TY - JOUR AB - D-cycloserine ameliorates breathing abnormalities and survival rate in a mouse model of Rett syndrome. AU - Novarino, Gaia ID - 715 IS - 405 JF - Science Translational Medicine SN - 19466234 TI - More excitation for Rett syndrome VL - 9 ER - TY - JOUR AB - Two-player games on graphs are central in many problems in formal verification and program analysis, such as synthesis and verification of open systems. In this work, we consider solving recursive game graphs (or pushdown game graphs) that model the control flow of sequential programs with recursion.While pushdown games have been studied before with qualitative objectives-such as reachability and ?-regular objectives- in this work, we study for the first time such games with the most well-studied quantitative objective, the mean-payoff objective. In pushdown games, two types of strategies are relevant: (1) global strategies, which depend on the entire global history; and (2) modular strategies, which have only local memory and thus do not depend on the context of invocation but rather only on the history of the current invocation of the module. Our main results are as follows: (1) One-player pushdown games with mean-payoff objectives under global strategies are decidable in polynomial time. (2) Two-player pushdown games with mean-payoff objectives under global strategies are undecidable. (3) One-player pushdown games with mean-payoff objectives under modular strategies are NP-hard. (4) Two-player pushdown games with mean-payoff objectives under modular strategies can be solved in NP (i.e., both one-player and two-player pushdown games with mean-payoff objectives under modular strategies are NP-complete). We also establish the optimal strategy complexity by showing that global strategies for mean-payoff objectives require infinite memory even in one-player pushdown games and memoryless modular strategies are sufficient in two-player pushdown games. Finally, we also show that all the problems have the same complexity if the stack boundedness condition is added, where along with the mean-payoff objective the player must also ensure that the stack height is bounded. AU - Chatterjee, Krishnendu AU - Velner, Yaron ID - 716 IS - 5 JF - Journal of the ACM SN - 00045411 TI - The complexity of mean-payoff pushdown games VL - 64 ER - TY - JOUR AB - We consider finite-state and recursive game graphs with multidimensional mean-payoff objectives. In recursive games two types of strategies are relevant: global strategies and modular strategies. Our contributions are: (1) We show that finite-state multidimensional mean-payoff games can be solved in polynomial time if the number of dimensions and the maximal absolute value of weights are fixed; whereas for arbitrary dimensions the problem is coNP-complete. (2) We show that one-player recursive games with multidimensional mean-payoff objectives can be solved in polynomial time. Both above algorithms are based on hyperplane separation technique. (3) For recursive games we show that under modular strategies the multidimensional problem is undecidable. We show that if the number of modules, exits, and the maximal absolute value of the weights are fixed, then one-dimensional recursive mean-payoff games under modular strategies can be solved in polynomial time, whereas for unbounded number of exits or modules the problem is NP-hard. AU - Chatterjee, Krishnendu AU - Velner, Yaron ID - 717 JF - Journal of Computer and System Sciences TI - Hyperplane separation technique for multidimensional mean-payoff games VL - 88 ER - TY - JOUR AB - The ubiquity of computation in modern machines and devices imposes a need to assert the correctness of their behavior. Especially in the case of safety-critical systems, their designers need to take measures that enforce their safe operation. Formal methods has emerged as a research field that addresses this challenge: by rigorously proving that all system executions adhere to their specifications, the correctness of an implementation under concern can be assured. To achieve this goal, a plethora of techniques are nowadays available, all of which are optimized for different system types and application domains. AU - Chatterjee, Krishnendu AU - Ehlers, Rüdiger ID - 719 IS - 6 JF - Acta Informatica SN - 00015903 TI - Special issue: Synthesis and SYNT 2014 VL - 54 ER - TY - JOUR AB - Advances in multi-unit recordings pave the way for statistical modeling of activity patterns in large neural populations. Recent studies have shown that the summed activity of all neurons strongly shapes the population response. A separate recent finding has been that neural populations also exhibit criticality, an anomalously large dynamic range for the probabilities of different population activity patterns. Motivated by these two observations, we introduce a class of probabilistic models which takes into account the prior knowledge that the neural population could be globally coupled and close to critical. These models consist of an energy function which parametrizes interactions between small groups of neurons, and an arbitrary positive, strictly increasing, and twice differentiable function which maps the energy of a population pattern to its probability. We show that: 1) augmenting a pairwise Ising model with a nonlinearity yields an accurate description of the activity of retinal ganglion cells which outperforms previous models based on the summed activity of neurons; 2) prior knowledge that the population is critical translates to prior expectations about the shape of the nonlinearity; 3) the nonlinearity admits an interpretation in terms of a continuous latent variable globally coupling the system whose distribution we can infer from data. Our method is independent of the underlying system’s state space; hence, it can be applied to other systems such as natural scenes or amino acid sequences of proteins which are also known to exhibit criticality. AU - Humplik, Jan AU - Tkacik, Gasper ID - 720 IS - 9 JF - PLoS Computational Biology SN - 1553734X TI - Probabilistic models for neural populations that naturally capture global coupling and criticality VL - 13 ER - TY - JOUR AB - Let S be a positivity-preserving symmetric linear operator acting on bounded functions. The nonlinear equation -1/m=z+Sm with a parameter z in the complex upper half-plane ℍ has a unique solution m with values in ℍ. We show that the z-dependence of this solution can be represented as the Stieltjes transforms of a family of probability measures v on ℝ. Under suitable conditions on S, we show that v has a real analytic density apart from finitely many algebraic singularities of degree at most 3. Our motivation comes from large random matrices. The solution m determines the density of eigenvalues of two prominent matrix ensembles: (i) matrices with centered independent entries whose variances are given by S and (ii) matrices with correlated entries with a translation-invariant correlation structure. Our analysis shows that the limiting eigenvalue density has only square root singularities or cubic root cusps; no other singularities occur. AU - Ajanki, Oskari H AU - Krüger, Torben H AU - Erdös, László ID - 721 IS - 9 JF - Communications on Pure and Applied Mathematics SN - 00103640 TI - Singularities of solutions to quadratic vector equations on the complex upper half plane VL - 70 ER - TY - JOUR AB - Plants are sessile organisms rooted in one place. The soil resources that plants require are often distributed in a highly heterogeneous pattern. To aid foraging, plants have evolved roots whose growth and development are highly responsive to soil signals. As a result, 3D root architecture is shaped by myriad environmental signals to ensure resource capture is optimised and unfavourable environments are avoided. The first signals sensed by newly germinating seeds — gravity and light — direct root growth into the soil to aid seedling establishment. Heterogeneous soil resources, such as water, nitrogen and phosphate, also act as signals that shape 3D root growth to optimise uptake. Root architecture is also modified through biotic interactions that include soil fungi and neighbouring plants. This developmental plasticity results in a ‘custom-made’ 3D root system that is best adapted to forage for resources in each soil environment that a plant colonises. AU - Morris, Emily AU - Griffiths, Marcus AU - Golebiowska, Agata AU - Mairhofer, Stefan AU - Burr Hersey, Jasmine AU - Goh, Tatsuaki AU - Von Wangenheim, Daniel AU - Atkinson, Brian AU - Sturrock, Craig AU - Lynch, Jonathan AU - Vissenberg, Kris AU - Ritz, Karl AU - Wells, Darren AU - Mooney, Sacha AU - Bennett, Malcolm ID - 722 IS - 17 JF - Current Biology SN - 09609822 TI - Shaping 3D root system architecture VL - 27 ER - TY - JOUR AB - Individual computations and social interactions underlying collective behavior in groups of animals are of great ethological, behavioral, and theoretical interest. While complex individual behaviors have successfully been parsed into small dictionaries of stereotyped behavioral modes, studies of collective behavior largely ignored these findings; instead, their focus was on inferring single, mode-independent social interaction rules that reproduced macroscopic and often qualitative features of group behavior. Here, we bring these two approaches together to predict individual swimming patterns of adult zebrafish in a group. We show that fish alternate between an “active” mode, in which they are sensitive to the swimming patterns of conspecifics, and a “passive” mode, where they ignore them. Using a model that accounts for these two modes explicitly, we predict behaviors of individual fish with high accuracy, outperforming previous approaches that assumed a single continuous computation by individuals and simple metric or topological weighing of neighbors’ behavior. At the group level, switching between active and passive modes is uncorrelated among fish, but correlated directional swimming behavior still emerges. Our quantitative approach for studying complex, multi-modal individual behavior jointly with emergent group behavior is readily extensible to additional behavioral modes and their neural correlates as well as to other species. AU - Harpaz, Roy AU - Tkacik, Gasper AU - Schneidman, Elad ID - 725 IS - 38 JF - PNAS SN - 00278424 TI - Discrete modes of social information processing predict individual behavior of fish in a group VL - 114 ER - TY - JOUR AB - We investigate the stationary and dynamical behavior of an Anderson localized chain coupled to a single central bound state. Although this coupling partially dilutes the Anderson localized peaks towards nearly resonant sites, the most weight of the original peaks remains unchanged. This leads to multifractal wave functions with a frozen spectrum of fractal dimensions, which is characteristic for localized phases in models with power-law hopping. Using a perturbative approach we identify two different dynamical regimes. At weak couplings to the central site, the transport of particles and information is logarithmic in time, a feature usually attributed to many-body localization. We connect such transport to the persistence of the Poisson statistics of level spacings in parts of the spectrum. In contrast, at stronger couplings the level repulsion is established in the entire spectrum, the problem can be mapped to the Fano resonance, and the transport is ballistic. AU - Hetterich, Daniel AU - Serbyn, Maksym AU - Domínguez, Fernando AU - Pollmann, Frank AU - Trauzettel, Björn ID - 724 IS - 10 JF - Physical Review B SN - 24699950 TI - Noninteracting central site model localization and logarithmic entanglement growth VL - 96 ER - TY - JOUR AB - Aprotic sodium–O2 batteries require the reversible formation/dissolution of sodium superoxide (NaO2) on cycling. Poor cycle life has been associated with parasitic chemistry caused by the reactivity of electrolyte and electrode with NaO2, a strong nucleophile and base. Its reactivity can, however, not consistently explain the side reactions and irreversibility. Herein we show that singlet oxygen (1O2) forms at all stages of cycling and that it is a main driver for parasitic chemistry. It was detected in‐ and ex‐situ via a 1O2 trap that selectively and rapidly forms a stable adduct with 1O2. The 1O2 formation mechanism involves proton‐mediated superoxide disproportionation on discharge, rest, and charge below ca. 3.3 V, and direct electrochemical 1O2 evolution above ca. 3.3 V. Trace water, which is needed for high capacities also drives parasitic chemistry. Controlling the highly reactive singlet oxygen is thus crucial for achieving highly reversible cell operation. AU - Schafzahl, Lukas AU - Mahne, Nika AU - Schafzahl, Bettina AU - Wilkening, Martin AU - Slugovc, Christian AU - Borisov, Sergey M. AU - Freunberger, Stefan Alexander ID - 7289 IS - 49 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Singlet oxygen during cycling of the aprotic sodium-O2 battery VL - 56 ER - TY - JOUR AB - Nowadays commercial supercapacitors are based on purely capacitive storage at the porous carbons that are used for the electrodes. However, the limits that capacitive storage imposes on energy density calls to investigate new materials to improve the capacitance of the device. This new type of electrodes (e.g., RuO2, MnO2…) involves pseudo-capacitive faradaic redox processes with the solid material. Ion exchange with solid materials is, however, much slower than the adsorption process in capacitive storage and inevitably leads to significant loss of power. Faradaic process in the liquid state, in contrast can be similarly fast as capacitive processes due to the fast ion transport. Designing new devices with liquid like dynamics and improved specific capacitance is challenging. We present a new approach to increase the specific capacitance using biredox ionic liquids, where redox moieties are tethered to the electrolyte ions, allowing high redox concentrations and significant pseudo-capacitive storage in the liquid state. Anions and cations are functionalized with anthraquinone (AQ) and 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) moieties, respectively. Glassy carbon, carbon-onion, and commercial activated carbon electrodes that exhibit different double layer structures and thus different diffusion dynamics were used to simultaneously study the electrochemical response of biredox ionic liquids at the positive and negative electrode. AU - Bodin, C. AU - Mourad, E. AU - Zigah, D. AU - Le Vot, S. AU - Freunberger, Stefan Alexander AU - Favier, F. AU - Fontaine, O. ID - 7288 JF - Faraday Discussions SN - 1359-6640 TI - Biredox ionic liquids: New opportunities toward high performance supercapacitors VL - 206 ER - TY - JOUR AB - We report a family of Pt and Pd benzoporphyrin dyes with versatile photophysical properties and easy access from cheap and abundant chemicals. Attaching 4 or 8 alkylsulfone groups onto a meso-tetraphenyltetrabenzoporphyrin (TPTBP) macrocylcle renders the dyes highly soluble in organic solvents, photostable, and electron-deficient with the redox potential raised up to 0.65 V versus the parent porphyrin. The new dyes intensively absorb in the blue (Soret band, 440–480 nm) and in the red (Q-band, 620–650 nm) parts of the electromagnetic spectrum and show bright phosphorescence at room-temperature in the NIR with quantum yields up to 30% in solution. The small singlet–triplet energy gap yields unusually efficient thermally activated delayed fluorescence (TADF) at elevated temperatures in solution and in polymeric matrices with quantum yields as high as 27% at 120 °C, which is remarkable for benzoporphyrins. Apart from oxygen sensing, these properties enable unprecedented simultaneous, self-referenced oxygen and temperature sensing with a single indicator dye: whereas oxygen can be determined either via the decay time of phosphorescence or TADF, the temperature is accessed via the ratio of the two emissions. Moreover, the dyes are efficient sensitizers for triplet–triplet annihilation (TTA)-based upconversion making possible longer sensitization wavelength than the conventional benzoporphyrin complexes. The Pt-octa-sulfone dye also features interesting semireversible transformation in basic media, which generates new NIR absorbing species. AU - Zach, Peter W. AU - Freunberger, Stefan Alexander AU - Klimant, Ingo AU - Borisov, Sergey M. ID - 7290 IS - 43 JF - ACS Applied Materials & Interfaces SN - 1944-8244 TI - Electron-deficient near-infrared Pt(II) and Pd(II) benzoporphyrins with dual phosphorescence and unusually efficient thermally activated delayed fluorescence: First demonstration of simultaneous oxygen and temperature sensing with a single emitter VL - 9 ER - TY - JOUR AB - Rechargeable Li–O2 batteries have amongst the highest formal energy and could store significantly more energy than other rechargeable batteries in practice if at least a large part of their promise could be realized. Realization, however, still faces many challenges than can only be overcome by fundamental understanding of the processes taking place. Here, we review recent advances in understanding the chemistry of the Li–O2 cathode and provide a perspective on dominant research needs. We put particular emphasis on issues that are often grossly misunderstood: realistic performance metrics and their reporting as well as identifying reversibility and quantitative measures to do so. Parasitic reactions are the prime obstacle for reversible cell operation and have recently been identified to be predominantly caused by singlet oxygen and not by reduced oxygen species as thought before. We discuss the far reaching implications of this finding on electrolyte and cathode stability, electrocatalysis, and future research needs. AU - Mahne, Nika AU - Fontaine, Olivier AU - Thotiyl, Musthafa Ottakam AU - Wilkening, Martin AU - Freunberger, Stefan Alexander ID - 7292 IS - 10 JF - Chemical Science SN - 2041-6520 TI - Mechanism and performance of lithium–oxygen batteries – a perspective VL - 8 ER - TY - JOUR AB - Na battery chemistries show poor passivation behavior of low voltage Na storage compounds and Na metal with organic carbonate‐based electrolytes adopted from Li‐ion batteries. Therefore, a suitable electrolyte remains a major challenge for establishing Na batteries. Here we report highly concentrated sodium bis(fluorosulfonyl)imide (NaFSI) in dimethoxyethane (DME) electrolytes and investigate them for Na metal and hard carbon anodes and intercalation cathodes. For a DME/NaFSI ratio of 2, a stable passivation of anode materials was found owing to the formation of a stable solid electrolyte interface, which was characterized spectroscopically. This permitted non‐dentritic Na metal cycling with approximately 98 % coulombic efficiency as shown for up to 300 cycles. The NaFSI/DME electrolyte may enable Na‐metal anodes and allows for more reliable assessment of electrode materials in Na‐ion half‐cells, as is demonstrated by comparing half‐cell cycling of hard carbon anodes and Na3V2(PO4)3 cathodes with a widely used carbonate and the NaFSI/DME electrolyte. AU - Schafzahl, Lukas AU - Hanzu, Ilie AU - Wilkening, Martin AU - Freunberger, Stefan Alexander ID - 7291 IS - 2 JF - ChemSusChem SN - 1864-5631 TI - An electrolyte for reversible cycling of sodium metal and intercalation compounds VL - 10 ER - TY - JOUR AB - Genetic variations in the oxytocin receptor gene affect patients with ASD and ADHD differently. AU - Novarino, Gaia ID - 731 IS - 411 JF - Science Translational Medicine SN - 19466234 TI - The science of love in ASD and ADHD VL - 9 ER - TY - JOUR AB - Inflammation, which is a highly regulated host response against danger signals, may be harmful if it is excessive and deregulated. Ideally, anti-inflammatory therapy should autonomously commence as soon as possible after the onset of inflammation, should be controllable by a physician, and should not systemically block beneficial immune response in the long term. We describe a genetically encoded anti-inflammatory mammalian cell device based on a modular engineered genetic circuit comprising a sensor, an amplifier, a “thresholder” to restrict activation of a positive-feedback loop, a combination of advanced clinically used biopharmaceutical proteins, and orthogonal regulatory elements that linked modules into the functional device. This genetic circuit was autonomously activated by inflammatory signals, including endogenous cecal ligation and puncture (CLP)-induced inflammation in mice and serum from a systemic juvenile idiopathic arthritis (sIJA) patient, and could be reset externally by a chemical signal. The microencapsulated anti-inflammatory device significantly reduced the pathology in dextran sodium sulfate (DSS)-induced acute murine colitis, demonstrating a synthetic immunological approach for autonomous anti-inflammatory therapy. AU - Smole, Anže AU - Lainšček, Duško AU - Bezeljak, Urban AU - Horvat, Simon AU - Jerala, Roman ID - 7360 IS - 1 JF - Molecular Therapy SN - 1525-0016 TI - A synthetic mammalian therapeutic gene circuit for sensing and suppressing inflammation VL - 25 ER - TY - CHAP AB - The essay focuses on individual and collective forms of liminality in John Marlyn’s Under the Ribs of Death. Set in early twentieth-century Winnipeg, the 1957 immigrant novel explores liminal experiences related to ethnic identity, male sexuality, social class, urban spaces and turbulent economic times. As the son of a poor working-class family from Hungary, Sandor Hunyadi makes every effort to become a true Canadian and a successful businessman, but, no matter how hard he tries to overcome contemporary ethnic prejudices and economic hardships, his personal and professional life remains in liminality. In other words, the protagonist undergoes separation, fails at incorporation, and becomes stuck in transition. AU - Bernhard Wenzl ED - Brandt, Stefan L. ID - 748 T2 - In-Between - Liminal Spaces in Canadian Literature and Culture TI - '...beyond the invisible barrier at Portage and Main': Liminality in John Marlyn's Under the Ribs of Death ER - TY - CONF AB - Modern communication technologies allow first responders to contact thousands of potential volunteers simultaneously for support during a crisis or disaster event. However, such volunteer efforts must be well coordinated and monitored, in order to offer an effective relief to the professionals. In this paper we extend earlier work on optimally assigning volunteers to selected landmark locations. In particular, we emphasize the aspect that obtaining good assignments requires not only advanced computational tools, but also a realistic measure of distance between volunteers and landmarks. Specifically, we propose the use of the Open Street Map (OSM) driving distance instead of he previously used flight distance. We find the OSM driving distance to be better aligned with the interests of volunteers and first responders. Furthermore, we show that relying on the flying distance leads to a substantial underestimation of the number of required volunteers, causing negative side effects in case of an actual crisis situation. AU - Pielorz, Jasmin AU - Prandtstetter, Matthias AU - Straub, Markus AU - Lampert, Christoph ID - 750 SN - 978-153862714-3 T2 - 2017 IEEE International Conference on Big Data TI - Optimal geospatial volunteer allocation needs realistic distances ER - TY - JOUR AB - Meta-analyses of genome-wide association studies, which dominate genetic discovery, are based on data from diverse historical time periods and populations. Genetic scores derived from genome-wide association studies explain only a fraction of the heritability estimates obtained from whole-genome studies on single populations, known as the ‘hidden heritability’ puzzle. Using seven sampling populations (n = 35,062), we test whether hidden heritability is attributed to heterogeneity across sampling populations and time, showing that estimates are substantially smaller across populations compared with within populations. We show that the hidden heritability varies substantially: from zero for height to 20% for body mass index, 37% for education, 40% for age at first birth and up to 75% for number of children. Simulations demonstrate that our results are more likely to reflect heterogeneity in phenotypic measurement or gene–environment interactions than genetic heterogeneity. These findings have substantial implications for genetic discovery, suggesting that large homogenous datasets are required for behavioural phenotypes and that gene–environment interaction may be a central challenge for genetic discovery. AU - Tropf, Felix C. AU - Lee, S. Hong AU - Verweij, Renske M. AU - Stulp, Gert AU - van der Most, Peter J. AU - de Vlaming, Ronald AU - Bakshi, Andrew AU - Briley, Daniel A. AU - Rahal, Charles AU - Hellpap, Robert AU - Iliadou, Anastasia N. AU - Esko, Tõnu AU - Metspalu, Andres AU - Medland, Sarah E. AU - Martin, Nicholas G. AU - Barban, Nicola AU - Snieder, Harold AU - Robinson, Matthew Richard AU - Mills, Melinda C. ID - 7728 IS - 10 JF - Nature Human Behaviour SN - 2397-3374 TI - Hidden heritability due to heterogeneity across seven populations VL - 1 ER - TY - JOUR AB - Genes of the major histocompatibility complex (MHC) have been shown to influence social signalling and mate preferences in many species, including humans. First observations suggest that MHC signalling may also affect female fertility. To test this hypothesis, we exposed 191 female horses (Equus caballus) to either an MHC-similar or an MHC-dissimilar stimulus male around the time of ovulation and conception. A within-subject experimental design controlled for non-MHC-linked male characteristics, and instrumental insemination with semen of other males (n = 106) controlled for potential confounding effects of semen or embryo characteristics. We found that females were more likely to become pregnant if exposed to an MHC-dissimilar than to an MHC-similar male, while overall genetic distance to the stimulus males (based on microsatellite markers on 20 chromosomes) had no effect. Our results demonstrate that early pregnancy failures can be due to maternal life-history decisions (cryptic female choice) influenced by MHC-linked social signalling. AU - Burger, D. AU - Thomas, S. AU - Aepli, H. AU - Dreyer, M. AU - Fabre, G. AU - Marti, E. AU - Sieme, H. AU - Robinson, Matthew Richard AU - Wedekind, C. ID - 7727 IS - 1868 JF - Proceedings of the Royal Society B: Biological Sciences SN - 0962-8452 TI - Major histocompatibility complex-linked social signalling affects female fertility VL - 284 ER - 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 - TY - JOUR AB - Synaptic plasticity is essential for the function of neural systems. It sets up initial circuitry and adjusts connection strengths according to the maintenance requirements of its host networks. Like all things biological, synaptic plasticity must rely on genetic programs to provide the molecular components of its machinery to integrate ongoing, often multi-sensory experience without destabilising effects. Because of its fundamental importance to healthy behaviour, understanding plasticity is thought to hold the key to understanding the brain. There are innumerable ways to approach this topic and a complete review of its status quo would be impossible. In the current issue we dig into some of the finer points of synaptic plasticity, starting small, at the level of genes, and slowly zooming out to synapses, populations of synapses, and finally entire systems and brain regions. At each level, we tried to represent different perspectives, different systems, and approaches to the same questions to give a broad sampling of how synaptic plasticity is being studied. AU - Vogels, Tim P AU - Griffith, Leslie C ID - 8019 JF - Current Opinion in Neurobiology SN - 0959-4388 TI - Editorial overview: Neurobiology of learning and plasticity 2017 VL - 43 ER - TY - JOUR AB - nhibitory neurons, although relatively few in number, exert powerful control over brain circuits. They stabilize network activity in the face of strong feedback excitation and actively engage in computations. Recent studies reveal the importance of a precise balance of excitation and inhibition in neural circuits, which often requires exquisite fine-tuning of inhibitory connections. We review inhibitory synaptic plasticity and its roles in shaping both feedforward and feedback control. We discuss the necessity of complex, codependent plasticity mechanisms to build nontrivial, functioning networks, and we end by summarizing experimental evidence of such interactions. AU - Hennequin, Guillaume AU - Agnes, Everton J. AU - Vogels, Tim P ID - 8017 IS - 1 JF - Annual Review of Neuroscience SN - 0147-006X TI - Inhibitory plasticity: Balance, control, and codependence VL - 40 ER - TY - JOUR AB - Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretation of simulations. However, the number of published models, and the lack of standardization, make the comparison of ion channel models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy (ICGenealogy) web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling. AU - Podlaski, William F AU - Seeholzer, Alexander AU - Groschner, Lukas N AU - Miesenböck, Gero AU - Ranjan, Rajnish AU - Vogels, Tim P ID - 8075 JF - eLife SN - 2050-084X TI - Mapping the function of neuronal ion channels in model and experiment VL - 6 ER - TY - JOUR AB - On January the 1st, 2016 a new agreement between 32 Austrian scientific libraries and the publisher Springer took its effect: this deal covers accessing the licensed content on the one hand, and publishing open access on the other hand. More than 1000 papers by Austrian authors were published open access at Springer in the first year alone. The working group "Springer Compact Evaluierung" made the data for these articles available via the platform OpenAPC and would like to use this opportunity to give a short account of what this publishing agreement actually entails and the working group intends to do. AU - Andrae, Magdalena AU - Villányi, Márton ID - 807 IS - 2 JF - Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare SN - 10222588 TI - Der Springer Compact-Deal – Ein erster Einblick in die Evaluierung einer Offsetting-Vereinbarung VL - 70 ER - TY - CONF AB - Cortical circuits exhibit intricate recurrent architectures that are remarkably similar across different brain areas. Such stereotyped structure suggests the existence of common computational principles. However, such principles have remained largely elusive. Inspired by gated-memory networks, namely long short-term memory networks (LSTMs), we introduce a recurrent neural network in which information is gated through inhibitory cells that are subtractive (subLSTM). We propose a natural mapping of subLSTMs onto known canonical excitatory-inhibitory cortical microcircuits. Our empirical evaluation across sequential image classification and language modelling tasks shows that subLSTM units can achieve similar performance to LSTM units. These results suggest that cortical circuits can be optimised to solve complex contextual problems and proposes a novel view on their computational function. Overall our work provides a step towards unifying recurrent networks as used in machine learning with their biological counterparts. AU - Costa, Rui Ponte AU - Assael, Yannis M. AU - Shillingford, Brendan AU - Freitas, Nando de AU - Vogels, Tim P ID - 8129 SN - 10495258 T2 - Advances in Neural Information Processing Systems TI - Cortical microcircuits as gated-recurrent neural networks VL - 30 ER - TY - JOUR AB - Cryo-electron tomography (cryo-ET) allows cellular ultrastructures and macromolecular complexes to be imaged in three-dimensions in their native environments. Cryo-electron tomograms are reconstructed from projection images taken at defined tilt-angles. In order to recover high-resolution information from cryo-electron tomograms, it is necessary to measure and correct for the contrast transfer function (CTF) of the microscope. Most commonly, this is performed using protocols that approximate the sample as a two-dimensional (2D) plane. This approximation accounts for differences in defocus and therefore CTF across the tilted sample. It does not account for differences in defocus of objects at different heights within the sample; instead, a 3D approach is required. Currently available approaches for 3D-CTF correction are computationally expensive and have not been widely implemented. Here we simulate the benefits of 3D-CTF correction for high-resolution subtomogram averaging, and present a user-friendly, computationally-efficient 3D-CTF correction tool, NovaCTF, that is compatible with standard tomogram reconstruction workflows in IMOD. We validate the approach on synthetic data and test it using subtomogram averaging of real data. Consistent with our simulations, we find that 3D-CTF correction allows high-resolution structures to be obtained with much smaller subtomogram averaging datasets than are required using 2D-CTF. We also show that using equivalent dataset sizes, 3D-CTF correction can be used to obtain higher-resolution structures. We present a 3.4. Å resolution structure determined by subtomogram averaging. AU - Turoňová, Beata AU - Schur, Florian AU - Wan, William AU - Briggs, John ID - 817 IS - 3 JF - Journal of Structural Biology TI - Efficient 3D-CTF correction for cryo-electron tomography using NovaCTF improves subtomogram averaging resolution to 3.4Å VL - 199 ER - TY - JOUR AB - Monoclonal antibodies find broad application as therapy for various types of cancer by employing multiple mechanisms of action against tumors. Manipulating the Fc-mediated functions of antibodies that engage immune effector cells, such as NK cells, represents a strategy to influence effector cell activation and to enhance antibody potency and potentially efficacy. We developed a novel approach to generate and ascertain the functional attributes of Fc mutant monoclonal antibodies. This entailed coupling single expression vector (pVitro1) antibody cloning, using polymerase incomplete primer extension (PIPE) polymerase chain reaction, together with simultaneous Fc region point mutagenesis and high yield transient expression in human mammalian cells. Employing this, we engineered wild type, low (N297Q, NQ), and high (S239D/I332E, DE) FcR-binding Fc mutant monoclonal antibody panels recognizing two cancer antigens, HER2/neu and chondroitin sulfate proteoglycan 4. Antibodies were generated with universal mutagenic primers applicable to any IgG1 pVitro1 constructs, with high mutagenesis and transfection efficiency, in small culture volumes, at high yields and within 12 days from design to purified material. Antibody variants conserved their Fab-mediated recognition of target antigens and their direct anti-proliferative effects against cancer cells. Fc mutations had a significant impact on antibody interactions with Fc receptors (FcRs) on human NK cells, and consequently on the potency of NK cell activation, quantified by immune complex-mediated calcium mobilization and by antibody-dependent cellular cytotoxicity (ADCC) of tumor cells. This strategy for manipulation and testing of Fc region engagement with cognate FcRs can facilitate the design of antibodies with defined effector functions and potentially enhanced efficacy against tumor cells. AU - Ilieva, Kristina M. AU - Fazekas-Singer, Judit AU - Achkova, Daniela Y. AU - Dodev, Tihomir S. AU - Mele, Silvia AU - Crescioli, Silvia AU - Bax, Heather J. AU - Cheung, Anthony AU - Karagiannis, Panagiotis AU - Correa, Isabel AU - Figini, Mariangela AU - Marlow, Rebecca AU - Josephs, Debra H. AU - Beavil, Andrew J. AU - Maher, John AU - Spicer, James F. AU - Jensen-Jarolim, Erika AU - Tutt, Andrew N. AU - Karagiannis, Sophia N. ID - 8237 JF - Frontiers in Immunology SN - 1664-3224 TI - Functionally active Fc mutant antibodies recognizing cancer antigens generated rapidly at high yields VL - 8 ER - TY - JOUR AB - Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE‐mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state‐of‐the‐art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE‐mediated tumour antigen cross‐presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment. AU - Jensen-Jarolim, E. AU - Bax, H. J. AU - Bianchini, R. AU - Capron, M. AU - Corrigan, C. AU - Castells, M. AU - Dombrowicz, D. AU - Daniels-Wells, T. R. AU - Fazekas, Judit AU - Fiebiger, E. AU - Gatault, S. AU - Gould, H. J. AU - Janda, J. AU - Josephs, D. H. AU - Karagiannis, P. AU - Levi-Schaffer, F. AU - Meshcheryakova, A. AU - Mechtcheriakova, D. AU - Mekori, Y. AU - Mungenast, F. AU - Nigro, E. A. AU - Penichet, M. L. AU - Redegeld, F. AU - Saul, L. AU - Singer, J. AU - Spicer, J. F. AU - Siccardi, A. G. AU - Spillner, E. AU - Turner, M. C. AU - Untersmayr, E. AU - Vangelista, L. AU - Karagiannis, S. N. ID - 8236 IS - 6 JF - Allergy SN - 0105-4538 TI - AllergoOncology - the impact of allergy in oncology: EAACI position paper VL - 72 ER - TY - JOUR AB - Acrolein, a highly reactive unsaturated aldehyde, is generated in large amounts during smoking and is best known for its genotoxic capacity. Here, we aimed to assess whether acrolein at concentrations relevant for smokers may also exert immunomodulatory effects that could be relevant in allergy or cancer. In a BALB/c allergy model repeated nasal exposure to acrolein abrogated allergen-specific antibody and cytokine formation, and led to a relative accumulation of regulatory T cells in the lungs. Only the acrolein-treated mice were protected from bronchial hyperreactivity as well as from anaphylactic reactions upon challenge with the specific allergen. Moreover, grafted D2F2 tumor cells grew faster and intratumoral Foxp3+ cell accumulation was observed in these mice compared to sham-treated controls. Results from reporter cell lines suggested that acrolein acts via the aryl-hydrocarbon receptor which could be inhibited by resveratrol and 3′-methoxy-4′-nitroflavone Acrolein- stimulation of human PBMCs increased Foxp3+ expression by T cells which could be antagonized by resveratrol. Our mouse and human data thus revealed that acrolein exerts systemic immunosuppression by promoting Foxp3+ regulatory cells. This provides a novel explanation why smokers have a lower allergy, but higher cancer risk. AU - Roth-Walter, Franziska AU - Bergmayr, Cornelia AU - Meitz, Sarah AU - Buchleitner, Stefan AU - Stremnitzer, Caroline AU - Fazekas, Judit AU - Moskovskich, Anna AU - Müller, Mario A. AU - Roth, Georg A. AU - Manzano-Szalai, Krisztina AU - Dvorak, Zdenek AU - Neunkirchner, Alina AU - Jensen-Jarolim, Erika ID - 8239 JF - Scientific Reports SN - 2045-2322 TI - Janus-faced Acrolein prevents allergy but accelerates tumor growth by promoting immunoregulatory Foxp3+ cells: Mouse model for passive respiratory exposure VL - 7 ER - TY - JOUR AB - Background/Aim: Cancer cell lines are indispensible surrogate models in cancer research, as they can be used off-the-shelf, expanded to the desired extent, easily modified and exchanged between research groups for affirmation, reproduction or follow-up experiments. As malignant cells are prone to genomic instability, phenotypical changes may occur after certain passages in culture. Thus, cell lines have to be regularly authenticated to ensure data quality. In between experiments these cell lines are often stored in liquid nitrogen for extended time periods. Although freezing of cells is a necessary evil, little research is performed on how long-term storage affects cancer cell lines. Therefore, this study investigated the effects of a 28-year long liquid nitrogen storage period on BT474 cells with regard to phenotypical changes, differences in cell-surface receptor expression as well as cytokine and gene expressional variations. Methods: Two batches of BT474 cells, one frozen in 1986, the other directly purchased from ATCC were investigated by light microscopy, cell growth analysis, flow cytometry and cytokine as well as whole-transcriptome expression profiling. Results: The cell lines were morphologically indifferent and showed similar growth rates and similar cell-surface receptor expression. Transcriptome analysis revealed significant differences in only 26 of 40,716 investigated RefSeq transcripts with 4 of them being up-regulated and 22 down-regulated. Conclusion: This study demonstrates that even after very long periods of storage in liquid nitrogen, cancer cell lines display only minimal changes in their gene expression profiles. However, also such minor changes should be carefully assessed before continuation of experiments, especially if phenotypic alterations can be additionally observed. AU - Fazekas, Judit AU - Grunt, Thomas W. AU - Jensen-Jarolim, Erika AU - Singer, Josef ID - 8240 JF - Oncotarget SN - 1949-2553 TI - Long term storage in liquid nitrogen leads to only minor phenotypic and gene expression changes in the mammary carcinoma model cell line BT474 VL - 8 ER - TY - JOUR AB - Due to large homology of human and canine EGFR, dogs suffering from spontaneous EGFR+ cancer can be considered as ideal translational models. Thereby, novel immunotherapeutic compounds can be developed for both human and veterinary patients. This study describes the radiolabeling of a canine anti-EGFR IgG antibody (can225IgG) with potential diagnostic and therapeutic value in comparative clinical settings. Can225IgG was functionalized with DTPA for subsequent chelation with the radionuclide 99mTc. Successful coupling of 10 DTPA molecules per antibody on average was proven by significant mass increase in MALDI-TOF spectroscopy, gel electrophoresis and immunoblots. Following functionalization and radiolabeling, 99mTc-DTPA-can225IgG fully retained its binding capacity towards human and canine EGFR in flow cytometry, immuno- and radioblots, and autoradiography. The affinity of radiolabeled can225IgG was determined to KD 0.8 ±0.0031 nM in a real-time kinetics assay on canine carcinoma cells by a competition binding technique. Stability tests of the radiolabeled compound identified TRIS buffered saline as the ideal formulation for short-term storage with 87.11 ±6.04% intact compound being still detected 60 minutes post radiolabeling. High stability, specificity and EGFR binding affinity pinpoint towards 99mTc-radiolabeled can225IgG antibody as an ideal lead compound for the first proof-of-concept diagnostic and therapeutic applications in canine cancer patients. AU - Fazekas-Singer, Judit AU - Berroterán-Infante, Neydher AU - Rami-Mark, Christina AU - Dumanic, Monika AU - Matz, Miroslawa AU - Willmann, Michael AU - Andreae, Fritz AU - Singer, Josef AU - Wadsak, Wolfgang AU - Mitterhauser, Markus AU - Jensen-Jarolim, Erika ID - 8235 JF - Oncotarget SN - 1949-2553 TI - Development of a radiolabeled caninized anti-EGFR antibody for comparative oncology trials VL - 8 ER - TY - JOUR AB - What data is needed about data? Describing the process to answer this question for the institutional data repository IST DataRep. AU - Petritsch, Barbara ID - 825 IS - 2 JF - Mitteilungen der Vereinigung Österreichischer Bibliothekarinnen & Bibliothekare SN - 10222588 TI - Metadata for research data in practice VL - 70 ER - TY - CONF AB - Permissionless blockchain-based cryptocurrencies commonly use proof-of-work (PoW) or proof-of-stake (PoS) to ensure their security, e.g. to prevent double spending attacks. However, both approaches have disadvantages: PoW leads to massive amounts of wasted electricity and re-centralization, whereas major stakeholders in PoS might be able to create a monopoly. In this work, we propose proof-of-personhood (PoP), a mechanism that binds physical entities to virtual identities in a way that enables accountability while preserving anonymity. Afterwards we introduce PoPCoin, a new cryptocurrency, whose consensus mechanism leverages PoP to eliminate the dis-advantages of PoW and PoS while ensuring security. PoPCoin leads to a continuously fair and democratic wealth creation process which paves the way for an experimental basic income infrastructure. AU - Borge, Maria AU - Kokoris Kogias, Eleftherios AU - Jovanovic, Philipp AU - Gasser, Linus AU - Gailly, Nicolas AU - Ford, Bryan ID - 8299 T2 - 2017 IEEE European Symposium on Security and Privacy Workshops TI - Proof-of-personhood: Redemocratizing permissionless cryptocurrencies ER - TY - CONF AB - Bias-resistant public randomness is a critical component in many (distributed) protocols. Generating public randomness is hard, however, because active adversaries may behave dishonestly to bias public random choices toward their advantage. Existing solutions do not scale to hundreds or thousands of participants, as is needed in many decentralized systems. We propose two large-scale distributed protocols, RandHound and RandHerd, which provide publicly-verifiable, unpredictable, and unbiasable randomness against Byzantine adversaries. RandHound relies on an untrusted client to divide a set of randomness servers into groups for scalability, and it depends on the pigeonhole principle to ensure output integrity, even for non-random, adversarial group choices. RandHerd implements an efficient, decentralized randomness beacon. RandHerd is structurally similar to a BFT protocol, but uses RandHound in a one-time setup to arrange participants into verifiably unbiased random secret-sharing groups, which then repeatedly produce random output at predefined intervals. Our prototype demonstrates that RandHound and RandHerd achieve good performance across hundreds of participants while retaining a low failure probability by properly selecting protocol parameters, such as a group size and secret-sharing threshold. For example, when sharding 512 nodes into groups of 32, our experiments show that RandHound can produce fresh random output after 240 seconds. RandHerd, after a setup phase of 260 seconds, is able to generate fresh random output in intervals of approximately 6 seconds. For this configuration, both protocols operate at a failure probability of at most 0.08% against a Byzantine adversary. AU - Syta, E. AU - Jovanovic, P. AU - Kokoris Kogias, Eleftherios AU - Gailly, N. AU - Gasser, L. AU - Khoffi, I. AU - Fischer, M. J. AU - Ford, B. ID - 8306 SN - 2375-1207 T2 - 2017 IEEE Symposium on Security and Privacy TI - Scalable bias-resistant distributed randomness ER - TY - CONF AB - Software-update mechanisms are critical to the security of modern systems, but their typically centralized design presents a lucrative and frequently attacked target. In this work, we propose CHAINIAC, a decentralized software-update framework that eliminates single points of failure, enforces transparency, and provides efficient verifiability of integrity and authenticity for software-release processes. Independent witness servers collectively verify conformance of software updates to release policies, build verifiers validate the source-to-binary correspondence, and a tamper-proof release log stores collectively signed updates, thus ensuring that no release is accepted by clients before being widely disclosed and validated. The release log embodies a skipchain, a novel data structure, enabling arbitrarily out-of-date clients to efficiently validate updates and signing keys. Evaluation of our CHAINIAC prototype on reproducible Debian packages shows that the automated update process takes the average of 5 minutes per release for individual packages, and only 20 seconds for the aggregate timeline. We further evaluate the framework using real-world data from the PyPI package repository and show that it offers clients security comparable to verifying every single update themselves while consuming only one-fifth of the bandwidth and having a minimal computational overhead. AU - Nikitin, Kirill AU - Kokoris Kogias, Eleftherios AU - Jovanovic, Philipp AU - Gasser, Linus AU - Gailly, Nicolas AU - Khoffi, Ismail AU - Cappos, Justin AU - Ford, Bryan ID - 8301 SN - 9781931971409 T2 - Proceedings of the 26th USENIX Conference on Security Symposium TI - CHAINIAC: Proactive software-update transparency via collectively signed skipchains and verified builds ER - TY - JOUR AB - Solid‐state NMR spectroscopy can provide insight into protein structure and dynamics at the atomic level without inherent protein size limitations. However, a major hurdle to studying large proteins by solid‐state NMR spectroscopy is related to spectral complexity and resonance overlap, which increase with molecular weight and severely hamper the assignment process. Here the use of two sets of experiments is shown to expand the tool kit of 1H‐detected assignment approaches, which correlate a given amide pair either to the two adjacent CO–CA pairs (4D hCOCANH/hCOCAcoNH), or to the amide 1H of the neighboring residue (3D HcocaNH/HcacoNH, which can be extended to 5D). The experiments are based on efficient coherence transfers between backbone atoms using INEPT transfers between carbons and cross‐polarization for heteronuclear transfers. The utility of these experiments is exemplified with application to assemblies of deuterated, fully amide‐protonated proteins from approximately 20 to 60 kDa monomer, at magic‐angle spinning (MAS) frequencies from approximately 40 to 55 kHz. These experiments will also be applicable to protonated proteins at higher MAS frequencies. The resonance assignment of a domain within the 50.4 kDa bacteriophage T5 tube protein pb6 is reported, and this is compared to NMR assignments of the isolated domain in solution. This comparison reveals contacts of this domain to the core of the polymeric tail tube assembly. AU - Fraga, Hugo AU - Arnaud, Charles‐Adrien AU - Gauto, Diego F. AU - Audin, Maxime AU - Kurauskas, Vilius AU - Macek, Pavel AU - Krichel, Carsten AU - Guan, Jia‐Ying AU - Boisbouvier, Jerome AU - Sprangers, Remco AU - Breyton, Cécile AU - Schanda, Paul ID - 8446 IS - 19 JF - ChemPhysChem KW - Physical and Theoretical Chemistry KW - Atomic and Molecular Physics KW - and Optics SN - 1439-4235 TI - Solid‐state NMR H–N–(C)–H and H–N–C–C 3D/4D correlation experiments for resonance assignment of large proteins VL - 18 ER - TY - JOUR AB - Proteins perform their functions in solution but their structures are most frequently studied inside crystals. Here we probe how the crystal packing alters microsecond dynamics, using solid-state NMR measurements and multi-microsecond MD simulations of different crystal forms of ubiquitin. In particular, near-rotary-resonance relaxation dispersion (NERRD) experiments probe angular backbone motion, while Bloch–McConnell relaxation dispersion data report on fluctuations of the local electronic environment. These experiments and simulations reveal that the packing of the protein can significantly alter the thermodynamics and kinetics of local conformational exchange. Moreover, we report small-amplitude reorientational motion of protein molecules in the crystal lattice with an ~3–5° amplitude on a tens-of-microseconds time scale in one of the crystals, but not in others. An intriguing possibility arises that overall motion is to some extent coupled to local dynamics. Our study highlights the importance of considering the packing when analyzing dynamics of crystalline proteins. AU - Kurauskas, Vilius AU - Izmailov, Sergei A. AU - Rogacheva, Olga N. AU - Hessel, Audrey AU - Ayala, Isabel AU - Woodhouse, Joyce AU - Shilova, Anastasya AU - Xue, Yi AU - Yuwen, Tairan AU - Coquelle, Nicolas AU - Colletier, Jacques-Philippe AU - Skrynnikov, Nikolai R. AU - Schanda, Paul ID - 8445 JF - Nature Communications SN - 2041-1723 TI - Slow conformational exchange and overall rocking motion in ubiquitin protein crystals VL - 8 ER - TY - JOUR AB - Biophysical investigation of membrane proteins generally requires their extraction from native sources using detergents, a step that can lead, possibly irreversibly, to protein denaturation. The propensity of dodecylphosphocholine (DPC), a detergent widely utilized in NMR studies of membrane proteins, to distort their structure has been the subject of much controversy. It has been recently proposed that the binding specificity of the yeast mitochondrial ADP/ATP carrier (yAAC3) toward cardiolipins is preserved in DPC, thereby suggesting that DPC is a suitable environment in which to study membrane proteins. In this communication, we used all-atom molecular dynamics simulations to investigate the specific binding of cardiolipins to yAAC3. Our data demonstrate that the interaction interface observed in a native-like environment differs markedly from that inferred from an NMR investigation in DPC, implying that in this detergent, the protein structure is distorted. We further investigated yAAC3 solubilized in DPC and in the milder dodecylmaltoside with thermal-shift assays. The loss of thermal transition observed in DPC confirms that the protein is no longer properly folded in this environment. AU - Dehez, François AU - Schanda, Paul AU - King, Martin S. AU - Kunji, Edmund R.S. AU - Chipot, Christophe ID - 8444 IS - 11 JF - Biophysical Journal KW - Biophysics SN - 0006-3495 TI - Mitochondrial ADP/ATP carrier in dodecylphosphocholine binds cardiolipins with non-native affinity VL - 113 ER - TY - JOUR AB - Magnetic anisotropy in strontium iridate (Sr2IrO4) is found to be large because of the strong spin-orbit interactions. In our work, we studied the in-plane magnetic anisotropy of Sr2IrO4 and traced the anisotropic exchange interactions between the isospins in the crystal. The magnetic-field-dependent torque τ(H) showed a prominent transition from the canted antiferromagnetic state to the weak ferromagnetic (WFM) state. A comprehensive analysis was conducted to examine the isotropic and anisotropic regimes and probe the easy magnetization axis along the a b plane. The angle-dependent torque τ(θ) revealed a deviation from the sinusoidal behavior, and small differences in hysteresis were observed around 0° and 90° in the low-magnetic-field regime. This indicates that the orientation of the easy axis of the FM component is along the b axis, where the antiferromagnetic to WFM spin-flop transition occurs. We compared the coefficients of the magnetic susceptibility tensors and captured the anisotropy of the material. The in-plane τ(θ) revealed a tendency toward isotropic behavior for fields with values above the field value of the WFM transition. AU - Nauman, Muhammad AU - Hong, Yunjeong AU - Hussain, Tayyaba AU - Seo, M. S. AU - Park, S. Y. AU - Lee, N. AU - Choi, Y. J. AU - Kang, Woun AU - Jo, Younjung ID - 9065 IS - 15 JF - Physical Review B SN - 2469-9950 TI - In-plane magnetic anisotropy in strontium iridate Sr2IrO4 VL - 96 ER - TY - JOUR AB - Advances in colloidal synthesis allow for the design of particles with controlled patches. This article reviews routes towards colloidal locomotion, where energy is consumed and converted into motion, and its implementation with active patchy particles. A special emphasis is given to phoretic swimmers, where the self-propulsion originates from an interfacial phenomenon, raising experimental challenges and opening up opportunities for particles with controlled anisotropic surface chemistry and novel behaviors. AU - Aubret, A. AU - Ramananarivo, S. AU - Palacci, Jérémie A ID - 9165 JF - Current Opinion in Colloid & Interface Science SN - 1359-0294 TI - Eppur si muove, and yet it moves: Patchy (phoretic) swimmers VL - 30 ER - TY - JOUR AB - Plant meristems carry pools of continuously active stem cells, whose activity is controlled by developmental and environmental signals. After stem cell division, daughter cells that exit the stem cell domain acquire transit amplifying cell identity before they are incorporated into organs and differentiate. In this study, we used an integrated approach to elucidate the role of HECATE (HEC) genes in regulating developmental trajectories of shoot stem cells in Arabidopsis thaliana. Our work reveals that HEC function stabilizes cell fate in distinct zones of the shoot meristem thereby controlling the spatio-temporal dynamics of stem cell differentiation. Importantly, this activity is concomitant with the local modulation of cellular responses to cytokinin and auxin, two key phytohormones regulating cell behaviour. Mechanistically, we show that HEC factors transcriptionally control and physically interact with MONOPTEROS (MP), a key regulator of auxin signalling, and modulate the autocatalytic stabilization of auxin signalling output. AU - Gaillochet, Christophe AU - Stiehl, Thomas AU - Wenzl, Christian AU - Ripoll, Juan-José AU - Bailey-Steinitz, Lindsay J AU - Li, Lanxin AU - Pfeiffer, Anne AU - Miotk, Andrej AU - Hakenjos, Jana P AU - Forner, Joachim AU - Yanofsky, Martin F AU - Marciniak-Czochra, Anna AU - Lohmann, Jan U ID - 9190 JF - eLife SN - 2050-084X TI - Control of plant cell fate transitions by transcriptional and hormonal signals VL - 6 ER - TY - JOUR AB - An electro-optomechanical device capable of microwave-to-optics conversion has recently been demonstrated, with the vision of enabling optical networks of superconducting qubits. Here we present an improved converter design that uses a three-dimensional microwave cavity for coupling between the microwave transmission line and an integrated LC resonator on the converter chip. The new design simplifies the optical assembly and decouples it from the microwave part of the setup. Experimental demonstrations show that the modular device assembly allows us to flexibly tune the microwave coupling to the converter chip while maintaining small loss. We also find that electromechanical experiments are not impacted by the additional microwave cavity. Our design is compatible with a high-finesse optical cavity and will improve optical performance. AU - Menke, Tim AU - Burns, Peter AU - Higginbotham, Andrew P AU - Kampel, N S AU - Peterson, Robert AU - Cicak, Katarina AU - Simmonds, Raymond AU - Regal, Cindy AU - Lehnert, Konrad ID - 93 IS - 9 JF - Review of Scientific Instruments TI - Reconfigurable re-entrant cavity for wireless coupling to an electro-optomechanical device VL - 88 ER - TY - JOUR AB - We introduce a method for breaking Lorentz reciprocity based upon the noncommutation of frequency conversion and delay. The method requires no magnetic materials or resonant physics, allowing for the design of scalable and broadband nonreciprocal circuits. With this approach, two types of gyrators - universal building blocks for linear, nonreciprocal circuits - are constructed. Using one of these gyrators, we create a circulator with >15 dB of isolation across the 5-9 GHz band. Our designs may be readily extended to any platform with suitable frequency conversion elements, including semiconducting devices for telecommunication or an on-chip superconducting implementation for quantum information processing. AU - Rosenthal, Eric AU - Chapman, Benjamin AU - Higginbotham, Andrew P AU - Kerckhoff, Joseph AU - Lehnert, Konrad ID - 94 IS - 14 JF - APS Physics, Physical Review Letters TI - Breaking Lorentz reciprocity with frequency conversion and delay VL - 119 ER - TY - JOUR AB - Cytosine methylation regulates essential genome functions across eukaryotes, but the fundamental question of whether nucleosomal or naked DNA is the preferred substrate of plant and animal methyltransferases remains unresolved. Here, we show that genetic inactivation of a single DDM1/Lsh family nucleosome remodeler biases methylation toward inter-nucleosomal linker DNA in Arabidopsis thaliana and mouse. We find that DDM1 enables methylation of DNA bound to the nucleosome, suggesting that nucleosome-free DNA is the preferred substrate of eukaryotic methyltransferases in vivo. Furthermore, we show that simultaneous mutation of DDM1 and linker histone H1 in Arabidopsis reproduces the strong linker-specific methylation patterns of species that diverged from flowering plants and animals over a billion years ago. Our results indicate that in the absence of remodeling, nucleosomes are strong barriers to DNA methyltransferases. Linker-specific methylation can evolve simply by breaking the connection between nucleosome remodeling and DNA methylation. AU - Lyons, David B AU - Zilberman, Daniel ID - 9445 JF - eLife TI - DDM1 and Lsh remodelers allow methylation of DNA wrapped in nucleosomes VL - 6 ER - TY - CHAP AB - Small molecule biosensors based on Forster resonance energy transfer (FRET) enable small molecule signaling to be monitored with high spatial and temporal resolution in complex cellular environments. FRET sensors can be constructed by fusing a pair of fluorescent proteins to a suitable recognition domain, such as a member of the solute-binding protein (SBP) superfamily. However, naturally occurring SBPs may be unsuitable for incorporation into FRET sensors due to their low thermostability, which may preclude imaging under physiological conditions, or because the positions of their N- and C-termini may be suboptimal for fusion of fluorescent proteins, which may limit the dynamic range of the resulting sensors. Here, we show how these problems can be overcome using ancestral protein reconstruction and circular permutation. Ancestral protein reconstruction, used as a protein engineering strategy, leverages phylogenetic information to improve the thermostability of proteins, while circular permutation enables the termini of an SBP to be repositioned to maximize the dynamic range of the resulting FRET sensor. We also provide a protocol for cloning the engineered SBPs into FRET sensor constructs using Golden Gate assembly and discuss considerations for in situ characterization of the FRET sensors. AU - Clifton, Ben AU - Whitfield, Jason AU - Sanchez Romero, Inmaculada AU - Herde, Michel AU - Henneberger, Christian AU - Janovjak, Harald L AU - Jackson, Colin ED - Stein, Viktor ID - 957 SN - 10643745 T2 - Synthetic Protein Switches TI - Ancestral protein reconstruction and circular permutation for improving the stability and dynamic range of FRET sensors VL - 1596 ER - TY - JOUR AB - Consider the sum X(ξ)=∑ni=1aiξi, where a=(ai)ni=1 is a sequence of non-zero reals and ξ=(ξi)ni=1 is a sequence of i.i.d. Rademacher random variables (that is, Pr[ξi=1]=Pr[ξi=−1]=1/2). The classical Littlewood-Offord problem asks for the best possible upper bound on the concentration probabilities Pr[X=x]. In this paper we study a resilience version of the Littlewood-Offord problem: how many of the ξi is an adversary typically allowed to change without being able to force concentration on a particular value? We solve this problem asymptotically, and present a few interesting open problems. AU - Bandeira, Afonso S. AU - Ferber, Asaf AU - Kwan, Matthew Alan ID - 9574 JF - Electronic Notes in Discrete Mathematics SN - 1571-0653 TI - Resilience for the Littlewood-Offord problem VL - 61 ER - TY - JOUR AB - We show that for any fixed dense graph G and bounded-degree tree T on the same number of vertices, a modest random perturbation of G will typically contain a copy of T . This combines the viewpoints of the well-studied problems of embedding trees into fixed dense graphs and into random graphs, and extends a sizeable body of existing research on randomly perturbed graphs. Specifically, we show that there is c=c(α,Δ) such that if G is an n-vertex graph with minimum degree at least αn, and T is an n-vertex tree with maximum degree at most Δ , then if we add cn uniformly random edges to G, the resulting graph will contain T asymptotically almost surely (as n→∞ ). Our proof uses a lemma concerning the decomposition of a dense graph into super-regular pairs of comparable sizes, which may be of independent interest. AU - Krivelevich, Michael AU - Kwan, Matthew Alan AU - Sudakov, Benny ID - 9590 IS - 1 JF - SIAM Journal on Discrete Mathematics SN - 0895-4801 TI - Bounded-degree spanning trees in randomly perturbed graphs VL - 31 ER - TY - JOUR AB - Consider the sum X(ξ)=∑ni=1aiξi , where a=(ai)ni=1 is a sequence of non-zero reals and ξ=(ξi)ni=1 is a sequence of i.i.d. Rademacher random variables (that is, Pr[ξi=1]=Pr[ξi=−1]=1/2 ). The classical Littlewood-Offord problem asks for the best possible upper bound on the concentration probabilities Pr[X=x] . In this paper we study a resilience version of the Littlewood-Offord problem: how many of the ξi is an adversary typically allowed to change without being able to force concentration on a particular value? We solve this problem asymptotically, and present a few interesting open problems. AU - Bandeira, Afonso S. AU - Ferber, Asaf AU - Kwan, Matthew Alan ID - 9588 JF - Advances in Mathematics SN - 0001-8708 TI - Resilience for the Littlewood–Offord problem VL - 319 ER - TY - JOUR AB - We give an asymptotic expression for the expected number of spanning trees in a random graph with a given degree sequence , provided that the number of edges is at least , where is the maximum degree. A key part of our argument involves establishing a concentration result for a certain family of functions over random trees with given degrees, using Prüfer codes. AU - Greenhill, Catherine AU - Isaev, Mikhail AU - Kwan, Matthew Alan AU - McKay, Brendan D. ID - 9589 JF - European Journal of Combinatorics SN - 0195-6698 TI - The average number of spanning trees in sparse graphs with given degrees VL - 63 ER - TY - CONF AB - Network games are widely used as a model for selfish resource-allocation problems. In the classical model, each player selects a path connecting her source and target vertex. The cost of traversing an edge depends on the number of players that traverse it. Thus, it abstracts the fact that different users may use a resource at different times and for different durations, which plays an important role in defining the costs of the users in reality. For example, when transmitting packets in a communication network, routing traffic in a road network, or processing a task in a production system, the traversal of the network involves an inherent delay, and so sharing and congestion of resources crucially depends on time. We study timed network games , which add a time component to network games. Each vertex v in the network is associated with a cost function, mapping the load on v to the price that a player pays for staying in v for one time unit with this load. In addition, each edge has a guard, describing time intervals in which the edge can be traversed, forcing the players to spend time on vertices. Unlike earlier work that add a time component to network games, the time in our model is continuous and cannot be discretized. In particular, players have uncountably many strategies, and a game may have uncountably many pure Nash equilibria. We study properties of timed network games with cost-sharing or congestion cost functions: their stability, equilibrium inefficiency, and complexity. In particular, we show that the answer to the question whether we can restrict attention to boundary strategies, namely ones in which edges are traversed only at the boundaries of guards, is mixed. AU - Avni, Guy AU - Guha, Shibashis AU - Kupferman, Orna ID - 963 SN - 18688969 TI - Timed network games with clocks VL - 83 ER - TY - GEN AB - Across the nervous system, certain population spiking patterns are observed far more frequently than others. A hypothesis about this structure is that these collective activity patterns function as population codewords–collective modes–carrying information distinct from that of any single cell. We investigate this phenomenon in recordings of ∼150 retinal ganglion cells, the retina’s output. We develop a novel statistical model that decomposes the population response into modes; it predicts the distribution of spiking activity in the ganglion cell population with high accuracy. We found that the modes represent localized features of the visual stimulus that are distinct from the features represented by single neurons. Modes form clusters of activity states that are readily discriminated from one another. When we repeated the same visual stimulus, we found that the same mode was robustly elicited. These results suggest that retinal ganglion cells’ collective signaling is endowed with a form of error-correcting code–a principle that may hold in brain areas beyond retina. AU - Prentice, Jason AU - Marre, Olivier AU - Ioffe, Mark AU - Loback, Adrianna AU - Tkačik, Gašper AU - Berry, Michael ID - 9709 TI - Data from: Error-robust modes of the retinal population code ER - TY - JOUR AB - While we have good understanding of bacterial metabolism at the population level, we know little about the metabolic behavior of individual cells: do single cells in clonal populations sometimes specialize on different metabolic pathways? Such metabolic specialization could be driven by stochastic gene expression and could provide individual cells with growth benefits of specialization. We measured the degree of phenotypic specialization in two parallel metabolic pathways, the assimilation of glucose and arabinose. We grew Escherichia coli in chemostats, and used isotope-labeled sugars in combination with nanometer-scale secondary ion mass spectrometry and mathematical modeling to quantify sugar assimilation at the single-cell level. We found large variation in metabolic activities between single cells, both in absolute assimilation and in the degree to which individual cells specialize in the assimilation of different sugars. Analysis of transcriptional reporters indicated that this variation was at least partially based on cell-to-cell variation in gene expression. Metabolic differences between cells in clonal populations could potentially reduce metabolic incompatibilities between different pathways, and increase the rate at which parallel reactions can be performed. AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 541 IS - 12 JF - PLoS Genetics SN - 15537390 TI - Cell-to-cell variation and specialization in sugar metabolism in clonal bacterial populations VL - 13 ER - TY - GEN AB - information on culture conditions, phage mutagenesis, verification and lysate preparation; Raw data AU - Pleska, Maros AU - Guet, Calin C ID - 9847 TI - Supplementary materials and methods; Full data set from effects of mutations in phage restriction sites during escape from restriction–modification ER - TY - GEN AB - Estimates of 13 C-arabinose and 2 H-glucose uptake from the fractions of heavy isotopes measured in single cells AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 9845 TI - Mathematical model ER - TY - GEN AB - This text provides additional information about the model, a derivation of the analytic results in Eq (4), and details about simulations of an additional parameter set. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9849 TI - Modelling and simulation details ER - TY - GEN AB - In this text, we discuss how a cost of resistance and the possibility of lethal mutations impact our model. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9850 TI - Extensions of the model ER - TY - GEN AU - Nikolic, Nela AU - Schreiber, Frank AU - Dal Co, Alma AU - Kiviet, Daniel AU - Bergmiller, Tobias AU - Littmann, Sten AU - Kuypers, Marcel AU - Ackermann, Martin ID - 9846 TI - Supplementary methods ER - TY - JOUR AB - In order to respond reliably to specific features of their environment, sensory neurons need to integrate multiple incoming noisy signals. Crucially, they also need to compete for the interpretation of those signals with other neurons representing similar features. The form that this competition should take depends critically on the noise corrupting these signals. In this study we show that for the type of noise commonly observed in sensory systems, whose variance scales with the mean signal, sensory neurons should selectively divide their input signals by their predictions, suppressing ambiguous cues while amplifying others. Any change in the stimulus context alters which inputs are suppressed, leading to a deep dynamic reshaping of neural receptive fields going far beyond simple surround suppression. Paradoxically, these highly variable receptive fields go alongside and are in fact required for an invariant representation of external sensory features. In addition to offering a normative account of context-dependent changes in sensory responses, perceptual inference in the presence of signal-dependent noise accounts for ubiquitous features of sensory neurons such as divisive normalization, gain control and contrast dependent temporal dynamics. AU - Chalk, Matthew J AU - Masset, Paul AU - Gutkin, Boris AU - Denève, Sophie ID - 680 IS - 6 JF - PLoS Computational Biology SN - 1553734X TI - Sensory noise predicts divisive reshaping of receptive fields VL - 13 ER - TY - GEN AB - Based on the intuitive derivation of the dynamics of SIM allele frequency pM in the main text, we present a heuristic prediction for the long-term SIM allele frequencies with χ > 1 stresses and compare it to numerical simulations. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9851 TI - Heuristic prediction for multiple stresses ER - TY - GEN AB - We show how different combination strategies affect the fraction of individuals that are multi-resistant. AU - Lukacisinova, Marta AU - Novak, Sebastian AU - Paixao, Tiago ID - 9852 TI - Resistance frequencies for different combination strategies ER - TY - GEN AB - Includes derivation of optimal estimation algorithm, generalisation to non-poisson noise statistics, correlated input noise, and implementation of in a multi-layer neural network. AU - Chalk, Matthew J AU - Masset, Paul AU - Gutkin, Boris AU - Denève, Sophie ID - 9855 TI - Supplementary appendix ER - TY - JOUR AB - In this paper we show that for a generic strictly convex domain, one can recover the eigendata corresponding to Aubry–Mather periodic orbits of the induced billiard map from the (maximal) marked length spectrum of the domain. AU - Huang, Guan AU - Kaloshin, Vadim AU - Sorrentino, Alfonso ID - 8423 IS - 1 JF - Duke Mathematical Journal SN - 0012-7094 TI - On the marked length spectrum of generic strictly convex billiard tables VL - 167 ER - TY - JOUR AB - We show that any sufficiently (finitely) smooth ℤ₂-symmetric strictly convex domain sufficiently close to a circle is dynamically spectrally rigid; i.e., all deformations among domains in the same class that preserve the length of all periodic orbits of the associated billiard flow must necessarily be isometric deformations. This gives a partial answer to a question of P. Sarnak. AU - De Simoi, Jacopo AU - Kaloshin, Vadim AU - Wei, Qiaoling ID - 8427 IS - 1 JF - Annals of Mathematics SN - 0003-486X TI - Dynamical spectral rigidity among Z2-symmetric strictly convex domains close to a circle VL - 186 ER - TY - JOUR AB - Ensuring the correct folding of RNA molecules in the cell is of major importance for a large variety of biological functions. Therefore, chaperone proteins that assist RNA in adopting their functionally active states are abundant in all living organisms. An important feature of RNA chaperone proteins is that they do not require an external energy source to perform their activity, and that they interact transiently and non-specifically with their RNA targets. So far, little is known about the mechanistic details of the RNA chaperone activity of these proteins. Prominent examples of RNA chaperones are bacterial cold shock proteins (Csp) that have been reported to bind single-stranded RNA and DNA. Here, we have used advanced NMR spectroscopy techniques to investigate at atomic resolution the RNA-melting activity of CspA, the major cold shock protein of Escherichia coli, upon binding to different RNA hairpins. Real-time NMR provides detailed information on the folding kinetics and folding pathways. Finally, comparison of wild-type CspA with single-point mutants and small peptides yields insights into the complementary roles of aromatic and positively charged amino-acid side chains for the RNA chaperone activity of the protein. AU - Rennella, Enrico AU - Sára, Tomáš AU - Juen, Michael AU - Wunderlich, Christoph AU - Imbert, Lionel AU - Solyom, Zsofia AU - Favier, Adrien AU - Ayala, Isabel AU - Weinhäupl, Katharina AU - Schanda, Paul AU - Konrat, Robert AU - Kreutz, Christoph AU - Brutscher, Bernhard ID - 8449 IS - 7 JF - Nucleic Acids Research SN - 0305-1048 TI - RNA binding and chaperone activity of the E.coli cold-shock protein CspA VL - 45 ER - TY - JOUR AB - Solid-state NMR spectroscopy can provide site-resolved information about protein dynamics over many time scales. Here we combine protein deuteration, fast magic-angle spinning (~45–60 kHz) and proton detection to study dynamics of ubiquitin in microcrystals, and in particular a mutant in a region that undergoes microsecond motions in a β-turn region in the wild-type protein. We use 15N R1ρ relaxation measurements as a function of the radio-frequency (RF) field strength, i.e. relaxation dispersion, to probe how the G53A mutation alters these dynamics. We report a population-inversion of conformational states: the conformation that in the wild-type protein is populated only sparsely becomes the predominant state. We furthermore explore the potential to use amide-1H R1ρ relaxation to obtain insight into dynamics. We show that while quantitative interpretation of 1H relaxation remains beyond reach under the experimental conditions, due to coherent contributions to decay, one may extract qualitative information about flexibility. AU - Gauto, Diego F. AU - Hessel, Audrey AU - Rovó, Petra AU - Kurauskas, Vilius AU - Linser, Rasmus AU - Schanda, Paul ID - 8447 IS - 10 JF - Solid State Nuclear Magnetic Resonance KW - Nuclear and High Energy Physics KW - Instrumentation KW - General Chemistry KW - Radiation SN - 0926-2040 TI - Protein conformational dynamics studied by 15N and 1HR1ρ relaxation dispersion: Application to wild-type and G53A ubiquitin crystals VL - 87 ER - TY - JOUR AB - We present an improved fast mixing device based on the rapid mixing of two solutions inside the NMR probe, as originally proposed by Hore and coworkers (J. Am. Chem. Soc. 125 (2003) 12484–12492). Such a device is important for off-equilibrium studies of molecular kinetics by multidimensional real-time NMR spectrsocopy. The novelty of this device is that it allows removing the injector from the NMR detection volume after mixing, and thus provides good magnetic field homogeneity independently of the initial sample volume placed in the NMR probe. The apparatus is simple to build, inexpensive, and can be used without any hardware modification on any type of liquid-state NMR spectrometer. We demonstrate the performance of our fast mixing device in terms of improved magnetic field homogeneity, and show an application to the study of protein folding and the structural characterization of transiently populated folding intermediates. AU - Franco, Rémi AU - Favier, Adrien AU - Schanda, Paul AU - Brutscher, Bernhard ID - 8448 IS - 8 JF - Journal of Magnetic Resonance KW - Nuclear and High Energy Physics KW - Biophysics KW - Biochemistry KW - Condensed Matter Physics SN - 1090-7807 TI - Optimized fast mixing device for real-time NMR applications VL - 281 ER - TY - JOUR AB - The structure, dynamics, and function of membrane proteins are intimately linked to the properties of the membrane environment in which the proteins are embedded. For structural and biophysical characterization, membrane proteins generally need to be extracted from the membrane and reconstituted in a suitable membrane‐mimicking environment. Ensuring functional and structural integrity in these environments is often a major concern. The styrene/maleic acid co‐polymer has recently been shown to be able to extract lipid/membrane protein patches directly from native membranes to form nanosize discoidal proteolipid particles, also referred to as native nanodiscs. In this work, we show that high‐resolution solid‐state NMR spectra can be obtained from an integral membrane protein in native nanodiscs, as exemplified by the 2×34 kDa bacterial cation diffusion facilitator CzcD. AU - Bersch, Beate AU - Dörr, Jonas M. AU - Hessel, Audrey AU - Killian, J. Antoinette AU - Schanda, Paul ID - 8451 IS - 9 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Proton-detected solid-state NMR spectroscopy of a Zinc diffusion facilitator protein in native nanodiscs VL - 56 ER - TY - CHAP AB - Methyl groups are very useful probes of structure, dynamics, and interactions in protein NMR spectroscopy. In particular, methyl-directed experiments provide high sensitivity even in very large proteins, such as membrane proteins in a membrane-mimicking environment. In this chapter, we discuss the approach for labeling methyl groups in E. coli-based protein expression, as exemplified with the mitochondrial carrier GGC. AU - Kurauskas, Vilius AU - Schanda, Paul AU - Sounier, Remy ID - 8450 SN - 1064-3745 T2 - Membrane protein structure and function characterization TI - Methyl-specific isotope labeling strategies for NMR studies of membrane proteins VL - 1635 ER - TY - JOUR AB - Pools of air cooled by partial rain evaporation span up to several hundreds of kilometers in nature and typically last less than 1 day, ultimately losing their identity to the large-scale flow. These fundamentally differ in character from the radiatively-driven dry pools defining convective aggregation. Advancement in remote sensing and in computer capabilities has promoted exploration of how precipitation-induced cold pool processes modify the convective spectrum and life cycle. This contribution surveys current understanding of such cold pools over the tropical and subtropical oceans. In shallow convection with low rain rates, the cold pools moisten, preserving the near-surface equivalent potential temperature or increasing it if the surface moisture fluxes cannot ventilate beyond the new surface layer; both conditions indicate downdraft origin air from within the boundary layer. When rain rates exceed ∼ 2 mm h−1, convective-scale downdrafts can bring down drier air of lower equivalent potential temperature from above the boundary layer. The resulting density currents facilitate the lifting of locally thermodynamically favorable air and can impose an arc-shaped mesoscale cloud organization. This organization allows clouds capable of reaching 4–5 km within otherwise dry environments. These are more commonly observed in the northern hemisphere trade wind regime, where the flow to the intertropical convergence zone is unimpeded by the equator. Their near-surface air properties share much with those shown from cold pools sampled in the equatorial Indian Ocean. Cold pools are most effective at influencing the mesoscale organization when the atmosphere is moist in the lower free troposphere and dry above, suggesting an optimal range of water vapor paths. Outstanding questions on the relationship between cold pools, their accompanying moisture distribution and cloud cover are detailed further. Near-surface water vapor rings are documented in one model inside but near the cold pool edge; these are not consistent with observations, but do improve with smaller horizontal grid spacings. AU - Zuidema, Paquita AU - Torri, Giuseppe AU - Muller, Caroline J AU - Chandra, Arunchandra ID - 9137 IS - 6 JF - Surveys in Geophysics KW - Geochemistry and Petrology KW - Geophysics SN - 0169-3298 TI - A survey of precipitation-induced atmospheric cold pools over oceans and their interactions with the larger-scale environment VL - 38 ER - TY - JOUR AB - Convective self-aggregation, the spontaneous organization of initially scattered convection into isolated convective clusters despite spatially homogeneous boundary conditions and forcing, was first recognized and studied in idealized numerical simulations. While there is a rich history of observational work on convective clustering and organization, there have been only a few studies that have analyzed observations to look specifically for processes related to self-aggregation in models. Here we review observational work in both of these categories and motivate the need for more of this work. We acknowledge that self-aggregation may appear to be far-removed from observed convective organization in terms of time scales, initial conditions, initiation processes, and mean state extremes, but we argue that these differences vary greatly across the diverse range of model simulations in the literature and that these comparisons are already offering important insights into real tropical phenomena. Some preliminary new findings are presented, including results showing that a self-aggregation simulation with square geometry has too broad distribution of humidity and is too dry in the driest regions when compared with radiosonde records from Nauru, while an elongated channel simulation has realistic representations of atmospheric humidity and its variability. We discuss recent work increasing our understanding of how organized convection and climate change may interact, and how model discrepancies related to this question are prompting interest in observational comparisons. We also propose possible future directions for observational work related to convective aggregation, including novel satellite approaches and a ground-based observational network. AU - Holloway, Christopher E. AU - Wing, Allison A. AU - Bony, Sandrine AU - Muller, Caroline J AU - Masunaga, Hirohiko AU - L’Ecuyer, Tristan S. AU - Turner, David D. AU - Zuidema, Paquita ID - 9138 IS - 6 JF - Surveys in Geophysics KW - Geochemistry and Petrology KW - Geophysics SN - 0169-3298 TI - Observing convective aggregation VL - 38 ER - TY - JOUR AB - Organized convection in the tropics occurs across a range of spatial and temporal scales and strongly influences cloud cover and humidity. One mode of organization found is “self-aggregation,” in which moist convection spontaneously organizes into one or several isolated clusters despite spatially homogeneous boundary conditions and forcing. Self-aggregation is driven by interactions between clouds, moisture, radiation, surface fluxes, and circulation, and occurs in a wide variety of idealized simulations of radiative–convective equilibrium. Here we provide a review of convective self-aggregation in numerical simulations, including its character, causes, and effects. We describe the evolution of self-aggregation including its time and length scales and the physical mechanisms leading to its triggering and maintenance, and we also discuss possible links to climate and climate change. AU - Wing, Allison A. AU - Emanuel, Kerry AU - Holloway, Christopher E. AU - Muller, Caroline J ID - 9139 IS - 6 JF - Surveys in Geophysics KW - Geochemistry and Petrology KW - Geophysics SN - 0169-3298 TI - Convective self-aggregation in numerical simulations: A review VL - 38 ER - TY - JOUR AB - Previous numerical studies of the dissipation of internal tides in idealized settings suggest the existence of a critical latitude (~29°) where dissipation is enhanced. But observations only indicate a modest enhancement at this latitude. To resolve this difference between observational and numerical results, the authors study the latitudinal dependence of internal tides’ dissipation in more realistic conditions. In particular, the ocean is not a quiescent medium; the presence of large-scale currents or mesoscale eddies can impact the propagation and dissipation of internal tides. This paper investigates the impact of a weak background mean current in numerical simulations. The authors focus on the local dissipation of high spatial mode internal waves near their generation site. The vertical profile of dissipation and its variation with latitude without the mean current are consistent with earlier studies. But adding a weak mean current has a major impact on the latitudinal distribution of dissipation. The peak at the critical latitude disappears, and the dissipation is closer to a constant, albeit with two weak peaks at ~25° and ~35° latitude. This disappearance results from the Doppler shift of the internal tides’ frequency, which hinders the nonlinear transfer of energy to small-scale secondary waves via the parametric subharmonic instability (PSI). The new two weak peaks correspond to the Doppler-shifted critical latitudes of the left- and right-propagating waves. The results are confirmed in simulations with simple sinusoidal topography. Thus, although nonlinear transfers via PSI are efficient at dissipating internal tides, the exact location of the dissipation is sensitive to large-scale oceanic conditions. AU - Richet, O. AU - Muller, Caroline J AU - Chomaz, J.-M. ID - 9152 IS - 6 JF - Journal of Physical Oceanography KW - Oceanography SN - 0022-3670 TI - Impact of a mean current on the internal tide energy dissipation at the critical latitude VL - 47 ER - TY - JOUR AB - During puberty, the mouse mammary gland develops into a highly branched epithelial network. Owing to the absence of exclusive stem cell markers, the location, multiplicity, dynamics and fate of mammary stem cells (MaSCs), which drive branching morphogenesis, are unknown. Here we show that morphogenesis is driven by proliferative terminal end buds that terminate or bifurcate with near equal probability, in a stochastic and time-invariant manner, leading to a heterogeneous epithelial network. We show that the majority of terminal end bud cells function as highly proliferative, lineage-committed MaSCs that are heterogeneous in their expression profile and short-term contribution to ductal extension. Yet, through cell rearrangements during terminal end bud bifurcation, each MaSC is able to contribute actively to long-term growth. Our study shows that the behaviour of MaSCs is not directly linked to a single expression profile. Instead, morphogenesis relies upon lineage-restricted heterogeneous MaSC populations that function as single equipotent pools in the long term. AU - Scheele, Colinda AU - Hannezo, Edouard B AU - Muraro, Mauro AU - Zomer, Anoek AU - Langedijk, Nathalia AU - Van Oudenaarden, Alexander AU - Simons, Benjamin AU - Van Rheenen, Jacco ID - 934 IS - 7641 JF - Nature SN - 00280836 TI - Identity and dynamics of mammary stem cells during branching morphogenesis VL - 542 ER - TY - JOUR AB - Homeostatic replacement of epithelial cells from basal precursors is a multistep process involving progenitor cell specification, radial intercalation and, finally, apical surface emergence. Recent data demonstrate that actin-based pushing under the control of the formin protein Fmn1 drives apical emergence in nascent multiciliated epithelial cells (MCCs), but little else is known about this actin network or the control of Fmn1. Here, we explore the role of the small GTPase RhoA in MCC apical emergence. Disruption of RhoA function reduced the rate of apical surface expansion and decreased the final size of the apical domain. Analysis of cell shapes suggests that RhoA alters the balance of forces exerted on the MCC apical surface. Finally, quantitative time-lapse imaging and fluorescence recovery after photobleaching studies argue that RhoA works in concert with Fmn1 to control assembly of the specialized apical actin network in MCCs. These data provide new molecular insights into epithelial apical surface assembly and could also shed light on mechanisms of apical lumen formation AU - Sedzinski, Jakub AU - Hannezo, Edouard B AU - Tu, Fan AU - Biro, Maté AU - Wallingford, John ID - 936 IS - 5 JF - Journal of Cell Science TI - RhoA regulates actin network dynamics during apical surface emergence in multiciliated epithelial cells VL - 130 ER - TY - JOUR AB - During epithelial cytokinesis, the remodelling of adhesive cell-cell contacts between the dividing cell and its neighbours has profound implications for the integrity, arrangement and morphogenesis of proliferative tissues. In both vertebrates and invertebrates, this remodelling requires the activity of non-muscle myosin II (MyoII) in the interphasic cells neighbouring the dividing cell. However, the mechanisms that coordinate cytokinesis and MyoII activity in the neighbours are unknown. Here we show that in the Drosophila notum epithelium, each cell division is associated with a mechanosensing and transmission event that controls MyoII dynamics in neighbouring cells. We find that the ring pulling forces promote local junction elongation, which results in local E-cadherin dilution at the ingressing adherens junction. In turn, the reduction in E-cadherin concentration and the contractility of the neighbouring cells promote self-organized actomyosin flows, ultimately leading to accumulation of MyoII at the base of the ingressing junction. Although force transduction has been extensively studied in the context of adherens junction reinforcement to stabilize adhesive cell-cell contacts, we propose an alternative mechanosensing mechanism that coordinates actomyosin dynamics between epithelial cells and sustains the remodelling of the adherens junction in response to mechanical forces. AU - Pinheiro, Diana AU - Hannezo, Edouard B AU - Herszterg, Sophie AU - Bosveld, Floris AU - Gaugué, Isabelle AU - Balakireva, Maria AU - Wang, Zhimin AU - Cristo, Inês AU - Rigaud, Stéphane AU - Markova, Olga AU - Bellaïche, Yohanns ID - 937 IS - 7652 JF - Nature SN - 00280836 TI - Transmission of cytokinesis forces via E cadherin dilution and actomyosin flows VL - 545 ER - TY - CONF AB - Recently there has been a proliferation of automated program repair (APR) techniques, targeting various programming languages. Such techniques can be generally classified into two families: syntactic- and semantics-based. Semantics-based APR, on which we focus, typically uses symbolic execution to infer semantic constraints and then program synthesis to construct repairs conforming to them. While syntactic-based APR techniques have been shown successful on bugs in real-world programs written in both C and Java, semantics-based APR techniques mostly target C programs. This leaves empirical comparisons of the APR families not fully explored, and developers without a Java-based semantics APR technique. We present JFix, a semantics-based APR framework that targets Java, and an associated Eclipse plugin. JFix is implemented atop Symbolic PathFinder, a well-known symbolic execution engine for Java programs. It extends one particular APR technique (Angelix), and is designed to be sufficiently generic to support a variety of such techniques. We demonstrate that semantics-based APR can indeed efficiently and effectively repair a variety of classes of bugs in large real-world Java programs. This supports our claim that the framework can both support developers seeking semantics-based repair of bugs in Java programs, as well as enable larger scale empirical studies comparing syntactic- and semantics-based APR targeting Java. The demonstration of our tool is available via the project website at: https://xuanbachle.github.io/semanticsrepair/ AU - Le, Xuan AU - Chu, Duc Hiep AU - Lo, David AU - Le Goues, Claire AU - Visser, Willem ID - 941 T2 - Proceedings of the 26th ACM SIGSOFT International Symposium on Software Testing and Analysis TI - JFIX: Semantics-based repair of Java programs via symbolic PathFinder ER - TY - JOUR AB - Methylation in the bodies of active genes is common in animals and vascular plants. Evolutionary patterns indicate homeostatic functions for this type of methylation. AU - Zilberman, Daniel ID - 9506 IS - 1 JF - Genome Biology SN - 1474-760X TI - An evolutionary case for functional gene body methylation in plants and animals VL - 18 ER - TY - CHAP AB - Biosensors that exploit Forster resonance energy transfer (FRET) can be used to visualize biological and physiological processes and are capable of providing detailed information in both spatial and temporal dimensions. In a FRET-based biosensor, substrate binding is associated with a change in the relative positions of two fluorophores, leading to a change in FRET efficiency that may be observed in the fluorescence spectrum. As a result, their design requires a ligand-binding protein that exhibits a conformational change upon binding. However, not all ligand-binding proteins produce responsive sensors upon conjugation to fluorescent proteins or dyes, and identifying the optimum locations for the fluorophores often involves labor-intensive iterative design or high-throughput screening. Combining the genetic fusion of a fluorescent protein to the ligand-binding protein with site-specific covalent attachment of a fluorescent dye can allow fine control over the positions of the two fluorophores, allowing the construction of very sensitive sensors. This relies upon the accurate prediction of the locations of the two fluorophores in bound and unbound states. In this chapter, we describe a method for computational identification of dye-attachment sites that allows the use of cysteine modification to attach synthetic dyes that can be paired with a fluorescent protein for the purposes of creating FRET sensors. AU - Mitchell, Joshua AU - Zhang, William AU - Herde, Michel AU - Henneberger, Christian AU - Janovjak, Harald L AU - O'Mara, Megan AU - Jackson, Colin ED - Stein, Viktor ID - 958 SN - 10643745 T2 - Synthetic Protein Switches TI - Method for developing optical sensors using a synthetic dye fluorescent protein FRET pair and computational modeling and assessment VL - 1596 ER - TY - JOUR AB - In this paper we discuss how the information contained in atomistic simulations of homogeneous nucleation should be used when fitting the parameters in macroscopic nucleation models. We show how the number of solid and liquid atoms in such simulations can be determined unambiguously by using a Gibbs dividing surface and how the free energy as a function of the number of solid atoms in the nucleus can thus be extracted. We then show that the parameters (the chemical potential, the interfacial free energy, and a Tolman correction) of a model based on classical nucleation theory can be fitted using the information contained in these free-energy profiles but that the parameters in such models are highly correlated. This correlation is unfortunate as it ensures that small errors in the computed free energy surface can give rise to large errors in the extrapolated properties of the fitted model. To resolve this problem we thus propose a method for fitting macroscopic nucleation models that uses simulations of planar interfaces and simulations of three-dimensional nuclei in tandem. We show that when the chemical potentials and the interface energy are pinned to their planar-interface values, more precise estimates for the Tolman length are obtained. Extrapolating the free energy profile obtained from small simulation boxes to larger nuclei is thus more reliable. AU - Cheng, Bingqing AU - Tribello, Gareth A. AU - Ceriotti, Michele ID - 9660 IS - 10 JF - The Journal of Chemical Physics SN - 0021-9606 TI - The Gibbs free energy of homogeneous nucleation: From atomistic nuclei to the planar limit VL - 147 ER - TY - JOUR AB - Macroscopic theories of nucleation such as classical nucleation theory envision that clusters of the bulk stable phase form inside the bulk metastable phase. Molecular dynamics simulations are often used to elucidate nucleation mechanisms, by capturing the microscopic configurations of all the atoms. In this paper, we introduce a thermodynamic model that links macroscopic theories and atomic-scale simulations and thus provide a simple and elegant framework for testing the limits of classical nucleation theory. AU - Cheng, Bingqing AU - Ceriotti, Michele ID - 9661 IS - 3 JF - The Journal of Chemical Physics SN - 0021-9606 TI - Bridging the gap between atomistic and macroscopic models of homogeneous nucleation VL - 146 ER -