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 - In 2013, a publication repository was implemented at IST Austria and 2015 after a thorough preparation phase a data repository was implemented - both based on the Open Source Software EPrints. In this text, designed as field report, we will reflect on our experiences with Open Source Software in general and specifically with EPrints regarding technical aspects but also regarding their characteristics of the user community. The second part is a pleading for including the end users in the process of implementation, adaption and evaluation. AU - Petritsch, Barbara AU - Porsche, Jana ID - 53 IS - 1 JF - VÖB Mitteilungen TI - IST PubRep and IST DataRep: the institutional repositories at IST Austria VL - 71 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 - Neurons develop elaborate morphologies that provide a model for understanding cellular architecture. By studying C. elegans sensory dendrites, we previously identified genes that act to promote the extension of ciliated sensory dendrites during embryogenesis. Interestingly, the nonciliated dendrite of the oxygen-sensing neuron URX is not affected by these genes, suggesting it develops through a distinct mechanism. Here, we use a visual forward genetic screen to identify mutants that affect URX dendrite morphogenesis. We find that disruption of the MAP kinase MAPK-15 or the βH-spectrin SMA-1 causes a phenotype opposite to what we had seen before: dendrites extend normally during embryogenesis but begin to overgrow as the animals reach adulthood, ultimately extending up to 150% of their normal length. SMA-1 is broadly expressed and acts non-cell-autonomously, while MAPK-15 is expressed in many sensory neurons including URX and acts cell-autonomously. MAPK-15 acts at the time of overgrowth, localizes at the dendrite ending, and requires its kinase activity, suggesting it acts locally in time and space to constrain dendrite growth. Finally, we find that the oxygen-sensing guanylate cyclase GCY-35, which normally localizes at the dendrite ending, is localized throughout the overgrown region, and that overgrowth can be suppressed by overexpressing GCY-35 or by genetically mimicking elevated cGMP signaling. These results suggest that overgrowth may correspond to expansion of a sensory compartment at the dendrite ending, reminiscent of the remodeling of sensory cilia or dendritic spines. Thus, in contrast to established pathways that promote dendrite growth during early development, our results reveal a distinct mechanism that constrains dendrite growth throughout the life of the animal, possibly by controlling the size of a sensory compartment at the dendrite ending. AU - McLachlan, Ian G. AU - Beets, Isabel AU - de Bono, Mario AU - Heiman, Maxwell G. ID - 6111 IS - 6 JF - PLOS Genetics SN - 1553-7404 TI - A neuronal MAP kinase constrains growth of a Caenorhabditis elegans sensory dendrite throughout the life of the organism VL - 14 ER - TY - JOUR AB - Neuropeptides are ubiquitous modulators of behavior and physiology. They are packaged in specialized secretory organelles called dense core vesicles (DCVs) that are released upon neural stimulation. Unlike synaptic vesicles, which can be recycled and refilled close to release sites, DCVs must be replenished by de novo synthesis in the cell body. Here, we dissect DCV cell biology in vivo in a Caenorhabditis elegans sensory neuron whose tonic activity we can control using a natural stimulus. We express fluorescently tagged neuropeptides in the neuron and define parameters that describe their subcellular distribution. We measure these parameters at high and low neural activity in 187 mutants defective in proteins implicated in membrane traffic, neuroendocrine secretion, and neuronal or synaptic activity. Using unsupervised hierarchical clustering methods, we analyze these data and identify 62 groups of genes with similar mutant phenotypes. We explore the function of a subset of these groups. We recapitulate many previous findings, validating our paradigm. We uncover a large battery of proteins involved in recycling DCV membrane proteins, something hitherto poorly explored. We show that the unfolded protein response promotes DCV production, which may contribute to intertissue communication of stress. We also find evidence that different mechanisms of priming and exocytosis may operate at high and low neural activity. Our work provides a defined framework to study DCV biology at different neural activity levels. AU - Laurent, Patrick AU - Ch’ng, QueeLim AU - Jospin, Maëlle AU - Chen, Changchun AU - Lorenzo, Ramiro AU - de Bono, Mario ID - 6109 IS - 29 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Genetic dissection of neuropeptide cell biology at high and low activity in a defined sensory neuron VL - 115 ER - TY - CONF AB - In this paper, we propose an algorithm to build discrete spherical shell having integer center and real-valued inner and outer radii on the face-centered cubic (FCC) grid. We address the problem by mapping it to a 2D scenario and building the shell layer by layer on hexagonal grids with additive manufacturing in mind. The layered hexagonal grids get shifted according to need as we move from one layer to another and forms the FCC grid in 3D. However, we restrict our computation strictly to 2D in order to utilize symmetry and simplicity. AU - Koshti, Girish AU - Biswas, Ranita AU - Largeteau-Skapin, Gaëlle AU - Zrour, Rita AU - Andres, Eric AU - Bhowmick, Partha ID - 6164 SN - 0302-9743 T2 - 19th International Workshop TI - Sphere construction on the FCC grid interpreted as layered hexagonal grids in 3D VL - 11255 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 - JOUR AB - An optical network of superconducting quantum bits (qubits) is an appealing platform for quantum communication and distributed quantum computing, but developing a quantum-compatible link between the microwave and optical domains remains an outstanding challenge. Operating at T < 100 mK temperatures, as required for quantum electrical circuits, we demonstrate a mechanically mediated microwave–optical converter with 47% conversion efficiency, and use a classical feed-forward protocol to reduce added noise to 38 photons. The feed-forward protocol harnesses our discovery that noise emitted from the two converter output ports is strongly correlated because both outputs record thermal motion of the same mechanical mode. We also discuss a quantum feed-forward protocol that, given high system efficiencies, would allow quantum information to be transferred even when thermal phonons enter the mechanical element faster than the electro-optic conversion rate. AU - Higginbotham, Andrew P AU - Burns, P. S. AU - Urmey, M. D. AU - Peterson, R. W. AU - Kampel, N. S. AU - Brubaker, B. M. AU - Smith, G. AU - Lehnert, K. W. AU - Regal, C. A. ID - 6368 IS - 10 JF - Nature Physics SN - 1745-2473 TI - Harnessing electro-optic correlations in an efficient mechanical converter VL - 14 ER - TY - JOUR AB - We construct a metamaterial from radio-frequency harmonic oscillators, and find two topologically distinct phases resulting from dissipation engineered into the system. These phases are distinguished by a quantized value of bulk energy transport. The impulse response of our circuit is measured and used to reconstruct the band structure and winding number of circuit eigenfunctions around a dark mode. Our results demonstrate that dissipative topological transport can occur in a wider class of physical systems than considered before. AU - Rosenthal, Eric I. AU - Ehrlich, Nicole K. AU - Rudner, Mark S. AU - Higginbotham, Andrew P AU - Lehnert, K. W. ID - 6369 IS - 22 JF - Physical Review B SN - 2469-9950 TI - Topological phase transition measured in a dissipative metamaterial VL - 97 ER - TY - GEN AU - Petritsch, Barbara ID - 6459 KW - Open Access KW - Publication Analysis TI - Open Access at IST Austria 2009-2017 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 - CONF AB - Reed-Muller (RM) and polar codes are a class of capacity-achieving channel coding schemes with the same factor graph representation. Low-complexity decoding algorithms fall short in providing a good error-correction performance for RM and polar codes. Using the symmetric group of RM and polar codes, the specific decoding algorithm can be carried out on multiple permutations of the factor graph to boost the error-correction performance. However, this approach results in high decoding complexity. In this paper, we first derive the total number of factor graph permutations on which the decoding can be performed. We further propose a successive permutation (SP) scheme which finds the permutations on the fly, thus the decoding always progresses on a single factor graph permutation. We show that SP can be used to improve the error-correction performance of RM and polar codes under successive-cancellation (SC) and SC list (SCL) decoding, while keeping the memory requirements of the decoders unaltered. Our results for RM and polar codes of length 128 and rate 0.5 show that when SP is used and at a target frame error rate of 10 -4 , up to 0.5 dB and 0.1 dB improvement can be achieved for RM and polar codes respectively. AU - Hashemi, Seyyed Ali AU - Doan, Nghia AU - Mondelli, Marco AU - Gross, Warren ID - 6664 T2 - 2018 IEEE 10th International Symposium on Turbo Codes & Iterative Information Processing TI - Decoding Reed-Muller and polar codes by successive factor graph permutations ER - TY - JOUR AB - Polar codes represent one of the major recent breakthroughs in coding theory and, because of their attractive features, they have been selected for the incoming 5G standard. As such, a lot of attention has been devoted to the development of decoding algorithms with good error performance and efficient hardware implementation. One of the leading candidates in this regard is represented by successive-cancellation list (SCL) decoding. However, its hardware implementation requires a large amount of memory. Recently, a partitioned SCL (PSCL) decoder has been proposed to significantly reduce the memory consumption. In this paper, we consider the paradigm of PSCL decoding from a practical standpoint, and we provide several improvements. First, by changing the target signal-to-noise ratio and consequently modifying the construction of the code, we are able to improve the performance at no additional computational, latency, or memory cost. Second, we bridge the performance gap between SCL and PSCL decoding by introducing a generalized PSCL decoder and a layered PSCL decoder. In this way, we obtain almost the same performance of the SCL decoder with a significantly lower memory requirement, as testified by hardware implementation results. Third, we present an optimal scheme to allocate cyclic redundancy checks. Finally, we provide a lower bound on the list size that guarantees optimal maximum a posteriori performance for the binary erasure channel. AU - Hashemi, Seyyed Ali AU - Mondelli, Marco AU - Hassani, S. Hamed AU - Condo, Carlo AU - Urbanke, Rudiger L. AU - Gross, Warren J. ID - 6674 IS - 9 JF - IEEE Transactions on Communications TI - Decoder partitioning: Towards practical list decoding of polar codes VL - 66 ER - TY - CONF AB - Polar codes are a channel coding scheme for the next generation of wireless communications standard (5G). The belief propagation (BP) decoder allows for parallel decoding of polar codes, making it suitable for high throughput applications. However, the error-correction performance of polar codes under BP decoding is far from the requirements of 5G. It has been shown that the error-correction performance of BP can be improved if the decoding is performed on multiple permuted factor graphs of polar codes. However, a different BP decoding scheduling is required for each factor graph permutation which results in the design of a different decoder for each permutation. Moreover, the selection of the different factor graph permutations is at random, which prevents the decoder to achieve a desirable error correction performance with a small number of permutations. In this paper, we first show that the permutations on the factor graph can be mapped into suitable permutations on the codeword positions. As a result, we can make use of a single decoder for all the permutations. In addition, we introduce a method to construct a set of predetermined permutations which can provide the correct codeword if the decoding fails on the original permutation. We show that for the 5G polar code of length 1024, the error-correction performance of the proposed decoder is more than 0.25 dB better than that of the BP decoder with the same number of random permutations at the frame error rate of 10 -4 . AU - Doan, Nghia AU - Hashemi, Seyyed Ali AU - Mondelli, Marco AU - Gross, Warren J. ID - 6728 SN - 9781538647271 T2 - 2018 IEEE Global Communications Conference TI - On the decoding of polar codes on permuted factor graphs ER - TY - JOUR AB - We survey coding techniques that enable reliable transmission at rates that approach the capacity of an arbitrary discrete memoryless channel. In particular, we take the point of view of modern coding theory and discuss how recent advances in coding for symmetric channels help provide more efficient solutions for the asymmetric case. We consider, in more detail, three basic coding paradigms. The first one is Gallager's scheme that consists of concatenating a linear code with a non-linear mapping so that the input distribution can be appropriately shaped. We explicitly show that both polar codes and spatially coupled codes can be employed in this scenario. Furthermore, we derive a scaling law between the gap to capacity, the cardinality of the input and output alphabets, and the required size of the mapper. The second one is an integrated scheme in which the code is used both for source coding, in order to create codewords distributed according to the capacity-achieving input distribution, and for channel coding, in order to provide error protection. Such a technique has been recently introduced by Honda and Yamamoto in the context of polar codes, and we show how to apply it also to the design of sparse graph codes. The third paradigm is based on an idea of Böcherer and Mathar, and separates the two tasks of source coding and channel coding by a chaining construction that binds together several codewords. We present conditions for the source code and the channel code, and we describe how to combine any source code with any channel code that fulfill those conditions, in order to provide capacity-achieving schemes for asymmetric channels. In particular, we show that polar codes, spatially coupled codes, and homophonic codes are suitable as basic building blocks of the proposed coding strategy. Rather than focusing on the exact details of the schemes, the purpose of this tutorial is to present different coding techniques that can then be implemented with many variants. There is no absolute winner and, in order to understand the most suitable technique for a specific application scenario, we provide a detailed comparison that takes into account several performance metrics. AU - Mondelli, Marco AU - Hassani, Hamed AU - Urbanke, Rudiger ID - 6678 IS - 5 JF - IEEE Transactions on Information Theory SN - 0018-9448 TI - How to achieve the capacity of asymmetric channels VL - 64 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 - CONF AB - We present a coding paradigm that provides a new achievable rate for the primitive relay channel by combining compress-and-forward and decode-and-forward with a chaining construction. In the primitive relay channel model, the source broadcasts a message to the relay and to the destination; and the relay facilitates this communication by sending an additional message to the destination through a separate channel. Two well-known coding approaches for this setting are decode-and-forward and compress-and-forward: in the former, the relay decodes the message and sends some of the information to the destination; in the latter, the relay does not attempt to decode, but it sends a compressed description of the received sequence to the destination via Wyner-Ziv coding. In our scheme, we transmit over pairs of blocks and we use compress-and-forward for the first block and decode-and-forward for the second. In particular, in the first block, the relay does not attempt to decode and it sends only a part of the compressed description of the received sequence; in the second block, the relay decodes the message and sends this information plus the remaining part of the compressed sequence relative to the first block. As a result, we strictly outperform both compress-and- forward and decode-and-forward. Furthermore, this paradigm can be implemented with a low-complexity polar coding scheme that has the typical attractive features of polar codes, i.e., quasi-linear encoding/decoding complexity and super-polynomial decay of the error probability. Throughout the paper we consider as a running example the special case of the erasure relay channel and we compare the rates achievable by our proposed scheme with the existing upper and lower bounds. AU - Mondelli, Marco AU - Hassani, Hamed AU - Urbanke, Rudiger ID - 6675 T2 - 2018 IEEE International Symposium on Information Theory TI - A new coding paradigm for the primitive relay channel 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 - JOUR AB - The high-pressure synthesis and incommensurately modulated structure are reported for the new compound Sr2Pt8−xAs, with x = 0.715 (5). The structure consists of Sr2Pt3As layers alternating with Pt-only corrugated grids. Ab initio calculations predict a metallic character with a dominant role of the Pt d electrons. The electrical resistivity (ρ) and Seebeck coefficient confirm the metallic character, but surprisingly, ρ showed a near-flat temperature dependence. This observation fits the description of the Mooij correlation for electrical resistivity in disordered metals, originally developed for statistically distributed point defects. The discussed material has a long-range crystallographic order, but the high concentration of Pt vacancies, incommensurately ordered, strongly influences the electronic conduction properties. This result extends the range of validity of the Mooij correlation to long-range ordered incommensurately modulated vacancies. Motivated by the layered structure, the resistivity anisotropy was measured in a focused-ion-beam micro-fabricated well oriented single crystal. A low resistivity anisotropy indicates that the layers are electrically coupled and conduction channels along different directions are intermixed. AU - Martino, Edoardo AU - Arakcheeva, Alla AU - Autès, Gabriel AU - Pisoni, Andrea AU - Bachmann, Maja D. AU - Modic, Kimberly A AU - Helm, Toni AU - Yazyev, Oleg V. AU - Moll, Philip J. W. AU - Forró, László AU - Katrych, Sergiy ID - 7063 IS - 4 JF - IUCrJ TI - Sr2Pt8−xAs: A layered incommensurately modulated metal with saturated resistivity VL - 5 ER - TY - JOUR AB - Weyl fermions are a recently discovered ingredient for correlated states of electronic matter. A key difficulty has been that real materials also contain non-Weyl quasiparticles, and disentangling the experimental signatures has proven challenging. Here we use magnetic fields up to 95 T to drive the Weyl semimetal TaAs far into its quantum limit, where only the purely chiral 0th Landau levels of the Weyl fermions are occupied. We find the electrical resistivity to be nearly independent of magnetic field up to 50 T: unusual for conventional metals but consistent with the chiral anomaly for Weyl fermions. Above 50 T we observe a two-order-of-magnitude increase in resistivity, indicating that a gap opens in the chiral Landau levels. Above 80 T we observe strong ultrasonic attenuation below 2 K, suggesting a mesoscopically textured state of matter. These results point the way to inducing new correlated states of matter in the quantum limit of Weyl semimetals. AU - Ramshaw, B. J. AU - Modic, Kimberly A AU - Shekhter, Arkady AU - Zhang, Yi AU - Kim, Eun-Ah AU - Moll, Philip J. W. AU - Bachmann, Maja D. AU - Chan, M. K. AU - Betts, J. B. AU - Balakirev, F. AU - Migliori, A. AU - Ghimire, N. J. AU - Bauer, E. D. AU - Ronning, F. AU - McDonald, R. D. ID - 7062 IS - 1 JF - Nature Communications SN - 2041-1723 TI - Quantum limit transport and destruction of the Weyl nodes in TaAs VL - 9 ER - TY - JOUR AB - Unusual behavior in quantum materials commonly arises from their effective low-dimensional physics, reflecting the underlying anisotropy in the spin and charge degrees of freedom. Here we introduce the magnetotropic coefficient k = ∂2F/∂θ2, the second derivative of the free energy F with respect to the magnetic field orientation θ in the crystal. We show that the magnetotropic coefficient can be quantitatively determined from a shift in the resonant frequency of a commercially available atomic force microscopy cantilever under magnetic field. This detection method enables part per 100 million sensitivity and the ability to measure magnetic anisotropy in nanogram-scale samples, as demonstrated on the Weyl semimetal NbP. Measurement of the magnetotropic coefficient in the spin-liquid candidate RuCl3 highlights its sensitivity to anisotropic phase transitions and allows a quantitative comparison to other thermodynamic coefficients via the Ehrenfest relations. AU - Modic, Kimberly A AU - Bachmann, Maja D. AU - Ramshaw, B. J. AU - Arnold, F. AU - Shirer, K. R. AU - Estry, Amelia AU - Betts, J. B. AU - Ghimire, Nirmal J. AU - Bauer, E. D. AU - Schmidt, Marcus AU - Baenitz, Michael AU - Svanidze, E. AU - McDonald, Ross D. AU - Shekhter, Arkady AU - Moll, Philip J. W. ID - 7059 IS - 1 JF - Nature Communications SN - 2041-1723 TI - Resonant torsion magnetometry in anisotropic quantum materials VL - 9 ER - TY - JOUR AB - We examine recent magnetic torque measurements in two compounds, γ−Li2IrO3 and RuCl3, which have been discussed as possible realizations of the Kitaev model. The analysis of the reported discontinuity in torque, as an external magnetic field is rotated across the c axis in both crystals, suggests that they have a translationally invariant chiral spin order of the form ⟨Si⋅(Sj×Sk)⟩≠0 in the ground state and persisting over a very wide range of magnetic field and temperature. An extraordinary |B|B2 dependence of the torque for small fields, beside the usual B2 part, is predicted by the chiral spin order. Data for small fields are available for γ−Li2IrO3 and are found to be consistent with the prediction upon further analysis. Other experiments such as inelastic scattering and thermal Hall effect and several questions raised by the discovery of chiral spin order, including its topological consequences, are discussed. AU - Modic, Kimberly A AU - Ramshaw, B. J. AU - Shekhter, A. AU - Varma, C. M. ID - 7058 IS - 20 JF - Physical Review B SN - 2469-9950 TI - Chiral spin order in some purported Kitaev spin-liquid compounds VL - 98 ER - TY - JOUR AB - The anomalous metallic state in the high-temperature superconducting cuprates is masked by superconductivity near a quantum critical point. Applying high magnetic fields to suppress superconductivity has enabled detailed studies of the normal state, yet the direct effect of strong magnetic fields on the metallic state is poorly understood. We report the high-field magnetoresistance of thin-film La2–xSrxCuO4 cuprate in the vicinity of the critical doping, 0.161 ≤ p ≤ 0.190. We find that the metallic state exposed by suppressing superconductivity is characterized by magnetoresistance that is linear in magnetic fields up to 80 tesla. The magnitude of the linear-in-field resistivity mirrors the magnitude and doping evolution of the well-known linear-in-temperature resistivity that has been associated with quantum criticality in high-temperature superconductors. AU - Giraldo-Gallo, P. AU - Galvis, J. A. AU - Stegen, Z. AU - Modic, Kimberly A AU - Balakirev, F. F. AU - Betts, J. B. AU - Lian, X. AU - Moir, C. AU - Riggs, S. C. AU - Wu, J. AU - Bollinger, A. T. AU - He, X. AU - Božović, I. AU - Ramshaw, B. J. AU - McDonald, R. D. AU - Boebinger, G. S. AU - Shekhter, A. ID - 7060 IS - 6401 JF - Science SN - 0036-8075 TI - Scale-invariant magnetoresistance in a cuprate superconductor VL - 361 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 - JOUR AB - In the Minimum Description Length (MDL) principle, learning from the data is equivalent to an optimal coding problem. We show that the codes that achieve optimal compression in MDL are critical in a very precise sense. First, when they are taken as generative models of samples, they generate samples with broad empirical distributions and with a high value of the relevance, defined as the entropy of the empirical frequencies. These results are derived for different statistical models (Dirichlet model, independent and pairwise dependent spin models, and restricted Boltzmann machines). Second, MDL codes sit precisely at a second order phase transition point where the symmetry between the sampled outcomes is spontaneously broken. The order parameter controlling the phase transition is the coding cost of the samples. The phase transition is a manifestation of the optimality of MDL codes, and it arises because codes that achieve a higher compression do not exist. These results suggest a clear interpretation of the widespread occurrence of statistical criticality as a characterization of samples which are maximally informative on the underlying generative process. AU - Cubero, Ryan J AU - Marsili, Matteo AU - Roudi, Yasser ID - 7126 IS - 10 JF - Entropy KW - Minimum Description Length KW - normalized maximum likelihood KW - statistical criticality KW - phase transitions KW - large deviations SN - 1099-4300 TI - Minimum description length codes are critical VL - 20 ER - TY - JOUR AB - Solid alkali metal carbonates are universal passivation layer components of intercalation battery materials and common side products in metal‐O2 batteries, and are believed to form and decompose reversibly in metal‐O2/CO2 cells. In these cathodes, Li2CO3 decomposes to CO2 when exposed to potentials above 3.8 V vs. Li/Li+. However, O2 evolution, as would be expected according to the decomposition reaction 2 Li2CO3→4 Li++4 e−+2 CO2+O2, is not detected. O atoms are thus unaccounted for, which was previously ascribed to unidentified parasitic reactions. Here, we show that highly reactive singlet oxygen (1O2) forms upon oxidizing Li2CO3 in an aprotic electrolyte and therefore does not evolve as O2. These results have substantial implications for the long‐term cyclability of batteries: they underpin the importance of avoiding 1O2 in metal‐O2 batteries, question the possibility of a reversible metal‐O2/CO2 battery based on a carbonate discharge product, and help explain the interfacial reactivity of transition‐metal cathodes with residual Li2CO3. AU - Mahne, Nika AU - Renfrew, Sara E. AU - McCloskey, Bryan D. AU - Freunberger, Stefan Alexander ID - 7277 IS - 19 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Electrochemical oxidation of Lithium Carbonate generates singlet oxygen VL - 57 ER - TY - JOUR AB - The recent demand of multifunctional materials and devices for advanced applications in energy conversion and data storage resulted into a revival of multiferroics, that is, materials characterized by the coexistence of ferromagnetism and ferroelectricity. Despite intense efforts made in the past decade, single-phase room temperature multiferroics are yet to be discovered/fabricated. Nanostructured ferroic materials could potentially exhibit multiferroism since a high fraction of their atoms/ions are superficial, thereby altering significantly the properties of the bulk phase. Alternately, a magnetic order can be induced into ferroelectric materials upon aliovalent doping with magnetic ions. Here, we report on the synthesis of aggregate-free single-phase transition-metal-doped BaTiO3 quasi-monodisperse cuboidal nanocrystals (NC) which exhibit multiferroic properties at room temperature and can be suitable for applications in data storage. The proposed synthetic route allows the inclusion of a high concentration of magnetic ions such as Mn+ (M = Cr, Mn, Fe, Co) up to a nominal concentration of 4% without the formation of any secondary phase. The size of the nanocrystals was controlled in a wide range from ∼15 up to ∼70 nm by varying the reaction time from 48 to 144 h. The presence of unpaired electrons and their magnetic ordering have been probed by electron paramagnetic resonance spectroscopy (EPR), and a vibrating sample magnetometer (VSM). Likewise, an acentric structure, associated with the existence of a dielectric polarization, was observed by lattice dynamics analysis and piezoresponse force microscopy (PFM). These results show that high-quality titanium-containing perovskite nanocrystals which display multiferroic properties at room temperature can be fabricated via soft solution-based synthetic routes, and the properties of these materials can be modulated by changing the size of the nanocrystals and the concentration of the dopant thereby opening the door to the design and study of single-phase multiferroic materials. AU - Costanzo, Tommaso AU - McCracken, John AU - Rotaru, Aurelian AU - Caruntu, Gabriel ID - 7271 IS - 9 JF - ACS Applied Nano Materials SN - 2574-0970 TI - Quasi-monodisperse transition-metal-doped BaTiO3 (M = Cr, Mn, Fe, Co) colloidal nanocrystals with multiferroic properties VL - 1 ER - TY - JOUR AB - Passivation layers on electrode materials are ubiquitous in nonaqueous battery chemistries and strongly govern performance and lifetime. They comprise breakdown products of the electrolyte including carbonate, alkyl carbonates, alkoxides, carboxylates, and polymers. Parasitic chemistry in metal–O2 batteries forms similar products and is tied to the deviation of the O2 balance from the ideal stoichiometry during formation/decomposition of alkaline peroxides or superoxides. Accurate and integral quantification of carbonaceous species and peroxides or superoxides in battery electrodes remains, however, elusive. We present a refined procedure to quantify them accurately and sensitively by pointing out and rectifying pitfalls of previous procedures. Carbonaceous compounds are differentiated into inorganic and organic ones. We combine mass and UV–vis spectrometry to quantify evolved O2 and complexed peroxide and CO2 evolved from carbonaceous compounds by acid treatment and Fenton’s reaction. The capabilities of the method are exemplified by means of Li–O2 and Na–O2 cathodes, graphite anodes, and LiNi0.8Co0.15Al0.05O2 cathodes. AU - Schafzahl, Bettina AU - Mourad, Eléonore AU - Schafzahl, Lukas AU - Petit, Yann K. AU - Raju, Anjana R. AU - Thotiyl, Musthafa Ottakam AU - Wilkening, Martin AU - Slugovc, Christian AU - Freunberger, Stefan Alexander ID - 7287 IS - 1 JF - ACS Energy Letters SN - 2380-8195 TI - Quantifying total superoxide, peroxide, and carbonaceous compounds in metal–O2 batteries and the solid electrolyte interphase VL - 3 ER - TY - JOUR AB - Hydrogelation, the self-assembly of molecules into soft, water-loaded networks, is one way to bridge the structural gap between single molecules and functional materials. The potential of hydrogels, such as those based on perylene bisimides, lies in their chemical, physical, optical, and electronic properties, which are governed by the supramolecular structure of the gel. However, the structural motifs and their precise role for long-range conductivity are yet to be explored. Here, we present a comprehensive structural picture of a perylene bisimide hydrogel, suggesting that its long-range conductivity is limited by charge transfer between electronic backbones. We reveal nanocrystalline ribbon-like structures as the electronic and structural backbone units between which charge transfer is mediated by polar solvent bridges. We exemplify this effect with sensing, where exposure to polar vapor enhances conductivity by 5 orders of magnitude, emphasizing the crucial role of the interplay between structural motif and surrounding medium for the rational design of devices based on nanocrystalline hydrogels. AU - Burian, Max AU - Rigodanza, Francesco AU - Demitri, Nicola AU - D̵ord̵ević, Luka AU - Marchesan, Silvia AU - Steinhartova, Tereza AU - Letofsky-Papst, Ilse AU - Khalakhan, Ivan AU - Mourad, Eléonore AU - Freunberger, Stefan Alexander AU - Amenitsch, Heinz AU - Prato, Maurizio AU - Syrgiannis, Zois ID - 7285 IS - 6 JF - ACS Nano SN - 1936-0851 TI - Inter-backbone charge transfer as prerequisite for long-range conductivity in perylene bisimide hydrogels VL - 12 ER - TY - JOUR AB - The solid electrolyte interphase (SEI) in Li and Na ion batteries forms when highly reducing or oxidizing electrode materials come into contact with a liquid organic electrolyte. Its ability to form a mechanically robust, ion-conducting, and electron-insulating layer critically determines performance, cycle life, and safety. Li or Na alkyl carbonates (LiAC and NaAC, respectively) are lead SEI components in state-of-the-art carbonate based electrolytes, and our fundamental understanding of their charge transport and mechanical properties may hold the key to designing electrolytes forming an improved SEI. We synthesized a homologous series of LiACs and NaACs from methyl to octyl analogues and characterized them with respect to structure, ionic conductivity, and stiffness. The compounds assume layered structures except for the lithium methyl carbonate. Room-temperature conductivities were found to be ∼10–9 S cm–1 for lithium methyl carbonate, <10–12 S cm–1 for the other LiACs, and <10–12 S cm–1 for the NaACs with ion transport mostly attributed to grain boundaries. While LiACs show stiffnesses of ∼1 GPa, NaACs become significantly softer with increasing chain lengths. These findings will help to more precisely interpret the complex results from charge transport and mechanical characterization of real SEIs and can give a rationale for influencing the SEI’s mechanical properties via the electrolyte. AU - Schafzahl, Lukas AU - Ehmann, Heike AU - Kriechbaum, Manfred AU - Sattelkow, Jürgen AU - Ganner, Thomas AU - Plank, Harald AU - Wilkening, Martin AU - Freunberger, Stefan Alexander ID - 7286 IS - 10 JF - Chemistry of Materials SN - 0897-4756 TI - Long-chain Li and Na alkyl carbonates as solid electrolyte interphase components: Structure, ion transport, and mechanical properties VL - 30 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 coupling between magnetic and electric subsystems in composites of ferromagnetic and ferroelectric phases is a product property that is facilitated by mechanical strain that arises due to magnetostriction and the piezoelectric effect in the constituent phases. Such multiferroic composites are of immense interests for studies on the physics of electromagnetic coupling and for use in a variety of applications. Here, we focus on magneto-electric (ME) coupling in nanocomposites. Particular emphasis is on core-shell particles and coaxial fibers, thin film heterostructures, and planar structures with a variety of mechanical connectivity. A brief review of models that predict strong ME effects in nanostructures is followed by synthesis and characterization. Core-shell particulate composites can be prepared by hydrothermal processes and chemical or deoxyribonucleic acid-assisted assembly. Electrospinning techniques have been utilized to prepare defect free core-shell nanofibers. Core-shell particles and fibers can be assembled into superstructures with the aid of magnetic and electric fields and characterized for possible use in advanced technologies. Chemical-vapor deposition techniques have been shown to be effective for the preparation of heterostructures of ferrites and ferroelectrics. Exotic planar multiferroic structures with potential for enhancing ME coupling strengths are also considered. Scanning probe microscopy techniques are ideal for probing the nature of direct- and converse-ME coupling in individual nanostructures. Magnetoelectric characterization of assemblies of nanocomposites can be done by ME voltage coefficient, magnetic field induced polarization, and magneto-dielectric effects. We conclude with a brief discussion on possible avenues for strengthening the product properties in the nanocomposites. AU - Viehland, Dwight AU - Li, Jie Fang AU - Yang, Yaodong AU - Costanzo, Tommaso AU - Yourdkhani, Amin AU - Caruntu, Gabriel AU - Zhou, Peng AU - Zhang, Tianjin AU - Li, Tianqian AU - Gupta, Arunava AU - Popov, Maksym AU - Srinivasan, Gopalan ID - 7458 IS - 6 JF - Journal of Applied Physics SN - 0021-8979 TI - Tutorial: Product properties in multiferroic nanocomposites VL - 124 ER - TY - JOUR AB - Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals. Methods: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2–4 time points (N = 2894) in 954 individuals (67–90 years). Results: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis. Genes in the vicinity of these rsCpGs were found to be enriched in Homeobox transcription factors and the Wnt signalling pathway, both of which are related to ageing processes. Furthermore, we investigated the SNP effect on the random slope. We found that 4 out of 1507 rsCpGs had one significant (P < 5 × 10−8/1507) SNP effect and 343 rsCpGs had at least one SNP effect (436 SNP-probe pairs) reaching genome-wide significance (P < 5 × 10−8). Ninety-five percent of the significant (P < 5 × 10−8) SNPs are on different chromosomes from their corresponding probes. Conclusions: We identified CpG sites that have variability in the rate of change of DNA methylation between individuals, and our results suggest a genetic basis of this variation. Genes around these CpG sites have been reported to be involved in the ageing process. AU - Zhang, Qian AU - Marioni, Riccardo E AU - Robinson, Matthew Richard AU - Higham, Jon AU - Sproul, Duncan AU - Wray, Naomi R AU - Deary, Ian J AU - McRae, Allan F AU - Visscher, Peter M ID - 7717 IS - 1 JF - Genome Medicine SN - 1756-994X TI - Genotype effects contribute to variation in longitudinal methylome patterns in older people VL - 10 ER - TY - JOUR AB - Flores Island, Indonesia, was inhabited by the small-bodied hominin species Homo floresiensis, which has an unknown evolutionary relationship to modern humans. This island is also home to an extant human pygmy population. Here we describe genome-scale single-nucleotide polymorphism data and whole-genome sequences from a contemporary human pygmy population living on Flores near the cave where H. floresiensis was found. The genomes of Flores pygmies reveal a complex history of admixture with Denisovans and Neanderthals but no evidence for gene flow with other archaic hominins. Modern individuals bear the signatures of recent positive selection encompassing the FADS (fatty acid desaturase) gene cluster, likely related to diet, and polygenic selection acting on standing variation that contributed to their short-stature phenotype. Thus, multiple independent instances of hominin insular dwarfism occurred on Flores. AU - Tucci, Serena AU - Vohr, Samuel H. AU - McCoy, Rajiv C. AU - Vernot, Benjamin AU - Robinson, Matthew Richard AU - Barbieri, Chiara AU - Nelson, Brad J. AU - Fu, Wenqing AU - Purnomo, Gludhug A. AU - Sudoyo, Herawati AU - Eichler, Evan E. AU - Barbujani, Guido AU - Visscher, Peter M. AU - Akey, Joshua M. AU - Green, Richard E. ID - 7718 IS - 6401 JF - Science SN - 0036-8075 TI - Evolutionary history and adaptation of a human pygmy population of Flores Island, Indonesia VL - 361 ER - TY - JOUR AB - Male pattern baldness (MPB) is a sex-limited, age-related, complex trait. We study MPB genetics in 205,327 European males from the UK Biobank. Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males. We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%. Autosomal genetic variance is enriched for common variants and regions of lower linkage disequilibrium. We identify plausible genetic correlations between MPB and multiple sex-limited markers of earlier puberty, increased bone mineral density (rg = 0.15) and pancreatic β-cell function (rg = 0.12). Correlations with reproductive traits imply an effect on fitness, consistent with an estimated linear selection gradient of -0.018 per MPB standard deviation. Overall, we provide genetic insights into MPB: a phenotype of interest in its own right, with value as a model sex-limited, complex trait. AU - Yap, Chloe X. AU - Sidorenko, Julia AU - Wu, Yang AU - Kemper, Kathryn E. AU - Yang, Jian AU - Wray, Naomi R. AU - Robinson, Matthew Richard AU - Visscher, Peter M. ID - 7712 JF - Nature Communications SN - 2041-1723 TI - Dissection of genetic variation and evidence for pleiotropy in male pattern baldness VL - 9 ER - TY - JOUR AB - Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. AU - Maier, Robert M. AU - Zhu, Zhihong AU - Lee, Sang Hong AU - Trzaskowski, Maciej AU - Ruderfer, Douglas M. AU - Stahl, Eli A. AU - Ripke, Stephan AU - Wray, Naomi R. AU - Yang, Jian AU - Visscher, Peter M. AU - Robinson, Matthew Richard ID - 7716 JF - Nature Communications SN - 2041-1723 TI - Improving genetic prediction by leveraging genetic correlations among human diseases and traits VL - 9 ER - TY - JOUR AB - Preference for mates with similar phenotypes; that is, assortative mating, is widely observed in humans1,2,3,4,5 and has evolutionary consequences6,7,8. Under Fisher's classical theory6, assortative mating is predicted to induce a signature in the genome at trait-associated loci that can be detected and quantified. Here, we develop and apply a method to quantify assortative mating on a specific trait by estimating the correlation (θ) between genetic predictors of the trait from single nucleotide polymorphisms on odd- versus even-numbered chromosomes. We show by theory and simulation that the effect of assortative mating can be quantified in the presence of population stratification. We applied this approach to 32 complex traits and diseases using single nucleotide polymorphism data from ~400,000 unrelated individuals of European ancestry. We found significant evidence of assortative mating for height (θ = 3.2%) and educational attainment (θ = 2.7%), both of which were consistent with theoretical predictions. Overall, our results imply that assortative mating involves multiple traits and affects the genomic architecture of loci that are associated with these traits, and that the consequence of mate choice can be detected from a random sample of genomes. AU - Yengo, Loic AU - Robinson, Matthew Richard AU - Keller, Matthew C. AU - Kemper, Kathryn E. AU - Yang, Yuanhao AU - Trzaskowski, Maciej AU - Gratten, Jacob AU - Turley, Patrick AU - Cesarini, David AU - Benjamin, Daniel J. AU - Wray, Naomi R. AU - Goddard, Michael E. AU - Yang, Jian AU - Visscher, Peter M. ID - 7715 IS - 12 JF - Nature Human Behaviour SN - 2397-3374 TI - Imprint of assortative mating on the human genome VL - 2 ER - TY - JOUR AB - Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer’s disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative). AU - Zhu, Zhihong AU - Zheng, Zhili AU - Zhang, Futao AU - Wu, Yang AU - Trzaskowski, Maciej AU - Maier, Robert AU - Robinson, Matthew Richard AU - McGrath, John J. AU - Visscher, Peter M. AU - Wray, Naomi R. AU - Yang, Jian ID - 7714 JF - Nature Communications SN - 2041-1723 TI - Causal associations between risk factors and common diseases inferred from GWAS summary data VL - 9 ER - TY - JOUR AB - There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height (P=2.46×10−5), waist-to-hip ratio (P=2.77×10−4), and schizophrenia (P=3.96×10−5) are significantly more differentiated among populations than matched “control” SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height (P=2.01×10−6) and schizophrenia (P=5.16×10−18) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations. AU - Guo, Jing AU - Wu, Yang AU - Zhu, Zhihong AU - Zheng, Zhili AU - Trzaskowski, Maciej AU - Zeng, Jian AU - Robinson, Matthew Richard AU - Visscher, Peter M. AU - Yang, Jian ID - 7713 JF - Nature Communications SN - 2041-1723 TI - Global genetic differentiation of complex traits shaped by natural selection in humans VL - 9 ER - TY - JOUR AB - The availability of genome-wide genetic data on hundreds of thousands of people has led to an equally rapid growth in methodologies available to analyse these data. While the motivation for undertaking genome-wide association studies (GWAS) is identification of genetic markers associated with complex traits, once generated these data can be used for many other analyses. GWAS have demonstrated that complex traits exhibit a highly polygenic genetic architecture, often with shared genetic risk factors across traits. New methods to analyse data from GWAS are increasingly being used to address a diverse set of questions about the aetiology of complex traits and diseases, including psychiatric disorders. Here, we give an overview of some of these methods and present examples of how they have contributed to our understanding of psychiatric disorders. We consider: (i) estimation of the extent of genetic influence on traits, (ii) uncovering of shared genetic control between traits, (iii) predictions of genetic risk for individuals, (iv) uncovering of causal relationships between traits, (v) identifying causal single-nucleotide polymorphisms and genes or (vi) the detection of genetic heterogeneity. This classification helps organise the large number of recently developed methods, although some could be placed in more than one category. While some methods require GWAS data on individual people, others simply use GWAS summary statistics data, allowing novel well-powered analyses to be conducted at a low computational burden. AU - Maier, R. M. AU - Visscher, P. M. AU - Robinson, Matthew Richard AU - Wray, N. R. ID - 7721 IS - 7 JF - Psychological Medicine SN - 0033-2917 TI - Embracing polygenicity: A review of methods and tools for psychiatric genetics research VL - 48 ER - TY - JOUR AB - Genome-wide association studies (GWAS) have identified thousands of loci that are robustly associated with complex diseases. The use of linear mixed model (LMM) methodology for GWAS is becoming more prevalent due to its ability to control for population structure and cryptic relatedness and to increase power. The odds ratio (OR) is a common measure of the association of a disease with an exposure (e.g., a genetic variant) and is readably available from logistic regression. However, when the LMM is applied to all-or-none traits it provides estimates of genetic effects on the observed 0–1 scale, a different scale to that in logistic regression. This limits the comparability of results across studies, for example in a meta-analysis, and makes the interpretation of the magnitude of an effect from an LMM GWAS difficult. In this study, we derived transformations from the genetic effects estimated under the LMM to the OR that only rely on summary statistics. To test the proposed transformations, we used real genotypes from two large, publicly available data sets to simulate all-or-none phenotypes for a set of scenarios that differ in underlying model, disease prevalence, and heritability. Furthermore, we applied these transformations to GWAS summary statistics for type 2 diabetes generated from 108,042 individuals in the UK Biobank. In both simulation and real-data application, we observed very high concordance between the transformed OR from the LMM and either the simulated truth or estimates from logistic regression. The transformations derived and validated in this study improve the comparability of results from prospective and already performed LMM GWAS on complex diseases by providing a reliable transformation to a common comparative scale for the genetic effects. AU - Lloyd-Jones, Luke R. AU - Robinson, Matthew Richard AU - Yang, Jian AU - Visscher, Peter M. ID - 7723 IS - 4 JF - Genetics SN - 0016-6731 TI - Transformation of summary statistics from linear mixed model association on all-or-none traits to odds ratio VL - 208 ER - TY - JOUR AB - We develop a Bayesian mixed linear model that simultaneously estimates single-nucleotide polymorphism (SNP)-based heritability, polygenicity (proportion of SNPs with nonzero effects), and the relationship between SNP effect size and minor allele frequency for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752) and show that on average, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (P < 0.05/28) signatures of natural selection in the genetic architecture of 23 traits, including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. The significant estimates of the relationship between effect size and minor allele frequency in complex traits are consistent with a model of negative (or purifying) selection, as confirmed by forward simulation. We conclude that negative selection acts pervasively on the genetic variants associated with human complex traits. AU - Zeng, Jian AU - de Vlaming, Ronald AU - Wu, Yang AU - Robinson, Matthew Richard AU - Lloyd-Jones, Luke R. AU - Yengo, Loic AU - Yap, Chloe X. AU - Xue, Angli AU - Sidorenko, Julia AU - McRae, Allan F. AU - Powell, Joseph E. AU - Montgomery, Grant W. AU - Metspalu, Andres AU - Esko, Tonu AU - Gibson, Greg AU - Wray, Naomi R. AU - Visscher, Peter M. AU - Yang, Jian ID - 7722 IS - 5 JF - Nature Genetics SN - 1061-4036 TI - Signatures of negative selection in the genetic architecture of human complex traits VL - 50 ER - TY - JOUR AB - Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species. AU - Sanjak, Jaleal S. AU - Sidorenko, Julia AU - Robinson, Matthew Richard AU - Thornton, Kevin R. AU - Visscher, Peter M. ID - 7724 IS - 1 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Evidence of directional and stabilizing selection in contemporary humans VL - 115 ER - TY - JOUR AB - Creating a selective gel that filters particles based on their interactions is a major goal of nanotechnology, with far-reaching implications from drug delivery to controlling assembly pathways. However, this is particularly difficult when the particles are larger than the gel’s characteristic mesh size because such particles cannot passively pass through the gel. Thus, filtering requires the interacting particles to transiently reorganize the gel’s internal structure. While significant advances, e.g., in DNA engineering, have enabled the design of nano-materials with programmable interactions, it is not clear what physical principles such a designer gel could exploit to achieve selective permeability. We present an equilibrium mechanism where crosslink binding dynamics are affected by interacting particles such that particle diffusion is enhanced. In addition to revealing specific design rules for manufacturing selective gels, our results have the potential to explain the origin of selective permeability in certain biological materials, including the nuclear pore complex. AU - Goodrich, Carl Peter AU - Brenner, Michael P. AU - Ribbeck, Katharina ID - 7754 JF - Nature Communications SN - 2041-1723 TI - Enhanced diffusion by binding to the crosslinks of a polymer gel VL - 9 ER - TY - GEN AB - The Drosophila Genetic Reference Panel (DGRP) serves as a valuable resource to better understand the genetic landscapes underlying quantitative traits. However, such DGRP studies have so far only focused on nuclear genetic variants. To address this, we sequenced the mitochondrial genomes of >170 DGRP lines, identifying 229 variants including 21 indels and 7 frameshifts. We used our mitochondrial variation data to identify 12 genetically distinct mitochondrial haplotypes, thus revealing important population structure at the mitochondrial level. We further examined whether this population structure was reflected on the nuclear genome by screening for the presence of potential mito-nuclear genetic incompatibilities in the form of significant genotype ratio distortions (GRDs) between mitochondrial and nuclear variants. In total, we detected a remarkable 1,845 mito-nuclear GRDs, with the highest enrichment observed in a 40 kb region around the gene Sex-lethal (Sxl). Intriguingly, downstream phenotypic analyses did not uncover major fitness effects associated with these GRDs, suggesting that a large number of mito-nuclear GRDs may reflect population structure at the mitochondrial level rather than actual genomic incompatibilities. This is further supported by the GRD landscape showing particular large genomic regions associated with a single mitochondrial haplotype. Next, we explored the functional relevance of the detected mitochondrial haplotypes through an association analysis on a set of 259 assembled, non-correlating DGRP phenotypes. We found multiple significant associations with stress- and metabolism-related phenotypes, including food intake in males. We validated the latter observation by reciprocal swapping of mitochondrial genomes from high food intake DGRP lines to low food intake ones. In conclusion, our study uncovered important mitochondrial population structure and haplotype-specific metabolic variation in the DGRP, thus demonstrating the significance of incorporating mitochondrial haplotypes in geno-phenotype relationship studies. AU - Bevers, Roel P.J. AU - Litovchenko, Maria AU - Kapopoulou, Adamandia AU - Braman, Virginie S. AU - Robinson, Matthew Richard AU - Auwerx, Johan AU - Hollis, Brian AU - Deplancke, Bart ID - 7783 T2 - bioRxiv TI - Extensive mitochondrial population structure and haplotype-specific phenotypic variation in the Drosophila Genetic Reference Panel 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 - JOUR AB - Feste Alkalicarbonate sind universelle Bestandteile von Passivierungsschichten an Materialien für Interkalationsbatterien, übliche Nebenprodukte in Metall‐O2‐Batterien, und es wird angenommen, dass sie sich reversibel in Metall‐O2 /CO2‐Zellen bilden und zersetzen. In all diesen Kathoden zersetzt sich Li2CO3 zu CO2, sobald es Spannungen >3.8 V vs. Li/Li+ ausgesetzt wird. Beachtenswert ist, dass keine O2‐Entwicklung detektiert wird, wie gemäß der Zersetzungsreaktion 2 Li2CO3 → 4 Li+ + 4 e− + 2 CO2 + O2 zu erwarten wäre. Deswegen war der Verbleib eines der O‐Atome ungeklärt und wurde nicht identifizierten parasitären Reaktionen zugerechnet. Hier zeigen wir, dass hochreaktiver Singulett‐Sauerstoff (1O2) bei der Oxidation von Li2CO3 in einem aprotischen Elektrolyten gebildet und daher nicht als O2 freigesetzt wird. Diese Ergebnisse haben weitreichende Auswirkungen auf die langfristige Zyklisierbarkeit von Batterien: sie untermauern die Wichtigkeit, 1O2 in Metall‐O2‐Batterien zu verhindern, stellen die Möglichkeit einer reversiblen Metall‐O2 /CO2‐Batterie basierend auf einem Carbonat‐Entladeprodukt in Frage und helfen, Grenzflächenreaktivität von Übergangsmetallkathoden mit Li2CO3‐Resten zu erklären. AU - Mahne, Nika AU - Renfrew, Sara E. AU - McCloskey, Bryan D. AU - Freunberger, Stefan Alexander ID - 7983 IS - 19 JF - Angewandte Chemie SN - 0044-8249 TI - Elektrochemische Oxidation von Lithiumcarbonat generiert Singulett-Sauerstoff VL - 130 ER - TY - JOUR AB - The neural code of cortical processing remains uncracked; however, it must necessarily rely on faithful signal propagation between cortical areas. In this issue of Neuron, Joglekar et al. (2018) show that strong inter-areal excitation balanced by local inhibition can enable reliable signal propagation in data-constrained network models of macaque cortex. AU - Stroud, Jake P. AU - Vogels, Tim P ID - 8015 IS - 1 JF - Neuron SN - 0896-6273 TI - Cortical signal propagation: Balance, amplify, transmit VL - 98 ER - TY - JOUR AB - Motor cortex (M1) exhibits a rich repertoire of neuronal activities to support the generation of complex movements. Although recent neuronal-network models capture many qualitative aspects of M1 dynamics, they can generate only a few distinct movements. Additionally, it is unclear how M1 efficiently controls movements over a wide range of shapes and speeds. We demonstrate that modulation of neuronal input–output gains in recurrent neuronal-network models with a fixed architecture can dramatically reorganize neuronal activity and thus downstream muscle outputs. Consistent with the observation of diffuse neuromodulatory projections to M1, a relatively small number of modulatory control units provide sufficient flexibility to adjust high-dimensional network activity using a simple reward-based learning rule. Furthermore, it is possible to assemble novel movements from previously learned primitives, and one can separately change movement speed while preserving movement shape. Our results provide a new perspective on the role of modulatory systems in controlling recurrent cortical activity. AU - Stroud, Jake P. AU - Porter, Mason A. AU - Hennequin, Guillaume AU - Vogels, Tim P ID - 8073 IS - 12 JF - Nature Neuroscience SN - 1097-6256 TI - Motor primitives in space and time via targeted gain modulation in cortical networks VL - 21 ER - TY - JOUR AU - Fazekas-Singer, Judit AU - Singer, Josef AU - Ilieva, Kristina M. AU - Matz, Miroslawa AU - Herrmann, Ina AU - Spillner, Edzard AU - Karagiannis, Sophia N. AU - Jensen-Jarolim, Erika ID - 8231 IS - 3 JF - Journal of Allergy and Clinical Immunology SN - 0091-6749 TI - AllergoOncology: Generating a canine anticancer IgE against the epidermal growth factor receptor VL - 142 ER - TY - JOUR AB - Molecular imaging probes such as PET-tracers have the potential to improve the accuracy of tumor characterization by directly visualizing the biochemical situation. Thus, molecular changes can be detected early before morphological manifestation. The A3 adenosine receptor (A3AR) is described to be highly expressed in colon cancer cell lines and human colorectal cancer (CRC), suggesting this receptor as a tumor marker. The aim of this preclinical study was the evaluation of FE@SUPPY as a PET-tracer for CRC using in vitro imaging and in vivo PET imaging. First, affinity and selectivity of FE@SUPPY and its metabolites were determined, proving the favorable binding profile of FE@SUPPY. The human adenocarcinoma cell line HT-29 was characterized regarding its hA3AR expression and was subsequently chosen as tumor graft. Promising results regarding the potential of FE@SUPPY as a PET-tracer for CRC imaging were obtained by autoradiography as ≥2.3-fold higher accumulation of FE@SUPPY was found in CRC tissue compared to adjacent healthy colon tissue from the same patient. Nevertheless, first in vivo studies using HT-29 xenografts showed insufficient tumor uptake due to (1) poor conservation of target expression in xenografts and (2) unfavorable pharmacokinetics of FE@SUPPY in mice. We therefore conclude that HT-29 xenografts are not adequate to visualize hA3ARs using FE@SUPPY. AU - Balber, T. AU - Singer, Judit AU - Berroterán-Infante, N. AU - Dumanic, M. AU - Fetty, L. AU - Fazekas-Singer, J. AU - Vraka, C. AU - Nics, L. AU - Bergmann, M. AU - Pallitsch, K. AU - Spreitzer, H. AU - Wadsak, W. AU - Hacker, M. AU - Jensen-Jarolim, E. AU - Viernstein, H. AU - Mitterhauser, M. ID - 8234 JF - Contrast Media & Molecular Imaging SN - 1555-4309 TI - Preclinical in vitro and in vivo evaluation of [18F]FE@SUPPY for cancer PET imaging: Limitations of a xenograft model for colorectal cancer VL - 2018 ER - TY - JOUR AB - Anti-epidermal growth factor receptor (EGFR) antibody therapy is used in EGFR expressing cancers including lung, colon, head and neck, and bladder cancers, however results have been modest. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate which is activated by NIR light. NIR-PIT is in clinical trials in patients with recurrent head and neck cancers using cetuximab-IR700 as the conjugate. However, its use has otherwise been restricted to mouse models. This is an effort to explore larger animal models with NIR-PIT. We describe the use of a recombinant canine anti-EGFR monoclonal antibody (mAb), can225IgG, conjugated to the photo-absorber, IR700DX, in three EGFR expressing canine transitional cell carcinoma (TCC) cell lines as a prelude to possible canine clinical studies. Can225-IR700 conjugate showed specific binding and cell-specific killing after NIR-PIT on EGFR expressing cells in vitro. In the in vivo study, can225-IR700 conjugate demonstrated accumulation of the fluorescent conjugate with high tumor-to-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 μg of can225-IR700 i.v. only; (3) NIR light exposure only; (4) 100 μg of can225-IR700 i.v., NIR light exposure. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.001 vs. other groups) in the treatment groups. In conclusion, NIR-PIT with can225-IR700 is a promising treatment for canine EGFR-expressing cancers, including invasive transitional cell carcinoma in pet dogs, that could provide a pathway to translation to humans. AU - Nagaya, Tadanobu AU - Okuyama, Shuhei AU - Ogata, Fusa AU - Maruoka, Yasuhiro AU - Knapp, Deborah W. AU - Karagiannis, Sophia N. AU - Fazekas-Singer, Judit AU - Choyke, Peter L. AU - LeBlanc, Amy K. AU - Jensen-Jarolim, Erika AU - Kobayashi, Hisataka ID - 8232 JF - Oncotarget TI - Near infrared photoimmunotherapy targeting bladder cancer with a canine anti-epidermal growth factor receptor (EGFR) antibody VL - 9 ER - TY - JOUR AB - The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1 and M2a cells on the cellular and molecular level. In analogy to activated human M2a cells, canine M2a, differentiated from both DH82 and MDMs, showed an increase in CD206 surface receptor expression compared to M1. Interestingly, canine M2a, but not M1 derived from MDM, upregulated the high-affinity IgE receptor (FcεRI). Transcription levels of M2a-associated genes (IL10, CCL22, TGFβ, CD163) showed a diverse pattern between the human and dog species, whereas M1 genes (IDO1, CXCL11, IL6, TNF-α) were similarly upregulated in canine and human M1 cells (cell lines and MDMs). We suggest that our novel in vitro method will be suitable in comparative allergology studies focussing on macrophages. AU - Herrmann, Ina AU - Gotovina, Jelena AU - Fazekas-Singer, Judit AU - Fischer, Michael B. AU - Hufnagl, Karin AU - Bianchini, Rodolfo AU - Jensen-Jarolim, Erika ID - 8233 IS - 5 JF - Developmental & Comparative Immunology SN - 0145-305X TI - Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy VL - 82 ER - TY - JOUR AB - Background: The genus Burkholderia consists of species that occupy remarkably diverse ecological niches. Its best known members are important pathogens, B. mallei and B. pseudomallei, which cause glanders and melioidosis, respectively. Burkholderia genomes are unusual due to their multichromosomal organization, generally comprised of 2-3 chromosomes. Results: We performed integrated genomic analysis of 127 Burkholderia strains. The pan-genome is open with the saturation to be reached between 86,000 and 88,000 genes. The reconstructed rearrangements indicate a strong avoidance of intra-replichore inversions that is likely caused by selection against the transfer of large groups of genes between the leading and the lagging strands. Translocated genes also tend to retain their position in the leading or the lagging strand, and this selection is stronger for large syntenies. Integrated reconstruction of chromosome rearrangements in the context of strains phylogeny reveals parallel rearrangements that may indicate inversion-based phase variation and integration of new genomic islands. In particular, we detected parallel inversions in the second chromosomes of B. pseudomallei with breakpoints formed by genes encoding membrane components of multidrug resistance complex, that may be linked to a phase variation mechanism. Two genomic islands, spreading horizontally between chromosomes, were detected in the B. cepacia group. Conclusions: This study demonstrates the power of integrated analysis of pan-genomes, chromosome rearrangements, and selection regimes. Non-random inversion patterns indicate selective pressure, inversions are particularly frequent in a recent pathogen B. mallei, and, together with periods of positive selection at other branches, may indicate adaptation to new niches. One such adaptation could be a possible phase variation mechanism in B. pseudomallei. AU - Bochkareva, Olga AU - Moroz, Elena V. AU - Davydov, Iakov I. AU - Gelfand, Mikhail S. ID - 8262 JF - BMC Genomics SN - 1471-2164 TI - Genome rearrangements and selection in multi-chromosome bacteria Burkholderia spp. VL - 19 ER - TY - JOUR AB - Genome rearrangements have played an important role in the evolution of Yersinia pestis from its progenitor Yersinia pseudotuberculosis. Traditional phylogenetic trees for Y. pestis based on sequence comparison have short internal branches and low bootstrap supports as only a small number of nucleotide substitutions have occurred. On the other hand, even a small number of genome rearrangements may resolve topological ambiguities in a phylogenetic tree. We reconstructed phylogenetic trees based on genome rearrangements using several popular approaches such as Maximum likelihood for Gene Order and the Bayesian model of genome rearrangements by inversions. We also reconciled phylogenetic trees for each of the three CRISPR loci to obtain an integrated scenario of the CRISPR cassette evolution. Analysis of contradictions between the obtained evolutionary trees yielded numerous parallel inversions and gain/loss events. Our data indicate that an integrated analysis of sequence-based and inversion-based trees enhances the resolution of phylogenetic reconstruction. In contrast, reconstructions of strain relationships based on solely CRISPR loci may not be reliable, as the history is obscured by large deletions, obliterating the order of spacer gains. Similarly, numerous parallel gene losses preclude reconstruction of phylogeny based on gene content. AU - Bochkareva, Olga AU - Dranenko, Natalia O. AU - Ocheredko, Elena S. AU - Kanevsky, German M. AU - Lozinsky, Yaroslav N. AU - Khalaycheva, Vera A. AU - Artamonova, Irena I. AU - Gelfand, Mikhail S. ID - 8265 JF - PeerJ SN - 2167-8359 TI - Genome rearrangements and phylogeny reconstruction in Yersinia pestis VL - 6 ER - TY - JOUR AB - Background/Aim: Our aim was to investigate the crosstalk between tumor and immune cells (M2 macrophages) and its effects on cyclo-oxygenase-2 (COX2) regulation in canine mammary tumors (CMT). Materials and Methods: Sh1b CMT cells and human BT474 mammary or HT29 colon cancer cells were co-cultured with canine peripheral blood mononuclear cells (PBMCs) or with macrophage-like differentiated THP1 monocytes (dTHP1). Intracellular COX2 expression by PBMCs, dTHP1 and cancer cells was evaluated by flow cytometry. Results: Co-culturing of Sh1b and canine PBMCs induced COX2 overexpression in CMT cells. In turn, COX2 expression by PBMCs, mostly CD68+ macrophages, was attenuated by co-culture with Sh1b (p=0.0001). In accordance, co-culture with dTHP1 prompted intracellular production of COX2 in both Sh1b CMT cells and HT29 human colon cancer cells and reduced production of COX2 in BT474 human mammary cancer cells. The intracellular COX2 expression from dTHP1 decreased when treated with conditioned medium from cultured Sh1b and HT29 cancer cells. Conclusion: Bidirectional COX2 regulation between cancer and monocytes/macrophages might shape a tolerogenic tumor microenvironment in CMT. AU - Carvalho, Maria Isabel AU - Bianchini, Rodolfo AU - Fazekas-Singer, Judit AU - Herrmann, Ina AU - Flickinger, Irene AU - Thalhammer, Johann G. AU - Pires, Isabel AU - Jensen-Jarolim, Erika AU - Queiroga, Felisbina L. ID - 8274 IS - 5 JF - Anticancer Research SN - 0250-7005 TI - Bidirectional regulation of COX-2 expression between cancer cells and macrophages VL - 38 ER - TY - CONF AB - Sharding, or partitioning the system’s state so that different subsets of participants handle it, is a proven approach to building distributed systems whose total capacity scales horizontally with the number of participants. Many distributed ledgers have adopted this approach to increase their performance, however, they focus on the permissionless setting that assumes the existence of a strong adversary. In this paper, we deploy channels for permissioned blockchains. Our first contribution is to adapt sharding on asset-management applications for the permissioned setting, while preserving liveness and safety even on transactions spanning across-channels. Our second contribution is to leverage channels as a confidentiality boundary, enabling different organizations and consortia to preserve their privacy within their channels and still be part of a bigger collaborative ecosystem. To make our system concrete we map it on top of Hyperledger Fabric. AU - Androulaki, Elli AU - Cachin, Christian AU - De Caro, Angelo AU - Kokoris Kogias, Eleftherios ID - 8298 SN - 0302-9743 T2 - Computer Security TI - Channels: Horizontal scaling and confidentiality on permissioned blockchains VL - 11098 ER - TY - CONF AB - Designing a secure permissionless distributed ledger (blockchain) that performs on par with centralized payment processors, such as Visa, is a challenging task. Most existing distributed ledgers are unable to scale-out, i.e., to grow their totalprocessing capacity with the number of validators; and those that do, compromise security or decentralization. We present OmniLedger, a novel scale-out distributed ledger that preserves longterm security under permissionless operation. It ensures security and correctness by using a bias-resistant public-randomness protocol for choosing large, statistically representative shards that process transactions, and by introducing an efficient crossshard commit protocol that atomically handles transactions affecting multiple shards. OmniLedger also optimizes performance via parallel intra-shard transaction processing, ledger pruning via collectively-signed state blocks, and low-latency “trust-butverify” validation for low-value transactions. An evaluation ofour experimental prototype shows that OmniLedger’s throughput scales linearly in the number of active validators, supporting Visa-level workloads and beyond, while confirming typical transactions in under two seconds. AU - Kokoris Kogias, Eleftherios AU - Jovanovic, Philipp AU - Gasser, Linus AU - Gailly, Nicolas AU - Syta, Ewa AU - Ford, Bryan ID - 8297 SN - 2375-1207 T2 - 2018 IEEE Symposium on Security and Privacy TI - OmniLedger: A secure, scale-out, decentralized ledger via sharding ER - TY - JOUR AB - Characterizing the structure of membrane proteins (MPs) generally requires extraction from their native environment, most commonly with detergents. Yet, the physicochemical properties of detergent micelles and lipid bilayers differ markedly and could alter the structural organization of MPs, albeit without general rules. Dodecylphosphocholine (DPC) is the most widely used detergent for MP structure determination by NMR, but the physiological relevance of several prominent structures has been questioned, though indirectly, by other biophysical techniques, e.g., functional/thermostability assay (TSA) and molecular dynamics (MD) simulations. Here, we resolve unambiguously this controversy by probing the functional relevance of three different mitochondrial carriers (MCs) in DPC at the atomic level, using an exhaustive set of solution-NMR experiments, complemented by functional/TSA and MD data. Our results provide atomic-level insight into the structure, substrate interaction and dynamics of the detergent–membrane protein complexes and demonstrates cogently that, while high-resolution NMR signals can be obtained for MCs in DPC, they systematically correspond to nonfunctional states. AU - Kurauskas, Vilius AU - Hessel, Audrey AU - Ma, Peixiang AU - Lunetti, Paola AU - Weinhäupl, Katharina AU - Imbert, Lionel AU - Brutscher, Bernhard AU - King, Martin S. AU - Sounier, Rémy AU - Dolce, Vincenza AU - Kunji, Edmund R. S. AU - Capobianco, Loredana AU - Chipot, Christophe AU - Dehez, François AU - Bersch, Beate AU - Schanda, Paul ID - 8443 IS - 5 JF - The Journal of Physical Chemistry Letters KW - General Materials Science SN - 1948-7185 TI - How detergent impacts membrane proteins: Atomic-level views of mitochondrial carriers in dodecylphosphocholine VL - 9 ER - TY - JOUR AB - Mycobacterium tuberculosis can remain dormant in the host, an ability that explains the failure of many current tuberculosis treatments. Recently, the natural products cyclomarin, ecumicin, and lassomycin have been shown to efficiently kill Mycobacterium tuberculosis persisters. Their target is the N-terminal domain of the hexameric AAA+ ATPase ClpC1, which recognizes, unfolds, and translocates protein substrates, such as proteins containing phosphorylated arginine residues, to the ClpP1P2 protease for degradation. Surprisingly, these antibiotics do not inhibit ClpC1 ATPase activity, and how they cause cell death is still unclear. Here, using NMR and small-angle X-ray scattering, we demonstrate that arginine-phosphate binding to the ClpC1 N-terminal domain induces millisecond dynamics. We show that these dynamics are caused by conformational changes and do not result from unfolding or oligomerization of this domain. Cyclomarin binding to this domain specifically blocked these N-terminal dynamics. On the basis of these results, we propose a mechanism of action involving cyclomarin-induced restriction of ClpC1 dynamics, which modulates the chaperone enzymatic activity leading eventually to cell death. AU - Weinhäupl, Katharina AU - Brennich, Martha AU - Kazmaier, Uli AU - Lelievre, Joel AU - Ballell, Lluis AU - Goldberg, Alfred AU - Schanda, Paul AU - Fraga, Hugo ID - 8440 IS - 22 JF - Journal of Biological Chemistry KW - Cell Biology KW - Biochemistry KW - Molecular Biology SN - 0021-9258 TI - The antibiotic cyclomarin blocks arginine-phosphate–induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis VL - 293 ER - TY - JOUR AB - Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for α-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents. AU - Chipot, Christophe AU - Dehez, François AU - Schnell, Jason R. AU - Zitzmann, Nicole AU - Pebay-Peyroula, Eva AU - Catoire, Laurent J. AU - Miroux, Bruno AU - Kunji, Edmund R. S. AU - Veglia, Gianluigi AU - Cross, Timothy A. AU - Schanda, Paul ID - 8442 IS - 7 JF - Chemical Reviews KW - General Chemistry SN - 0009-2665 TI - Perturbations of native membrane protein structure in alkyl phosphocholine detergents: A critical assessment of NMR and biophysical studies VL - 118 ER - TY - JOUR AB - Solid-state near-rotary-resonance measurements of the spin–lattice relaxation rate in the rotating frame (R1ρ) is a powerful NMR technique for studying molecular dynamics in the microsecond time scale. The small difference between the spin-lock (SL) and magic-angle-spinning (MAS) frequencies allows sampling very slow motions, at the same time it brings up some methodological challenges. In this work, several issues affecting correct measurements and analysis of 15N R1ρ data are considered in detail. Among them are signal amplitude as a function of the difference between SL and MAS frequencies, “dead time” in the initial part of the relaxation decay caused by transient spin-dynamic oscillations, measurements under HORROR condition and proper treatment of the multi-exponential relaxation decays. The multiple 15N R1ρ measurements at different SL fields and temperatures have been conducted in 1D mode (i.e. without site-specific resolution) for a set of four different microcrystalline protein samples (GB1, SH3, MPD-ubiquitin and cubic-PEG-ubiquitin) to study the overall protein rocking in a crystal. While the amplitude of this motion varies very significantly, its correlation time for all four sample is practically the same, 30–50 μs. The amplitude of the rocking motion correlates with the packing density of a protein crystal. It has been suggested that the rocking motion is not diffusive but likely a jump-like dynamic process. AU - Krushelnitsky, Alexey AU - Gauto, Diego AU - Rodriguez Camargo, Diana C. AU - Schanda, Paul AU - Saalwächter, Kay ID - 8441 IS - 1 JF - Journal of Biomolecular NMR SN - 0925-2738 TI - Microsecond motions probed by near-rotary-resonance R1ρ 15N MAS NMR experiments: The model case of protein overall-rocking in crystals VL - 71 ER - TY - JOUR AB - Lipopolysaccharides (LPS) are complex glycolipids forming the outside layer of Gram-negative bacteria. Their hydrophobic and heterogeneous nature greatly hampers their structural study in an environment similar to the bacterial surface. We have studied LPS purified from E. coli and pathogenic P. aeruginosa with long O-antigen polysaccharides assembled in solution as vesicles or elongated micelles. Solid-state NMR with magic-angle spinning permitted the identification of NMR signals arising from regions with different flexibilities in the LPS, from the lipid components to the O-antigen polysaccharides. Atomic scale data on the LPS enabled the study of the interaction of gentamicin antibiotic bound to P. aeruginosa LPS, for which we could confirm that a specific oligosaccharide is involved in the antibiotic binding. The possibility to study LPS alone and bound to a ligand when it is assembled in membrane-like structures opens great prospects for the investigation of proteins and antibiotics that specifically target such an important molecule at the surface of Gram-negative bacteria. AU - Laguri, Cedric AU - Silipo, Alba AU - Martorana, Alessandra M. AU - Schanda, Paul AU - Marchetti, Roberta AU - Polissi, Alessandra AU - Molinaro, Antonio AU - Simorre, Jean-Pierre ID - 8439 IS - 8 JF - ACS Chemical Biology KW - Molecular Medicine KW - Biochemistry KW - General Medicine SN - 1554-8929 TI - Solid state NMR studies of intact lipopolysaccharide endotoxin VL - 13 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 AB - Self-assembly is the autonomous organization of components into patterns or structures: an essential ingredient of biology and a desired route to complex organization1. At equilibrium, the structure is encoded through specific interactions2,3,4,5,6,7,8, at an unfavourable entropic cost for the system. An alternative approach, widely used by nature, uses energy input to bypass the entropy bottleneck and develop features otherwise impossible at equilibrium9. Dissipative building blocks that inject energy locally were made available by recent advances in colloidal science10,11 but have not been used to control self-assembly. Here we show the targeted formation of self-powered microgears from active particles and their autonomous synchronization into dynamical superstructures. We use a photoactive component that consumes fuel, haematite, to devise phototactic microswimmers that form self-spinning microgears following spatiotemporal light patterns. The gears are coupled via their chemical clouds by diffusiophoresis12 and constitute the elementary bricks of synchronized superstructures, which autonomously regulate their dynamics. The results are quantitatively rationalized on the basis of a stochastic description of diffusio-phoretic oscillators dynamically coupled by chemical gradients. Our findings harness non-equilibrium phoretic phenomena to program interactions and direct self-assembly with fidelity and specificity. It lays the groundwork for the autonomous construction of dynamical architectures and functional micro-machinery. AU - Aubret, Antoine AU - Youssef, Mena AU - Sacanna, Stefano AU - Palacci, Jérémie A ID - 9062 IS - 11 JF - Nature Physics SN - 1745-2473 TI - Targeted assembly and synchronization of self-spinning microgears VL - 14 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 - Estimating the homogeneous ice nucleation rate from undercooled liquid water is crucial for understanding many important physical phenomena and technological applications, and challenging for both experiments and theory. From a theoretical point of view, difficulties arise due to the long time scales required, as well as the numerous nucleation pathways involved to form ice nuclei with different stacking disorders. We computed the homogeneous ice nucleation rate at a physically relevant undercooling for a single-site water model, taking into account the diffuse nature of ice–water interfaces, stacking disorders in ice nuclei, and the addition rate of particles to the critical nucleus. We disentangled and investigated the relative importance of all the terms, including interfacial free energy, entropic contributions and the kinetic prefactor, that contribute to the overall nucleation rate. Breaking down the problem into pieces not only provides physical insights into ice nucleation, but also sheds light on the long-standing discrepancy between different theoretical predictions, as well as between theoretical and experimental determinations of the nucleation rate. Moreover, we pinpoint the main shortcomings and suggest strategies to systematically improve the existing simulation methods. AU - Cheng, Bingqing AU - Dellago, Christoph AU - Ceriotti, Michele ID - 9668 IS - 45 JF - Physical Chemistry Chemical Physics SN - 1463-9076 TI - Theoretical prediction of the homogeneous ice nucleation rate: Disentangling thermodynamics and kinetics VL - 20 ER - TY - JOUR AB - The Gibbs free energy is the fundamental thermodynamic potential underlying the relative stability of different states of matter under constant-pressure conditions. However, computing this quantity from atomic-scale simulations is far from trivial, so the potential energy of a system is often used as a proxy. In this paper, we use a combination of thermodynamic integration methods to accurately evaluate the Gibbs free energies associated with defects in crystals, including the vacancy formation energy in bcc iron, and the stacking fault energy in fcc nickel, iron, and cobalt. We quantify the importance of entropic and anharmonic effects in determining the free energies of defects at high temperatures, and show that the potential energy approximation as well as the harmonic approximation may produce inaccurate or even qualitatively wrong results. Our calculations manifest the necessity to employ accurate free energy methods such as thermodynamic integration to estimate the stability of crystallographic defects at high temperatures. AU - Cheng, Bingqing AU - Ceriotti, Michele ID - 9687 IS - 5 JF - Physical Review B SN - 2469-9950 TI - Computing the absolute Gibbs free energy in atomistic simulations: Applications to defects in solids VL - 97 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 restricted planar elliptic three body problem (RPETBP) describes the motion of a massless particle (a comet or an asteroid) under the gravitational field of two massive bodies (the primaries, say the Sun and Jupiter) revolving around their center of mass on elliptic orbits with some positive eccentricity. The aim of this paper is to show the existence of orbits whose angular momentum performs arbitrary excursions in a large region. In particular, there exist diffusive orbits, that is, with a large variation of angular momentum. The leading idea of the proof consists in analyzing parabolic motions of the comet. By a well-known result of McGehee, the union of future (resp. past) parabolic orbits is an analytic manifold P+ (resp. P−). In a properly chosen coordinate system these manifolds are stable (resp. unstable) manifolds of a manifold at infinity P∞, which we call the manifold at parabolic infinity. On P∞ it is possible to define two scattering maps, which contain the map structure of the homoclinic trajectories to it, i.e. orbits parabolic both in the future and the past. Since the inner dynamics inside P∞ is trivial, two different scattering maps are used. The combination of these two scattering maps permits the design of the desired diffusive pseudo-orbits. Using shadowing techniques and these pseudo orbits we show the existence of true trajectories of the RPETBP whose angular momentum varies in any predetermined fashion. AU - Delshams, Amadeu AU - Kaloshin, Vadim AU - de la Rosa, Abraham AU - Seara, Tere M. ID - 8417 IS - 3 JF - Communications in Mathematical Physics KW - Mathematical Physics KW - Statistical and Nonlinear Physics SN - 0010-3616 TI - Global instability in the restricted planar elliptic three body problem VL - 366 ER - TY - JOUR AB - The Birkhoff conjecture says that the boundary of a strictly convex integrable billiard table is necessarily an ellipse. In this article, we consider a stronger notion of integrability, namely integrability close to the boundary, and prove a local version of this conjecture: a small perturbation of an ellipse of small eccentricity which preserves integrability near the boundary, is itself an ellipse. This extends the result in Avila et al. (Ann Math 184:527–558, ADK16), where integrability was assumed on a larger set. In particular, it shows that (local) integrability near the boundary implies global integrability. One of the crucial ideas in the proof consists in analyzing Taylor expansion of the corresponding action-angle coordinates with respect to the eccentricity parameter, deriving and studying higher order conditions for the preservation of integrable rational caustics. AU - Huang, Guan AU - Kaloshin, Vadim AU - Sorrentino, Alfonso ID - 8422 IS - 2 JF - Geometric and Functional Analysis KW - Geometry and Topology KW - Analysis SN - 1016-443X TI - Nearly circular domains which are integrable close to the boundary are ellipses VL - 28 ER - TY - JOUR AB - The classical Birkhoff conjecture claims that the boundary of a strictly convex integrable billiard table is necessarily an ellipse (or a circle as a special case). In this article we prove a complete local version of this conjecture: a small integrable perturbation of an ellipse must be an ellipse. This extends and completes the result in Avila-De Simoi-Kaloshin, where nearly circular domains were considered. One of the crucial ideas in the proof is to extend action-angle coordinates for elliptic billiards into complex domains (with respect to the angle), and to thoroughly analyze the nature of their complex singularities. As an application, we are able to prove some spectral rigidity results for elliptic domains. AU - Kaloshin, Vadim AU - Sorrentino, Alfonso ID - 8421 IS - 1 JF - Annals of Mathematics KW - Statistics KW - Probability and Uncertainty KW - Statistics and Probability SN - 0003-486X TI - On the local Birkhoff conjecture for convex billiards VL - 188 ER - TY - JOUR AB - In this survey, we provide a concise introduction to convex billiards and describe some recent results, obtained by the authors and collaborators, on the classification of integrable billiards, namely the so-called Birkhoff conjecture. This article is part of the theme issue ‘Finite dimensional integrable systems: new trends and methods’. AU - Kaloshin, Vadim AU - Sorrentino, Alfonso ID - 8419 IS - 2131 JF - Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences KW - General Engineering KW - General Physics and Astronomy KW - General Mathematics SN - 1364-503X TI - On the integrability of Birkhoff billiards VL - 376 ER - TY - JOUR AB - We show that in the space of all convex billiard boundaries, the set of boundaries with rational caustics is dense. More precisely, the set of billiard boundaries with caustics of rotation number 1/q is polynomially sense in the smooth case, and exponentially dense in the analytic case. AU - Kaloshin, Vadim AU - Zhang, Ke ID - 8420 IS - 11 JF - Nonlinearity KW - Mathematical Physics KW - General Physics and Astronomy KW - Applied Mathematics KW - Statistical and Nonlinear Physics SN - 0951-7715 TI - Density of convex billiards with rational caustics VL - 31 ER - TY - JOUR AB - Chaperonins are ubiquitous protein assemblies present in bacteria, eukaryota, and archaea, facilitating the folding of proteins, preventing protein aggregation, and thus participating in maintaining protein homeostasis in the cell. During their functional cycle, they bind unfolded client proteins inside their double ring structure and promote protein folding by closing the ring chamber in an adenosine 5′-triphosphate (ATP)–dependent manner. Although the static structures of fully open and closed forms of chaperonins were solved by x-ray crystallography or electron microscopy, elucidating the mechanisms of such ATP-driven molecular events requires studying the proteins at the structural level under working conditions. We introduce an approach that combines site-specific nuclear magnetic resonance observation of very large proteins, enabled by advanced isotope labeling methods, with an in situ ATP regeneration system. Using this method, we provide functional insight into the 1-MDa large hsp60 chaperonin while processing client proteins and reveal how nucleotide binding, hydrolysis, and release control switching between closed and open states. While the open conformation stabilizes the unfolded state of client proteins, the internalization of the client protein inside the chaperonin cavity speeds up its functional cycle. This approach opens new perspectives to study structures and mechanisms of various ATP-driven biological machineries in the heat of action. AU - Mas, Guillaume AU - Guan, Jia-Ying AU - Crublet, Elodie AU - Debled, Elisa Colas AU - Moriscot, Christine AU - Gans, Pierre AU - Schoehn, Guy AU - Macek, Pavel AU - Schanda, Paul AU - Boisbouvier, Jerome ID - 8437 IS - 9 JF - Science Advances SN - 2375-2548 TI - Structural investigation of a chaperonin in action reveals how nucleotide binding regulates the functional cycle VL - 4 ER - TY - JOUR AB - The exchange of metabolites between the mitochondrial matrix and the cytosol depends on β-barrel channels in the outer membrane and α-helical carrier proteins in the inner membrane. The essential translocase of the inner membrane (TIM) chaperones escort these proteins through the intermembrane space, but the structural and mechanistic details remain elusive. We have used an integrated structural biology approach to reveal the functional principle of TIM chaperones. Multiple clamp-like binding sites hold the mitochondrial membrane proteins in a translocation-competent elongated form, thus mimicking characteristics of co-translational membrane insertion. The bound preprotein undergoes conformational dynamics within the chaperone binding clefts, pointing to a multitude of dynamic local binding events. Mutations in these binding sites cause cell death or growth defects associated with impairment of carrier and β-barrel protein biogenesis. Our work reveals how a single mitochondrial “transfer-chaperone” system is able to guide α-helical and β-barrel membrane proteins in a “nascent chain-like” conformation through a ribosome-free compartment. AU - Weinhäupl, Katharina AU - Lindau, Caroline AU - Hessel, Audrey AU - Wang, Yong AU - Schütze, Conny AU - Jores, Tobias AU - Melchionda, Laura AU - Schönfisch, Birgit AU - Kalbacher, Hubert AU - Bersch, Beate AU - Rapaport, Doron AU - Brennich, Martha AU - Lindorff-Larsen, Kresten AU - Wiedemann, Nils AU - Schanda, Paul ID - 8436 IS - 5 JF - Cell KW - General Biochemistry KW - Genetics and Molecular Biology SN - 0092-8674 TI - Structural basis of membrane protein chaperoning through the mitochondrial intermembrane space VL - 175 ER - TY - JOUR AB - For any strictly convex planar domain Ω ⊂ R2 with a C∞ boundary one can associate an infinite sequence of spectral invariants introduced by Marvizi–Merlose [5]. These invariants can generically be determined using the spectrum of the Dirichlet problem of the Laplace operator. A natural question asks if this collection is sufficient to determine Ω up to isometry. In this paper we give a counterexample, namely, we present two nonisometric domains Ω and Ω¯ with the same collection of Marvizi–Melrose invariants. Moreover, each domain has countably many periodic orbits {Sn}n≥1 (resp. {S¯n}n⩾1) of period going to infinity such that Sn and S¯n have the same period and perimeter for each n. AU - Buhovsky, Lev AU - Kaloshin, Vadim ID - 8426 JF - Regular and Chaotic Dynamics SN - 1560-3547 TI - Nonisometric domains with the same Marvizi-Melrose invariants VL - 23 ER - TY - JOUR AU - Kurauskas, Vilius AU - Hessel, Audrey AU - Dehez, François AU - Chipot, Christophe AU - Bersch, Beate AU - Schanda, Paul ID - 8438 IS - 9 JF - Nature Structural & Molecular Biology KW - Molecular Biology KW - Structural Biology SN - 1545-9993 TI - Dynamics and interactions of AAC3 in DPC are not functionally relevant VL - 25 ER - TY - JOUR AB - The development of strategies to assemble microscopic machines from dissipative building blocks are essential on the route to novel active materials. We recently demonstrated the hierarchical self-assembly of phoretic microswimmers into self-spinning microgears and their synchronization by diffusiophoretic interactions [Aubret et al., Nat. Phys., 2018]. In this paper, we adopt a pedagogical approach and expose our strategy to control self-assembly and build machines using phoretic phenomena. We notably introduce Highly Inclined Laminated Optical sheets microscopy (HILO) to image and characterize anisotropic and dynamic diffusiophoretic interactions, which cannot be performed by conventional fluorescence microscopy. The dynamics of a (haematite) photocatalytic material immersed in (hydrogen peroxide) fuel under various illumination patterns is first described and quantitatively rationalized by a model of diffusiophoresis, the migration of a colloidal particle in a concentration gradient. It is further exploited to design phototactic microswimmers that direct towards the high intensity of light, as a result of the reorientation of the haematite in a light gradient. We finally show the assembly of self-spinning microgears from colloidal microswimmers and carefully characterize the interactions using HILO techniques. The results are compared with analytical and numerical predictions and agree quantitatively, stressing the important role played by concentration gradients induced by chemical activity to control and design interactions. Because the approach described hereby is generic, this works paves the way for the rational design of machines by controlling phoretic phenomena. AU - Aubret, Antoine AU - Palacci, Jérémie A ID - 9053 IS - 47 JF - Soft Matter KW - General Chemistry KW - Condensed Matter Physics SN - 1744-683X TI - Diffusiophoretic design of self-spinning microgears from colloidal microswimmers VL - 14 ER - TY - JOUR AB - The novel electronic state of the canted antiferromagnetic (AFM) insulator, strontium iridate (Sr2IrO4) has been well described by the spin-orbit-entangled isospin Jeff = 1/2, but the role of isospin in transport phenomena remains poorly understood. In this study, antiferromagnet-based spintronic functionality is demonstrated by combining unique characteristics of the isospin state in Sr2IrO4. Based on magnetic and transport measurements, large and highly anisotropic magnetoresistance (AMR) is obtained by manipulating the antiferromagnetic isospin domains. First-principles calculations suggest that electrons whose isospin directions are strongly coupled to in-plane net magnetic moment encounter the isospin mismatch when moving across antiferromagnetic domain boundaries, which generates a high resistance state. By rotating a magnetic field that aligns in-plane net moments and removes domain boundaries, the macroscopically-ordered isospins govern dynamic transport through the system, which leads to the extremely angle-sensitive AMR. As with this work that establishes a link between isospins and magnetotransport in strongly spin-orbit-coupled AFM Sr2IrO4, the peculiar AMR effect provides a beneficial foundation for fundamental and applied research on AFM spintronics. AU - Lee, Nara AU - Ko, Eunjung AU - Choi, Hwan Young AU - Hong, Yun Jeong AU - Nauman, Muhammad AU - Kang, Woun AU - Choi, Hyoung Joon AU - Choi, Young Jai AU - Jo, Younjung ID - 9066 IS - 52 JF - Advanced Materials KW - Mechanical Engineering KW - General Materials Science KW - Mechanics of Materials SN - 0935-9648 TI - Antiferromagnet‐based spintronic functionality by controlling isospin domains in a layered perovskite iridate VL - 30 ER - TY - JOUR AB - We report the temperature-dependent resistivity ρ(T) of chalcogenide NiS2-xSex (x = 0.1) using hydrostatic pressure as a control parameter in the temperature range of 4–300 K. The insulating behavior of ρ(T) survives at low temperatures in the pressure regime below 7.5 kbar, whereas a clear insulator-to-metallic transition is observed above 7.5 kbar. Two types of magnetic transitions, from the paramagnetic (PM) to the antiferromagnetic (AFM) state and from the AFM state to the weak ferromagnetic (WF) state, were evaluated and confirmed by magnetization measurement. According to the temperature–pressure phase diagram, the WF phase survives up to 7.5 kbar, and the transition temperature of the WF transition decreases as the pressure increases, whereas the metal–insulator transition temperature increases up to 9.4 kbar. We analyzed the metallic behavior and proposed Fermi-liquid behavior of NiS1.9Se0.1. AU - Hussain, Tayyaba AU - Oh, Myeong-jun AU - Nauman, Muhammad AU - Jo, Younjung AU - Han, Garam AU - Kim, Changyoung AU - Kang, Woun ID - 9068 JF - Physica B: Condensed Matter SN - 0921-4526 TI - Pressure-induced metal–insulator transitions in chalcogenide NiS2-Se VL - 536 ER - TY - JOUR AB - In this study we investigate the scaling of precipitation extremes with temperature in the Mediterranean region by assessing against observations the present day and future regional climate simulations performed in the frame of the HyMeX and MED-CORDEX programs. Over the 1979–2008 period, despite differences in quantitative precipitation simulation across the various models, the change in precipitation extremes with respect to temperature is robust and consistent. The spatial variability of the temperature–precipitation extremes relationship displays a hook shape across the Mediterranean, with negative slope at high temperatures and a slope following Clausius–Clapeyron (CC)-scaling at low temperatures. The temperature at which the slope of the temperature–precipitation extreme relation sharply changes (or temperature break), ranges from about 20 °C in the western Mediterranean to <10 °C in Greece. In addition, this slope is always negative in the arid regions of the Mediterranean. The scaling of the simulated precipitation extremes is insensitive to ocean–atmosphere coupling, while it depends very weakly on the resolution at high temperatures for short precipitation accumulation times. In future climate scenario simulations covering the 2070–2100 period, the temperature break shifts to higher temperatures by a value which is on average the mean regional temperature change due to global warming. The slope of the simulated future temperature–precipitation extremes relationship is close to CC-scaling at temperatures below the temperature break, while at high temperatures, the negative slope is close, but somewhat flatter or steeper, than in the current climate depending on the model. Overall, models predict more intense precipitation extremes in the future. Adjusting the temperature–precipitation extremes relationship in the present climate using the CC law and the temperature shift in the future allows the recovery of the temperature–precipitation extremes relationship in the future climate. This implies negligible regional changes of relative humidity in the future despite the large warming and drying over the Mediterranean. This suggests that the Mediterranean Sea is the primary source of moisture which counteracts the drying and warming impacts on relative humidity in parts of the Mediterranean region. AU - Drobinski, Philippe AU - Silva, Nicolas Da AU - Panthou, Gérémy AU - Bastin, Sophie AU - Muller, Caroline J AU - Ahrens, Bodo AU - Borga, Marco AU - Conte, Dario AU - Fosser, Giorgia AU - Giorgi, Filippo AU - Güttler, Ivan AU - Kotroni, Vassiliki AU - Li, Laurent AU - Morin, Efrat AU - Önol, Bariş AU - Quintana-Segui, Pere AU - Romera, Raquel AU - Torma, Csaba Zsolt ID - 9136 IS - 3 JF - Climate Dynamics KW - Atmospheric Science SN - 0930-7575 TI - Scaling precipitation extremes with temperature in the Mediterranean: Past climate assessment and projection in anthropogenic scenarios VL - 51 ER - TY - JOUR AB - Several studies have shown the existence of a critical latitude where the dissipation of internal tides is strongly enhanced. Internal tides are internal waves generated by barotropic tidal currents impinging rough topography at the seafloor. Their dissipation and concomitant diapycnal mixing are believed to be important for water masses and the large‐scale ocean circulation. The purpose of this study is to clarify the physical processes at the origin of this strong latitudinal dependence of tidal energy dissipation. We find that different mechanisms are involved equatorward and poleward of the critical latitude. Triadic resonant instabilities are responsible for the dissipation of internal tides equatorward of the critical latitude. In particular, a dominant triad involving the primary internal tide and near‐inertial waves is key. At the critical latitude, the peak of energy dissipation is explained by both increased instability growth rates, and smaller scales of secondary waves thus more prone to break and dissipate their energy. Surprisingly, poleward of the critical latitude, the generation of evanescent waves appears to be crucial. Triadic instabilities have been widely studied, but the transfer of energy to evanescent waves has received comparatively little attention. Our work suggests that the nonlinear transfer of energy from the internal tide to evanescent waves (corresponding to the 2f‐pump mechanism described by Young et al., 2008, https://doi.org/10.1017/S0022112008001742) is an efficient mechanism to dissipate internal tide energy near and poleward of the critical latitude. The theoretical results are confirmed in idealized high‐resolution numerical simulations of a barotropic M2 tide impinging sinusoidal topography in a linearly stratified fluid. AU - Richet, O. AU - Chomaz, J.-M. AU - Muller, Caroline J ID - 9134 IS - 9 JF - Journal of Geophysical Research: Oceans SN - 2169-9275 TI - Internal tide dissipation at topography: Triadic resonant instability equatorward and evanescent waves poleward of the critical latitude VL - 123 ER - TY - JOUR AB - Idealized simulations of tropical moist convection have revealed that clouds can spontaneously clump together in a process called self-aggregation. This results in a state where a moist cloudy region with intense deep convection is surrounded by extremely dry subsiding air devoid of deep convection. Because of the idealized settings of the simulations where it was discovered, the relevance of self-aggregation to the real world is still debated. Here, we show that self-aggregation feedbacks play a leading-order role in the spontaneous genesis of tropical cyclones in cloud-resolving simulations. Those feedbacks accelerate the cyclogenesis process by a factor of 2, and the feedbacks contributing to the cyclone formation show qualitative and quantitative agreement with the self-aggregation process. Once the cyclone is formed, wind-induced surface heat exchange (WISHE) effects dominate, although we find that self-aggregation feedbacks have a small but nonnegligible contribution to the maintenance of the mature cyclone. Our results suggest that self-aggregation, and the framework developed for its study, can help shed more light into the physical processes leading to cyclogenesis and cyclone intensification. In particular, our results point out the importance of the longwave radiative cooling outside the cyclone. AU - Muller, Caroline J AU - Romps, David M. ID - 9135 IS - 12 JF - Proceedings of the National Academy of Sciences KW - Multidisciplinary SN - 0027-8424 TI - Acceleration of tropical cyclogenesis by self-aggregation feedbacks VL - 115 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 - JOUR AB - Electrostatic charging of insulating fine particles can be responsible for numerous phenomena ranging from lightning in volcanic plumes to dust explosions. However, even basic aspects of how fine particles become charged are still unclear. Studying particle charging is challenging because it usually involves the complexities associated with many-particle collisions. To address these issues, we introduce a method based on acoustic levitation, which makes it possible to initiate sequences of repeated collisions of a single submillimeter particle with a flat plate, and to precisely measure the particle charge in situ after each collision. We show that collisional charge transfer between insulators is dependent on the hydrophobicity of the contacting surfaces. We use glass, which we modify by attaching nonpolar molecules to the particle, the plate, or both. We find that hydrophilic surfaces develop significant positive charges after contacting hydrophobic surfaces. Moreover, we demonstrate that charging between a hydrophilic and a hydrophobic surface is suppressed in an acidic environment and enhanced in a basic one. Application of an electric field during each collision is found to modify the charge transfer, again depending on surface hydrophobicity. We discuss these results within the context of contact charging due to ion transfer, and we show that they lend strong support to OH− ions as the charge carriers. AU - Lee, Victor AU - James, Nicole AU - Waitukaitis, Scott R AU - Jaeger, Heinrich ID - 95 IS - 3 JF - Physical Review Materials TI - Collisional charging of individual submillimeter particles: Using ultrasonic levitation to initiate and track charge transfer VL - 2 ER - TY - JOUR AB - Let P be a graph property which is preserved by removal of edges, and consider the random graph process that starts with the empty n-vertex graph and then adds edges one-by-one, each chosen uniformly at random subject to the constraint that P is not violated. These types of random processes have been the subject of extensive research over the last 20 years, having striking applications in extremal combinatorics, and leading to the discovery of important probabilistic tools. In this paper we consider the k-matching-free process, where P is the property of not containing a matching of size k. We are able to analyse the behaviour of this process for a wide range of values of k; in particular we prove that if k=o(n) or if n−2k=o(n−−√/logn) then this process is likely to terminate in a k-matching-free graph with the maximum possible number of edges, as characterised by Erdős and Gallai. We also show that these bounds on k are essentially best possible, and we make a first step towards understanding the behaviour of the process in the intermediate regime. AU - Krivelevich, Michael AU - Kwan, Matthew Alan AU - Loh, Po‐Shen AU - Sudakov, Benny ID - 9567 IS - 4 JF - Random Structures and Algorithms SN - 1042-9832 TI - The random k‐matching‐free process VL - 53 ER - TY - JOUR AB - Let D(n,p) be the random directed graph on n vertices where each of the n(n-1) possible arcs is present independently with probability p. A celebrated result of Frieze shows that if p≥(logn+ω(1))/n then D(n,p) typically has a directed Hamilton cycle, and this is best possible. In this paper, we obtain a strengthening of this result, showing that under the same condition, the number of directed Hamilton cycles in D(n,p) is typically n!(p(1+o(1)))n. We also prove a hitting-time version of this statement, showing that in the random directed graph process, as soon as every vertex has in-/out-degrees at least 1, there are typically n!(logn/n(1+o(1)))n directed Hamilton cycles. AU - Ferber, Asaf AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9565 IS - 4 JF - Random Structures and Algorithms SN - 1042-9832 TI - Counting Hamilton cycles in sparse random directed graphs VL - 53 ER - TY - JOUR AB - An intercalate in a Latin square is a 2×2 Latin subsquare. Let N be the number of intercalates in a uniformly random n×n Latin square. We prove that asymptotically almost surely N≥(1−o(1))n2/4, and that EN≤(1+o(1))n2/2 (therefore asymptotically almost surely N≤fn2 for any f→∞). This significantly improves the previous best lower and upper bounds. We also give an upper tail bound for the number of intercalates in two fixed rows of a random Latin square. In addition, we discuss a problem of Linial and Luria on low-discrepancy Latin squares. AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9568 IS - 2 JF - Random Structures and Algorithms SN - 1042-9832 TI - Intercalates and discrepancy in random Latin squares VL - 52 ER - TY - JOUR AB - We say a family of sets is intersecting if any two of its sets intersect, and we say it is trivially intersecting if there is an element which appears in every set of the family. In this paper we study the maximum size of a non-trivially intersecting family in a natural “multi-part” setting. Here the ground set is divided into parts, and one considers families of sets whose intersection with each part is of a prescribed size. Our work is motivated by classical results in the single-part setting due to Erdős, Ko and Rado, and Hilton and Milner, and by a theorem of Frankl concerning intersecting families in this multi-part setting. In the case where the part sizes are sufficiently large we determine the maximum size of a non-trivially intersecting multi-part family, disproving a conjecture of Alon and Katona. AU - Kwan, Matthew Alan AU - Sudakov, Benny AU - Vieira, Pedro ID - 9587 JF - Journal of Combinatorial Theory Series A SN - 0097-3165 TI - Non-trivially intersecting multi-part families VL - 156 ER - TY - JOUR AB - We investigate the thermodynamics and kinetics of a hydrogen interstitial in magnetic α-iron, taking account of the quantum fluctuations of the proton as well as the anharmonicities of lattice vibrations and hydrogen hopping. We show that the diffusivity of hydrogen in the lattice of bcc iron deviates strongly from an Arrhenius behavior at and below room temperature. We compare a quantum transition state theory to explicit ring polymer molecular dynamics in the calculation of diffusivity. We then address the trapping of hydrogen by a vacancy as a prototype lattice defect. By a sequence of steps in a thought experiment, each involving a thermodynamic integration, we are able to separate out the binding free energy of a proton to a defect into harmonic and anharmonic, and classical and quantum contributions. We find that about 30% of a typical binding free energy of hydrogen to a lattice defect in iron is accounted for by finite temperature effects, and about half of these arise from quantum proton fluctuations. This has huge implications for the comparison between thermal desorption and permeation experiments and standard electronic structure theory. The implications are even greater for the interpretation of muon spin resonance experiments. AU - Cheng, Bingqing AU - Paxton, Anthony T. AU - Ceriotti, Michele ID - 9665 IS - 22 JF - Physical Review Letters SN - 0031-9007 TI - Hydrogen diffusion and trapping in α-iron: The role of quantum and anharmonic fluctuations VL - 120 ER -