task. Another dependency type arises in the multi-task setting when the tasks are dependent on each other even though the data for them can be i.i.d. In both cases we model the data (samples or tasks) as stochastic processes and introduce new algorithms for both settings that take into account and exploit the resulting dependencies. We prove the theoretical guarantees on the performance of the introduced algorithms under different evaluation criteria and, in addition, we compliment the theoretical study by the empirical one, where we evaluate some of the algorithms on two real world datasets to highlight their practical applicability. AU - Zimin, Alexander ID - 68 SN - 2663-337X TI - Learning from dependent data ER - TY - THES AB - A proof system is a protocol between a prover and a verifier over a common input in which an honest prover convinces the verifier of the validity of true statements. Motivated by the success of decentralized cryptocurrencies, exemplified by Bitcoin, the focus of this thesis will be on proof systems which found applications in some sustainable alternatives to Bitcoin, such as the Spacemint and Chia cryptocurrencies. In particular, we focus on proofs of space and proofs of sequential work. Proofs of space (PoSpace) were suggested as more ecological, economical, and egalitarian alternative to the energy-wasteful proof-of-work mining of Bitcoin. However, the state-of-the-art constructions of PoSpace are based on sophisticated graph pebbling lower bounds, and are therefore complex. Moreover, when these PoSpace are used in cryptocurrencies like Spacemint, miners can only start mining after ensuring that a commitment to their space is already added in a special transaction to the blockchain. Proofs of sequential work (PoSW) are proof systems in which a prover, upon receiving a statement x and a time parameter T, computes a proof which convinces the verifier that T time units had passed since x was received. Whereas Spacemint assumes synchrony to retain some interesting Bitcoin dynamics, Chia requires PoSW with unique proofs, i.e., PoSW in which it is hard to come up with more than one accepting proof for any true statement. In this thesis we construct simple and practically-efficient PoSpace and PoSW. When using our PoSpace in cryptocurrencies, miners can start mining on the fly, like in Bitcoin, and unlike current constructions of PoSW, which either achieve efficient verification of sequential work, or faster-than-recomputing verification of correctness of proofs, but not both at the same time, ours achieve the best of these two worlds. AU - Abusalah, Hamza M ID - 83 SN - 2663-337X TI - Proof systems for sustainable decentralized cryptocurrencies ER - TY - THES AB - Modern computer vision systems heavily rely on statistical machine learning models, which typically require large amounts of labeled data to be learned reliably. Moreover, very recently computer vision research widely adopted techniques for representation learning, which further increase the demand for labeled data. However, for many important practical problems there is relatively small amount of labeled data available, so it is problematic to leverage full potential of the representation learning methods. One way to overcome this obstacle is to invest substantial resources into producing large labelled datasets. Unfortunately, this can be prohibitively expensive in practice. In this thesis we focus on the alternative way of tackling the aforementioned issue. We concentrate on methods, which make use of weakly-labeled or even unlabeled data. Specifically, the first half of the thesis is dedicated to the semantic image segmentation task. We develop a technique, which achieves competitive segmentation performance and only requires annotations in a form of global image-level labels instead of dense segmentation masks. Subsequently, we present a new methodology, which further improves segmentation performance by leveraging tiny additional feedback from a human annotator. By using our methods practitioners can greatly reduce the amount of data annotation effort, which is required to learn modern image segmentation models. In the second half of the thesis we focus on methods for learning from unlabeled visual data. We study a family of autoregressive models for modeling structure of natural images and discuss potential applications of these models. Moreover, we conduct in-depth study of one of these applications, where we develop the state-of-the-art model for the probabilistic image colorization task. AU - Kolesnikov, Alexander ID - 197 SN - 2663-337X TI - Weakly-Supervised Segmentation and Unsupervised Modeling of Natural Images ER - TY - JOUR AB - A central problem of algebraic topology is to understand the homotopy groups 𝜋𝑑(𝑋) of a topological space X. For the computational version of the problem, it is well known that there is no algorithm to decide whether the fundamental group 𝜋1(𝑋) of a given finite simplicial complex X is trivial. On the other hand, there are several algorithms that, given a finite simplicial complex X that is simply connected (i.e., with 𝜋1(𝑋) trivial), compute the higher homotopy group 𝜋𝑑(𝑋) for any given 𝑑≥2 . However, these algorithms come with a caveat: They compute the isomorphism type of 𝜋𝑑(𝑋) , 𝑑≥2 as an abstract finitely generated abelian group given by generators and relations, but they work with very implicit representations of the elements of 𝜋𝑑(𝑋) . Converting elements of this abstract group into explicit geometric maps from the d-dimensional sphere 𝑆𝑑 to X has been one of the main unsolved problems in the emerging field of computational homotopy theory. Here we present an algorithm that, given a simply connected space X, computes 𝜋𝑑(𝑋) and represents its elements as simplicial maps from a suitable triangulation of the d-sphere 𝑆𝑑 to X. For fixed d, the algorithm runs in time exponential in size(𝑋) , the number of simplices of X. Moreover, we prove that this is optimal: For every fixed 𝑑≥2 , we construct a family of simply connected spaces X such that for any simplicial map representing a generator of 𝜋𝑑(𝑋) , the size of the triangulation of 𝑆𝑑 on which the map is defined, is exponential in size(𝑋) . AU - Filakovský, Marek AU - Franek, Peter AU - Wagner, Uli AU - Zhechev, Stephan Y ID - 6774 IS - 3-4 JF - Journal of Applied and Computational Topology SN - 2367-1726 TI - Computing simplicial representatives of homotopy group elements VL - 2 ER - TY - CONF AB - Synchronous programs are easy to specify because the side effects of an operation are finished by the time the invocation of the operation returns to the caller. Asynchronous programs, on the other hand, are difficult to specify because there are side effects due to pending computation scheduled as a result of the invocation of an operation. They are also difficult to verify because of the large number of possible interleavings of concurrent computation threads. We present synchronization, a new proof rule that simplifies the verification of asynchronous programs by introducing the fiction, for proof purposes, that asynchronous operations complete synchronously. Synchronization summarizes an asynchronous computation as immediate atomic effect. Modular verification is enabled via pending asynchronous calls in atomic summaries, and a complementary proof rule that eliminates pending asynchronous calls when components and their specifications are composed. We evaluate synchronization in the context of a multi-layer refinement verification methodology on a collection of benchmark programs. AU - Kragl, Bernhard AU - Qadeer, Shaz AU - Henzinger, Thomas A ID - 133 SN - 18688969 TI - Synchronizing the asynchronous VL - 118 ER - TY - CONF AB - Given a locally finite X ⊆ ℝd and a radius r ≥ 0, the k-fold cover of X and r consists of all points in ℝd that have k or more points of X within distance r. We consider two filtrations - one in scale obtained by fixing k and increasing r, and the other in depth obtained by fixing r and decreasing k - and we compute the persistence diagrams of both. While standard methods suffice for the filtration in scale, we need novel geometric and topological concepts for the filtration in depth. In particular, we introduce a rhomboid tiling in ℝd+1 whose horizontal integer slices are the order-k Delaunay mosaics of X, and construct a zigzag module from Delaunay mosaics that is isomorphic to the persistence module of the multi-covers. AU - Edelsbrunner, Herbert AU - Osang, Georg F ID - 187 TI - The multi-cover persistence of Euclidean balls VL - 99 ER - TY - JOUR AB - We consider families of confocal conics and two pencils of Apollonian circles having the same foci. We will show that these families of curves generate trivial 3-webs and find the exact formulas describing them. AU - Akopyan, Arseniy ID - 692 IS - 1 JF - Geometriae Dedicata TI - 3-Webs generated by confocal conics and circles VL - 194 ER - TY - JOUR AB - Holes confined in quantum dots have gained considerable interest in the past few years due to their potential as spin qubits. Here we demonstrate two-axis control of a spin 3/2 qubit in natural Ge. The qubit is formed in a hut wire double quantum dot device. The Pauli spin blockade principle allowed us to demonstrate electric dipole spin resonance by applying a radio frequency electric field to one of the electrodes defining the double quantum dot. Coherent hole spin oscillations with Rabi frequencies reaching 140 MHz are demonstrated and dephasing times of 130 ns are measured. The reported results emphasize the potential of Ge as a platform for fast and electrically tunable hole spin qubit devices. AU - Watzinger, Hannes AU - Kukucka, Josip AU - Vukusic, Lada AU - Gao, Fei AU - Wang, Ting AU - Schäffler, Friedrich AU - Zhang, Jian AU - Katsaros, Georgios ID - 77 IS - 3902 JF - Nature Communications TI - A germanium hole spin qubit VL - 9 ER - TY - JOUR AB - The actomyosin cytoskeleton, a key stress-producing unit in epithelial cells, oscillates spontaneously in a wide variety of systems. Although much of the signal cascade regulating myosin activity has been characterized, the origin of such oscillatory behavior is still unclear. Here, we show that basal myosin II oscillation in Drosophila ovarian epithelium is not controlled by actomyosin cortical tension, but instead relies on a biochemical oscillator involving ROCK and myosin phosphatase. Key to this oscillation is a diffusive ROCK flow, linking junctional Rho1 to medial actomyosin cortex, and dynamically maintained by a self-activation loop reliant on ROCK kinase activity. In response to the resulting myosin II recruitment, myosin phosphatase is locally enriched and shuts off ROCK and myosin II signals. Coupling Drosophila genetics, live imaging, modeling, and optogenetics, we uncover an intrinsic biochemical oscillator at the core of myosin II regulatory network, shedding light on the spatio-temporal dynamics of force generation. AU - Qin, Xiang AU - Hannezo, Edouard B AU - Mangeat, Thomas AU - Liu, Chang AU - Majumder, Pralay AU - Liu, Jjiaying AU - Choesmel Cadamuro, Valerie AU - Mcdonald, Jocelyn AU - Liu, Yinyao AU - Yi, Bin AU - Wang, Xiaobo ID - 401 IS - 1 JF - Nature Communications TI - A biochemical network controlling basal myosin oscillation VL - 9 ER - TY - JOUR AB - The insect’s fat body combines metabolic and immunological functions. In this issue of Developmental Cell, Franz et al. (2018) show that in Drosophila, cells of the fat body are not static, but can actively “swim” toward sites of epithelial injury, where they physically clog the wound and locally secrete antimicrobial peptides. AU - Casano, Alessandra M AU - Sixt, Michael K ID - 318 IS - 4 JF - Developmental Cell TI - A fat lot of good for wound healing VL - 44 ER - TY - JOUR AB - Lesion verification and quantification is traditionally done via histological examination of sectioned brains, a time-consuming process that relies heavily on manual estimation. Such methods are particularly problematic in posterior cortical regions (e.g. visual cortex), where sectioning leads to significant damage and distortion of tissue. Even more challenging is the post hoc localization of micro-electrodes, which relies on the same techniques, suffers from similar drawbacks and requires even higher precision. Here, we propose a new, simple method for quantitative lesion characterization and electrode localization that is less labor-intensive and yields more detailed results than conventional methods. We leverage staining techniques standard in electron microscopy with the use of commodity micro-CT imaging. We stain whole rat and zebra finch brains in osmium tetroxide, embed these in resin and scan entire brains in a micro-CT machine. The scans result in 3D reconstructions of the brains with section thickness dependent on sample size (12–15 and 5–6 microns for rat and zebra finch respectively) that can be segmented manually or automatically. Because the method captures the entire intact brain volume, comparisons within and across studies are more tractable, and the extent of lesions and electrodes may be studied with higher accuracy than with current methods. AU - Masís, Javier AU - Mankus, David AU - Wolff, Steffen AU - Guitchounts, Grigori AU - Jösch, Maximilian A AU - Cox, David ID - 410 IS - 1 JF - Scientific Reports TI - A micro-CT-based method for quantitative brain lesion characterization and electrode localization VL - 8 ER - TY - JOUR AB - Arabidopsis and human ARM protein interact with telomerase. Deregulated mRNA levels of DNA repair and ribosomal protein genes in an Arabidopsis arm mutant suggest non-telomeric ARM function. The human homolog ARMC6 interacts with hTRF2. Abstract: Telomerase maintains telomeres and has proposed non-telomeric functions. We previously identified interaction of the C-terminal domain of Arabidopsis telomerase reverse transcriptase (AtTERT) with an armadillo/β-catenin-like repeat (ARM) containing protein. Here we explore protein–protein interactions of the ARM protein, AtTERT domains, POT1a, TRF-like family and SMH family proteins, and the chromatin remodeling protein CHR19 using bimolecular fluorescence complementation (BiFC), yeast two-hybrid (Y2H) analysis, and co-immunoprecipitation. The ARM protein interacts with both the N- and C-terminal domains of AtTERT in different cellular compartments. ARM interacts with CHR19 and TRF-like I family proteins that also bind AtTERT directly or through interaction with POT1a. The putative human ARM homolog co-precipitates telomerase activity and interacts with hTRF2 protein in vitro. Analysis of Arabidopsis arm mutants shows no obvious changes in telomere length or telomerase activity, suggesting that ARM is not essential for telomere maintenance. The observed interactions with telomerase and Myb-like domain proteins (TRF-like family I) may therefore reflect possible non-telomeric functions. Transcript levels of several DNA repair and ribosomal genes are affected in arm mutants, and ARM, likely in association with other proteins, suppressed expression of XRCC3 and RPSAA promoter constructs in luciferase reporter assays. In conclusion, ARM can participate in non-telomeric functions of telomerase, and can also perform its own telomerase-independent functions. AU - Dokládal, Ladislav AU - Benková, Eva AU - Honys, David AU - Dupláková, Nikoleta AU - Lee, Lan AU - Gelvin, Stanton AU - Sýkorová, Eva ID - 277 IS - 5 JF - Plant Molecular Biology TI - An armadillo-domain protein participates in a telomerase interaction network VL - 97 ER - TY - CONF AB - We introduce in this paper AMT 2.0 , a tool for qualitative and quantitative analysis of hybrid continuous and Boolean signals that combine numerical values and discrete events. The evaluation of the signals is based on rich temporal specifications expressed in extended Signal Temporal Logic (xSTL), which integrates Timed Regular Expressions (TRE) within Signal Temporal Logic (STL). The tool features qualitative monitoring (property satisfaction checking), trace diagnostics for explaining and justifying property violations and specification-driven measurement of quantitative features of the signal. AU - Nickovic, Dejan AU - Lebeltel, Olivier AU - Maler, Oded AU - Ferrere, Thomas AU - Ulus, Dogan ED - Beyer, Dirk ED - Huisman, Marieke ID - 299 TI - AMT 2.0: Qualitative and quantitative trace analysis with extended signal temporal logic VL - 10806 ER - TY - JOUR AB - Being cared for when sick is a benefit of sociality that can reduce disease and improve survival of group members. However, individuals providing care risk contracting infectious diseases themselves. If they contract a low pathogen dose, they may develop low-level infections that do not cause disease but still affect host immunity by either decreasing or increasing the host’s vulnerability to subsequent infections. Caring for contagious individuals can thus significantly alter the future disease susceptibility of caregivers. Using ants and their fungal pathogens as a model system, we tested if the altered disease susceptibility of experienced caregivers, in turn, affects their expression of sanitary care behavior. We found that low-level infections contracted during sanitary care had protective or neutral effects on secondary exposure to the same (homologous) pathogen but consistently caused high mortality on superinfection with a different (heterologous) pathogen. In response to this risk, the ants selectively adjusted the expression of their sanitary care. Specifically, the ants performed less grooming and more antimicrobial disinfection when caring for nestmates contaminated with heterologous pathogens compared with homologous ones. By modulating the components of sanitary care in this way the ants acquired less infectious particles of the heterologous pathogens, resulting in reduced superinfection. The performance of risk-adjusted sanitary care reveals the remarkable capacity of ants to react to changes in their disease susceptibility, according to their own infection history and to flexibly adjust collective care to individual risk. AU - Konrad, Matthias AU - Pull, Christopher AU - Metzler, Sina AU - Seif, Katharina AU - Naderlinger, Elisabeth AU - Grasse, Anna V AU - Cremer, Sylvia ID - 413 IS - 11 JF - PNAS TI - Ants avoid superinfections by performing risk-adjusted sanitary care VL - 115 ER - TY - JOUR AB - We demonstrate that identical impurities immersed in a two-dimensional many-particle bath can be viewed as flux-tube-charged-particle composites described by fractional statistics. In particular, we find that the bath manifests itself as an external magnetic flux tube with respect to the impurities, and hence the time-reversal symmetry is broken for the effective Hamiltonian describing the impurities. The emerging flux tube acts as a statistical gauge field after a certain critical coupling. This critical coupling corresponds to the intersection point between the quasiparticle state and the phonon wing, where the angular momentum is transferred from the impurity to the bath. This amounts to a novel configuration with emerging anyons. The proposed setup paves the way to realizing anyons using electrons interacting with superfluid helium or lattice phonons, as well as using atomic impurities in ultracold gases. AU - Yakaboylu, Enderalp AU - Lemeshko, Mikhail ID - 195 IS - 4 JF - Physical Review B - Condensed Matter and Materials Physics TI - Anyonic statistics of quantum impurities in two dimensions VL - 98 ER - TY - CONF AB - The task of a monitor is to watch, at run-time, the execution of a reactive system, and signal the occurrence of a safety violation in the observed sequence of events. While finite-state monitors have been studied extensively, in practice, monitoring software also makes use of unbounded memory. We define a model of automata equipped with integer-valued registers which can execute only a bounded number of instructions between consecutive events, and thus can form the theoretical basis for the study of infinite-state monitors. We classify these register monitors according to the number k of available registers, and the type of register instructions. In stark contrast to the theory of computability for register machines, we prove that for every k 1, monitors with k + 1 counters (with instruction set 〈+1, =〉) are strictly more expressive than monitors with k counters. We also show that adder monitors (with instruction set 〈1, +, =〉) are strictly more expressive than counter monitors, but are complete for monitoring all computable safety -languages for k = 6. Real-time monitors are further required to signal the occurrence of a safety violation as soon as it occurs. The expressiveness hierarchy for counter monitors carries over to real-time monitors. We then show that 2 adders cannot simulate 3 counters in real-time. Finally, we show that real-time adder monitors with inequalities are as expressive as real-time Turing machines. AU - Ferrere, Thomas AU - Henzinger, Thomas A AU - Saraç, Ege ID - 144 TI - A theory of register monitors VL - Part F138033 ER - TY - JOUR AB - Asymmetric auxin distribution is instrumental for the differential growth that causes organ bending on tropic stimuli and curvatures during plant development. Local differences in auxin concentrations are achieved mainly by polarized cellular distribution of PIN auxin transporters, but whether other mechanisms involving auxin homeostasis are also relevant for the formation of auxin gradients is not clear. Here we show that auxin methylation is required for asymmetric auxin distribution across the hypocotyl, particularly during its response to gravity. We found that loss-of-function mutants in Arabidopsis IAA CARBOXYL METHYLTRANSFERASE1 (IAMT1) prematurely unfold the apical hook, and that their hypocotyls are impaired in gravitropic reorientation. This defect is linked to an auxin-dependent increase in PIN gene expression, leading to an increased polar auxin transport and lack of asymmetric distribution of PIN3 in the iamt1 mutant. Gravitropic reorientation in the iamt1 mutant could be restored with either endodermis-specific expression of IAMT1 or partial inhibition of polar auxin transport, which also results in normal PIN gene expression levels. We propose that IAA methylation is necessary in gravity-sensing cells to restrict polar auxin transport within the range of auxin levels that allow for differential responses. AU - Abbas, Mohamad AU - Hernández, García J AU - Pollmann, Stephan AU - Samodelov, Sophia L AU - Kolb, Martina AU - Friml, Jirí AU - Hammes, Ulrich Z AU - Zurbriggen, Matias D AU - Blázquez, Miguel AU - Alabadí, David ID - 203 IS - 26 JF - PNAS TI - Auxin methylation is required for differential growth in Arabidopsis VL - 115 ER - TY - JOUR AB - Following an earlier calculation in 3D, we calculate the 2D critical temperature of a dilute, translation-invariant Bose gas using a variational formulation of the Bogoliubov approximation introduced by Critchley and Solomon in 1976. This provides the first analytical calculation of the Kosterlitz-Thouless transition temperature that includes the constant in the logarithm. AU - Napiórkowski, Marcin M AU - Reuvers, Robin AU - Solovej, Jan ID - 399 IS - 1 JF - EPL TI - Calculation of the critical temperature of a dilute Bose gas in the Bogoliubov approximation VL - 121 ER - TY - JOUR AB - CLE peptides have been implicated in various developmental processes of plants and mediate their responses to environmental stimuli. However, the biological relevance of most CLE genes remains to be functionally characterized. Here, we report that CLE9, which is expressed in stomata, acts as an essential regulator in the induction of stomatal closure. Exogenous application of CLE9 peptides or overexpression of CLE9 effectively led to stomatal closure and enhanced drought tolerance, whereas CLE9 loss-of-function mutants were sensitivity to drought stress. CLE9-induced stomatal closure was impaired in abscisic acid (ABA)-deficient mutants, indicating that ABA is required for CLE9-medaited guard cell signalling. We further deciphered that two guard cell ABA-signalling components, OST1 and SLAC1, were responsible for CLE9-induced stomatal closure. MPK3 and MPK6 were activated by the CLE9 peptide, and CLE9 peptides failed to close stomata in mpk3 and mpk6 mutants. In addition, CLE9 peptides stimulated the induction of hydrogen peroxide (H2O2) and nitric oxide (NO) synthesis associated with stomatal closure, which was abolished in the NADPH oxidase-deficient mutants or nitric reductase mutants, respectively. Collectively, our results reveal a novel ABA-dependent function of CLE9 in the regulation of stomatal apertures, thereby suggesting a potential role of CLE9 in the stress acclimatization of plants. AU - Zhang, Luosha AU - Shi, Xiong AU - Zhang, Yutao AU - Wang, Jiajing AU - Yang, Jingwei AU - Ishida, Takashi AU - Jiang, Wenqian AU - Han, Xiangyu AU - Kang, Jingke AU - Wang, Xuening AU - Pan, Lixia AU - Lv, Shuo AU - Cao, Bing AU - Zhang, Yonghong AU - Wu, Jinbin AU - Han, Huibin AU - Hu, Zhubing AU - Cui, Langjun AU - Sawa, Shinichiro AU - He, Junmin AU - Wang, Guodong ID - 5830 JF - Plant Cell and Environment SN - 01407791 TI - CLE9 peptide-induced stomatal closure is mediated by abscisic acid, hydrogen peroxide, and nitric oxide in arabidopsis thaliana ER - TY - JOUR AB - Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer. AU - Lilja, Anna AU - Rodilla, Veronica AU - Huyghe, Mathilde AU - Hannezo, Edouard B AU - Landragin, Camille AU - Renaud, Olivier AU - Leroy, Olivier AU - Rulands, Steffen AU - Simons, Benjamin AU - Fré, Silvia ID - 288 IS - 6 JF - Nature Cell Biology TI - Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland VL - 20 ER - TY - JOUR AB - Additive manufacturing has recently seen drastic improvements in resolution, making it now possible to fabricate features at scales of hundreds or even dozens of nanometers, which previously required very expensive lithographic methods. As a result, additive manufacturing now seems poised for optical applications, including those relevant to computer graphics, such as material design, as well as display and imaging applications. In this work, we explore the use of additive manufacturing for generating structural colors, where the structures are designed using a fabrication-aware optimization process. This requires a combination of full-wave simulation, a feasible parameterization of the design space, and a tailored optimization procedure. Many of these components should be re-usable for the design of other optical structures at this scale. We show initial results of material samples fabricated based on our designs. While these suffer from the prototype character of state-of-the-art fabrication hardware, we believe they clearly demonstrate the potential of additive nanofabrication for structural colors and other graphics applications. AU - Auzinger, Thomas AU - Heidrich, Wolfgang AU - Bickel, Bernd ID - 304 IS - 4 JF - ACM Transactions on Graphics TI - Computational design of nanostructural color for additive manufacturing VL - 37 ER - TY - JOUR AB - Molding is a popular mass production method, in which the initial expenses for the mold are offset by the low per-unit production cost. However, the physical fabrication constraints of the molding technique commonly restrict the shape of moldable objects. For a complex shape, a decomposition of the object into moldable parts is a common strategy to address these constraints, with plastic model kits being a popular and illustrative example. However, conducting such a decomposition requires considerable expertise, and it depends on the technical aspects of the fabrication technique, as well as aesthetic considerations. We present an interactive technique to create such decompositions for two-piece molding, in which each part of the object is cast between two rigid mold pieces. Given the surface description of an object, we decompose its thin-shell equivalent into moldable parts by first performing a coarse decomposition and then utilizing an active contour model for the boundaries between individual parts. Formulated as an optimization problem, the movement of the contours is guided by an energy reflecting fabrication constraints to ensure the moldability of each part. Simultaneously, the user is provided with editing capabilities to enforce aesthetic guidelines. Our interactive interface provides control of the contour positions by allowing, for example, the alignment of part boundaries with object features. Our technique enables a novel workflow, as it empowers novice users to explore the design space, and it generates fabrication-ready two-piece molds that can be used either for casting or industrial injection molding of free-form objects. AU - Nakashima, Kazutaka AU - Auzinger, Thomas AU - Iarussi, Emmanuel AU - Zhang, Ran AU - Igarashi, Takeo AU - Bickel, Bernd ID - 12 IS - 4 JF - ACM Transaction on Graphics TI - CoreCavity: Interactive shell decomposition for fabrication with two-piece rigid molds VL - 37 ER - TY - JOUR AB - Direct reciprocity is a mechanism for cooperation among humans. Many of our daily interactions are repeated. We interact repeatedly with our family, friends, colleagues, members of the local and even global community. In the theory of repeated games, it is a tacit assumption that the various games that a person plays simultaneously have no effect on each other. Here we introduce a general framework that allows us to analyze “crosstalk” between a player’s concurrent games. In the presence of crosstalk, the action a person experiences in one game can alter the person’s decision in another. We find that crosstalk impedes the maintenance of cooperation and requires stronger levels of forgiveness. The magnitude of the effect depends on the population structure. In more densely connected social groups, crosstalk has a stronger effect. A harsh retaliator, such as Tit-for-Tat, is unable to counteract crosstalk. The crosstalk framework provides a unified interpretation of direct and upstream reciprocity in the context of repeated games. AU - Reiter, Johannes AU - Hilbe, Christian AU - Rand, David AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 454 IS - 1 JF - Nature Communications TI - Crosstalk in concurrent repeated games impedes direct reciprocity and requires stronger levels of forgiveness VL - 9 ER - TY - JOUR AB - Fast-spiking, parvalbumin-expressing GABAergic interneurons (PV+-BCs) express a complex machinery of rapid signaling mechanisms, including specialized voltage-gated ion channels to generate brief action potentials (APs). However, short APs are associated with overlapping Na+ and K+ fluxes and are therefore energetically expensive. How the potentially vicious combination of high AP frequency and inefficient spike generation can be reconciled with limited energy supply is presently unclear. To address this question, we performed direct recordings from the PV+-BC axon, the subcellular structure where active conductances for AP initiation and propagation are located. Surprisingly, the energy required for the AP was, on average, only ∼1.6 times the theoretical minimum. High energy efficiency emerged from the combination of fast inactivation of Na+ channels and delayed activation of Kv3-type K+ channels, which minimized ion flux overlap during APs. Thus, the complementary tuning of axonal Na+ and K+ channel gating optimizes both fast signaling properties and metabolic efficiency. Hu et al. demonstrate that action potentials in parvalbumin-expressing GABAergic interneuron axons are energetically efficient, which is highly unexpected given their brief duration. High energy efficiency emerges from the combination of fast inactivation of voltage-gated Na+ channels and delayed activation of Kv3 channels in the axon. AU - Hu, Hua AU - Roth, Fabian AU - Vandael, David H AU - Jonas, Peter M ID - 320 IS - 1 JF - Neuron TI - Complementary tuning of Na+ and K+ channel gating underlies fast and energy-efficient action potentials in GABAergic interneuron axons VL - 98 ER - TY - JOUR AB - Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity. AU - Payne, Pavel AU - Geyrhofer, Lukas AU - Barton, Nicholas H AU - Bollback, Jonathan P ID - 423 JF - eLife TI - CRISPR-based herd immunity can limit phage epidemics in bacterial populations VL - 7 ER - TY - CONF AB - Due to data compression or low resolution, nearby vertices and edges of a graph drawing may be bundled to a common node or arc. We model such a “compromised” drawing by a piecewise linear map φ:G → ℝ. We wish to perturb φ by an arbitrarily small ε>0 into a proper drawing (in which the vertices are distinct points, any two edges intersect in finitely many points, and no three edges have a common interior point) that minimizes the number of crossings. An ε-perturbation, for every ε>0, is given by a piecewise linear map (Formula Presented), where with ||·|| is the uniform norm (i.e., sup norm). We present a polynomial-time solution for this optimization problem when G is a cycle and the map φ has no spurs (i.e., no two adjacent edges are mapped to overlapping arcs). We also show that the problem becomes NP-complete (i) when G is an arbitrary graph and φ has no spurs, and (ii) when φ may have spurs and G is a cycle or a union of disjoint paths. AU - Fulek, Radoslav AU - Tóth, Csaba D. ID - 5791 SN - 9783030044138 TI - Crossing minimization in perturbed drawings VL - 11282 ER -