TY - JOUR AB - Motivation Computational prediction of the effect of mutations on protein stability is used by researchers in many fields. The utility of the prediction methods is affected by their accuracy and bias. Bias, a systematic shift of the predicted change of stability, has been noted as an issue for several methods, but has not been investigated systematically. Presence of the bias may lead to misleading results especially when exploring the effects of combination of different mutations. Results Here we use a protocol to measure the bias as a function of the number of introduced mutations. It is based on a self-consistency test of the reciprocity the effect of a mutation. An advantage of the used approach is that it relies solely on crystal structures without experimentally measured stability values. We applied the protocol to four popular algorithms predicting change of protein stability upon mutation, FoldX, Eris, Rosetta and I-Mutant, and found an inherent bias. For one program, FoldX, we manage to substantially reduce the bias using additional relaxation by Modeller. Authors using algorithms for predicting effects of mutations should be aware of the bias described here. AU - Usmanova, Dinara R AU - Bogatyreva, Natalya S AU - Ariño Bernad, Joan AU - Eremina, Aleksandra A AU - Gorshkova, Anastasiya A AU - Kanevskiy, German M AU - Lonishin, Lyubov R AU - Meister, Alexander V AU - Yakupova, Alisa G AU - Kondrashov, Fyodor AU - Ivankov, Dmitry ID - 5995 IS - 21 JF - Bioinformatics SN - 1367-4803 TI - Self-consistency test reveals systematic bias in programs for prediction change of stability upon mutation VL - 34 ER - TY - JOUR AB - Lamellipodia are flat membrane protrusions formed during mesenchymal motion. Polymerization at the leading edge assembles the actin filament network and generates protrusion force. How this force is supported by the network and how the assembly rate is shared between protrusion and network retrograde flow determines the protrusion rate. We use mathematical modeling to understand experiments changing the F-actin density in lamellipodia of B16-F1 melanoma cells by modulation of Arp2/3 complex activity or knockout of the formins FMNL2 and FMNL3. Cells respond to a reduction of density with a decrease of protrusion velocity, an increase in the ratio of force to filament number, but constant network assembly rate. The relation between protrusion force and tension gradient in the F-actin network and the density dependency of friction, elasticity, and viscosity of the network explain the experimental observations. The formins act as filament nucleators and elongators with differential rates. Modulation of their activity suggests an effect on network assembly rate. Contrary to these expectations, the effect of changes in elongator composition is much weaker than the consequences of the density change. We conclude that the force acting on the leading edge membrane is the force required to drive F-actin network retrograde flow. AU - Dolati, Setareh AU - Kage, Frieda AU - Mueller, Jan AU - Müsken, Mathias AU - Kirchner, Marieluise AU - Dittmar, Gunnar AU - Sixt, Michael K AU - Rottner, Klemens AU - Falcke, Martin ID - 5992 IS - 22 JF - Molecular Biology of the Cell TI - On the relation between filament density, force generation, and protrusion rate in mesenchymal cell motility VL - 29 ER - TY - JOUR AB - The optic tectum (TeO), or superior colliculus, is a multisensory midbrain center that organizes spatially orienting responses to relevant stimuli. To define the stimulus with the highest priority at each moment, a network of reciprocal connections between the TeO and the isthmi promotes competition between concurrent tectal inputs. In the avian midbrain, the neurons mediating enhancement and suppression of tectal inputs are located in separate isthmic nuclei, facilitating the analysis of the neural processes that mediate competition. A specific subset of radial neurons in the intermediate tectal layers relay retinal inputs to the isthmi, but at present it is unclear whether separate neurons innervate individual nuclei or a single neural type sends a common input to several of them. In this study, we used in vitro neural tracing and cell-filling experiments in chickens to show that single neurons innervate, via axon collaterals, the three nuclei that comprise the isthmotectal network. This demonstrates that the input signals representing the strength of the incoming stimuli are simultaneously relayed to the mechanisms promoting both enhancement and suppression of the input signals. By performing in vivo recordings in anesthetized chicks, we also show that this common input generates synchrony between both antagonistic mechanisms, demonstrating that activity enhancement and suppression are closely coordinated. From a computational point of view, these results suggest that these tectal neurons constitute integrative nodes that combine inputs from different sources to drive in parallel several concurrent neural processes, each performing complementary functions within the network through different firing patterns and connectivity. AU - Garrido-Charad, Florencia AU - Vega Zuniga, Tomas A AU - Gutiérrez-Ibáñez, Cristián AU - Fernandez, Pedro AU - López-Jury, Luciana AU - González-Cabrera, Cristian AU - Karten, Harvey J. AU - Luksch, Harald AU - Marín, Gonzalo J. ID - 6010 IS - 32 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - “Shepherd’s crook” neurons drive and synchronize the enhancing and suppressive mechanisms of the midbrain stimulus selection network VL - 115 ER - TY - JOUR AB - Digital fabrication devices are powerful tools for creating tangible reproductions of 3D digital models. Most available printing technologies aim at producing an accurate copy of a tridimensional shape. However, fabrication technologies can also be used to create a stylistic representation of a digital shape. We refer to this class of methods as ‘stylized fabrication methods’. These methods abstract geometric and physical features of a given shape to create an unconventional representation, to produce an optical illusion or to devise a particular interaction with the fabricated model. In this state‐of‐the‐art report, we classify and overview this broad and emerging class of approaches and also propose possible directions for future research. AU - Bickel, Bernd AU - Cignoni, Paolo AU - Malomo, Luigi AU - Pietroni, Nico ID - 6003 IS - 6 JF - Computer Graphics Forum SN - 0167-7055 TI - State of the art on stylized fabrication VL - 37 ER - TY - JOUR AB - The Bogoliubov free energy functional is analysed. The functional serves as a model of a translation-invariant Bose gas at positive temperature. We prove the existence of minimizers in the case of repulsive interactions given by a sufficiently regular two-body potential. Furthermore, we prove the existence of a phase transition in this model and provide its phase diagram. AU - Napiórkowski, Marcin M AU - Reuvers, Robin AU - Solovej, Jan Philip ID - 6002 IS - 3 JF - Archive for Rational Mechanics and Analysis SN - 0003-9527 TI - The Bogoliubov free energy functional I: Existence of minimizers and phase diagram VL - 229 ER - TY - JOUR AB - In pipes, turbulence sets in despite the linear stability of the laminar Hagen–Poiseuille flow. The Reynolds number ( ) for which turbulence first appears in a given experiment – the ‘natural transition point’ – depends on imperfections of the set-up, or, more precisely, on the magnitude of finite amplitude perturbations. At onset, turbulence typically only occupies a certain fraction of the flow, and this fraction equally is found to differ from experiment to experiment. Despite these findings, Reynolds proposed that after sufficiently long times, flows may settle to steady conditions: below a critical velocity, flows should (regardless of initial conditions) always return to laminar, while above this velocity, eddying motion should persist. As will be shown, even in pipes several thousand diameters long, the spatio-temporal intermittent flow patterns observed at the end of the pipe strongly depend on the initial conditions, and there is no indication that different flow patterns would eventually settle to a (statistical) steady state. Exploiting the fact that turbulent puffs do not age (i.e. they are memoryless), we continuously recreate the puff sequence exiting the pipe at the pipe entrance, and in doing so introduce periodic boundary conditions for the puff pattern. This procedure allows us to study the evolution of the flow patterns for arbitrary long times, and we find that after times in excess of advective time units, indeed a statistical steady state is reached. Although the resulting flows remain spatio-temporally intermittent, puff splitting and decay rates eventually reach a balance, so that the turbulent fraction fluctuates around a well-defined level which only depends on . In accordance with Reynolds’ proposition, we find that at lower (here 2020), flows eventually always resume to laminar, while for higher ( ), turbulence persists. The critical point for pipe flow hence falls in the interval of $2020 , which is in very good agreement with the recently proposed value of . The latter estimate was based on single-puff statistics and entirely neglected puff interactions. Unlike in typical contact processes where such interactions strongly affect the percolation threshold, in pipe flow, the critical point is only marginally influenced. Interactions, on the other hand, are responsible for the approach to the statistical steady state. As shown, they strongly affect the resulting flow patterns, where they cause ‘puff clustering’, and these regions of large puff densities are observed to travel across the puff pattern in a wave-like fashion. AU - Vasudevan, Mukund AU - Hof, Björn ID - 5996 JF - Journal of Fluid Mechanics SN - 0022-1120 TI - The critical point of the transition to turbulence in pipe flow VL - 839 ER - TY - JOUR AB - In this article, we consider the termination problem of probabilistic programs with real-valued variables. Thequestions concerned are: qualitative ones that ask (i) whether the program terminates with probability 1(almost-sure termination) and (ii) whether the expected termination time is finite (finite termination); andquantitative ones that ask (i) to approximate the expected termination time (expectation problem) and (ii) tocompute a boundBsuch that the probability not to terminate afterBsteps decreases exponentially (con-centration problem). To solve these questions, we utilize the notion of ranking supermartingales, which isa powerful approach for proving termination of probabilistic programs. In detail, we focus on algorithmicsynthesis of linear ranking-supermartingales over affine probabilistic programs (Apps) with both angelic anddemonic non-determinism. An important subclass of Apps is LRApp which is defined as the class of all Appsover which a linear ranking-supermartingale exists.Our main contributions are as follows. Firstly, we show that the membership problem of LRApp (i) canbe decided in polynomial time for Apps with at most demonic non-determinism, and (ii) isNP-hard and inPSPACEfor Apps with angelic non-determinism. Moreover, theNP-hardness result holds already for Appswithout probability and demonic non-determinism. Secondly, we show that the concentration problem overLRApp can be solved in the same complexity as for the membership problem of LRApp. Finally, we show thatthe expectation problem over LRApp can be solved in2EXPTIMEand isPSPACE-hard even for Apps withoutprobability and non-determinism (i.e., deterministic programs). Our experimental results demonstrate theeffectiveness of our approach to answer the qualitative and quantitative questions over Apps with at mostdemonic non-determinism. AU - Chatterjee, Krishnendu AU - Fu, Hongfei AU - Novotný, Petr AU - Hasheminezhad, Rouzbeh ID - 5993 IS - 2 JF - ACM Transactions on Programming Languages and Systems SN - 0164-0925 TI - Algorithmic analysis of qualitative and quantitative termination problems for affine probabilistic programs VL - 40 ER - TY - JOUR AB - We introduce for each quiver Q and each algebraic oriented cohomology theory A, the cohomological Hall algebra (CoHA) of Q, as the A-homology of the moduli of representations of the preprojective algebra of Q. This generalizes the K-theoretic Hall algebra of commuting varieties defined by Schiffmann-Vasserot. When A is the Morava K-theory, we show evidence that this algebra is a candidate for Lusztig's reformulated conjecture on modular representations of algebraic groups. We construct an action of the preprojective CoHA on the A-homology of Nakajima quiver varieties. We compare this with the action of the Borel subalgebra of Yangian when A is the intersection theory. We also give a shuffle algebra description of this CoHA in terms of the underlying formal group law of A. As applications, we obtain a shuffle description of the Yangian. AU - Yang, Yaping AU - Zhao, Gufang ID - 5999 IS - 5 JF - Proceedings of the London Mathematical Society SN - 0024-6115 TI - The cohomological Hall algebra of a preprojective algebra VL - 116 ER - TY - JOUR AB - Schistosomes are the causative agents of schistosomiasis, a neglected tropical disease affecting over 230 million people worldwide.Additionally to their major impact on human health, they are also models of choice in evolutionary biology. These parasitic flatwormsare unique among the common hermaphroditic trematodes as they have separate sexes. This so-called “evolutionary scandal”displays a female heterogametic genetic sex-determination system (ZZ males and ZW females), as well as a pronounced adult sexualdimorphism. These phenotypic differences are determined by a shared set of genes in both sexes, potentially leading to intralocussexual conflicts. To resolve these conflicts in sexually selected traits, molecular mechanisms such as sex-biased gene expression couldoccur, but parent-of-origin gene expression also provides an alternative. In this work we investigated the latter mechanism, that is,genes expressed preferentially from either the maternal or the paternal allele, inSchistosoma mansonispecies. To this end, tran-scriptomes from male and female hybrid adults obtained by strain crosses were sequenced. Strain-specific single nucleotide poly-morphism (SNP) markers allowed us to discriminate the parental origin, while reciprocal crosses helped to differentiate parentalexpression from strain-specific expression. We identified genes containing SNPs expressed in a parent-of-origin manner consistentwith paternal and maternal imprints. Although the majority of the SNPs was identified in mitochondrial and Z-specific loci, theremaining SNPs found in male and female transcriptomes were situated in genes that have the potential to explain sexual differencesin schistosome parasites. Furthermore, we identified and validated four new Z-specific scaffolds. AU - Kincaid-Smith, Julien AU - Picard, Marion A L AU - Cosseau, Céline AU - Boissier, Jérôme AU - Severac, Dany AU - Grunau, Christoph AU - Toulza, Eve ID - 5989 IS - 3 JF - Genome Biology and Evolution SN - 1759-6653 TI - Parent-of-Origin-Dependent Gene Expression in Male and Female Schistosome Parasites VL - 10 ER - TY - CONF AB - We introduce Clover, a new library for efficient computation using low-precision data, providing mathematical routines required by fundamental methods in optimization and sparse recovery. Our library faithfully implements variants of stochastic quantization that guarantee convergence at low precision, and supports data formats from 4-bit quantized to 32-bit IEEE-754 on current Intel processors. In particular, we show that 4-bit can be implemented efficiently using Intel AVX despite the lack of native support for this data format. Experimental results with dot product, matrix-vector multiplication (MVM), gradient descent (GD), and iterative hard thresholding (IHT) demonstrate that the attainable speedups are in many cases close to linear with respect to the reduction of precision due to reduced data movement. Finally, for GD and IHT, we show examples of absolute speedup achieved by 4-bit versus 32-bit, by iterating until a given target error is achieved. AU - Stojanov, Alen AU - Smith, Tyler Michael AU - Alistarh, Dan-Adrian AU - Puschel, Markus ID - 6031 T2 - 2018 IEEE International Workshop on Signal Processing Systems TI - Fast quantized arithmetic on x86: Trading compute for data movement VL - 2018-October ER -