TY - JOUR AB - Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between −2.3 and −5.2 phenotypic SDs for complete inbreeding; P<0.001). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data. AU - Yengo, Loic AU - Zhu, Zhihong AU - Wray, Naomi R. AU - Weir, Bruce S. AU - Yang, Jian AU - Robinson, Matthew Richard AU - Visscher, Peter M. ID - 7729 IS - 32 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Detection and quantification of inbreeding depression for complex traits from SNP data VL - 114 ER - TY - JOUR AB - Phenotypic plasticity is the ability of an individual genotype to alter aspects of its phenotype depending on the current environment. It is central to the persistence, resistance and resilience of populations facing variation in physical or biological factors. Genetic variation in plasticity is pervasive, which suggests its local adaptation is plausible. Existing studies on the adaptation of plasticity typically focus on single traits and a few populations, while theory about interactions among genes (for example, pleiotropy) suggests that a multi-trait, landscape scale (for example, multiple populations) perspective is required. We present data from a landscape scale, replicated, multi-trait experiment using a classic predator–prey system centred on the water flea Daphnia pulex. We find predator regime-driven differences in genetic variation of multivariate plasticity. These differences are associated with strong divergent selection linked to a predation regime. Our findings are evidence for local adaptation of plasticity, suggesting that responses of populations to environmental variation depend on the conditions in which they evolved in the past. AU - Reger, Julia AU - Lind, Martin I. AU - Robinson, Matthew Richard AU - Beckerman, Andrew P. ID - 7725 JF - Nature Ecology & Evolution SN - 2397-334X TI - Predation drives local adaptation of phenotypic plasticity VL - 2 ER - TY - JOUR AB - Sections PDFPDF Tools Share Abstract Background: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. Methods: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS‐relevant variants were cross‐checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.” Results: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. Conclusions: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS. AU - Garton, Fleur C. AU - Benyamin, Beben AU - Zhao, Qiongyi AU - Liu, Zhijun AU - Gratten, Jacob AU - Henders, Anjali K. AU - Zhang, Zong-Hong AU - Edson, Janette AU - Furlong, Sarah AU - Morgan, Sarah AU - Heggie, Susan AU - Thorpe, Kathryn AU - Pfluger, Casey AU - Mather, Karen A. AU - Sachdev, Perminder S. AU - McRae, Allan F. AU - Robinson, Matthew Richard AU - Shah, Sonia AU - Visscher, Peter M. AU - Mangelsdorf, Marie AU - Henderson, Robert D. AU - Wray, Naomi R. AU - McCombe, Pamela A. ID - 7733 IS - 4 JF - Molecular Genetics & Genomic Medicine SN - 2324-9269 TI - Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort VL - 5 ER - TY - JOUR AB - Genetic association studies in admixed populations are underrepresented in the genomics literature, with a key concern for researchers being the adequate control of spurious associations due to population structure. Linear mixed models (LMMs) are well suited for genome-wide association studies (GWAS) because they account for both population stratification and cryptic relatedness and achieve increased statistical power by jointly modeling all genotyped markers. Additionally, Bayesian LMMs allow for more flexible assumptions about the underlying distribution of genetic effects, and can concurrently estimate the proportion of phenotypic variance explained by genetic markers. Using three recently published Bayesian LMMs, Bayes R, BSLMM, and BOLT-LMM, we investigate an existing data set on eye (n = 625) and skin (n = 684) color from Cape Verde, an island nation off West Africa that is home to individuals with a broad range of phenotypic values for eye and skin color due to the mix of West African and European ancestry. We use simulations to demonstrate the utility of Bayesian LMMs for mapping loci and studying the genetic architecture of quantitative traits in admixed populations. The Bayesian LMMs provide evidence for two new pigmentation loci: one for eye color (AHRR) and one for skin color (DDB1). AU - Lloyd-Jones, Luke R. AU - Robinson, Matthew Richard AU - Moser, Gerhard AU - Zeng, Jian AU - Beleza, Sandra AU - Barsh, Gregory S. AU - Tang, Hua AU - Visscher, Peter M. ID - 7731 IS - 2 JF - Genetics SN - 0016-6731 TI - Inference on the genetic basis of eye and skin color in an admixed population via Bayesian linear mixed models VL - 206 ER - TY - JOUR AB - We give a bird's-eye view of the plastic deformation of crystals aimed at the statistical physics community, as well as a broad introduction to the statistical theories of forced rigid systems aimed at the plasticity community. Memory effects in magnets, spin glasses, charge density waves, and dilute colloidal suspensions are discussed in relation to the onset of plastic yielding in crystals. Dislocation avalanches and complex dislocation tangles are discussed via a brief introduction to the renormalization group and scaling. Analogies to emergent scale invariance in fracture, jamming, coarsening, and a variety of depinning transitions are explored. Dislocation dynamics in crystals challenge nonequilibrium statistical physics. Statistical physics provides both cautionary tales of subtle memory effects in nonequilibrium systems and systematic tools designed to address complex scale-invariant behavior on multiple length scales and timescales. AU - Sethna, James P. AU - Bierbaum, Matthew K. AU - Dahmen, Karin A. AU - Goodrich, Carl Peter AU - Greer, Julia R. AU - Hayden, Lorien X. AU - Kent-Dobias, Jaron P. AU - Lee, Edward D. AU - Liarte, Danilo B. AU - Ni, Xiaoyue AU - Quinn, Katherine N. AU - Raju, Archishman AU - Rocklin, D. Zeb AU - Shekhawat, Ashivni AU - Zapperi, Stefano ID - 7755 JF - Annual Review of Materials Research SN - 1531-7331 TI - Deformation of crystals: Connections with statistical physics VL - 47 ER - TY - JOUR AB - Recent advances in designing metamaterials have demonstrated that global mechanical properties of disordered spring networks can be tuned by selectively modifying only a small subset of bonds. Here, using a computationally efficient approach, we extend this idea to tune more general properties of networks. With nearly complete success, we are able to produce a strain between any two target nodes in a network in response to an applied source strain on any other pair of nodes by removing only ∼1% of the bonds. We are also able to control multiple pairs of target nodes, each with a different individual response, from a single source, and to tune multiple independent source/target responses simultaneously into a network. We have fabricated physical networks in macroscopic 2D and 3D systems that exhibit these responses. This work is inspired by the long-range coupled conformational changes that constitute allosteric function in proteins. The fact that allostery is a common means for regulation in biological molecules suggests that it is a relatively easy property to develop through evolution. In analogy, our results show that long-range coupled mechanical responses are similarly easy to achieve in disordered networks. AU - Rocks, Jason W. AU - Pashine, Nidhi AU - Bischofberger, Irmgard AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Nagel, Sidney R. ID - 7757 IS - 10 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Designing allostery-inspired response in mechanical networks VL - 114 ER - TY - JOUR AB - Controlling motion at the microscopic scale is a fundamental goal in the development of biologically inspired systems. We show that the motion of active, self-propelled colloids can be sufficiently controlled for use as a tool to assemble complex structures such as braids and weaves out of microscopic filaments. Unlike typical self-assembly paradigms, these structures are held together by geometric constraints rather than adhesive bonds. The out-of-equilibrium assembly that we propose involves precisely controlling the 2D motion of active colloids so that their path has a nontrivial topology. We demonstrate with proof-of-principle Brownian dynamics simulations that, when the colloids are attached to long semiflexible filaments, this motion causes the filaments to braid. The ability of the active particles to provide sufficient force necessary to bend the filaments into a braid depends on a number of factors, including the self-propulsion mechanism, the properties of the filament, and the maximum curvature in the braid. Our work demonstrates that nonequilibrium assembly pathways can be designed using active particles. AU - Goodrich, Carl Peter AU - Brenner, Michael P. ID - 7758 IS - 2 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Using active colloids as machines to weave and braid on the micrometer scale VL - 114 ER - TY - JOUR AB - We study the shear jamming of athermal frictionless soft spheres, and find that in the thermodynamic limit, a shear-jammed state exists with different elastic properties from the isotropically-jammed state. For example, shear-jammed states can have a non-zero residual shear stress in the thermodynamic limit that arises from long-range stress-stress correlations. As a result, the ratio of the shear and bulk moduli, which in isotropically-jammed systems vanishes as the jamming transition is approached from above, instead approaches a constant. Despite these striking differences, we argue that in a deeper sense, the shear jamming and isotropic jamming transitions actually have the same symmetry, and that the differences can be fully understood by rotating the six-dimensional basis of the elastic modulus tensor. AU - Baity-Jesi, Marco AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Nagel, Sidney R. AU - Sethna, James P. ID - 7756 IS - 3-4 JF - Journal of Statistical Physics SN - 0022-4715 TI - Emergent SO(3) symmetry of the frictionless shear jamming transition VL - 167 ER - TY - CONF AB - In contrast to electronic computation, chemical computation is noisy and susceptible to a variety of sources of error, which has prevented the construction of robust complex systems. To be effective, chemical algorithms must be designed with an appropriate error model in mind. Here we consider the model of chemical reaction networks that preserve molecular count (population protocols), and ask whether computation can be made robust to a natural model of unintended “leak” reactions. Our definition of leak is motivated by both the particular spurious behavior seen when implementing chemical reaction networks with DNA strand displacement cascades, as well as the unavoidable side reactions in any implementation due to the basic laws of chemistry. We develop a new “Robust Detection” algorithm for the problem of fast (logarithmic time) single molecule detection, and prove that it is robust to this general model of leaks. Besides potential applications in single molecule detection, the error-correction ideas developed here might enable a new class of robust-by-design chemical algorithms. Our analysis is based on a non-standard hybrid argument, combining ideas from discrete analysis of population protocols with classic Markov chain techniques. AU - Alistarh, Dan-Adrian AU - Dudek, Bartłomiej AU - Kosowski, Adrian AU - Soloveichik, David AU - Uznański, Przemysław ID - 788 TI - Robust detection in leak-prone population protocols VL - 10467 LNCS ER - TY - CONF AB - Population protocols are a popular model of distributed computing, in which randomly-interacting agents with little computational power cooperate to jointly perform computational tasks. Inspired by developments in molecular computation, and in particular DNA computing, recent algorithmic work has focused on the complexity of solving simple yet fundamental tasks in the population model, such as leader election (which requires convergence to a single agent in a special "leader" state), and majority (in which agents must converge to a decision as to which of two possible initial states had higher initial count). Known results point towards an inherent trade-off between the time complexity of such algorithms, and the space complexity, i.e. size of the memory available to each agent. In this paper, we explore this trade-off and provide new upper and lower bounds for majority and leader election. First, we prove a unified lower bound, which relates the space available per node with the time complexity achievable by a protocol: for instance, our result implies that any protocol solving either of these tasks for n agents using O(log log n) states must take (n=polylogn) expected time. This is the first result to characterize time complexity for protocols which employ super-constant number of states per node, and proves that fast, poly-logarithmic running times require protocols to have relatively large space costs. On the positive side, we give algorithms showing that fast, poly-logarithmic convergence time can be achieved using O(log2 n) space per node, in the case of both tasks. Overall, our results highlight a time complexity separation between O(log log n) and (log2 n) state space size for both majority and leader election in population protocols, and introduce new techniques, which should be applicable more broadly. AU - Alistarh, Dan-Adrian AU - Aspnes, James AU - Eisenstat, David AU - Rivest, Ronald AU - Gelashvili, Rati ID - 787 TI - Time-space trade-offs in population protocols ER - TY - CONF AB - The problem of efficient concurrent memory reclamation in unmanaged languages such as C or C++ is one of the major challenges facing the parallelization of billions of lines of legacy code. Garbage collectors for C/C++ can be inefficient; thus, programmers are often forced to use finely-crafted concurrent memory reclamation techniques. These techniques can provide good performance, but require considerable programming effort to deploy, and have strict requirements, allowing the programmer very little room for error. In this work, we present Forkscan, a new conservative concurrent memory reclamation scheme which is fully automatic and surprisingly scalable. Forkscan's semantics place it between automatic garbage collectors (it requires the programmer to explicitly retire nodes before they can be reclaimed), and concurrent memory reclamation techniques (as it does not assume that nodes are completely unlinked from the data structure for correctness). Forkscan's implementation exploits these new semantics for efficiency: we leverage parallelism and optimized implementations of signaling and copy-on-write in modern operating systems to efficiently obtain and process consistent snapshots of memory that can be scanned concurrently with the normal program operation. Empirical evaluation on a range of classical concurrent data structure microbenchmarks shows that Forkscan can preserve the scalability of the original code, while maintaining an order of magnitude lower latency than automatic garbage collection, and demonstrating competitive performance with finely crafted memory reclamation techniques. AU - Alistarh, Dan-Adrian AU - Leiserson, William AU - Matveev, Alexander AU - Shavit, Nir ID - 789 TI - Forkscan: Conservative memory reclamation for modern operating systems ER - TY - CONF AB - Stochastic gradient descent (SGD) is a commonly used algorithm for training linear machine learning models. Based on vector algebra, it benefits from the inherent parallelism available in an FPGA. In this paper, we first present a single-precision floating-point SGD implementation on an FPGA that provides similar performance as a 10-core CPU. We then adapt the design to make it capable of processing low-precision data. The low-precision data is obtained from a novel compression scheme - called stochastic quantization, specifically designed for machine learning applications. We test both full-precision and low-precision designs on various regression and classification data sets. We achieve up to an order of magnitude training speedup when using low-precision data compared to a full-precision SGD on the same FPGA and a state-of-the-art multi-core solution, while maintaining the quality of training. We open source the designs presented in this paper. AU - Kara, Kaan AU - Alistarh, Dan-Adrian AU - Alonso, Gustavo AU - Mutlu, Onur AU - Zhang, Ce ID - 790 TI - FPGA-accelerated dense linear machine learning: A precision-convergence trade-off ER - TY - JOUR AB - We introduce a common generalization of the strong Hanani–Tutte theorem and the weak Hanani–Tutte theorem: if a graph G has a drawing D in the plane where every pair of independent edges crosses an even number of times, then G has a planar drawing preserving the rotation of each vertex whose incident edges cross each other evenly in D. The theorem is implicit in the proof of the strong Hanani–Tutte theorem by Pelsmajer, Schaefer and Štefankovič. We give a new, somewhat simpler proof. AU - Fulek, Radoslav AU - Kynčl, Jan AU - Pálvölgyi, Dömötör ID - 795 IS - 3 JF - Electronic Journal of Combinatorics SN - 10778926 TI - Unified Hanani Tutte theorem VL - 24 ER - TY - JOUR AB - Aprotische Natrium‐O2‐Batterien basieren auf der reversiblen Bildung und Auflösung von Natriumsuperoxid (NaO2) während des Zellbetriebs. Nebenreaktionen des Elektrolyten und der Elektrode mit dem stark nukleophilen und basischen NaO2 führen zu mangelhafter Zyklenstabilität. Seine Reaktivität allein kann die Nebenreaktionen und schlechte Reversibilität jedoch nicht schlüssig erklären. Hier wird gezeigt, dass Singulett‐Sauerstoff (1O2) in allen Phasen des Betriebs entsteht und eine Hauptursache für Nebenreaktionen ist. 1O2 wurde in situ und ex situ mit einem 1O2‐Fänger detektiert, der schnell und selektiv ein Addukt mit 1O2 bildet. Mechanistisch betrachtet entsteht 1O2 entweder durch protonenunterstützte Disproportionierung von Superoxid während des Entladens, Lagerns und Ladens unter ca. 3.3 V oder durch direkte elektrochemische 1O2‐Entwicklung über ca. 3.3 V. Spuren von Wasser ermöglichen hohe Kapazitäten, beschleunigen aber auch Nebenreaktionen. Daher muss das hochreaktive 1O2 unbedingt kontrolliert werden, um die Zelle reversibel zu betreiben. AU - Schafzahl, Lukas AU - Mahne, Nika AU - Schafzahl, Bettina AU - Wilkening, Martin AU - Slugovc, Christian AU - Borisov, Sergey M. AU - Freunberger, Stefan Alexander ID - 7981 IS - 49 JF - Angewandte Chemie SN - 0044-8249 TI - Singulett-Sauerstoff in der aprotischen Natrium-O2-Batterie VL - 129 ER - TY - CHAP AB - In this part, the use of polysaccharides, either directly through composite approaches, or by carbonization will be described. In many cases, materials are obtained which are competitive in terms of capacitance and cycle lifetime. In this part, the use of polysaccharides, either directly through composite approaches, or by carbonization will be described. In many cases, materials are obtained which are competitive in terms of capacitance and cycle lifetime. The following part will focus mainly on cellulosic composites with conductive polymers since cellulose is most abundant and therefore has attracted much more research interest in this field whereas in the second part also other polysaccharides, such as chitin, xylans, alginates, pectins, dextrans and caragenaans have been used in carbonization experiments. AU - Yee Liew, Soon AU - Thielemans, Wim AU - Freunberger, Stefan Alexander AU - Spirk, Stefan ED - Yee Liew, Soon ED - Thielemans, Wim ED - Freunberger, Stefan Alexander ED - Spirk, Stefan ID - 7980 SN - 2191-5407 T2 - Polysaccharide Based Supercapacitors TI - Polysaccharides in supercapacitors ER - TY - JOUR AB - Beyond-intercalation batteries promise a step-change in energy storage compared to intercalation-based lithium-ion and sodium-ion batteries. However, only performance metrics that include all cell components and operation parameters can tell whether a true advance over intercalation batteries has been achieved. AU - Freunberger, Stefan Alexander ID - 7982 IS - 7 JF - Nature Energy SN - 2058-7546 TI - True performance metrics in beyond-intercalation batteries VL - 2 ER - TY - JOUR AU - Mahne, Nika AU - Schafzahl, Bettina AU - Leypold, Christian AU - Leypold, Mario AU - Grumm, Sandra AU - Leitgeb, Anita AU - Strohmeier, Gernot A. AU - Wilkening, Martin AU - Fontaine, Olivier AU - Kramer, Denis AU - Slugovc, Christian AU - Borisov, Sergey M. AU - Freunberger, Stefan Alexander ID - 7986 IS - 5 JF - Nature Energy SN - 2058-7546 TI - Singlet oxygen generation as a major cause for parasitic reactions during cycling of aprotic lithium–oxygen batteries VL - 2 ER - TY - JOUR AB - Phasenübergänge helfen beim Verständnis von Vielteilchensystemen in der Festkörperphysik und Fluiddynamik bis hin zur Teilchenphysik. Unserer internationalen Kollaboration ist es gelungen, einen neuartigen Phasenübergang in einem Quantensystem zu beobachten [1]. In einem Mikrowellenresonator konnte erstmals die spontane Zustandsänderung von undurchsichtig zu transparent nachgewiesen werden. AU - Fink, Johannes M ID - 797 IS - 3 JF - Physik in unserer Zeit TI - Photonenblockade aufgelöst VL - 48 ER - TY - JOUR AB - Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression—pre- or postsynaptic—is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity. AU - Costa, Rui Ponte AU - Padamsey, Zahid AU - D’Amour, James A. AU - Emptage, Nigel J. AU - Froemke, Robert C. AU - Vogels, Tim P ID - 8016 IS - 1 JF - Neuron SN - 0896-6273 TI - Synaptic transmission optimization predicts expression loci of long-term plasticity VL - 96 ER - TY - JOUR AB - Nervous systems use excitatory cell assemblies to encode and represent sensory percepts. Similarly, synaptically connected cell assemblies or "engrams" are thought to represent memories of past experience. Multiple lines of recent evidence indicate that brain systems create and use inhibitory replicas of excitatory representations for important cognitive functions. Such matched "inhibitory engrams" can form through homeostatic potentiation of inhibition onto postsynaptic cells that show increased levels of excitation. Inhibitory engrams can reduce behavioral responses to familiar stimuli, thereby resulting in behavioral habituation. In addition, by preventing inappropriate activation of excitatory memory engrams, inhibitory engrams can make memories quiescent, stored in a latent form that is available for context-relevant activation. In neural networks with balanced excitatory and inhibitory engrams, the release of innate responses and recall of associative memories can occur through focused disinhibition. Understanding mechanisms that regulate the formation and expression of inhibitory engrams in vivo may help not only to explain key features of cognition but also to provide insight into transdiagnostic traits associated with psychiatric conditions such as autism, schizophrenia, and posttraumatic stress disorder. AU - Barron, Helen C. AU - Vogels, Tim P AU - Behrens, Timothy E. AU - Ramaswami, Mani ID - 8018 IS - 26 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Inhibitory engrams in perception and memory VL - 114 ER -