TY - JOUR AB - During embryonic development, mechanical forces are essential for cellular rearrangements driving tissue morphogenesis. Here, we show that in the early zebrafish embryo, friction forces are generated at the interface between anterior axial mesoderm (prechordal plate, ppl) progenitors migrating towards the animal pole and neurectoderm progenitors moving in the opposite direction towards the vegetal pole of the embryo. These friction forces lead to global rearrangement of cells within the neurectoderm and determine the position of the neural anlage. Using a combination of experiments and simulations, we show that this process depends on hydrodynamic coupling between neurectoderm and ppl as a result of E-cadherin-mediated adhesion between those tissues. Our data thus establish the emergence of friction forces at the interface between moving tissues as a critical force-generating process shaping the embryo. AU - Smutny, Michael AU - Ákos, Zsuzsa AU - Grigolon, Silvia AU - Shamipour, Shayan AU - Ruprecht, Verena AU - Capek, Daniel AU - Behrndt, Martin AU - Papusheva, Ekaterina AU - Tada, Masazumi AU - Hof, Björn AU - Vicsek, Tamás AU - Salbreux, Guillaume AU - Heisenberg, Carl-Philipp J ID - 661 JF - Nature Cell Biology SN - 14657392 TI - Friction forces position the neural anlage VL - 19 ER - TY - JOUR AB - Let G = SL(2, R) ⋉R2 and Γ = SL(2, Z) ⋉Z2. Building on recent work of Strömbergsson, we prove a rate of equidistribution for the orbits of a certain one-dimensional unipotent flow of Γ\G, which projects to a closed horocycle in the unit tangent bundle to the modular surface. We use this to answer a question of Elkies and McMullen by making effective the convergence of the gap distribution of √n mod 1. AU - Timothy Browning AU - Vinogradov, Ilya ID - 261 IS - 1 JF - Journal of the London Mathematical Society TI - Effective ratner theorem for SL (2, R) ⋉R2 and gaps in √n modulo 1 VL - 94 ER - TY - JOUR AB - For any number field we calculate the exact proportion of rational numbers which are everywhere locally a norm but not globally a norm from the number field. AU - Timothy Browning AU - Newton, Rachel ID - 262 IS - 2 JF - Mathematika TI - The proportion of failures of the Hasse norm principle VL - 62 ER - TY - JOUR AB - We count rational points of bounded height on the Cayley ruled cubic surface and interpret the result in the context of general conjectures due to Batyrev and Tschinkel. AU - de la Bretèche, Régis AU - Timothy Browning AU - Salberger, Per ID - 263 IS - 1 JF - European Journal of Mathematics TI - Counting rational points on the Cayley ruled cubic VL - 2 ER - TY - JOUR AB - Given a family of varieties over a number field, we determine conditions under which there is a Brauer-Manin obstruction to weak approximation for 100% of the fibres which are everywhere locally soluble. AU - Bright, Maritn J AU - Timothy Browning AU - Loughran, Daniel ID - 264 IS - 7 JF - Compositio Mathematica TI - Failures of weak approximation in families VL - 152 ER - TY - JOUR AB - Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked. AU - Barron, H.C. AU - Vogels, Tim P AU - Emir, U.E. AU - Makin, T.R. AU - O’Shea, J. AU - Clare, S. AU - Jbabdi, S. AU - Dolan, R.J. AU - Behrens, T.E.J. ID - 8020 IS - 1 JF - Neuron SN - 0896-6273 TI - Unmasking latent inhibitory connections in human cortex to reveal dormant cortical memories VL - 90 ER - TY - CONF AB - With the accelerated development of robot technologies, optimal control becomes one of the central themes of research. In traditional approaches, the controller, by its internal functionality, finds appropriate actions on the basis of the history of sensor values, guided by the goals, intentions, objectives, learning schemes, and so forth. The idea is that the controller controls the world---the body plus its environment---as reliably as possible. This paper focuses on new lines of self-organization for developmental robotics. We apply the recently developed differential extrinsic synaptic plasticity to a muscle-tendon driven arm-shoulder system from the Myorobotics toolkit. In the experiments, we observe a vast variety of self-organized behavior patterns: when left alone, the arm realizes pseudo-random sequences of different poses. By applying physical forces, the system can be entrained into definite motion patterns like wiping a table. Most interestingly, after attaching an object, the controller gets in a functional resonance with the object's internal dynamics, starting to shake spontaneously bottles half-filled with water or sensitively driving an attached pendulum into a circular mode. When attached to the crank of a wheel the neural system independently discovers how to rotate it. In this way, the robot discovers affordances of objects its body is interacting with. AU - Martius, Georg S AU - Hostettler, Rafael AU - Knoll, Alois AU - Der, Ralf ID - 8094 SN - 9780262339360 T2 - Proceedings of the Artificial Life Conference 2016 TI - Self-organized control of an tendon driven arm by differential extrinsic plasticity VL - 28 ER - TY - GEN AB - The stimulus selectivity of synaptic currents in cortical neurons often shows a co-tuning of excitation and inhibition, but the mechanisms that underlie the emergence and plasticity of this co-tuning are not fully understood. Using a computational model, we show that an interaction of excitatory and inhibitory synaptic plasticity reproduces both the developmental and – when combined with a disinhibitory gate – the adult plasticity of excitatory and inhibitory receptive fields in auditory cortex. The co-tuning arises from inhibitory plasticity that balances excitation and inhibition, while excitatory stimulus selectivity can result from two different mechanisms. Inhibitory inputs with a broad stimulus tuning introduce a sliding threshold as in Bienenstock-Cooper-Munro rules, introducing an excitatory stimulus selectivity at the cost of a broader inhibitory receptive field. Alternatively, input asymmetries can be amplified by synaptic competition. The latter leaves any receptive field plasticity transient, a prediction we verify in recordings in auditory cortex. AU - Clopath, Claudia AU - Vogels, Tim P AU - Froemke, Robert C. AU - Sprekeler, Henning ID - 8128 T2 - bioRxiv TI - Receptive field formation by interacting excitatory and inhibitory synaptic plasticity ER - TY - JOUR AB - The Gag polyprotein of retroviruses drives immature virus assembly by forming hexameric protein lattices. The assembly is primarily mediated by protein-protein interactions between capsid (CA) domains and by interactions between nucleocapsid (NC) domains and RNA. Specific interactions between NC and the viral RNA are required for genome packaging. Previously reported cryoelectron microscopy analysis of immature Mason-Pfizer monkey virus (M-PMV) particles suggested that a basic region (residues RKK) in CA may serve as an additional binding site for nucleic acids. Here, we have introduced mutations into the RKK region in both bacterial and proviral M-PMV vectors and have assessed their impact on M-PMV assembly, structure, RNA binding, budding/release, nuclear trafficking, and infectivity using in vitro and in vivo systems. Our data indicate that the RKK region binds and structures nucleic acid that serves to promote virus particle assembly in the cytoplasm. Moreover, the RKK region appears to be important for recruitment of viral genomic RNA into Gag particles, and this function could be linked to changes in nuclear trafficking. Together these observations suggest that in M-PMV, direct interactions between CA and nucleic acid play important functions in the late stages of the viral life cycle. AU - Füzik, Tibor AU - Píchalová, Růžena AU - Florian Schur AU - Strohalmová, Karolína AU - Křížová, Ivana AU - Hadravová, Romana AU - Rumlová, Michaela AU - Briggs, John A AU - Ulbrich, Pavel AU - Ruml, Tomáš ID - 813 IS - 9 JF - Journal of Virology TI - Nucleic acid binding by Mason-Pfizer monkey virus CA promotes virus assembly and genome packaging VL - 90 ER - TY - JOUR AB - Immature HIV-1 assembles at and buds from the plasma membrane before proteolytic cleavage of the viral Gag polyprotein induces structural maturation. Maturation can be blocked by maturation inhibitors (MIs), thereby abolishing infectivity. The CA (capsid) and SP1 (spacer peptide 1) region of Gag is the key regulator of assembly and maturation and is the target of MIs.We applied optimized cryo-electron tomography and subtomogram averaging to resolve this region within assembled immature HIV-1 particles at 3.9 angstrom resolution and built an atomic model. The structure reveals a network of intra- And intermolecular interactions mediating immature HIV-1 assembly. The proteolytic cleavage site between CA and SP1 is inaccessible to protease.We suggest that MIs prevent CA-SP1 cleavage by stabilizing the structure, and MI resistance develops by destabilizing CA-SP1. AU - Florian Schur AU - Martin Obr AU - Hagen, Wim J AU - Wan, William AU - Jakobi, Arjen J AU - Kirkpatrick, Joanna M AU - Sachse, Carsten AU - Kraüsslich, Hans Georg AU - Briggs, John A ID - 816 IS - 6298 JF - Science TI - An atomic model of HIV-1 capsid-SP1 reveals structures regulating assembly and maturation VL - 353 ER - TY - JOUR AB - Background: Anticancer vaccines could represent a valuable complementary strategy to established therapies, especially in settings of early stage and minimal residual disease. HER-2 is an important target for immunotherapy and addressed by the monoclonal antibody trastuzumab. We have previously generated HER-2 mimotope peptides from phage display libraries. The synthesized peptides were coupled to carriers and applied for epitope-specific induction of trastuzumab-like IgG. For simplification and to avoid methodological limitations of synthesis and coupling chemistry, we herewith present a novel and optimized approach by using adeno-associated viruses (AAV) as effective and high-density mimotope-display system, which can be directly used for vaccination. Methods: An AAV capsid display library was constructed by genetically incorporating random peptides in a plasmid encoding the wild-type AAV2 capsid protein. AAV clones, expressing peptides specifically reactive to trastuzumab, were employed to immunize BALB/c mice. Antibody titers against human HER-2 were determined, and the isotype composition and functional properties of these were tested. Finally, prophylactically immunized mice were challenged with human HER-2 transfected mouse D2F2/E2 cells. Results: HER-2 mimotope AAV-vaccines induced antibodies specific to human HER-2. Two clones were selected for immunization of mice, which were subsequently grafted D2F2/E2 cells. Both mimotope AAV clones delayed the growth of tumors significantly, as compared to controls. Conclusion: In this study, a novel mimotope AAV-based platform was created allowing the isolation of mimotopes, which can be directly used as anticancer vaccines. The example of trastuzumab AAV-mimotopes demonstrates that this vaccine strategy could help to establish active immunotherapy for breast-cancer patients. AU - Singer, Josef AU - Manzano-Szalai, Krisztina AU - Fazekas, Judit AU - Thell, Kathrin AU - Bentley-Lukschal, Anna AU - Stremnitzer, Caroline AU - Roth-Walter, Franziska AU - Weghofer, Margit AU - Ritter, Mirko AU - Pino Tossi, Kerstin AU - Hörer, Markus AU - Michaelis, Uwe AU - Jensen-Jarolim, Erika ID - 8241 IS - 7 JF - OncoImmunology SN - 2162-402X TI - Proof of concept study with an HER-2 mimotope anticancer vaccine deduced from a novel AAV-mimotope library platform VL - 5 ER - TY - CONF AB - The integration of social networking concepts into Internet of Things systems is a burgeoning topic of research that promises to support novel and more powerful applications. In this paper we focus on the design and implementation of a highly scalable Trust and Reputation Model for the Internet of Things based on the social approach that the COSMOS project introduces, as part of its final results. We create our model by combining popular solutions proposed for Peer-to-Peer and mobile ad-hoc networks and adapting them on the Internet of Things concept. Each Thing can compute the Trust index of another Thing based on its own experiences, while it has the capability of determining its Reputation Index either by consulting its other “friends” (Followees) or referring to the Platform, a management system used in COSMOS. The model is tested through simulations of the proposed social system, demonstrating the ability of TRM-SIoT to achieve the Social Exclusion of malicious nodes and collectives from the network, with low computational overhead and high scalability. Furthermore, due to the adaptive nature of the system, Social Reintegration of these nodes is also possible. AU - Kokoris Kogias, Eleftherios AU - Voutyras, Orfefs AU - Varvarigou, Theodora ID - 8300 SN - 9781509013142 T2 - 2016 IEEE 21st International Conference on Emerging Technologies and Factory Automation TI - TRM-SIoT: A scalable hybrid trust & reputation model for the social Internet of Things ER - TY - CONF AB - While showing great promise, Bitcoin requires users to wait tens of minutes for transactions to commit, and even then, offering only probabilistic guarantees. This paper introduces ByzCoin, a novel Byzantine consensus protocol that leverages scalable collective signing to commit Bitcoin transactions irreversibly within seconds. ByzCoin achieves Byzantine consensus while preserving Bitcoin’s open membership by dynamically forming hash power-proportionate consensus groups that represent recently-successful block miners. ByzCoin employs communication trees to optimize transaction commitment and verification under normal operation while guaranteeing safety and liveness under Byzantine faults, up to a near-optimal tolerance of f faulty group members among 3f + 2 total. ByzCoin mitigates double spending and selfish mining attacks by producing collectively signed transaction blocks within one minute of transaction submission. Tree-structured communication further reduces this latency to less than 30 seconds. Due to these optimizations, ByzCoin achieves a throughput higher than Paypal currently handles, with a confirmation latency of 15-20 seconds. AU - Kokoris Kogias, Eleftherios AU - Jovanovic, Philipp AU - Gailly, Nicolas AU - Khoffi, Ismail AU - Gasser, Linus AU - Ford, Bryan ID - 8302 SN - 9781931971324 T2 - Proceedings of the 25th USENIX Conference on Security Symposium TI - Enhancing bitcoin security and performance with strong consistency via collective signing ER - TY - JOUR AB - During spore formation in Bacillus subtilis a transenvelope complex is assembled across the double membrane that separates the mother cell and forespore. This complex (called the “A–Q complex”) is required to maintain forespore development and is composed of proteins with remote homology to components of type II, III, and IV secretion systems found in Gram-negative bacteria. Here, we show that one of these proteins, SpoIIIAG, which has remote homology to ring-forming proteins found in type III secretion systems, assembles into an oligomeric ring in the periplasmic-like space between the two membranes. Three-dimensional reconstruction of images generated by cryo-electron microscopy indicates that the SpoIIIAG ring has a cup-and-saucer architecture with a 6-nm central pore. Structural modeling of SpoIIIAG generated a 24-member ring with dimensions similar to those of the EM-derived saucer. Point mutations in the predicted oligomeric interface disrupted ring formation in vitro and impaired forespore gene expression and efficient spore formation in vivo. Taken together, our data provide strong support for the model in which the A–Q transenvelope complex contains a conduit that connects the mother cell and forespore. We propose that a set of stacked rings spans the intermembrane space, as has been found for type III secretion systems. AU - Rodrigues, Christopher D. A. AU - Henry, Xavier AU - Neumann, Emmanuelle AU - Kurauskas, Vilius AU - Bellard, Laure AU - Fichou, Yann AU - Schanda, Paul AU - Schoehn, Guy AU - Rudner, David Z. AU - Morlot, Cecile ID - 8452 IS - 41 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - A ring-shaped conduit connects the mother cell and forespore during sporulation in Bacillus subtilis VL - 113 ER - TY - JOUR AB - Transverse relaxation rate measurements in magic-angle spinning solid-state nuclear magnetic resonance provide information about molecular motions occurring on nanosecond-to-millisecond (ns–ms) time scales. The measurement of heteronuclear (13C, 15N) relaxation rate constants in the presence of a spin-lock radiofrequency field (R1ρ relaxation) provides access to such motions, and an increasing number of studies involving R1ρ relaxation in proteins have been reported. However, two factors that influence the observed relaxation rate constants have so far been neglected, namely, (1) the role of CSA/dipolar cross-correlated relaxation (CCR) and (2) the impact of fast proton spin flips (i.e., proton spin diffusion and relaxation). We show that CSA/D CCR in R1ρ experiments is measurable and that the CCR rate constant depends on ns–ms motions; it can thus provide insight into dynamics. We find that proton spin diffusion attenuates this CCR due to its decoupling effect on the doublet components. For measurements of dynamics, the use of R1ρ rate constants has practical advantages over the use of CCR rates, and this article reveals factors that have so far been disregarded and which are important for accurate measurements and interpretation. AU - Kurauskas, Vilius AU - Weber, Emmanuelle AU - Hessel, Audrey AU - Ayala, Isabel AU - Marion, Dominique AU - Schanda, Paul ID - 8453 IS - 34 JF - The Journal of Physical Chemistry B KW - Physical and Theoretical Chemistry KW - Materials Chemistry KW - Surfaces KW - Coatings and Films SN - 1520-6106 TI - Cross-correlated relaxation of dipolar coupling and chemical-shift anisotropy in magic-angle spinning R1ρ NMR measurements: Application to protein backbone dynamics measurements VL - 120 ER - TY - JOUR AB - Magic-angle spinning solid-state NMR spectroscopy is an important technique to study molecular structure, dynamics and interactions, and is rapidly gaining importance in biomolecular sciences. Here we provide an overview of experimental approaches to study molecular dynamics by MAS solid-state NMR, with an emphasis on the underlying theoretical concepts and differences of MAS solid-state NMR compared to solution-state NMR. The theoretical foundations of nuclear spin relaxation are revisited, focusing on the particularities of spin relaxation in solid samples under magic-angle spinning. We discuss the range of validity of Redfield theory, as well as the inherent multi-exponential behavior of relaxation in solids. Experimental challenges for measuring relaxation parameters in MAS solid-state NMR and a few recently proposed relaxation approaches are discussed, which provide information about time scales and amplitudes of motions ranging from picoseconds to milliseconds. We also discuss the theoretical basis and experimental measurements of anisotropic interactions (chemical-shift anisotropies, dipolar and quadrupolar couplings), which give direct information about the amplitude of motions. The potential of combining relaxation data with such measurements of dynamically-averaged anisotropic interactions is discussed. Although the focus of this review is on the theoretical foundations of dynamics studies rather than their application, we close by discussing a small number of recent dynamics studies, where the dynamic properties of proteins in crystals are compared to those in solution. AU - Schanda, Paul AU - Ernst, Matthias ID - 8454 IS - 8 JF - Progress in Nuclear Magnetic Resonance Spectroscopy SN - 0079-6565 TI - Studying dynamics by magic-angle spinning solid-state NMR spectroscopy: Principles and applications to biomolecules VL - 96 ER - TY - JOUR AB - Solid-state NMR spectroscopy allows the characterization of the structure, interactions and dynamics of insoluble and/or very large proteins. Sensitivity and resolution are often major challenges for obtaining atomic-resolution information, in particular for very large protein complexes. Here we show that the use of deuterated, specifically CH3-labelled proteins result in significant sensitivity gains compared to previously employed CHD2 labelling, while line widths increase only marginally. We apply this labelling strategy to a 468 kDa-large dodecameric aminopeptidase, TET2, and the 1.6 MDa-large 50S ribosome subunit of Thermus thermophilus. AU - Kurauskas, Vilius AU - Crublet, Elodie AU - Macek, Pavel AU - Kerfah, Rime AU - Gauto, Diego F. AU - Boisbouvier, Jérôme AU - Schanda, Paul ID - 8455 IS - 61 JF - Chemical Communications KW - Materials Chemistry KW - Electronic KW - Optical and Magnetic Materials KW - General Chemistry KW - Surfaces KW - Coatings and Films KW - Metals and Alloys KW - Ceramics and Composites KW - Catalysis SN - 1359-7345 TI - Sensitive proton-detected solid-state NMR spectroscopy of large proteins with selective CH3labelling: Application to the 50S ribosome subunit VL - 52 ER - TY - JOUR AB - Understanding the principles that led to the current complexity of the genetic code is a central question in evolution. Expansion of the genetic code required the selection of new transfer RNAs (tRNAs) with specific recognition signals that allowed them to be matured, modified, aminoacylated, and processed by the ribosome without compromising the fidelity or efficiency of protein synthesis. We show that saturation of recognition signals blocks the emergence of new tRNA identities and that the rate of nucleotide substitutions in tRNAs is higher in species with fewer tRNA genes. We propose that the growth of the genetic code stalled because a limit was reached in the number of identity elements that can be effectively used in the tRNA structure. AU - Saint-Léger, Adélaïde AU - Bello, Carla AU - Dans, Pablo D AU - Torres, Adrian G AU - Novoa, Eva M AU - Camacho, Noelia AU - Orozco, Modesto AU - Fyodor Kondrashov AU - Ribas De Pouplana, Lluís ID - 849 IS - 4 JF - Science advances TI - Saturation of recognition elements blocks evolution of new tRNA identities VL - 2 ER - TY - JOUR AB - In this paper we study a so-called separatrix map introduced by Zaslavskii–Filonenko (Sov Phys JETP 27:851–857, 1968) and studied by Treschev (Physica D 116(1–2):21–43, 1998; J Nonlinear Sci 12(1):27–58, 2002), Piftankin (Nonlinearity (19):2617–2644, 2006) Piftankin and Treshchëv (Uspekhi Mat Nauk 62(2(374)):3–108, 2007). We derive a second order expansion of this map for trigonometric perturbations. In Castejon et al. (Random iteration of maps of a cylinder and diffusive behavior. Preprint available at arXiv:1501.03319, 2015), Guardia and Kaloshin (Stochastic diffusive behavior through big gaps in a priori unstable systems (in preparation), 2015), and Kaloshin et al. (Normally Hyperbolic Invariant Laminations and diffusive behavior for the generalized Arnold example away from resonances. Preprint available at http://www.terpconnect.umd.edu/vkaloshi/, 2015), applying the results of the present paper, we describe a class of nearly integrable deterministic systems with stochastic diffusive behavior. AU - Guardia, M. AU - Kaloshin, Vadim AU - Zhang, J. ID - 8493 JF - Communications in Mathematical Physics SN - 0010-3616 TI - A second order expansion of the separatrix map for trigonometric perturbations of a priori unstable systems VL - 348 ER - TY - JOUR AB - We prove a form of Arnold diffusion in the a-priori stable case. Let H0(p)+ϵH1(θ,p,t),θ∈Tn,p∈Bn,t∈T=R/T, be a nearly integrable system of arbitrary degrees of freedom n⩾2 with a strictly convex H0. We show that for a “generic” ϵH1, there exists an orbit (θ,p) satisfying ∥p(t)−p(0)∥>l(H1)>0, where l(H1) is independent of ϵ. The diffusion orbit travels along a codimension-1 resonance, and the only obstruction to our construction is a finite set of additional resonances. For the proof we use a combination of geometric and variational methods, and manage to adapt tools which have recently been developed in the a-priori unstable case. AU - Bernard, Patrick AU - Kaloshin, Vadim AU - Zhang, Ke ID - 8494 IS - 1 JF - Acta Mathematica SN - 0001-5962 TI - Arnold diffusion in arbitrary degrees of freedom and normally hyperbolic invariant cylinders VL - 217 ER - TY - JOUR AU - Avila, Artur AU - De Simoi, Jacopo AU - Kaloshin, Vadim ID - 8496 IS - 2 JF - Annals of Mathematics SN - 0003-486X TI - An integrable deformation of an ellipse of small eccentricity is an ellipse VL - 184 ER - TY - JOUR AB - We study the dynamics of the restricted planar three-body problem near mean motion resonances, i.e. a resonance involving the Keplerian periods of the two lighter bodies revolving around the most massive one. This problem is often used to model Sun–Jupiter–asteroid systems. For the primaries (Sun and Jupiter), we pick a realistic mass ratio μ=10−3 and a small eccentricity e0>0. The main result is a construction of a variety of non local diffusing orbits which show a drastic change of the osculating (instant) eccentricity of the asteroid, while the osculating semi major axis is kept almost constant. The proof relies on the careful analysis of the circular problem, which has a hyperbolic structure, but for which diffusion is prevented by KAM tori. In the proof we verify certain non-degeneracy conditions numerically. Based on the work of Treschev, it is natural to conjecture that the time of diffusion for this problem is ∼−ln(μe0)μ3/2e0. We expect our instability mechanism to apply to realistic values of e0 and we give heuristic arguments in its favor. If so, the applicability of Nekhoroshev theory to the three-body problem as well as the long time stability become questionable. It is well known that, in the Asteroid Belt, located between the orbits of Mars and Jupiter, the distribution of asteroids has the so-called Kirkwood gaps exactly at mean motion resonances of low order. Our mechanism gives a possible explanation of their existence. To relate the existence of Kirkwood gaps with Arnol'd diffusion, we also state a conjecture on its existence for a typical ϵ-perturbation of the product of the pendulum and the rotator. Namely, we predict that a positive conditional measure of initial conditions concentrated in the main resonance exhibits Arnol’d diffusion on time scales −lnϵϵ2. AU - Féjoz, Jacques AU - Guàrdia, Marcel AU - Kaloshin, Vadim AU - Roldán, Pablo ID - 8497 IS - 10 JF - Journal of the European Mathematical Society SN - 1435-9855 TI - Kirkwood gaps and diffusion along mean motion resonances in the restricted planar three-body problem VL - 18 ER - TY - JOUR AB - Fitness landscapes depict how genotypes manifest at the phenotypic level and form the basis of our understanding of many areas of biology, yet their properties remain elusive. Previous studies have analysed specific genes, often using their function as a proxy for fitness, experimentally assessing the effect on function of single mutations and their combinations in a specific sequence or in different sequences. However, systematic high-throughput studies of the local fitness landscape of an entire protein have not yet been reported. Here we visualize an extensive region of the local fitness landscape of the green fluorescent protein from Aequorea Victoria (avGFP) by measuring the native function (fluorescence) of tens of thousands of derivative genotypes of avGFP. We show that the fitness landscape of avGFP is narrow, with 3/4 of the derivatives with a single mutation showing reduced fluorescence and half of the derivatives with four mutations being completely non-fluorescent. The narrowness is enhanced by epistasis, which was detected in up to 30% of genotypes with multiple mutations and mostly occurred through the cumulative effect of slightly deleterious mutations causing a threshold-like decrease in protein stability and a concomitant loss of fluorescence. A model of orthologous sequence divergence spanning hundreds of millions of years predicted the extent of epistasis in our data, indicating congruence between the fitness landscape properties at the local and global scales. The characterization of the local fitness landscape of avGFP has important implications for several fields including molecular evolution, population genetics and protein design. AU - Karen Sarkisyan AU - Bolotin, Dmitry A AU - Meer, Margarita V AU - Usmanova, Dinara R AU - Mishin, Alexander S AU - Sharonov, George V AU - Ivankov, Dmitry N AU - Bozhanova, Nina G AU - Baranov, Mikhail S AU - Soylemez, Onuralp AU - Bogatyreva, Natalya S AU - Vlasov, Peter K AU - Egorov, Evgeny S AU - Logacheva, Maria D AU - Kondrashov, Alexey S AU - Chudakov, Dmitriy M AU - Putintseva, Ekaterina V AU - Mamedov, Ilgar Z AU - Tawfik, Dan S AU - Lukyanov, Konstantin A AU - Fyodor Kondrashov ID - 850 JF - Nature TI - Local fitness landscape of the green fluorescent protein VL - 533 ER - TY - JOUR AB - A comparative analysis of the metagenomes from two 30 000-year-old permafrost samples, one of lake-alluvial origin and the other from late Pleistocene Ice Complex sediments, revealed significant differences within microbial communities. The late Pleistocene Ice Complex sediments (which have been characterized by the absence of methane with lower values of redox potential and Fe2+ content) showed a low abundance of methanogenic archaea and enzymes from both the carbon and nitrogen cycles, but a higher abundance of enzymes associated with the sulfur cycle. The metagenomic and geochemical analyses described in the paper provide evidence that the formation of the sampled late Pleistocene Ice Complex sediments likely took place under much more aerobic conditions than lake-alluvial sediments. AU - Rivkina, Elizaveta AU - Petrovskaya, Lada E AU - Vishnivetskaya, Tatiana A AU - Krivushin, Kirill V AU - Shmakova, Lyubov A AU - Tutukina, Maria AU - Meyers, Arthur J AU - Fyodor Kondrashov ID - 853 IS - 7 JF - Biogeosciences TI - Metagenomic analyses of the late Pleistocene permafrost - Additional tools for reconstruction of environmental conditions VL - 13 ER - TY - JOUR AB - Hybrid systems represent an important and powerful formalism for modeling real-world applications such as embedded systems. A verification tool like SpaceEx is based on the exploration of a symbolic search space (the region space). As a verification tool, it is typically optimized towards proving the absence of errors. In some settings, e.g., when the verification tool is employed in a feedback-directed design cycle, one would like to have the option to call a version that is optimized towards finding an error trajectory in the region space. A recent approach in this direction is based on guided search. Guided search relies on a cost function that indicates which states are promising to be explored, and preferably explores more promising states first. In this paper, we propose an abstraction-based cost function based on coarse-grained space abstractions for guiding the reachability analysis. For this purpose, a suitable abstraction technique that exploits the flexible granularity of modern reachability analysis algorithms is introduced. The new cost function is an effective extension of pattern database approaches that have been successfully applied in other areas. The approach has been implemented in the SpaceEx model checker. The evaluation shows its practical potential. AU - Bogomolov, Sergiy AU - Donzé, Alexandre AU - Frehse, Goran AU - Grosu, Radu AU - Johnson, Taylor AU - Ladan, Hamed AU - Podelski, Andreas AU - Wehrle, Martin ID - 1705 IS - 4 JF - International Journal on Software Tools for Technology Transfer TI - Guided search for hybrid systems based on coarse-grained space abstractions VL - 18 ER - TY - CONF AB - Volunteer supporters play an important role in modern crisis and disaster management. In the times of mobile Internet devices, help from thousands of volunteers can be requested within a short time span, thus relieving professional helpers from minor chores or geographically spread-out tasks. However, the simultaneous availability of many volunteers also poses new problems. In particular, the volunteer efforts must be well coordinated, or otherwise situations might emerge in which too many idle volunteers at one location become more of a burden than a relief to the professionals. In this work, we study the task of optimally assigning volunteers to selected locations, e.g. in order to perform regular measurements, to report on damage, or to distribute information or resources to the population in a crisis situation. We formulate the assignment tasks as an optimization problem and propose an effective and efficient solution procedure. Experiments on real data of the Team Österreich, consisting of over 36,000 Austrian volunteers, show the effectiveness and efficiency of our approach. AU - Pielorz, Jasmin AU - Lampert, Christoph ID - 1707 TI - Optimal geospatial allocation of volunteers for crisis management ER - TY - JOUR AB - We calculate admissible values of r such that a square-free polynomial with integer coefficients, no fixed prime divisor and irreducible factors of degree at most 3 takes infinitely many values that are a product of at most r distinct primes. AU - Browning, Timothy D AU - Booker, Andrew ID - 173 JF - Discrete Analysis TI - Square-free values of reducible polynomials VL - 8 ER - TY - JOUR AB - We consider Conditional random fields (CRFs) with pattern-based potentials defined on a chain. In this model the energy of a string (labeling) (Formula presented.) is the sum of terms over intervals [i, j] where each term is non-zero only if the substring (Formula presented.) equals a prespecified pattern w. Such CRFs can be naturally applied to many sequence tagging problems. We present efficient algorithms for the three standard inference tasks in a CRF, namely computing (i) the partition function, (ii) marginals, and (iii) computing the MAP. Their complexities are respectively (Formula presented.), (Formula presented.) and (Formula presented.) where L is the combined length of input patterns, (Formula presented.) is the maximum length of a pattern, and D is the input alphabet. This improves on the previous algorithms of Ye et al. (NIPS, 2009) whose complexities are respectively (Formula presented.), (Formula presented.) and (Formula presented.), where (Formula presented.) is the number of input patterns. In addition, we give an efficient algorithm for sampling, and revisit the case of MAP with non-positive weights. AU - Kolmogorov, Vladimir AU - Takhanov, Rustem ID - 1794 IS - 1 JF - Algorithmica TI - Inference algorithms for pattern-based CRFs on sequence data VL - 76 ER - TY - JOUR AB - Relational models for contingency tables are generalizations of log-linear models, allowing effects associated with arbitrary subsets of cells in the table, and not necessarily containing the overall effect, that is, a common parameter in every cell. Similarly to log-linear models, relational models can be extended to non-negative distributions, but the extension requires more complex methods. An extended relational model is defined as an algebraic variety, and it turns out to be the closure of the original model with respect to the Bregman divergence. In the extended relational model, the MLE of the cell parameters always exists and is unique, but some of its properties may be different from those of the MLE under log-linear models. The MLE can be computed using a generalized iterative scaling procedure based on Bregman projections. AU - Klimova, Anna AU - Rudas, Tamás ID - 1833 JF - Journal of Multivariate Analysis TI - On the closure of relational models VL - 143 ER - TY - JOUR AB - We consider random matrices of the form H=W+λV, λ∈ℝ+, where W is a real symmetric or complex Hermitian Wigner matrix of size N and V is a real bounded diagonal random matrix of size N with i.i.d.\ entries that are independent of W. We assume subexponential decay for the matrix entries of W and we choose λ∼1, so that the eigenvalues of W and λV are typically of the same order. Further, we assume that the density of the entries of V is supported on a single interval and is convex near the edges of its support. In this paper we prove that there is λ+∈ℝ+ such that the largest eigenvalues of H are in the limit of large N determined by the order statistics of V for λ>λ+. In particular, the largest eigenvalue of H has a Weibull distribution in the limit N→∞ if λ>λ+. Moreover, for N sufficiently large, we show that the eigenvectors associated to the largest eigenvalues are partially localized for λ>λ+, while they are completely delocalized for λ<λ+. Similar results hold for the lowest eigenvalues. AU - Lee, Jioon AU - Schnelli, Kevin ID - 1881 IS - 1-2 JF - Probability Theory and Related Fields TI - Extremal eigenvalues and eigenvectors of deformed Wigner matrices VL - 164 ER - TY - JOUR AB - Kinetics of electrochemical reactions are several orders of magnitude slower in solids than in liquids as a result of the much lower ion diffusivity. Yet, the solid state maximizes the density of redox species, which is at least two orders of magnitude lower in liquids because of solubility limitations. With regard to electrochemical energy storage devices, this leads to high-energy batteries with limited power and high-power supercapacitors with a well-known energy deficiency. For such devices the ideal system should endow the liquid state with a density of redox species close to the solid state. Here we report an approach based on biredox ionic liquids to achieve bulk-like redox density at liquid-like fast kinetics. The cation and anion of these biredox ionic liquids bear moieties that undergo very fast reversible redox reactions. As a first demonstration of their potential for high-capacity/high-rate charge storage, we used them in redox supercapacitors. These ionic liquids are able to decouple charge storage from an ion-accessible electrode surface, by storing significant charge in the pores of the electrodes, to minimize self-discharge and leakage current as a result of retaining the redox species in the pores, and to raise working voltage due to their wide electrochemical window. AU - Mourad, Eléonore AU - Coustan, Laura AU - Lannelongue, Pierre AU - Zigah, Dodzi AU - Mehdi, Ahmad AU - Vioux, André AU - Freunberger, Stefan Alexander AU - Favier, Frédéric AU - Fontaine, Olivier ID - 7279 IS - 4 JF - Nature Materials SN - 1476-1122 TI - Biredox ionic liquids with solid-like redox density in the liquid state for high-energy supercapacitors VL - 16 ER - TY - JOUR AB - If proton exchange membrane fuel cells (PEMFC) are ever to succeed in sustainable energy landscape as a potential zero emission technology, it is inevitable to reduce electricity production cost associated mainly with its MEAs, cell hardware and gas storage units. We demonstrate a diverse strategy for achieving this target with a concomitant amplification of its specific energy and power, by rolling a thin graphene oxide (GO) based MEA alone into a tubular and air breathing architecture with internal fuel storage. The unique properties of GO being a barrier for molecular fuels and proton conducting to construct a GO based cylindrical MEA. This makes the tubular PEMFC ∼75 times lighter, featuring ∼37 and ∼92 times respectively, the power and energy per overall weight, making it a potential candidate for portable applications. The intrinsic electrochemical kinetics at the three-phase boundary are somewhat affected by the bending of the MEA, albeit at overall reduction in power production cost. AU - Thimmappa, Ravikumar AU - Chattanahalli Devendrachari, Mruthyunjayachari AU - Shafi, Shahid AU - Freunberger, Stefan Alexander AU - Ottakam Thotiyl, Musthafa ID - 7293 IS - 47 JF - International Journal of Hydrogen Energy SN - 0360-3199 TI - Proton conducting hollow graphene oxide cylinder as molecular fuel barrier for tubular H2-air fuel cell VL - 41 ER - TY - JOUR AB - Mesoporous nanocrystalline TiO2 and TiO2–V2O5 microspheres were prepared by non-hydrolytic sol–gel from TiCl4, VOCl3, and iPr2O at 110 °C without any solvent or additives. The samples were characterized by elemental analysis, X-ray diffraction, Raman spectroscopy, scanning electron microscopy, nitrogen physisorption, and impedance measurements. At low vanadium loadings, only TiO2 anatase was detected, and V2O5 scherbinaite was also detected at high vanadium loadings. The texture of the samples depended on the V loading, but all the samples appeared built of primary nanoparticles (≈10–20 nm in size) that aggregate to form mesoporous micron-sized spheres. The lithium insertion properties of these materials were evaluated by galvanostatic measurements taken using coin-type cells, in view of their application as electrode for rechargeable Li-ion batteries. The mesoporous TiO2 microspheres showed good performances, with a specific reversible capacity of 145 and 128 mAh g−1 at C/2 and C, respectively (C = 335.6 mA g−1), good coulombic efficiency, and a moderate capacity fade (6 %) from the 2nd to the 20th cycle at C/20. Although the addition of V effectively increased the electronic conductivity of the powders, the specific reversible capacity and cycling performances of the TiO2–V2O5 samples were only minimally improved for a 5 at% V loading and were lower at higher V loading. AU - Escamilla-Pérez, A. M. AU - Louvain, N. AU - Kaschowitz, M. AU - Freunberger, Stefan Alexander AU - Fontaine, O. AU - Boury, B. AU - Brun, N. AU - Mutin, P. H. ID - 7294 IS - 2 JF - Journal of Sol-Gel Science and Technology SN - 0928-0707 TI - Lithium insertion properties of mesoporous nanocrystalline TiO2 and TiO2–V2O5 microspheres prepared by non-hydrolytic sol–gel VL - 79 ER - TY - JOUR AB - Redox ionic liquids consisting of ions bearing redox moieties are receiving increasing interest in electrochemical applications, as they associate electroactive properties with the classical properties of ionic liquids. Here, biredox ionic liquid electrolytes are described in which both anion and cation are functionalized with anthraquinone and 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) groups, respectively. In-depth investigations based on crossed experimental and theoretical studies were carried out to elucidate how the bulkiness of ions bearing a redox moiety impacted electron and mass transfers, and accordingly the efficiency of electrochemical devices. The values of solvated radii of different redox ions, as well as the related kinetic constants, were extracted from cyclic voltammetry experiments. Reformulating the basic relations of electron transfer theory (based on Marcus-Hush theory) evidenced that in such redox species, with an unsymmetrical located redox centre, the electron transfer was not governed by the overall size of the solvated redox species, but rather by the radius of the redox active subunit, which takes preferential orientation towards the surface, thus allowing higher kinetic constants than what classical theory would predict. This vision opens ample opportunities for biredox ILs as electrolytes in electrochemical devices. AU - Mourad, Eléonore AU - Coustan, Laura AU - Freunberger, Stefan Alexander AU - Mehdi, Ahmad AU - Vioux, André AU - Favier, Frédérique AU - Fontaine, Olivier ID - 7295 IS - 7 JF - Electrochimica Acta SN - 0013-4686 TI - Biredox ionic liquids: Electrochemical investigation and impact of ion size on electron transfer VL - 206 ER - TY - JOUR AB - Within the scope of developing a multi-physical model describing battery behavior during and after the mechanical load (accelerations, intrusions) of a vehicle’s high voltage battery, an internal short circuit model is of deep interest for a virtual hazard assessment. The internal short resistance and the size of the affected area must be known as a minimum for determining the released heat and, in consequence, the temperatures. The internal short resistance of purpose-built dummy pouch cells, filled with electrolyte-like solvent without conductive salt, has thus been measured in a given short area under various compressive loads. The resistances for different short scenarios obtained are analyzed and described in a mathematical form. Short circuit experiments with dummy cells using an external power source have also been carried out. This set-up allows the measurement of the temperature evolution at a known current and a determination of the actual short resistance. The post-mortem analysis of the samples shows a correlation between the maximum temperatures, released short heat and the separator melt diameter. AU - Volck, Theo AU - Sinz, Wolfgang AU - Gstrein, Gregor AU - Breitfuss, Christoph AU - Heindl, Simon AU - Steffan, Hermann AU - Freunberger, Stefan Alexander AU - Wilkening, Martin AU - Uitz, Marlena AU - Fink, Clemens AU - Geier, Alexander ID - 7296 IS - 2 JF - Batteries SN - 2313-0105 TI - Method for determination of the internal short resistance and heat evolution at different mechanical loads of a Lithium ion battery cell based on dummy pouch cells VL - 2 ER - TY - JOUR AB - Redox mediators facilitate the oxidation of the highly insulating discharge product in metal–oxygen batteries during recharge and offer opportunities to achieve high reversible capacities. Now a design principle for selecting redox mediators that can recharge the batteries more efficiently is suggested. AU - Freunberger, Stefan Alexander ID - 7297 IS - 6 JF - Nature Energy SN - 2058-7546 TI - Batteries: Charging ahead rationally VL - 1 ER - TY - JOUR AB - Lithium-ion batteries are in widespread use in electric vehicles and hybrid vehicles. Besides features like energy density, cost, lifetime, and recyclability the safety of a battery system is of prime importance. The separator material impacts all these properties and requires therefore an informed selection. The interplay between the mechanical and electrochemical properties as key selection criteria is investigated. Mechanical properties were investigated using tensile and puncture penetration tests at abuse relevant conditions. To investigate the electrochemical performance in terms of effective conductivity a method based on impedance spectroscopy was introduced. This methodology is applied to evaluate ten commercial separators which allows for a trade-off analysis of mechanical versus electrochemical performance. Based on the results, and in combination with other factors, this offers an effective approach to select suitable separators for automotive applications. AU - Plaimer, Martin AU - Breitfuß, Christoph AU - Sinz, Wolfgang AU - Heindl, Simon F. AU - Ellersdorfer, Christian AU - Steffan, Hermann AU - Wilkening, Martin AU - Hennige, Volker AU - Tatschl, Reinhard AU - Geier, Alexander AU - Schramm, Christian AU - Freunberger, Stefan Alexander ID - 7298 IS - 2 JF - Journal of Power Sources SN - 0378-7753 TI - Evaluating the trade-off between mechanical and electrochemical performance of separators for lithium-ion batteries: Methodology and application VL - 306 ER - TY - JOUR AB - Normal leaf margin development is important for leaf morphogenesis and contributes to diverse leaf shapes in higher plants. We here show the crucial roles of an atypical type II phosphatidylinositol 4-kinase, PI4Kγ5, in Arabidopsis leaf margin development. PI4Kγ5 presents a dynamics expression pattern along with leaf development and a T-DNA mutant lacking PI4Kγ5, pi4kγ5–1, presents serrated leaves, which is resulted from the accelerated cell division and increased auxin concentration at serration tips. Studies revealed that PI4Kγ5 interacts with and phosphorylates a membrane-bound NAC transcription factor, ANAC078. Previous studies demonstrated that membrane-bound transcription factors regulate gene transcription by undergoing proteolytic process to translocate into nucleus, and ANAC078 undergoes proteolysis by cleaving off the transmembrane region and carboxyl terminal. Western blot analysis indeed showed that ANAC078 deleting of carboxyl terminal is significantly reduced in pi4kγ5–1, indicating that PI4Kγ5 is important for the cleavage of ANAC078. This is consistent with the subcellular localization observation showing that fluorescence by GFP-ANAC078 is detected at plasma membrane but not nucleus in pi4kγ5–1 mutant and that expression of ANAC078 deleting of carboxyl terminal, driven by PI4Kγ5 promoter, could rescue the leaf serration defects of pi4kγ5–1. Further analysis showed that ANAC078 suppresses the auxin synthesis by directly binding and regulating the expression of auxin synthesis-related genes. These results indicate that PI4Kγ5 interacts with ANAC078 to negatively regulate auxin synthesis and hence influences cell proliferation and leaf development, providing informative clues for the regulation of in situ auxin synthesis and cell division, as well as the cleavage and functional mechanism of membrane-bound transcription factors. AU - Tang, Yong AU - Zhao, Chun-Yan AU - Tan, Shutang AU - Xue, Hong-Wei ID - 7599 IS - 8 JF - PLOS Genetics SN - 1553-7404 TI - Arabidopsis type II phosphatidylinositol 4-kinase PI4Kγ5 regulates auxin biosynthesis and leaf margin development through interacting with membrane-bound transcription factor ANAC078 VL - 12 ER - TY - JOUR AB - Importance: Considerable partner resemblances have been found for a wide range of psychiatric disorders, meaning that partners of affected individuals have an increased risk of being affected compared with partners of unaffected individuals. If this resemblance is reflected in genetic similarity between partners, genetic risk is anticipated to accumulate in offspring, but these potential consequences have not been quantified and have been left implicit. Observations: The anticipated consequences of partner resemblance on prevalence and heritability of psychiatric traits in the offspring generation were modeled for disorders with varying heritabilities, population prevalence (lifetime risk), and magnitudes of partner resemblance. These models facilitate interpretation for a wide range of psychiatric disorders, such as autism, schizophrenia, and depression. The genetic consequences of partner resemblance are most pronounced when attributable to phenotypic assortment (driven by the psychiatric trait). Phenotypic assortment results in increased genetic variance in the offspring generation, which may result in increased heritability and population prevalence. These consequences add generation after generation to a limit, but assortative mating is unlikely to balance the impact of reduced fecundity of patients with psychiatric disorders in the long term. This modeling suggests that the heritabilities of psychiatric disorders are unlikely to increase by more than 5% from 1 generation of assortative mating (maximally 13% across multiple generations). The population prevalence will increase most for less common disorders with high heritability; for example, the prevalence of autism might increase by 1.5-fold after 1 generation of assortative mating (≥2.4-fold in the long term) depending on several assumptions. Conclusions and Relevance: The considerable partner resemblances found for psychiatric disorders deserve more detailed interpretation than has been provided thus far. Although the limitations of modeling are emphasized, the anticipated consequences are at most modest for the heritability but may be considerable for the population prevalence of rare disorders with a high heritability. AU - Peyrot, Wouter J. AU - Robinson, Matthew Richard AU - Penninx, Brenda W. J. H. AU - Wray, Naomi R. ID - 7734 IS - 11 JF - JAMA Psychiatry SN - 2168-622X TI - Exploring boundaries for the genetic consequences of assortative mating for psychiatric traits VL - 73 ER - TY - JOUR AB - We develop a novel approach to identify regions of the genome underlying population genetic differentiation in any genetic data where the underlying population structure is unknown, or where the interest is assessing divergence along a gradient. By combining the statistical framework for genome-wide association studies (GWASs) with eigenvector decomposition (EigenGWAS), which is commonly used in population genetics to characterize the structure of genetic data, loci under selection can be identified without a requirement for discrete populations. We show through theory and simulation that our approach can identify regions under selection along gradients of ancestry, and in real data we confirm this by demonstrating LCT to be under selection between HapMap CEU–TSI cohorts, and we then validate this selection signal across European countries in the POPRES samples. HERC2 was also found to be differentiated between both the CEU–TSI cohort and within the POPRES sample, reflecting the likely anthropological differences in skin and hair colour between northern and southern European populations. Controlling for population stratification is of great importance in any quantitative genetic study and our approach also provides a simple, fast and accurate way of predicting principal components in independent samples. With ever increasing sample sizes across many fields, this approach is likely to be greatly utilized to gain individual-level eigenvectors avoiding the computational challenges associated with conducting singular value decomposition in large data sets. We have developed freely available software, Genetic Analysis Repository (GEAR), to facilitate the application of the methods. AU - Chen, G-B AU - Lee, S H AU - Zhu, Z-X AU - Benyamin, B AU - Robinson, Matthew Richard ID - 7736 JF - Heredity SN - 0018-067X TI - EigenGWAS: Finding loci under selection through genome-wide association studies of eigenvectors in structured populations VL - 117 ER - TY - JOUR AB - Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with human complex traits. However, the genes or functional DNA elements through which these variants exert their effects on the traits are often unknown. We propose a method (called SMR) that integrates summary-level data from GWAS with data from expression quantitative trait locus (eQTL) studies to identify genes whose expression levels are associated with a complex trait because of pleiotropy. We apply the method to five human complex traits using GWAS data on up to 339,224 individuals and eQTL data on 5,311 individuals, and we prioritize 126 genes (for example, TRAF1 and ANKRD55 for rheumatoid arthritis and SNX19 and NMRAL1 for schizophrenia), of which 25 genes are new candidates; 77 genes are not the nearest annotated gene to the top associated GWAS SNP. These genes provide important leads to design future functional studies to understand the mechanism whereby DNA variation leads to complex trait variation. AU - Zhu, Zhihong AU - Zhang, Futao AU - Hu, Han AU - Bakshi, Andrew AU - Robinson, Matthew Richard AU - Powell, Joseph E AU - Montgomery, Grant W AU - Goddard, Michael E AU - Wray, Naomi R AU - Visscher, Peter M AU - Yang, Jian ID - 7737 IS - 5 JF - Nature Genetics SN - 1061-4036 TI - Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets VL - 48 ER - TY - JOUR AB - We propose a Widom-like scaling ansatz for the critical jamming transition. Our ansatz for the elastic energy shows that the scaling of the energy, compressive strain, shear strain, system size, pressure, shear stress, bulk modulus, and shear modulus are all related to each other via scaling relations, with only three independent scaling exponents. We extract the values of these exponents from already known numerical or theoretical results, and we numerically verify the resulting predictions of the scaling theory for the energy and residual shear stress. We also derive a scaling relation between pressure and residual shear stress that yields insight into why the shear and bulk moduli scale differently. Our theory shows that the jamming transition exhibits an emergent scale invariance, setting the stage for the potential development of a renormalization group theory for jamming. AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Sethna, James P. ID - 7760 IS - 35 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Scaling ansatz for the jamming transition VL - 113 ER - TY - JOUR AB - We study the effect of dilute pinning on the jamming transition. Pinning reduces the average contact number needed to jam unpinned particles and shifts the jamming threshold to lower densities, leading to a pinning susceptibility, χp. Our main results are that this susceptibility obeys scaling form and diverges in the thermodynamic limit as χp∝|ϕ−ϕ∞c|−γp where ϕ∞c is the jamming threshold in the absence of pins. Finite-size scaling arguments yield these values with associated statistical (systematic) errors γp=1.018±0.026(0.291) in d=2 and γp=1.534±0.120(0.822) in d=3. Logarithmic corrections raise the exponent in d=2 to close to the d=3 value, although the systematic errors are very large. AU - Graves, Amy L. AU - Nashed, Samer AU - Padgett, Elliot AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Sethna, James P. ID - 7761 IS - 23 JF - Physical Review Letters SN - 0031-9007 TI - Pinning susceptibility: The effect of dilute, quenched disorder on jamming VL - 116 ER - TY - JOUR AB - Characterizing structural inhomogeneity is an essential step in understanding the mechanical response of amorphous materials. We introduce a threshold-free measure based on the field of vectors pointing from the center of each particle to the centroid of the Voronoi cell in which the particle resides. These vectors tend to point in toward regions of high free volume and away from regions of low free volume, reminiscent of sinks and sources in a vector field. We compute the local divergence of these vectors, where positive values correspond to overpacked regions and negative values identify underpacked regions within the material. Distributions of this divergence are nearly Gaussian with zero mean, allowing for structural characterization using only the moments of the distribution. We explore how the standard deviation and skewness vary with the packing fraction for simulations of bidisperse systems and find a kink in these moments that coincides with the jamming transition. AU - Rieser, Jennifer M. AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Durian, Douglas J. ID - 7762 IS - 8 JF - Physical Review Letters SN - 0031-9007 TI - Divergence of Voronoi cell anisotropy vector: A threshold-free characterization of local structure in amorphous materials VL - 116 ER - TY - JOUR AB - An orthogonal wavelet basis is characterized by its approximation order, which relates to the ability of the basis to represent general smooth functions on a given scale. It is known, though perhaps not widely known, that there are ways of exceeding the approximation order, i.e., achieving higher-order error in the discretized wavelet transform and its inverse. The focus here is on the development of a practical formulation to accomplish this first for 1D smooth functions, then for 1D functions with discontinuities and then for multidimensional (here 2D) functions with discontinuities. It is shown how to transcend both the wavelet approximation order and the 2D Gibbs phenomenon in representing electromagnetic fields at discontinuous dielectric interfaces that do not simply follow the wavelet-basis grid. AU - Lombardini, Richard AU - Acevedo, Ramiro AU - Kuczala, Alexander AU - Keys, Kerry P. AU - Goodrich, Carl Peter AU - Johnson, Bruce R. ID - 7763 JF - Journal of Computational Physics SN - 0021-9991 TI - Higher-order wavelet reconstruction/differentiation filters and Gibbs phenomena VL - 305 ER - TY - JOUR AB - States of self stress, organizations of internal forces in many-body systems that are in equilibrium with an absence of external forces, can be thought of as the constitutive building blocks of the elastic response of a material. In overconstrained disordered packings they have a natural mathematical correspondence with the zero-energy vibrational modes in underconstrained systems. While substantial attention in the literature has been paid to diverging length scales associated with zero- and finite-energy vibrational modes in jammed systems, less is known about the spatial structure of the states of self stress. In this work we define a natural way in which a unique state of self stress can be associated with each bond in a disordered spring network derived from a jammed packing, and then investigate the spatial structure of these bond-localized states of self stress. This allows for an understanding of how the elastic properties of a system would change upon changing the strength or even existence of any bond in the system. AU - Sussman, Daniel M. AU - Goodrich, Carl Peter AU - Liu, Andrea J. ID - 7764 IS - 17 JF - Soft Matter SN - 1744-683X TI - Spatial structure of states of self stress in jammed systems VL - 12 ER - TY - CONF AB - High memory contention is generally agreed to be a worst-case scenario for concurrent data structures. There has been a significant amount of research effort spent investigating designs which minimize contention, and several programming techniques have been proposed to mitigate its effects. However, there are currently few architectural mechanisms to allow scaling contended data structures at high thread counts. In this paper, we investigate hardware support for scalable contended data structures. We propose Lease/Release, a simple addition to standard directory-based MSI cache coherence protocols, allowing participants to lease memory, at the granularity of cache lines, by delaying coherence messages for a short, bounded period of time. Our analysis shows that Lease/Release can significantly reduce the overheads of contention for both non-blocking (lock-free) and lock-based data structure implementations, while ensuring that no deadlocks are introduced. We validate Lease/Release empirically on the Graphite multiprocessor simulator, on a range of data structures, including queue, stack, and priority queue implementations, as well as on transactional applications. Results show that Lease/Release consistently improves both throughput and energy usage, by up to 5x, both for lock-free and lock-based data structure designs. AU - Haider, Syed AU - Hasenplaugh, William AU - Alistarh, Dan-Adrian ID - 785 TI - Lease/Release: Architectural support for scaling contended data structures VL - 12-16-March-2016 ER - TY - JOUR AB - Lock-free concurrent algorithms guarantee that some concurrent operation will always make progress in a finite number of steps. Yet programmers prefer to treat concurrent code as if it were wait-free, guaranteeing that all operations always make progress. Unfortunately, designing wait-free algorithms is generally a very complex task, and the resulting algorithms are not always efficient. Although obtaining efficient wait-free algorithms has been a long-time goal for the theory community, most nonblocking commercial code is only lock-free. This article suggests a simple solution to this problem.We show that for a large class of lock-free algorithms, under scheduling conditions that approximate those found in commercial hardware architectures, lock-free algorithms behave as if they are wait-free. In other words, programmers can continue to design simple lock-free algorithms instead of complex wait-free ones, and in practice, they will get wait-free progress. Our main contribution is a new way of analyzing a general class of lock-free algorithms under a stochastic scheduler. Our analysis relates the individual performance of processes to the global performance of the system using Markov chain lifting between a complex per-process chain and a simpler system progress chain. We show that lock-free algorithms are not only wait-free with probability 1 but that in fact a general subset of lock-free algorithms can be closely bounded in terms of the average number of steps required until an operation completes. To the best of our knowledge, this is the first attempt to analyze progress conditions, typically stated in relation to a worst-case adversary, in a stochastic model capturing their expected asymptotic behavior. AU - Alistarh, Dan-Adrian AU - Censor Hillel, Keren AU - Shavit, Nir ID - 786 IS - 4 JF - Journal of the ACM TI - Are lock free concurrent algorithms practically wait free VL - 63 ER - TY - JOUR AB - NF-κB signaling is a central pathway of immunity and integrates signal transduction upon a wide array of inflammatory stimuli. Noncanonical NF-κB signaling is activated by a small subset of TNF family receptors and characterized by NF-κB2/p52 transcriptional activity. The medical relevance of this pathway has recently re-emerged from the discovery of primary immunodeficiency patients that have loss-of-function mutations in the MAP3K14 gene encoding NIK. Nevertheless, knowledge of protein interactions that regulate noncanonical NF-κB signaling is sparse. Here we report a detailed state-of-the-art mass spectrometry-based protein–protein interaction network including the noncanonical NF-κB signaling nodes TRAF2, TRAF3, IKKα, NIK, and NF-κB2/p100. The value of the data set was confirmed by the identification of interactions already known to regulate this pathway. In addition, a remarkable number of novel interactors were identified. We provide validation of the novel NIK and IKKα interactor FKBP8, which may regulate processes downstream of noncanonical NF-κB signaling. To understand perturbed noncanonical NF-κB signaling in the context of misregulated NIK in disease, we also provide a differential interactome of NIK mutants that cause immunodeficiency. Altogether, this data set not only provides critical insight into how protein–protein interactions can regulate immune signaling but also offers a novel resource on noncanonical NF-κB signaling. AU - Willmann, Katharina L AU - Roberto Sacco AU - Martins, Rui AU - Garncarz, Wojciech AU - Krolo, Ana AU - Knapp, Sylvia AU - Bennett, Keiryn L AU - Boztug, Kaan ID - 460 IS - 9 JF - Journal of Proteome Research TI - Expanding the interactome of the noncanonical NF-κB signaling pathway VL - 15 ER - TY - CONF AB - Magic: the Gathering is a game about magical combat for any number of players. Formally it is a zero-sum, imperfect information stochastic game that consists of a potentially unbounded number of steps. We consider the problem of deciding if a move is legal in a given single step of Magic. We show that the problem is (a) coNP-complete in general; and (b) in P if either of two small sets of cards are not used. Our lower bound holds even for single-player Magic games. The significant aspects of our results are as follows: First, in most real-life game problems, the task of deciding whether a given move is legal in a single step is trivial, and the computationally hard task is to find the best sequence of legal moves in the presence of multiple players. In contrast, quite uniquely our hardness result holds for single step and with only one-player. Second, we establish efficient algorithms for important special cases of Magic. AU - Chatterjee, Krishnendu AU - Ibsen-Jensen, Rasmus ID - 478 TI - The complexity of deciding legality of a single step of magic: The gathering VL - 285 ER -