TY - JOUR
AB - Long-lasting memories are formed when the stimulus is temporally distributed (spacing effect). However, the synaptic mechanisms underlying this robust phenomenon and the precise time course of the synaptic modifications that occur during learning remain unclear. Here we examined the adaptation of horizontal optokinetic response in mice that underwent 1 h of massed and spaced training at varying intervals. Despite similar acquisition by all training protocols, 1 h of spacing produced the highest memory retention at 24 h, which lasted for 1 mo. The distinct kinetics of memory are strongly correlated with the reduction of floccular parallel fiber-Purkinje cell synapses but not with AMPA receptor (AMPAR) number and synapse size. After the spaced training, we observed 25%, 23%, and 12% reduction in AMPAR density, synapse size, and synapse number, respectively. Four hours after the spaced training, half of the synapses and Purkinje cell spines had been eliminated, whereas AMPAR density and synapse size were recovered in remaining synapses. Surprisingly, massed training also produced long-term memory and halving of synapses; however, this occurred slowly over days, and the memory lasted for only 1 wk. This distinct kinetics of structural plasticity may serve as a basis for unique temporal profiles in the formation and decay of memory with or without intervals.
AU - Aziz, Wajeeha
AU - Wang, Wen
AU - Kesaf, Sebnem
AU - Mohamed, Alsayed
AU - Fukazawa, Yugo
AU - Shigemoto, Ryuichi
ID - 1919
IS - 1
JF - PNAS
TI - Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning
VL - 111
ER -
TY - JOUR
AB - Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-termadaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short- and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.
AU - Wang, Wen
AU - Nakadate, Kazuhiko
AU - Masugi Tokita, Miwako
AU - Shutoh, Fumihiro
AU - Aziz, Wajeeha
AU - Tarusawa, Etsuko
AU - Lörincz, Andrea
AU - Molnár, Elek
AU - Kesaf, Sebnem
AU - Li, Yunqing
AU - Fukazawa, Yugo
AU - Nagao, Soichi
AU - Shigemoto, Ryuichi
ID - 1920
IS - 1
JF - PNAS
TI - Distinct cerebellar engrams in short-term and long-term motor learning
VL - 111
ER -
TY - JOUR
AB - Cell polarity manifested by asymmetric distribution of cargoes, such as receptors and transporters, within the plasma membrane (PM) is crucial for essential functions in multicellular organisms. In plants, cell polarity (re)establishment is intimately linked to patterning processes. Despite the importance of cell polarity, its underlying mechanisms are still largely unknown, including the definition and distinctiveness of the polar domains within the PM. Here, we show in Arabidopsis thaliana that the signaling membrane components, the phosphoinositides phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4, 5-bisphosphate [PtdIns(4, 5)P2] as well as PtdIns4P 5-kinases mediating their interconversion, are specifically enriched at apical and basal polar plasma membrane domains. The PtdIns4P 5-kinases PIP5K1 and PIP5K2 are redundantly required for polar localization of specifically apical and basal cargoes, such as PIN-FORMED transporters for the plant hormone auxin. As a consequence of the polarity defects, instructive auxin gradients as well as embryonic and postembryonic patterning are severely compromised. Furthermore, auxin itself regulates PIP5K transcription and PtdIns4P and PtdIns(4, 5)P2 levels, in particular their association with polar PM domains. Our results provide insight into the polar domain-delineating mechanisms in plant cells that depend on apical and basal distribution of membrane lipids and are essential for embryonic and postembryonic patterning.
AU - Tejos, Ricardo
AU - Sauer, Michael
AU - Vanneste, Steffen
AU - Palacios-Gomez, MiriamPalacios
AU - Li, Hongjiang
AU - Heilmann, Mareike
AU - Van Wijk, Ringo
AU - Vermeer, Joop
AU - Heilmann, Ingo
AU - Munnik, Teun
AU - Friml, Jirí
ID - 1921
IS - 5
JF - Plant Cell
TI - Bipolar plasma membrane distribution of phosphoinositides and their requirement for auxin-mediated cell polarity and patterning in Arabidopsis
VL - 26
ER -
TY - JOUR
AB - Germination of Arabidopsis seeds in darkness induces apical hook development, based on a tightly regulated differential growth coordinated by a multiple hormone cross-talk. Here, we endeavoured to clarify the function of brassinosteroids (BRs) and cross-talk with ethylene in hook development. An automated infrared imaging system was developed to study the kinetics of hook development in etiolated Arabidopsis seedlings. To ascertain the photomorphogenic control of hook opening, the system was equipped with an automatic light dimmer. We demonstrate that ethylene and BRs are indispensable for hook formation and maintenance. Ethylene regulation of hook formation functions partly through BRs, with BR feedback inhibition of ethylene action. Conversely, BR-mediated extension of hook maintenance functions partly through ethylene. Furthermore, we revealed that a short light pulse is sufficient to induce rapid hook opening. Our dynamic infrared imaging system allows high-resolution, kinetic imaging of up to 112 seedlings in a single experimental run. At this high throughput, it is ideally suited to rapidly gain insight in pathway networks. We demonstrate that BRs and ethylene cooperatively regulate apical hook development in a phase-dependent manner. Furthermore, we show that light is a predominant regulator of hook opening, inhibiting ethylene- and BR-mediated postponement of hook opening.
AU - Smet, Dajo
AU - Žádníková, Petra
AU - Vandenbussche, Filip
AU - Benková, Eva
AU - Van Der Straeten, Dominique
ID - 1922
IS - 4
JF - New Phytologist
TI - Dynamic infrared imaging analysis of apical hook development in Arabidopsis: The case of brassinosteroids
VL - 202
ER -
TY - JOUR
AB - We derive the equations for a thin, axisymmetric elastic shell subjected to an internal active stress giving rise to active tension and moments within the shell. We discuss the stability of a cylindrical elastic shell and its response to a localized change in internal active stress. This description is relevant to describe the cellular actomyosin cortex, a thin shell at the cell surface behaving elastically at a short timescale and subjected to active internal forces arising from myosin molecular motor activity. We show that the recent observations of cell deformation following detachment of adherent cells (Maître J-L et al 2012 Science 338 253-6) are well accounted for by this mechanical description. The actin cortex elastic and bending moduli can be obtained from a quantitative analysis of cell shapes observed in these experiments. Our approach thus provides a non-invasive, imaging-based method for the extraction of cellular physical parameters.
AU - Berthoumieux, Hélène
AU - Maître, Jean-Léon
AU - Heisenberg, Carl-Philipp J
AU - Paluch, Ewa
AU - Julicher, Frank
AU - Salbreux, Guillaume
ID - 1923
JF - New Journal of Physics
TI - Active elastic thin shell theory for cellular deformations
VL - 16
ER -
TY - JOUR
AB - Stomata are two-celled valves that control epidermal pores whose spacing optimizes shoot-atmosphere gas exchange. They develop from protodermal cells after unequal divisions followed by an equal division and differentiation. The concentration of the hormone auxin, a master plant developmental regulator, is tightly controlled in time and space, but its role, if any, in stomatal formation is obscure. Here dynamic changes of auxin activity during stomatal development are monitored using auxin input (DII-VENUS) and output (DR5:VENUS) markers by time-lapse imaging. A decrease in auxin levels in the smaller daughter cell after unequal division presages the acquisition of a guard mother cell fate whose equal division produces the two guard cells. Thus, stomatal patterning requires auxin pathway control of stem cell compartment size, as well as auxin depletion that triggers a developmental switch from unequal to equal division.
AU - Le, Jie
AU - Liu, Xuguang
AU - Yang, Kezhen
AU - Chen, Xiaolan
AU - Zhu, Lingling
AU - Wang, Hongzhe
AU - Wang, Ming
AU - Vanneste, Steffen
AU - Morita, Miyo
AU - Tasaka, Masao
AU - Ding, Zhaojun
AU - Friml, Jirí
AU - Beeckman, Tom
AU - Sack, Fred
ID - 1924
JF - Nature Communications
TI - Auxin transport and activity regulate stomatal patterning and development
VL - 5
ER -
TY - JOUR
AB - In the past decade carbon nanotubes (CNTs) have been widely studied as a potential drug-delivery system, especially with functionality for cellular targeting. Yet, little is known about the actual process of docking to cell receptors and transport dynamics after internalization. Here we performed single-particle studies of folic acid (FA) mediated CNT binding to human carcinoma cells and their transport inside the cytosol. In particular, we employed molecular recognition force spectroscopy, an atomic force microscopy based method, to visualize and quantify docking of FA functionalized CNTs to FA binding receptors in terms of binding probability and binding force. We then traced individual fluorescently labeled, FA functionalized CNTs after specific uptake, and created a dynamic 'roadmap' that clearly showed trajectories of directed diffusion and areas of nanotube confinement in the cytosol. Our results demonstrate the potential of a single-molecule approach for investigation of drug-delivery vehicles and their targeting capacity.
AU - Lamprecht, Constanze
AU - Plochberger, Birgit
AU - Ruprecht, Verena
AU - Wieser, Stefan
AU - Rankl, Christian
AU - Heister, Elena
AU - Unterauer, Barbara
AU - Brameshuber, Mario
AU - Danzberger, Jürgen
AU - Lukanov, Petar
AU - Flahaut, Emmanuel
AU - Schütz, Gerhard
AU - Hinterdorfer, Peter
AU - Ebner, Andreas
ID - 1925
IS - 12
JF - Nanotechnology
TI - A single-molecule approach to explore binding uptake and transport of cancer cell targeting nanotubes
VL - 25
ER -
TY - JOUR
AB - We consider cross products of finite graphs with a class of trees that have arbitrarily but finitely long line segments, such as the Fibonacci tree. Such cross products are called tree-strips. We prove that for small disorder random Schrödinger operators on such tree-strips have purely absolutely continuous spectrum in a certain set.
AU - Sadel, Christian
ID - 1926
IS - 3-4
JF - Mathematical Physics, Analysis and Geometry
TI - Absolutely continuous spectrum for random Schrödinger operators on the Fibonacci and similar Tree-strips
VL - 17
ER -
TY - CONF
AB - Constrained pseudorandom functions have recently been introduced independently by Boneh and Waters (Asiacrypt’13), Kiayias et al. (CCS’13), and Boyle et al. (PKC’14). In a standard pseudorandom function (PRF) a key k is used to evaluate the PRF on all inputs in the domain. Constrained PRFs additionally offer the functionality to delegate “constrained” keys kS which allow to evaluate the PRF only on a subset S of the domain. The three above-mentioned papers all show that the classical GGM construction (J.ACM’86) of a PRF from a pseudorandom generator (PRG) directly yields a constrained PRF where one can compute constrained keys to evaluate the PRF on all inputs with a given prefix. This constrained PRF has already found many interesting applications. Unfortunately, the existing security proofs only show selective security (by a reduction to the security of the underlying PRG). To achieve full security, one has to use complexity leveraging, which loses an exponential factor 2N in security, where N is the input length. The first contribution of this paper is a new reduction that only loses a quasipolynomial factor qlog N, where q is the number of adversarial queries. For this we develop a new proof technique which constructs a distinguisher by interleaving simple guessing steps and hybrid arguments a small number of times. This approach might be of interest also in other contexts where currently the only technique to achieve full security is complexity leveraging. Our second contribution is concerned with another constrained PRF, due to Boneh and Waters, which allows for constrained keys for the more general class of bit-fixing functions. Their security proof also suffers from a 2N loss, which we show is inherent. We construct a meta-reduction which shows that any “simple” reduction of full security from a noninteractive hardness assumption must incur an exponential security loss.
AU - Georg Fuchsbauer
AU - Konstantinov, Momchil
AU - Krzysztof Pietrzak
AU - Rao, Vanishree
ID - 1927
TI - Adaptive security of constrained PRFs
VL - 8874
ER -
TY - JOUR
AB - In infectious disease epidemiology the basic reproductive ratio, R0, is defined as the average number of new infections caused by a single infected individual in a fully susceptible population. Many models describing competition for hosts between non-interacting pathogen strains in an infinite population lead to the conclusion that selection favors invasion of new strains if and only if they have higher R0 values than the resident. Here we demonstrate that this picture fails in finite populations. Using a simple stochastic SIS model, we show that in general there is no analogous optimization principle. We find that successive invasions may in some cases lead to strains that infect a smaller fraction of the host population, and that mutually invasible pathogen strains exist. In the limit of weak selection we demonstrate that an optimization principle does exist, although it differs from R0 maximization. For strains with very large R0, we derive an expression for this local fitness function and use it to establish a lower bound for the error caused by neglecting stochastic effects. Furthermore, we apply this weak selection limit to investigate the selection dynamics in the presence of a trade-off between the virulence and the transmission rate of a pathogen.
AU - Humplik, Jan
AU - Hill, Alison
AU - Nowak, Martin
ID - 1928
JF - Journal of Theoretical Biology
TI - Evolutionary dynamics of infectious diseases in finite populations
VL - 360
ER -
TY - JOUR
AB - We propose an algorithm for the generalization of cartographic objects that can be used to represent maps on different scales.
AU - Alexeev, V V
AU - Bogaevskaya, V G
AU - Preobrazhenskaya, M M
AU - Ukhalov, A Y
AU - Edelsbrunner, Herbert
AU - Yakimova, Olga
ID - 1929
IS - 6
JF - Journal of Mathematical Sciences (United States)
TI - An algorithm for cartographic generalization that preserves global topology
VL - 203
ER -
TY - JOUR
AB - (Figure Presented) Data acquisition, numerical inaccuracies, and sampling often introduce noise in measurements and simulations. Removing this noise is often necessary for efficient analysis and visualization of this data, yet many denoising techniques change the minima and maxima of a scalar field. For example, the extrema can appear or disappear, spatially move, and change their value. This can lead to wrong interpretations of the data, e.g., when the maximum temperature over an area is falsely reported being a few degrees cooler because the denoising method is unaware of these features. Recently, a topological denoising technique based on a global energy optimization was proposed, which allows the topology-controlled denoising of 2D scalar fields. While this method preserves the minima and maxima, it is constrained by the size of the data. We extend this work to large 2D data and medium-sized 3D data by introducing a novel domain decomposition approach. It allows processing small patches of the domain independently while still avoiding the introduction of new critical points. Furthermore, we propose an iterative refinement of the solution, which decreases the optimization energy compared to the previous approach and therefore gives smoother results that are closer to the input. We illustrate our technique on synthetic and real-world 2D and 3D data sets that highlight potential applications.
AU - Günther, David
AU - Jacobson, Alec
AU - Reininghaus, Jan
AU - Seidel, Hans
AU - Sorkine Hornung, Olga
AU - Weinkauf, Tino
ID - 1930
IS - 12
JF - IEEE Transactions on Visualization and Computer Graphics
TI - Fast and memory-efficient topological denoising of 2D and 3D scalar fields
VL - 20
ER -
TY - JOUR
AB - A wealth of experimental evidence suggests that working memory circuits preferentially represent information that is behaviorally relevant. Still, we are missing a mechanistic account of how these representations come about. Here we provide a simple explanation for a range of experimental findings, in light of prefrontal circuits adapting to task constraints by reward-dependent learning. In particular, we model a neural network shaped by reward-modulated spike-timing dependent plasticity (r-STDP) and homeostatic plasticity (intrinsic excitability and synaptic scaling). We show that the experimentally-observed neural representations naturally emerge in an initially unstructured circuit as it learns to solve several working memory tasks. These results point to a critical, and previously unappreciated, role for reward-dependent learning in shaping prefrontal cortex activity.
AU - Savin, Cristina
AU - Triesch, Jochen
ID - 1931
IS - MAY
JF - Frontiers in Computational Neuroscience
TI - Emergence of task-dependent representations in working memory circuits
VL - 8
ER -
TY - JOUR
AB - The existence of complex (multiple-step) genetic adaptations that are "irreducible" (i.e., all partial combinations are less fit than the original genotype) is one of the longest standing problems in evolutionary biology. In standard genetics parlance, these adaptations require the crossing of a wide adaptive valley of deleterious intermediate stages. Here, we demonstrate, using a simple model, that evolution can cross wide valleys to produce "irreducibly complex" adaptations by making use of previously cryptic mutations. When revealed by an evolutionary capacitor, previously cryptic mutants have higher initial frequencies than do new mutations, bringing them closer to a valley-crossing saddle in allele frequency space. Moreover, simple combinatorics implies an enormous number of candidate combinations exist within available cryptic genetic variation. We model the dynamics of crossing of a wide adaptive valley after a capacitance event using both numerical simulations and analytical approximations. Although individual valley crossing events become less likely as valleys widen, by taking the combinatorics of genotype space into account, we see that revealing cryptic variation can cause the frequent evolution of complex adaptations.
AU - Trotter, Meredith
AU - Weissman, Daniel
AU - Peterson, Grant
AU - Peck, Kayla
AU - Masel, Joanna
ID - 1932
IS - 12
JF - Evolution
TI - Cryptic genetic variation can make "irreducible complexity" a common mode of adaptation in sexual populations
VL - 68
ER -
TY - JOUR
AB - The development of the vertebrate brain requires an exquisite balance between proliferation and differentiation of neural progenitors. Notch signaling plays a pivotal role in regulating this balance, yet the interaction between signaling and receiving cells remains poorly understood. We have found that numerous nascent neurons and/or intermediate neurogenic progenitors expressing the ligand of Notch retain apical endfeet transiently at the ventricular lumen that form adherens junctions (AJs) with the endfeet of progenitors. Forced detachment of the apical endfeet of those differentiating cells by disrupting AJs resulted in precocious neurogenesis that was preceded by the downregulation of Notch signaling. Both Notch1 and its ligand Dll1 are distributed around AJs in the apical endfeet, and these proteins physically interact with ZO-1, a constituent of the AJ. Furthermore, live imaging of a fluorescently tagged Notch1 demonstrated its trafficking from the apical endfoot to the nucleus upon cleavage. Our results identified the apical endfoot as the central site of active Notch signaling to securely prohibit inappropriate differentiation of neural progenitors.
AU - Hatakeyama, Jun
AU - Wakamatsu, Yoshio
AU - Nagafuchi, Akira
AU - Kageyama, Ryoichiro
AU - Shigemoto, Ryuichi
AU - Shimamura, Kenji
ID - 1933
IS - 8
JF - Development
TI - Cadherin-based adhesions in the apical endfoot are required for active Notch signaling to control neurogenesis in vertebrates
VL - 141
ER -
TY - JOUR
AB - The plant hormones auxin and cytokinin mutually coordinate their activities to control various aspects of development [1-9], and their crosstalk occurs at multiple levels [10, 11]. Cytokinin-mediated modulation of auxin transport provides an efficient means to regulate auxin distribution in plant organs. Here, we demonstrate that cytokinin does not merely control the overall auxin flow capacity, but might also act as a polarizing cue and control the auxin stream directionality during plant organogenesis. Cytokinin enhances the PIN-FORMED1 (PIN1) auxin transporter depletion at specific polar domains, thus rearranging the cellular PIN polarities and directly regulating the auxin flow direction. This selective cytokinin sensitivity correlates with the PIN protein phosphorylation degree. PIN1 phosphomimicking mutations, as well as enhanced phosphorylation in plants with modulated activities of PIN-specific kinases and phosphatases, desensitize PIN1 to cytokinin. Our results reveal conceptually novel, cytokinin-driven polarization mechanism that operates in developmental processes involving rapid auxin stream redirection, such as lateral root organogenesis, in which a gradual PIN polarity switch defines the growth axis of the newly formed organ.
AU - Marhavy, Peter
AU - Duclercq, Jérôme
AU - Weller, Benjamin
AU - Feraru, Elena
AU - Bielach, Agnieszka
AU - Offringa, Remko
AU - Friml, Jirí
AU - Schwechheimer, Claus
AU - Murphy, Angus
AU - Benková, Eva
ID - 1934
IS - 9
JF - Current Biology
TI - Cytokinin controls polarity of PIN1-dependent Auxin transport during lateral root organogenesis
VL - 24
ER -
TY - JOUR
AB - We consider Ising models in d = 2 and d = 3 dimensions with nearest neighbor ferromagnetic and long-range antiferromagnetic interactions, the latter decaying as (distance)-p, p > 2d, at large distances. If the strength J of the ferromagnetic interaction is larger than a critical value J c, then the ground state is homogeneous. It has been conjectured that when J is smaller than but close to J c, the ground state is periodic and striped, with stripes of constant width h = h(J), and h → ∞ as J → Jc -. (In d = 3 stripes mean slabs, not columns.) Here we rigorously prove that, if we normalize the energy in such a way that the energy of the homogeneous state is zero, then the ratio e 0(J)/e S(J) tends to 1 as J → Jc -, with e S(J) being the energy per site of the optimal periodic striped/slabbed state and e 0(J) the actual ground state energy per site of the system. Our proof comes with explicit bounds on the difference e 0(J)-e S(J) at small but positive J c-J, and also shows that in this parameter range the ground state is striped/slabbed in a certain sense: namely, if one looks at a randomly chosen window, of suitable size ℓ (very large compared to the optimal stripe size h(J)), one finds a striped/slabbed state with high probability.
AU - Giuliani, Alessandro
AU - Lieb, Élliott
AU - Seiringer, Robert
ID - 1935
IS - 1
JF - Communications in Mathematical Physics
TI - Formation of stripes and slabs near the ferromagnetic transition
VL - 331
ER -
TY - JOUR
AB - The social intelligence hypothesis states that the need to cope with complexities of social life has driven the evolution of advanced cognitive abilities. It is usually invoked in the context of challenges arising from complex intragroup structures, hierarchies, and alliances. However, a fundamental aspect of group living remains largely unexplored as a driving force in cognitive evolution: the competition between individuals searching for resources (producers) and conspecifics that parasitize their findings (scroungers). In populations of social foragers, abilities that enable scroungers to steal by outsmarting producers, and those allowing producers to prevent theft by outsmarting scroungers, are likely to be beneficial and may fuel a cognitive arms race. Using analytical theory and agent-based simulations, we present a general model for such a race that is driven by the producer-scrounger game and show that the race's plausibility is dramatically affected by the nature of the evolving abilities. If scrounging and scrounging avoidance rely on separate, strategy-specific cognitive abilities, arms races are short-lived and have a limited effect on cognition. However, general cognitive abilities that facilitate both scrounging and scrounging avoidance undergo stable, long-lasting arms races. Thus, ubiquitous foraging interactions may lead to the evolution of general cognitive abilities in social animals, without the requirement of complex intragroup structures.
AU - Arbilly, Michal
AU - Weissman, Daniel
AU - Feldman, Marcus
AU - Grodzinski, Uri
ID - 1936
IS - 3
JF - Behavioral Ecology
TI - An arms race between producers and scroungers can drive the evolution of social cognition
VL - 25
ER -
TY - JOUR
AB - We prove the edge universality of the beta ensembles for any β ≥ 1, provided that the limiting spectrum is supported on a single interval, and the external potential is C4 and regular. We also prove that the edge universality holds for generalized Wigner matrices for all symmetry classes. Moreover, our results allow us to extend bulk universality for beta ensembles from analytic potentials to potentials in class C4.
AU - Bourgade, Paul
AU - Erdös, László
AU - Yau, Horngtzer
ID - 1937
IS - 1
JF - Communications in Mathematical Physics
TI - Edge universality of beta ensembles
VL - 332
ER -
TY - JOUR
AB - NADH-ubiquinone oxidoreductase (complex I) is the first and largest enzyme in the respiratory chain of mitochondria and many bacteria. It couples the transfer of two electrons between NADH and ubiquinone to the translocation of four protons across the membrane. Complex I is an L-shaped assembly formed by the hydrophilic (peripheral) arm, containing all the redox centres performing electron transfer and the membrane arm, containing proton-translocating machinery. Mitochondrial complex I consists of 44 subunits of about 1 MDa in total, whilst the prokaryotic enzyme is simpler and generally consists of 14 conserved “core” subunits. Recently we have determined the first atomic structure of the entire complex I, using the enzyme from Thermus thermophilus (536 kDa, 16 subunits, 9 Fe-S clusters, 64 TM helices). Structure suggests a unique coupling mechanism, with redox energy of electron transfer driving proton translocation via long-range (up to ~200 Å) conformational changes. It resembles a steam engine, with coupling elements (akin to coupling rods) linking parts of this molecular machine.
AU - Leonid Sazanov
ID - 1979
IS - 4
JF - Journal of Bioenergetics and Biomembranes
TI - The mechanism of coupling between electron transfer and proton translocation in respiratory complex I
VL - 46
ER -
TY - JOUR
AB - Non-proton pumping type II NADH dehydrogenase (NDH-2) plays a central role in the respiratory metabolism of bacteria, and in the mitochondria of fungi, plants and protists. The lack of NDH-2 in mammalian mitochondria and its essentiality in important bacterial pathogens suggests these enzymes may represent a potential new drug target to combat microbial pathogens. Here, we report the first crystal structure of a bacterial NDH-2 enzyme at 2.5Å resolution from Caldalkalibacillus thermarum. The NDH-2 structure reveals a homodimeric organization that has a unique dimer interface. NDH-2 is localized to the cytoplasmic membrane by two separated C-terminal membrane-anchoring regions that are essential for membrane localization and FAD binding, but not NDH-2 dimerization. Comparison of bacterial NDH-2 with the yeast NADH dehydrogenase (Ndi1) structure revealed non-overlapping binding sites for quinone and NADH in the bacterial enzyme. The bacterial NDH-2 structure establishes a framework for the structure-based design of small-molecule inhibitors.
AU - Heikal, Adam
AU - Nakatani, Yoshio
AU - Dunn, Elyse A
AU - Weimar, Marion R
AU - Day, Catherine
AU - Baker, Edward N
AU - Lott, Shaun J
AU - Leonid Sazanov
AU - Cook, Gregory
ID - 1980
IS - 5
JF - Molecular Microbiology
TI - Structure of the bacterial type II NADH dehydrogenase: a monotopic membrane protein with an essential role in energy generation
VL - 91
ER -
TY - GEN
AB - Variation in mitochondrial DNA is often assumed to be neutral and is used to construct the genealogical relationships among populations and species. However, if extant variation is the result of episodes of positive selection, these genealogies may be incorrect, although this information itself may provide biologically and evolutionary meaningful information. In fact, positive Darwinian selection has been detected in the mitochondrial-encoded subunits that comprise complex I from diverse taxa with seemingly dissimilar bioenergetic life histories, but the functional implications of the selected sites are unknown. Complex I produces roughly 40% of the proton flux that is used to synthesize ATP from ADP, and a functional model based on the high-resolution structure of complex I described a unique biomechanical apparatus for proton translocation. We reported positive selection at sites in this apparatus during the evolution of Pacific salmon, and it appeared this was also the case in published reports from other taxa, but a comparison among studies was difficult because different statistical tests were used to detect selection and oftentimes, specific sites were not reported. Here we review the literature of positive selection in mitochondrial genomes, the statistical tests used to detect selection, and the structural and functional models that are currently available to study the physiological implications of selection. We then search for signatures of positive selection among the coding mitochondrial genomes of 237 species with a common set of tests and verify that the ND5 subunit of complex I is a repeated target of positive Darwinian selection in diverse taxa. We propose a novel hypothesis to explain the results based on their bioenergetic life histories and provide a guide for laboratory and field studies to test this hypothesis.
AU - Garvin, Michael R
AU - Bielawski, Joseph P
AU - Leonid Sazanov
AU - Gharrett, Anthony J
ID - 1981
IS - 1
T2 - Journal of Zoological Systematics and Evolutionary Research
TI - Review and meta-analysis of natural selection in mitochondrial complex I in metazoans
VL - 53
ER -
TY - JOUR
AB - During animal cell division, the cleavage furrow is positioned by microtubules that signal to the actin cortex at the cell midplane. We developed a cell-free system to recapitulate cytokinesis signaling using cytoplasmic extract from Xenopus eggs. Microtubules grew out as asters from artificial centrosomes and met to organize antiparallel overlap zones. These zones blocked the interpenetration of neighboring asters and recruited cytokinesis midzone proteins, including the chromosomal passenger complex (CPC) and centralspindlin. The CPC was transported to overlap zones, which required two motor proteins, Kif4A and a Kif20A paralog. Using supported lipid bilayers to mimic the plasma membrane, we observed the recruitment of cleavage furrow markers, including an active RhoA reporter, at microtubule overlaps. This system opens further approaches to understanding the biophysics of cytokinesis signaling.
AU - Nguyen, Phuong A
AU - Groen, Aaron C
AU - Martin Loose
AU - Ishihara, Keisuke
AU - Wühr, Martin
AU - Field, Christine M
AU - Mitchison, Timothy J
ID - 1989
IS - 6206
JF - Science
TI - Spatial organization of cytokinesis signaling reconstituted in a cell-free system
VL - 346
ER -
TY - JOUR
AB - Bacterial cytokinesis is commonly initiated by the Z-ring, a cytoskeletal structure that assembles at the site of division. Its primary component is FtsZ, a tubulin superfamily GTPase, which is recruited to the membrane by the actin-related protein FtsA. Both proteins are required for the formation of the Z-ring, but if and how they influence each other's assembly dynamics is not known. Here, we reconstituted FtsA-dependent recruitment of FtsZ polymers to supported membranes, where both proteins self-organize into complex patterns, such as fast-moving filament bundles and chirally rotating rings. Using fluorescence microscopy and biochemical perturbations, we found that these large-scale rearrangements of FtsZ emerge from its polymerization dynamics and a dual, antagonistic role of FtsA: recruitment of FtsZ filaments to the membrane and negative regulation of FtsZ organization. Our findings provide a model for the initial steps of bacterial cell division and illustrate how dynamic polymers can self-organize into large-scale structures.
AU - Martin Loose
AU - Mitchison, Timothy J
ID - 1990
IS - 1
JF - Nature Cell Biology
TI - The bacterial cell division proteins ftsA and ftsZ self-organize into dynamic cytoskeletal patterns
VL - 16
ER -
TY - JOUR
AB - The emergence and radiation of multicellular land plants was driven by crucial innovations to their body plans [1]. The directional transport of the phytohormone auxin represents a key, plant-specific mechanism for polarization and patterning in complex seed plants [2-5]. Here, we show that already in the early diverging land plant lineage, as exemplified by the moss Physcomitrella patens, auxin transport by PIN transporters is operational and diversified into ER-localized and plasma membrane-localized PIN proteins. Gain-of-function and loss-of-function analyses revealed that PIN-dependent intercellular auxin transport in Physcomitrella mediates crucial developmental transitions in tip-growing filaments and waves of polarization and differentiation in leaf-like structures. Plasma membrane PIN proteins localize in a polar manner to the tips of moss filaments, revealing an unexpected relation between polarization mechanisms in moss tip-growing cells and multicellular tissues of seed plants. Our results trace the origins of polarization and auxin-mediated patterning mechanisms and highlight the crucial role of polarized auxin transport during the evolution of multicellular land plants.
AU - Viaene, Tom
AU - Landberg, Katarina
AU - Thelander, Mattias
AU - Medvecka, Eva
AU - Pederson, Eric
AU - Feraru, Elena
AU - Cooper, Endymion
AU - Karimi, Mansour
AU - Delwiche, Charles
AU - Ljung, Karin
AU - Geisler, Markus
AU - Sundberg, Eva
AU - Friml, Jirí
ID - 1994
IS - 23
JF - Current Biology
TI - Directional auxin transport mechanisms in early diverging land plants
VL - 24
ER -
TY - JOUR
AB - Optical transport represents a natural route towards fast communications, and it is currently used in large scale data transfer. The progressive miniaturization of devices for information processing calls for the microscopic tailoring of light transport and confinement at length scales appropriate for upcoming technologies. With this goal in mind, we present a theoretical analysis of a one-dimensional Fabry-Perot interferometer built with two highly saturable nonlinear mirrors: a pair of two-level systems. Our approach captures nonlinear and nonreciprocal effects of light transport that were not reported previously. Remarkably, we show that such an elementary device can operate as a microscopic integrated optical rectifier.
AU - Fratini, Filippo
AU - Mascarenhas, Eduardo
AU - Safari, Laleh
AU - Poizat, Jean
AU - Valente, Daniel
AU - Auffèves, Alexia
AU - Gerace, Dario
AU - Santos, Marcelo
ID - 1995
IS - 24
JF - Physical Review Letters
TI - Fabry-Perot interferometer with quantum mirrors: Nonlinear light transport and rectification
VL - 113
ER -
TY - JOUR
AB - Auxin polar transport, local maxima, and gradients have become an importantmodel system for studying self-organization. Auxin distribution is regulated by auxin-dependent positive feedback loops that are not well-understood at the molecular level. Previously, we showed the involvement of the RHO of Plants (ROP) effector INTERACTOR of CONSTITUTIVELY active ROP 1 (ICR1) in regulation of auxin transport and that ICR1 levels are posttranscriptionally repressed at the site of maximum auxin accumulation at the root tip. Here, we show that bimodal regulation of ICR1 levels by auxin is essential for regulating formation of auxin local maxima and gradients. ICR1 levels increase concomitant with increase in auxin response in lateral root primordia, cotyledon tips, and provascular tissues. However, in the embryo hypophysis and root meristem, when auxin exceeds critical levels, ICR1 is rapidly destabilized by an SCF(TIR1/AFB) [SKP, Cullin, F-box (transport inhibitor response 1/auxin signaling F-box protein)]-dependent auxin signaling mechanism. Furthermore, ectopic expression of ICR1 in the embryo hypophysis resulted in reduction of auxin accumulation and concomitant root growth arrest. ICR1 disappeared during root regeneration and lateral root initiation concomitantly with the formation of a local auxin maximum in response to external auxin treatments and transiently after gravitropic stimulation. Destabilization of ICR1 was impaired after inhibition of auxin transport and signaling, proteasome function, and protein synthesis. A mathematical model based on these findings shows that an in vivo-like auxin distribution, rootward auxin flux, and shootward reflux can be simulated without assuming preexisting tissue polarity. Our experimental results and mathematical modeling indicate that regulation of auxin distribution is tightly associated with auxin-dependent ICR1 levels.
AU - Hazak, Ora
AU - Obolski, Uri
AU - Prat, Tomas
AU - Friml, Jiří
AU - Hadany, Lilach
AU - Yalovsky, Shaul
ID - 1996
IS - 50
JF - PNAS
TI - Bimodal regulation of ICR1 levels generates self-organizing auxin distribution
VL - 111
ER -
TY - JOUR
AB - Immune systems are able to protect the body against secondary infection with the same parasite. In insect colonies, this protection is not restricted to the level of the individual organism, but also occurs at the societal level. Here, we review recent evidence for and insights into the mechanisms underlying individual and social immunisation in insects. We disentangle general immune-protective effects from specific immune memory (priming), and examine immunisation in the context of the lifetime of an individual and that of a colony, and of transgenerational immunisation that benefits offspring. When appropriate, we discuss parallels with disease defence strategies in human societies. We propose that recurrent parasitic threats have shaped the evolution of both the individual immune systems and colony-level social immunity in insects.
AU - El Masri, Leila
AU - Cremer, Sylvia
ID - 1998
IS - 10
JF - Trends in Immunology
TI - Individual and social immunisation in insects
VL - 35
ER -
TY - JOUR
AB - Antibiotics affect bacterial cell physiology at many levels. Rather than just compensating for the direct cellular defects caused by the drug, bacteria respond to antibiotics by changing their morphology, macromolecular composition, metabolism, gene expression and possibly even their mutation rate. Inevitably, these processes affect each other, resulting in a complex response with changes in the expression of numerous genes. Genome‐wide approaches can thus help in gaining a comprehensive understanding of bacterial responses to antibiotics. In addition, a combination of experimental and theoretical approaches is needed for identifying general principles that underlie these responses. Here, we review recent progress in our understanding of bacterial responses to antibiotics and their combinations, focusing on effects at the levels of growth rate and gene expression. We concentrate on studies performed in controlled laboratory conditions, which combine promising experimental techniques with quantitative data analysis and mathematical modeling. While these basic research approaches are not immediately applicable in the clinic, uncovering the principles and mechanisms underlying bacterial responses to antibiotics may, in the long term, contribute to the development of new treatment strategies to cope with and prevent the rise of resistant pathogenic bacteria.
AU - Mitosch, Karin
AU - Bollenbach, Tobias
ID - 2001
IS - 6
JF - Environmental Microbiology Reports
TI - Bacterial responses to antibiotics and their combinations
VL - 6
ER -
TY - JOUR
AB - Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outsideout patch recordings from CA1 pyramidal neuron axons revealed a high density of a-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.
AU - Kim, Sooyun
ID - 2002
IS - 11
JF - PLoS One
TI - Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus
VL - 9
ER -
TY - JOUR
AB - Learning can be facilitated by previous knowledge when it is organized into relational representations forming schemas. In this issue of Neuron, McKenzie et al. (2014) demonstrate that the hippocampus rapidly forms interrelated, hierarchical memory representations to support schema-based learning.
AU - O'Neill, Joseph
AU - Csicsvari, Jozsef L
ID - 2003
IS - 1
JF - Neuron
TI - Learning by example in the hippocampus
VL - 83
ER -
TY - JOUR
AB - We have assembled a network of cell-fate determining transcription factors that play a key role in the specification of the ventral neuronal subtypes of the spinal cord on the basis of published transcriptional interactions. Asynchronous Boolean modelling of the network was used to compare simulation results with reported experimental observations. Such comparison highlighted the need to include additional regulatory connections in order to obtain the fixed point attractors of the model associated with the five known progenitor cell types located in the ventral spinal cord. The revised gene regulatory network reproduced previously observed cell state switches between progenitor cells observed in knock-out animal models or in experiments where the transcription factors were overexpressed. Furthermore the network predicted the inhibition of Irx3 by Nkx2.2 and this prediction was tested experimentally. Our results provide evidence for the existence of an as yet undescribed inhibitory connection which could potentially have significance beyond the ventral spinal cord. The work presented in this paper demonstrates the strength of Boolean modelling for identifying gene regulatory networks.
AU - Lovrics, Anna
AU - Gao, Yu
AU - Juhász, Bianka
AU - Bock, István
AU - Byrne, Helen
AU - Dinnyés, András
AU - Kovács, Krisztián
ID - 2004
IS - 11
JF - PLoS One
TI - Boolean modelling reveals new regulatory connections between transcription factors orchestrating the development of the ventral spinal cord
VL - 9
ER -
TY - JOUR
AB - By eliciting a natural exploratory behavior in rats, head scanning, a study reveals that hippocampal place cells form new, stable firing fields in those locations where the behavior has just occurred.
AU - Dupret, David
AU - Csicsvari, Jozsef L
ID - 2005
IS - 5
JF - Nature Neuroscience
TI - Turning heads to remember places
VL - 17
ER -
TY - GEN
AU - Anna Klimova
AU - Rudas, Tamás
ID - 2007
TI - gIPFrm: Generalized iterative proportional fitting for relational models
ER -
TY - JOUR
AB - The protection of privacy of individual-level information in genome-wide association study (GWAS) databases has been a major concern of researchers following the publication of “an attack” on GWAS data by Homer et al. (2008). Traditional statistical methods for confidentiality and privacy protection of statistical databases do not scale well to deal with GWAS data, especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach that provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees may come at a serious price in terms of data utility. Building on such notions, Uhler et al. (2013) proposed new methods to release aggregate GWAS data without compromising an individual’s privacy. We extend the methods developed in Uhler et al. (2013) for releasing differentially-private χ2χ2-statistics by allowing for arbitrary number of cases and controls, and for releasing differentially-private allelic test statistics. We also provide a new interpretation by assuming the controls’ data are known, which is a realistic assumption because some GWAS use publicly available data as controls. We assess the performance of the proposed methods through a risk-utility analysis on a real data set consisting of DNA samples collected by the Wellcome Trust Case Control Consortium and compare the methods with the differentially-private release mechanism proposed by Johnson and Shmatikov (2013).
AU - Yu, Fei
AU - Fienberg, Stephen
AU - Slaković, Alexandra
AU - Uhler, Caroline
ID - 2011
JF - Journal of Biomedical Informatics
TI - Scalable privacy-preserving data sharing methodology for genome-wide association studies
VL - 50
ER -
TY - CONF
AB - The classical sphere packing problem asks for the best (infinite) arrangement of non-overlapping unit balls which cover as much space as possible. We define a generalized version of the problem, where we allow each ball a limited amount of overlap with other balls. We study two natural choices of overlap measures and obtain the optimal lattice packings in a parameterized family of lattices which contains the FCC, BCC, and integer lattice.
AU - Iglesias Ham, Mabel
AU - Kerber, Michael
AU - Uhler, Caroline
ID - 2012
TI - Sphere packing with limited overlap
ER -
TY - JOUR
AB - An asymptotic theory is developed for computing volumes of regions in the parameter space of a directed Gaussian graphical model that are obtained by bounding partial correlations. We study these volumes using the method of real log canonical thresholds from algebraic geometry. Our analysis involves the computation of the singular loci of correlation hypersurfaces. Statistical applications include the strong-faithfulness assumption for the PC algorithm and the quantification of confounder bias in causal inference. A detailed analysis is presented for trees, bow ties, tripartite graphs, and complete graphs.
AU - Lin, Shaowei
AU - Uhler, Caroline
AU - Sturmfels, Bernd
AU - Bühlmann, Peter
ID - 2013
IS - 5
JF - Foundations of Computational Mathematics
TI - Hypersurfaces and their singularities in partial correlation testing
VL - 14
ER -
TY - GEN
AB - Gaussian graphical models have received considerable attention during the past four decades from the statistical and machine learning communities. In Bayesian treatments of this model, the G-Wishart distribution serves as the conjugate prior for inverse covariance matrices satisfying graphical constraints. While it is straightforward to posit the unnormalized densities, the normalizing constants of these distributions have been known only for graphs that are chordal, or decomposable. Up until now, it was unknown whether the normalizing constant for a general graph could be represented explicitly, and a considerable body of computational literature emerged that attempted to avoid this apparent intractability. We close this question by providing an explicit representation of the G-Wishart normalizing constant for general graphs.
AU - Caroline Uhler
AU - Lenkoski, Alex
AU - Richards, Donald
ID - 2017
T2 - ArXiv
TI - Exact formulas for the normalizing constants of Wishart distributions for graphical models
ER -
TY - JOUR
AB - Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.
AU - Matsukawa, Hiroshi
AU - Akiyoshi Nishimura, Sachiko
AU - Zhang, Qi
AU - Luján, Rafael
AU - Yamaguchi, Kazuhiko
AU - Goto, Hiromichi
AU - Yaguchi, Kunio
AU - Hashikawa, Tsutomu
AU - Sano, Chie
AU - Shigemoto, Ryuichi
AU - Nakashiba, Toshiaki
AU - Itohara, Shigeyoshi
ID - 2018
IS - 47
JF - Journal of Neuroscience
TI - Netrin-G/NGL complexes encode functional synaptic diversification
VL - 34
ER -
TY - JOUR
AB - We prove that the empirical density of states of quantum spin glasses on arbitrary graphs converges to a normal distribution as long as the maximal degree is negligible compared with the total number of edges. This extends the recent results of Keating et al. (2014) that were proved for graphs with bounded chromatic number and with symmetric coupling distribution. Furthermore, we generalise the result to arbitrary hypergraphs. We test the optimality of our condition on the maximal degree for p-uniform hypergraphs that correspond to p-spin glass Hamiltonians acting on n distinguishable spin- 1/2 particles. At the critical threshold p = n1/2 we find a sharp classical-quantum phase transition between the normal distribution and the Wigner semicircle law. The former is characteristic to classical systems with commuting variables, while the latter is a signature of noncommutative random matrix theory.
AU - Erdös, László
AU - Schröder, Dominik J
ID - 2019
IS - 3-4
JF - Mathematical Physics, Analysis and Geometry
TI - Phase transition in the density of states of quantum spin glasses
VL - 17
ER -
TY - JOUR
AB - The mammalian heart has long been considered a postmitotic organ, implying that the total number of cardiomyocytes is set at birth. Analysis of cell division in the mammalian heart is complicated by cardiomyocyte binucleation shortly after birth, which makes it challenging to interpret traditional assays of cell turnover [Laflamme MA, Murray CE (2011) Nature 473(7347):326–335; Bergmann O, et al. (2009) Science 324(5923):98–102]. An elegant multi-isotope imaging-mass spectrometry technique recently calculated the low, discrete rate of cardiomyocyte generation in mice [Senyo SE, et al. (2013) Nature 493(7432):433–436], yet our cellular-level understanding of postnatal cardiomyogenesis remains limited. Herein, we provide a new line of evidence for the differentiated α-myosin heavy chain-expressing cardiomyocyte as the cell of origin of postnatal cardiomyogenesis using the “mosaic analysis with double markers” mouse model. We show limited, life-long, symmetric division of cardiomyocytes as a rare event that is evident in utero but significantly diminishes after the first month of life in mice; daughter cardiomyocytes divide very seldom, which this study is the first to demonstrate, to our knowledge. Furthermore, ligation of the left anterior descending coronary artery, which causes a myocardial infarction in the mosaic analysis with double-marker mice, did not increase the rate of cardiomyocyte division above the basal level for up to 4 wk after the injury. The clonal analysis described here provides direct evidence of postnatal mammalian cardiomyogenesis.
AU - Ali, Shah
AU - Hippenmeyer, Simon
AU - Saadat, Lily
AU - Luo, Liqun
AU - Weissman, Irving
AU - Ardehali, Reza
ID - 2020
IS - 24
JF - PNAS
TI - Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice
VL - 111
ER -
TY - JOUR
AB - Neurotrophins regulate diverse aspects of neuronal development and plasticity, but their precise in vivo functions during neural circuit assembly in the central brain remain unclear. We show that the neurotrophin receptor tropomyosin-related kinase C (TrkC) is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse TrkC knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of the TrkC ligand neurotrophin-3 (NT-3) from cerebellar granule cells, which provide major afferent input to developing Purkinje cell dendrites, rescued the dendrite defects caused by sparse TrkC disruption in Purkinje cells. Our data demonstrate that NT-3 from presynaptic neurons (granule cells) is required for TrkC-dependent competitive dendrite morphogenesis in postsynaptic neurons (Purkinje cells)—a previously unknown mechanism of neural circuit development.
AU - William, Joo
AU - Hippenmeyer, Simon
AU - Luo, Liqun
ID - 2021
IS - 6209
JF - Science
TI - Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling
VL - 346
ER -
TY - JOUR
AB - Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ∼8–9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ∼1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.
AU - Gao, Peng
AU - Postiglione, Maria P
AU - Krieger, Teresa
AU - Hernandez, Luisirene
AU - Wang, Chao
AU - Han, Zhi
AU - Streicher, Carmen
AU - Papusheva, Ekaterina
AU - Insolera, Ryan
AU - Chugh, Kritika
AU - Kodish, Oren
AU - Huang, Kun
AU - Simons, Benjamin
AU - Luo, Liqun
AU - Hippenmeyer, Simon
AU - Shi, Song
ID - 2022
IS - 4
JF - Cell
TI - Deterministic progenitor behavior and unitary production of neurons in the neocortex
VL - 159
ER -
TY - JOUR
AB - The yeast Rab5 homologue, Vps21p, is known to be involved both in the vacuolar protein sorting (VPS) pathway from the trans-Golgi network to the vacuole, and in the endocytic pathway from the plasma membrane to the vacuole. However, the intracellular location at which these two pathways converge remains unclear. In addition, the endocytic pathway is not completely blocked in yeast cells lacking all Rab5 genes, suggesting the existence of an unidentified route that bypasses the Rab5-dependent endocytic pathway. Here we show that convergence of the endocytic and VPS pathways occurs upstream of the requirement for Vps21p in these pathways. We also identify a previously unidentified endocytic pathway mediated by the AP-3 complex. Importantly, the AP-3-mediated pathway appears mostly intact in Rab5-disrupted cells, and thus works as an alternative route to the vacuole/lysosome. We propose that the endocytic traffic branches into two routes to reach the vacuole: a Rab5-dependent VPS pathway and a Rab5-independent AP-3-mediated pathway.
AU - Toshima, Junko
AU - Nishinoaki, Show
AU - Sato, Yoshifumi
AU - Yamamoto, Wataru
AU - Furukawa, Daiki
AU - Siekhaus, Daria E
AU - Sawaguchi, Akira
AU - Toshima, Jiro
ID - 2024
JF - Nature Communications
TI - Bifurcation of the endocytic pathway into Rab5-dependent and -independent transport to the vacuole
VL - 5
ER -
TY - CONF
AB - We present a tool for translating LTL formulae into deterministic ω-automata. It is the first tool that covers the whole LTL that does not use Safra’s determinization or any of its variants. This leads to smaller automata. There are several outputs of the tool: firstly, deterministic Rabin automata, which are the standard input for probabilistic model checking, e.g. for the probabilistic model-checker PRISM; secondly, deterministic generalized Rabin automata, which can also be used for probabilistic model checking and are sometimes by orders of magnitude smaller. We also link our tool to PRISM and show that this leads to a significant speed-up of probabilistic LTL model checking, especially with the generalized Rabin automata.
AU - Komárková, Zuzana
AU - Kretinsky, Jan
ED - Cassez, Franck
ED - Raskin, Jean-François
ID - 2026
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Rabinizer 3: Safraless translation of ltl to small deterministic automata
VL - 8837
ER -
TY - CONF
AB - We present a general framework for applying machine-learning algorithms to the verification of Markov decision processes (MDPs). The primary goal of these techniques is to improve performance by avoiding an exhaustive exploration of the state space. Our framework focuses on probabilistic reachability, which is a core property for verification, and is illustrated through two distinct instantiations. The first assumes that full knowledge of the MDP is available, and performs a heuristic-driven partial exploration of the model, yielding precise lower and upper bounds on the required probability. The second tackles the case where we may only sample the MDP, and yields probabilistic guarantees, again in terms of both the lower and upper bounds, which provides efficient stopping criteria for the approximation. The latter is the first extension of statistical model checking for unbounded properties inMDPs. In contrast with other related techniques, our approach is not restricted to time-bounded (finite-horizon) or discounted properties, nor does it assume any particular properties of the MDP. We also show how our methods extend to LTL objectives. We present experimental results showing the performance of our framework on several examples.
AU - Brázdil, Tomáš
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Forejt, Vojtěch
AU - Kretinsky, Jan
AU - Kwiatkowska, Marta
AU - Parker, David
AU - Ujma, Mateusz
ED - Cassez, Franck
ED - Raskin, Jean-François
ID - 2027
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Verification of markov decision processes using learning algorithms
VL - 8837
ER -
TY - JOUR
AB - Understanding the dynamics of noisy neurons remains an important challenge in neuroscience. Here, we describe a simple probabilistic model that accurately describes the firing behavior in a large class (type II) of neurons. To demonstrate the usefulness of this model, we show how it accurately predicts the interspike interval (ISI) distributions, bursting patterns and mean firing rates found by: (1) simulations of the classic Hodgkin-Huxley model with channel noise, (2) experimental data from squid giant axon with a noisy input current and (3) experimental data on noisy firing from a neuron within the suprachiasmatic nucleus (SCN). This simple model has 6 parameters, however, in some cases, two of these parameters are coupled and only 5 parameters account for much of the known behavior. From these parameters, many properties of spiking can be found through simple calculation. Thus, we show how the complex effects of noise can be understood through a simple and general probabilistic model.
AU - Bodova, Katarina
AU - Paydarfar, David
AU - Forger, Daniel
ID - 2028
JF - Journal of Theoretical Biology
TI - Characterizing spiking in noisy type II neurons
VL - 365
ER -
TY - JOUR
AB - Spin-wave theory is a key ingredient in our comprehension of quantum spin systems, and is used successfully for understanding a wide range of magnetic phenomena, including magnon condensation and stability of patterns in dipolar systems. Nevertheless, several decades of research failed to establish the validity of spin-wave theory rigorously, even for the simplest models of quantum spins. A rigorous justification of the method for the three-dimensional quantum Heisenberg ferromagnet at low temperatures is presented here. We derive sharp bounds on its free energy by combining a bosonic formulation of the model introduced by Holstein and Primakoff with probabilistic estimates and operator inequalities.
AU - Correggi, Michele
AU - Giuliani, Alessandro
AU - Seiringer, Robert
ID - 2029
IS - 2
JF - EPL
TI - Validity of spin-wave theory for the quantum Heisenberg model
VL - 108
ER -
TY - JOUR
AB - A puzzling property of synaptic transmission, originally established at the neuromuscular junction, is that the time course of transmitter release is independent of the extracellular Ca2+ concentration ([Ca2+]o), whereas the rate of release is highly [Ca2+]o-dependent. Here, we examine the time course of release at inhibitory basket cell-Purkinje cell synapses and show that it is independent of [Ca2+]o. Modeling of Ca2+-dependent transmitter release suggests that the invariant time course of release critically depends on tight coupling between Ca2+ channels and release sensors. Experiments with exogenous Ca2+ chelators reveal that channel-sensor coupling at basket cell-Purkinje cell synapses is very tight, with a mean distance of 10–20 nm. Thus, tight channel-sensor coupling provides a mechanistic explanation for the apparent [Ca2+]o independence of the time course of release.
AU - Arai, Itaru
AU - Jonas, Peter M
ID - 2031
JF - eLife
TI - Nanodomain coupling explains Ca^2+ independence of transmitter release time course at a fast central synapse
VL - 3
ER -
TY - JOUR
AB - As light-based control of fundamental signaling pathways is becoming a reality, the field of optogenetics is rapidly moving beyond neuroscience. We have recently developed receptor tyrosine kinases that are activated by light and control cell proliferation, epithelial–mesenchymal transition, and angiogenic sprouting—cell behaviors central to cancer progression.
AU - Inglés Prieto, Álvaro
AU - Gschaider-Reichhart, Eva
AU - Schelch, Karin
AU - Janovjak, Harald L
AU - Grusch, Michael
ID - 2032
IS - 4
JF - Molecular and Cellular Oncology
TI - The optogenetic promise for oncology: Episode I
VL - 1
ER -
TY - CONF
AB - The learning with privileged information setting has recently attracted a lot of attention within the machine learning community, as it allows the integration of additional knowledge into the training process of a classifier, even when this comes in the form of a data modality that is not available at test time. Here, we show that privileged information can naturally be treated as noise in the latent function of a Gaussian process classifier (GPC). That is, in contrast to the standard GPC setting, the latent function is not just a nuisance but a feature: it becomes a natural measure of confidence about the training data by modulating the slope of the GPC probit likelihood function. Extensive experiments on public datasets show that the proposed GPC method using privileged noise, called GPC+, improves over a standard GPC without privileged knowledge, and also over the current state-of-the-art SVM-based method, SVM+. Moreover, we show that advanced neural networks and deep learning methods can be compressed as privileged information.
AU - Hernandez Lobato, Daniel
AU - Sharmanska, Viktoriia
AU - Kersting, Kristian
AU - Lampert, Christoph
AU - Quadrianto, Novi
ID - 2033
IS - January
T2 - Advances in Neural Information Processing Systems
TI - Mind the nuisance: Gaussian process classification using privileged noise
VL - 1
ER -
TY - JOUR
AB - In rapidly changing environments, selection history may impact the dynamics of adaptation. Mutations selected in one environment may result in pleiotropic fitness trade-offs in subsequent novel environments, slowing the rates of adaptation. Epistatic interactions between mutations selected in sequential stressful environments may slow or accelerate subsequent rates of adaptation, depending on the nature of that interaction. We explored the dynamics of adaptation during sequential exposure to herbicides with different modes of action in Chlamydomonas reinhardtii. Evolution of resistance to two of the herbicides was largely independent of selection history. For carbetamide, previous adaptation to other herbicide modes of action positively impacted the likelihood of adaptation to this herbicide. Furthermore, while adaptation to all individual herbicides was associated with pleiotropic fitness costs in stress-free environments, we observed that accumulation of resistance mechanisms was accompanied by a reduction in overall fitness costs. We suggest that antagonistic epistasis may be a driving mechanism that enables populations to more readily adapt in novel environments. These findings highlight the potential for sequences of xenobiotics to facilitate the rapid evolution of multiple-drug and -pesticide resistance, as well as the potential for epistatic interactions between adaptive mutations to facilitate evolutionary rescue in rapidly changing environments.
AU - Lagator, Mato
AU - Colegrave, Nick
AU - Neve, Paul
ID - 2036
IS - 1794
JF - Proceedings of the Royal Society of London Series B Biological Sciences
TI - Selection history and epistatic interactions impact dynamics of adaptation to novel environmental stresses
VL - 281
ER -
TY - JOUR
AB - Recently, there has been an effort to add quantitative objectives to formal verification and synthesis. We introduce and investigate the extension of temporal logics with quantitative atomic assertions. At the heart of quantitative objectives lies the accumulation of values along a computation. It is often the accumulated sum, as with energy objectives, or the accumulated average, as with mean-payoff objectives. We investigate the extension of temporal logics with the prefix-accumulation assertions Sum(v) ≥ c and Avg(v) ≥ c, where v is a numeric (or Boolean) variable of the system, c is a constant rational number, and Sum(v) and Avg(v) denote the accumulated sum and average of the values of v from the beginning of the computation up to the current point in time. We also allow the path-accumulation assertions LimInfAvg(v) ≥ c and LimSupAvg(v) ≥ c, referring to the average value along an entire infinite computation. We study the border of decidability for such quantitative extensions of various temporal logics. In particular, we show that extending the fragment of CTL that has only the EX, EF, AX, and AG temporal modalities with both prefix-accumulation assertions, or extending LTL with both path-accumulation assertions, results in temporal logics whose model-checking problem is decidable. Moreover, the prefix-accumulation assertions may be generalized with "controlled accumulation," allowing, for example, to specify constraints on the average waiting time between a request and a grant. On the negative side, we show that this branching-time logic is, in a sense, the maximal logic with one or both of the prefix-accumulation assertions that permits a decidable model-checking procedure. Extending a temporal logic that has the EG or EU modalities, such as CTL or LTL, makes the problem undecidable.
AU - Boker, Udi
AU - Chatterjee, Krishnendu
AU - Henzinger, Thomas A
AU - Kupferman, Orna
ID - 2038
IS - 4
JF - ACM Transactions on Computational Logic (TOCL)
TI - Temporal specifications with accumulative values
VL - 15
ER -
TY - JOUR
AB - A fundamental question in biology is the following: what is the time scale that is needed for evolutionary innovations? There are many results that characterize single steps in terms of the fixation time of new mutants arising in populations of certain size and structure. But here we ask a different question, which is concerned with the much longer time scale of evolutionary trajectories: how long does it take for a population exploring a fitness landscape to find target sequences that encode new biological functions? Our key variable is the length, (Formula presented.) of the genetic sequence that undergoes adaptation. In computer science there is a crucial distinction between problems that require algorithms which take polynomial or exponential time. The latter are considered to be intractable. Here we develop a theoretical approach that allows us to estimate the time of evolution as function of (Formula presented.) We show that adaptation on many fitness landscapes takes time that is exponential in (Formula presented.) even if there are broad selection gradients and many targets uniformly distributed in sequence space. These negative results lead us to search for specific mechanisms that allow evolution to work on polynomial time scales. We study a regeneration process and show that it enables evolution to work in polynomial time.
AU - Chatterjee, Krishnendu
AU - Pavlogiannis, Andreas
AU - Adlam, Ben
AU - Nowak, Martin
ID - 2039
IS - 9
JF - PLoS Computational Biology
TI - The time scale of evolutionary innovation
VL - 10
ER -
TY - JOUR
AB - Development requires tissue growth as well as cell diversification. To address how these processes are coordinated, we analyzed the development of molecularly distinct domains of neural progenitors in the mouse and chick neural tube. We show that during development, these domains undergo changes in size that do not scale with changes in overall tissue size. Our data show that domain proportions are first established by opposing morphogen gradients and subsequently controlled by domain-specific regulation of differentiation rate but not differences in proliferation rate. Regulation of differentiation rate is key to maintaining domain proportions while accommodating both intra- and interspecies variations in size. Thus, the sequential control of progenitor specification and differentiation elaborates pattern without requiring that signaling gradients grow as tissues expand.
AU - Kicheva, Anna
AU - Bollenbach, Mark Tobias
AU - Ribeiro, Ana
AU - Pérez Valle, Helena
AU - Lovell Badge, Robin
AU - Episkopou, Vasso
AU - Briscoe, James
ID - 2040
IS - 6204
JF - Science
TI - Coordination of progenitor specification and growth in mouse and chick spinal cord
VL - 345
ER -
TY - JOUR
AB - The hippocampus mediates several higher brain functions, such as learning, memory, and spatial coding. The input region of the hippocampus, the dentate gyrus, plays a critical role in these processes. Several lines of evidence suggest that the dentate gyrus acts as a preprocessor of incoming information, preparing it for subsequent processing in CA3. For example, the dentate gyrus converts input from the entorhinal cortex, where cells have multiple spatial fields, into the spatially more specific place cell activity characteristic of the CA3 region. Furthermore, the dentate gyrus is involved in pattern separation, transforming relatively similar input patterns into substantially different output patterns. Finally, the dentate gyrus produces a very sparse coding scheme in which only a very small fraction of neurons are active at any one time.
AU - Jonas, Peter M
AU - Lisman, John
ID - 2041
JF - Frontiers in Neural Circuits
TI - Structure, function and plasticity of hippocampal dentate gyrus microcircuits
VL - 8
ER -
TY - JOUR
AB - Background: CRISPR is a microbial immune system likely to be involved in host-parasite coevolution. It functions using target sequences encoded by the bacterial genome, which interfere with invading nucleic acids using a homology-dependent system. The system also requires protospacer associated motifs (PAMs), short motifs close to the target sequence that are required for interference in CRISPR types I and II. Here, we investigate whether PAMs are depleted in phage genomes due to selection pressure to escape recognition.Results: To this end, we analyzed two data sets. Phages infecting all bacterial hosts were analyzed first, followed by a detailed analysis of phages infecting the genus Streptococcus, where PAMs are best understood. We use two different measures of motif underrepresentation that control for codon bias and the frequency of submotifs. We compare phages infecting species with a particular CRISPR type to those infecting species without that type. Since only known PAMs were investigated, the analysis is restricted to CRISPR types I-C and I-E and in Streptococcus to types I-C and II. We found evidence for PAM depletion in Streptococcus phages infecting hosts with CRISPR type I-C, in Vibrio phages infecting hosts with CRISPR type I-E and in Streptococcus thermopilus phages infecting hosts with type II-A, known as CRISPR3.Conclusions: The observed motif depletion in phages with hosts having CRISPR can be attributed to selection rather than to mutational bias, as mutational bias should affect the phages of all hosts. This observation implies that the CRISPR system has been efficient in the groups discussed here.
AU - Kupczok, Anne
AU - Bollback, Jonathan P
ID - 2042
IS - 1
JF - BMC Genomics
TI - Motif depletion in bacteriophages infecting hosts with CRISPR systems
VL - 15
ER -
TY - CONF
AB - Persistent homology is a popular and powerful tool for capturing topological features of data. Advances in algorithms for computing persistent homology have reduced the computation time drastically – as long as the algorithm does not exhaust the available memory. Following up on a recently presented parallel method for persistence computation on shared memory systems [1], we demonstrate that a simple adaption of the standard reduction algorithm leads to a variant for distributed systems. Our algorithmic design ensures that the data is distributed over the nodes without redundancy; this permits the computation of much larger instances than on a single machine. Moreover, we observe that the parallelism at least compensates for the overhead caused by communication between nodes, and often even speeds up the computation compared to sequential and even parallel shared memory algorithms. In our experiments, we were able to compute the persistent homology of filtrations with more than a billion (109) elements within seconds on a cluster with 32 nodes using less than 6GB of memory per node.
AU - Bauer, Ulrich
AU - Kerber, Michael
AU - Reininghaus, Jan
ED - McGeoch, Catherine
ED - Meyer, Ulrich
ID - 2043
T2 - Proceedings of the Workshop on Algorithm Engineering and Experiments
TI - Distributed computation of persistent homology
ER -
TY - CHAP
AB - We present a parallel algorithm for computing the persistent homology of a filtered chain complex. Our approach differs from the commonly used reduction algorithm by first computing persistence pairs within local chunks, then simplifying the unpaired columns, and finally applying standard reduction on the simplified matrix. The approach generalizes a technique by Günther et al., which uses discrete Morse Theory to compute persistence; we derive the same worst-case complexity bound in a more general context. The algorithm employs several practical optimization techniques, which are of independent interest. Our sequential implementation of the algorithm is competitive with state-of-the-art methods, and we further improve the performance through parallel computation.
AU - Bauer, Ulrich
AU - Kerber, Michael
AU - Reininghaus, Jan
ED - Bremer, Peer-Timo
ED - Hotz, Ingrid
ED - Pascucci, Valerio
ED - Peikert, Ronald
ID - 2044
T2 - Topological Methods in Data Analysis and Visualization III
TI - Clear and Compress: Computing Persistent Homology in Chunks
ER -
TY - CONF
AB - We introduce and study a new notion of enhanced chosen-ciphertext security (ECCA) for public-key encryption. Loosely speaking, in the ECCA security experiment, the decryption oracle provided to the adversary is augmented to return not only the output of the decryption algorithm on a queried ciphertext but also of a randomness-recovery algorithm associated to the scheme. Our results mainly concern the case where the randomness-recovery algorithm is efficient. We provide constructions of ECCA-secure encryption from adaptive trapdoor functions as defined by Kiltz et al. (EUROCRYPT 2010), resulting in ECCA encryption from standard number-theoretic assumptions. We then give two applications of ECCA-secure encryption: (1) We use it as a unifying concept in showing equivalence of adaptive trapdoor functions and tag-based adaptive trapdoor functions, resolving an open question of Kiltz et al. (2) We show that ECCA-secure encryption can be used to securely realize an approach to public-key encryption with non-interactive opening (PKENO) originally suggested by Damgård and Thorbek (EUROCRYPT 2007), resulting in new and practical PKENO schemes quite different from those in prior work. Our results demonstrate that ECCA security is of both practical and theoretical interest.
AU - Dachman Soled, Dana
AU - Fuchsbauer, Georg
AU - Mohassel, Payman
AU - O’Neill, Adam
ED - Krawczyk, Hugo
ID - 2045
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Enhanced chosen-ciphertext security and applications
VL - 8383
ER -
TY - CONF
AB - We introduce policy-based signatures (PBS), where a signer can only sign messages conforming to some authority-specified policy. The main requirements are unforgeability and privacy, the latter meaning that signatures not reveal the policy. PBS offers value along two fronts: (1) On the practical side, they allow a corporation to control what messages its employees can sign under the corporate key. (2) On the theoretical side, they unify existing work, capturing other forms of signatures as special cases or allowing them to be easily built. Our work focuses on definitions of PBS, proofs that this challenging primitive is realizable for arbitrary policies, efficient constructions for specific policies, and a few representative applications.
AU - Bellare, Mihir
AU - Fuchsbauer, Georg
ED - Krawczyk, Hugo
ID - 2046
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Policy-based signatures
VL - 8383
ER -
TY - CONF
AB - Following the publication of an attack on genome-wide association studies (GWAS) data proposed by Homer et al., considerable attention has been given to developing methods for releasing GWAS data in a privacy-preserving way. Here, we develop an end-to-end differentially private method for solving regression problems with convex penalty functions and selecting the penalty parameters by cross-validation. In particular, we focus on penalized logistic regression with elastic-net regularization, a method widely used to in GWAS analyses to identify disease-causing genes. We show how a differentially private procedure for penalized logistic regression with elastic-net regularization can be applied to the analysis of GWAS data and evaluate our method’s performance.
AU - Yu, Fei
AU - Rybar, Michal
AU - Uhler, Caroline
AU - Fienberg, Stephen
ED - Domingo Ferrer, Josep
ID - 2047
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Differentially-private logistic regression for detecting multiple-SNP association in GWAS databases
VL - 8744
ER -
TY - JOUR
AB - The flow instability and further transition to turbulence in a toroidal pipe (torus) with curvature ratio (tube-to-coiling diameter) 0.049 is investigated experimentally. The flow inside the toroidal pipe is driven by a steel sphere fitted to the inner pipe diameter. The sphere is moved with constant azimuthal velocity from outside the torus by a moving magnet. The experiment is designed to investigate curved pipe flow by optical measurement techniques. Using stereoscopic particle image velocimetry, laser Doppler velocimetry and pressure drop measurements, the flow is measured for Reynolds numbers ranging from 1000 to 15 000. Time- and space-resolved velocity fields are obtained and analysed. The steady axisymmetric basic flow is strongly influenced by centrifugal effects. On an increase of the Reynolds number we find a sequence of bifurcations. For Re=4075±2% a supercritical bifurcation to an oscillatory flow is found in which waves travel in the streamwise direction with a phase velocity slightly faster than the mean flow. The oscillatory flow is superseded by a presumably quasi-periodic flow at a further increase of the Reynolds number before turbulence sets in. The results are found to be compatible, in general, with earlier experimental and numerical investigations on transition to turbulence in helical and curved pipes. However, important aspects of the bifurcation scenario differ considerably.
AU - Kühnen, Jakob
AU - Holzner, Markus
AU - Hof, Björn
AU - Kuhlmann, Hendrik
ID - 2050
JF - Journal of Fluid Mechanics
TI - Experimental investigation of transitional flow in a toroidal pipe
VL - 738
ER -
TY - CONF
AB - We show that the usual score function for conditional Markov networks can be written as the expectation over the scores of their spanning trees. We also show that a small random sample of these output trees can attain a significant fraction of the margin obtained by the complete graph and we provide conditions under which we can perform tractable inference. The experimental results confirm that practical learning is scalable to realistic datasets using this approach.
AU - Marchand, Mario
AU - Hongyu, Su
AU - Emilie Morvant
AU - Rousu, Juho
AU - Shawe-Taylor, John
ID - 2051
TI - Multilabel structured output learning with random spanning trees of max-margin Markov networks
ER -
TY - CONF
AB - A standard technique for solving the parameterized model checking problem is to reduce it to the classic model checking problem of finitely many finite-state systems. This work considers some of the theoretical power and limitations of this technique. We focus on concurrent systems in which processes communicate via pairwise rendezvous, as well as the special cases of disjunctive guards and token passing; specifications are expressed in indexed temporal logic without the next operator; and the underlying network topologies are generated by suitable Monadic Second Order Logic formulas and graph operations. First, we settle the exact computational complexity of the parameterized model checking problem for some of our concurrent systems, and establish new decidability results for others. Second, we consider the cases that model checking the parameterized system can be reduced to model checking some fixed number of processes, the number is known as a cutoff. We provide many cases for when such cutoffs can be computed, establish lower bounds on the size of such cutoffs, and identify cases where no cutoff exists. Third, we consider cases for which the parameterized system is equivalent to a single finite-state system (more precisely a Büchi word automaton), and establish tight bounds on the sizes of such automata.
AU - Aminof, Benjamin
AU - Kotek, Tomer
AU - Rubin, Sacha
AU - Spegni, Francesco
AU - Veith, Helmut
ED - Baldan, Paolo
ED - Gorla, Daniele
ID - 2052
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Parameterized model checking of rendezvous systems
VL - 8704
ER -
TY - CONF
AB - In contrast to the usual understanding of probabilistic systems as stochastic processes, recently these systems have also been regarded as transformers of probabilities. In this paper, we give a natural definition of strong bisimulation for probabilistic systems corresponding to this view that treats probability distributions as first-class citizens. Our definition applies in the same way to discrete systems as well as to systems with uncountable state and action spaces. Several examples demonstrate that our definition refines the understanding of behavioural equivalences of probabilistic systems. In particular, it solves a longstanding open problem concerning the representation of memoryless continuous time by memoryfull continuous time. Finally, we give algorithms for computing this bisimulation not only for finite but also for classes of uncountably infinite systems.
AU - Hermanns, Holger
AU - Krčál, Jan
AU - Kretinsky, Jan
ED - Baldan, Paolo
ED - Gorla, Daniele
ID - 2053
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Probabilistic bisimulation: Naturally on distributions
VL - 8704
ER -
TY - CONF
AB - We study two-player concurrent games on finite-state graphs played for an infinite number of rounds, where in each round, the two players (player 1 and player 2) choose their moves independently and simultaneously; the current state and the two moves determine the successor state. The objectives are ω-regular winning conditions specified as parity objectives. We consider the qualitative analysis problems: the computation of the almost-sure and limit-sure winning set of states, where player 1 can ensure to win with probability 1 and with probability arbitrarily close to 1, respectively. In general the almost-sure and limit-sure winning strategies require both infinite-memory as well as infinite-precision (to describe probabilities). While the qualitative analysis problem for concurrent parity games with infinite-memory, infinite-precision randomized strategies was studied before, we study the bounded-rationality problem for qualitative analysis of concurrent parity games, where the strategy set for player 1 is restricted to bounded-resource strategies. In terms of precision, strategies can be deterministic, uniform, finite-precision, or infinite-precision; and in terms of memory, strategies can be memoryless, finite-memory, or infinite-memory. We present a precise and complete characterization of the qualitative winning sets for all combinations of classes of strategies. In particular, we show that uniform memoryless strategies are as powerful as finite-precision infinite-memory strategies, and infinite-precision memoryless strategies are as powerful as infinite-precision finite-memory strategies. We show that the winning sets can be computed in (n2d+3) time, where n is the size of the game structure and 2d is the number of priorities (or colors), and our algorithms are symbolic. The membership problem of whether a state belongs to a winning set can be decided in NP ∩ coNP. Our symbolic algorithms are based on a characterization of the winning sets as μ-calculus formulas, however, our μ-calculus formulas are crucially different from the ones for concurrent parity games (without bounded rationality); and our memoryless witness strategy constructions are significantly different from the infinite-memory witness strategy constructions for concurrent parity games.
AU - Chatterjee, Krishnendu
ED - Baldan, Paolo
ED - Gorla, Daniele
ID - 2054
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Qualitative concurrent parity games: Bounded rationality
VL - 8704
ER -
TY - JOUR
AB - We consider a continuous-time Markov chain (CTMC) whose state space is partitioned into aggregates, and each aggregate is assigned a probability measure. A sufficient condition for defining a CTMC over the aggregates is presented as a variant of weak lumpability, which also characterizes that the measure over the original process can be recovered from that of the aggregated one. We show how the applicability of de-aggregation depends on the initial distribution. The application section is devoted to illustrate how the developed theory aids in reducing CTMC models of biochemical systems particularly in connection to protein-protein interactions. We assume that the model is written by a biologist in form of site-graph-rewrite rules. Site-graph-rewrite rules compactly express that, often, only a local context of a protein (instead of a full molecular species) needs to be in a certain configuration in order to trigger a reaction event. This observation leads to suitable aggregate Markov chains with smaller state spaces, thereby providing sufficient reduction in computational complexity. This is further exemplified in two case studies: simple unbounded polymerization and early EGFR/insulin crosstalk.
AU - Ganguly, Arnab
AU - Petrov, Tatjana
AU - Koeppl, Heinz
ID - 2056
IS - 3
JF - Journal of Mathematical Biology
TI - Markov chain aggregation and its applications to combinatorial reaction networks
VL - 69
ER -
TY - CONF
AB - In the past few years, a lot of attention has been devoted to multimedia indexing by fusing multimodal informations. Two kinds of fusion schemes are generally considered: The early fusion and the late fusion. We focus on late classifier fusion, where one combines the scores of each modality at the decision level. To tackle this problem, we investigate a recent and elegant well-founded quadratic program named MinCq coming from the machine learning PAC-Bayesian theory. MinCq looks for the weighted combination, over a set of real-valued functions seen as voters, leading to the lowest misclassification rate, while maximizing the voters’ diversity. We propose an extension of MinCq tailored to multimedia indexing. Our method is based on an order-preserving pairwise loss adapted to ranking that allows us to improve Mean Averaged Precision measure while taking into account the diversity of the voters that we want to fuse. We provide evidence that this method is naturally adapted to late fusion procedures and confirm the good behavior of our approach on the challenging PASCAL VOC’07 benchmark.
AU - Morvant, Emilie
AU - Habrard, Amaury
AU - Ayache, Stéphane
ID - 2057
T2 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
TI - Majority vote of diverse classifiers for late fusion
VL - 8621
ER -
TY - CONF
AB - We present a method for smoothly blending between existing liquid animations. We introduce a semi-automatic method for matching two existing liquid animations, which we use to create new fluid motion that plausibly interpolates the input. Our contributions include a new space-time non-rigid iterative closest point algorithm that incorporates user guidance, a subsampling technique for efficient registration of meshes with millions of vertices, and a fast surface extraction algorithm that produces 3D triangle meshes from a 4D space-time surface. Our technique can be used to instantly create hundreds of new simulations, or to interactively explore complex parameter spaces. Our method is guaranteed to produce output that does not deviate from the input animations, and it generalizes to multiple dimensions. Because our method runs at interactive rates after the initial precomputation step, it has potential applications in games and training simulations.
AU - Raveendran, Karthik
AU - Wojtan, Christopher J
AU - Thuerey, Nils
AU - Türk, Greg
ID - 2058
IS - 4
T2 - ACM Transactions on Graphics
TI - Blending liquids
VL - 33
ER -
TY - JOUR
AB - Plant embryogenesis is regulated by differential distribution of the plant hormone auxin. However, the cells establishing these gradients during microspore embryogenesis remain to be identified. For the first time, we describe, using the DR5 or DR5rev reporter gene systems, the GFP- and GUS-based auxin biosensors to monitor auxin during Brassica napus androgenesis at cellular resolution in the initial stages. Our study provides evidence that the distribution of auxin changes during embryo development and depends on the temperature-inducible in vitro culture conditions. For this, microspores (mcs) were induced to embryogenesis by heat treatment and then subjected to genetic modification via Agrobacterium tumefaciens. The duration of high temperature treatment had a significant influence on auxin distribution in isolated and in vitro-cultured microspores and on microspore-derived embryo development. In the “mild” heat-treated (1 day at 32 °C) mcs, auxin localized in a polar way already at the uni-nucleate microspore, which was critical for the initiation of embryos with suspensor-like structure. Assuming a mean mcs radius of 20 μm, endogenous auxin content in a single cell corresponded to concentration of 1.01 μM. In mcs subjected to a prolonged heat (5 days at 32 °C), although auxin concentration increased dozen times, auxin polarization was set up at a few-celled pro-embryos without suspensor. Those embryos were enclosed in the outer wall called the exine. The exine rupture was accompanied by the auxin gradient polarization. Relative quantitative estimation of auxin, using time-lapse imaging, revealed that primordia possess up to 1.3-fold higher amounts than those found in the root apices of transgenic MDEs in the presence of exogenous auxin. Our results show, for the first time, which concentration of endogenous auxin coincides with the first cell division and how the high temperature interplays with auxin, by what affects delay early establishing microspore polarity. Moreover, we present how the local auxin accumulation demonstrates the apical–basal axis formation of the androgenic embryo and directs the axiality of the adult haploid plant.
AU - Dubas, Ewa
AU - Moravčíková, Jana
AU - Libantová, Jana
AU - Matušíková, Ildikó
AU - Benková, Eva
AU - Zur, Iwona
AU - Krzewska, Monika
ID - 2059
IS - 5
JF - Protoplasma
TI - The influence of heat stress on auxin distribution in transgenic B napus microspores and microspore derived embryos
VL - 251
ER -
TY - JOUR
AB - Development of cambium and its activity is important for our knowledge of the mechanism of secondary growth. Arabidopsis thaliana emerges as a good model plant for such a kind of study. Thus, this paper reports on cellular events taking place in the interfascicular regions of inflorescence stems of A. thaliana, leading to the development of interfascicular cambium from differentiated interfascicular parenchyma cells (IPC). These events are as follows: appearance of auxin accumulation, PIN1 gene expression, polar PIN1 protein localization in the basal plasma membrane and periclinal divisions. Distribution of auxin was observed to be higher in differentiating into cambium parenchyma cells compared to cells within the pith and cortex. Expression of PIN1 in IPC was always preceded by auxin accumulation. Basal localization of PIN1 was already established in the cells prior to their periclinal division. These cellular events initiated within parenchyma cells adjacent to the vascular bundles and successively extended from that point towards the middle region of the interfascicular area, located between neighboring vascular bundles. The final consequence of which was the closure of the cambial ring within the stem. Changes in the chemical composition of IPC walls were also detected and included changes of pectic epitopes, xyloglucans (XG) and extensins rich in hydroxyproline (HRGPs). In summary, results presented in this paper describe interfascicular cambium ontogenesis in terms of successive cellular events in the interfascicular regions of inflorescence stems of Arabidopsis.
AU - Mazur, Ewa
AU - Kurczyñska, Ewa
AU - Friml, Jiří
ID - 2061
IS - 5
JF - Protoplasma
TI - Cellular events during interfascicular cambium ontogenesis in inflorescence stems of Arabidopsis
VL - 251
ER -
TY - JOUR
AB - The success story of fast-spiking, parvalbumin-positive (PV+) GABAergic interneurons (GABA, γ-aminobutyric acid) in the mammalian central nervous system is noteworthy. In 1995, the properties of these interneurons were completely unknown. Twenty years later, thanks to the massive use of subcellular patch-clamp techniques, simultaneous multiple-cell recording, optogenetics, in vivo measurements, and computational approaches, our knowledge about PV+ interneurons became more extensive than for several types of pyramidal neurons. These findings have implications beyond the “small world” of basic research on GABAergic cells. For example, the results provide a first proof of principle that neuroscientists might be able to close the gaps between the molecular, cellular, network, and behavioral levels, representing one of the main challenges at the present time. Furthermore, the results may form the basis for PV+ interneurons as therapeutic targets for brain disease in the future. However, much needs to be learned about the basic function of these interneurons before clinical neuroscientists will be able to use PV+ interneurons for therapeutic purposes.
AU - Hu, Hua
AU - Gan, Jian
AU - Jonas, Peter M
ID - 2062
IS - 6196
JF - Science
TI - Fast-spiking parvalbumin^+ GABAergic interneurons: From cellular design to microcircuit function
VL - 345
ER -
TY - CONF
AB - We consider Markov decision processes (MDPs) which are a standard model for probabilistic systems.We focus on qualitative properties forMDPs that can express that desired behaviors of the system arise almost-surely (with probability 1) or with positive probability. We introduce a new simulation relation to capture the refinement relation ofMDPs with respect to qualitative properties, and present discrete graph theoretic algorithms with quadratic complexity to compute the simulation relation.We present an automated technique for assume-guarantee style reasoning for compositional analysis ofMDPs with qualitative properties by giving a counterexample guided abstraction-refinement approach to compute our new simulation relation. We have implemented our algorithms and show that the compositional analysis leads to significant improvements.
AU - Chatterjee, Krishnendu
AU - Chmelik, Martin
AU - Daca, Przemyslaw
ID - 2063
TI - CEGAR for qualitative analysis of probabilistic systems
VL - 8559
ER -
TY - JOUR
AB - We examined the synaptic structure, quantity, and distribution of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-type glutamate receptors (AMPARs and NMDARs, respectively) in rat cochlear nuclei by a highly sensitive freeze-fracture replica labeling technique. Four excitatory synapses formed by two distinct inputs, auditory nerve (AN) and parallel fibers (PF), on different cell types were analyzed. These excitatory synapse types included AN synapses on bushy cells (AN-BC synapses) and fusiform cells (AN-FC synapses) and PF synapses on FC (PF-FC synapses) and cartwheel cell spines (PF-CwC synapses). Immunogold labeling revealed differences in synaptic structure as well as AMPAR and NMDAR number and/or density in both AN and PF synapses, indicating a target-dependent organization. The immunogold receptor labeling also identified differences in the synaptic organization of FCs based on AN or PF connections, indicating an input-dependent organization in FCs. Among the four excitatory synapse types, the AN-BC synapses were the smallest and had the most densely packed intramembrane particles (IMPs), whereas the PF-CwC synapses were the largest and had sparsely packed IMPs. All four synapse types showed positive correlations between the IMP-cluster area and the AMPAR number, indicating a common intrasynapse-type relationship for glutamatergic synapses. Immunogold particles for AMPARs were distributed over the entire area of individual AN synapses; PF synapses often showed synaptic areas devoid of labeling. The gold-labeling for NMDARs occurred in a mosaic fashion, with less positive correlations between the IMP-cluster area and the NMDAR number. Our observations reveal target- and input-dependent features in the structure, number, and organization of AMPARs and NMDARs in AN and PF synapses.
AU - Rubio, Maía
AU - Fukazawa, Yugo
AU - Kamasawa, Naomi
AU - Clarkson, Cheryl
AU - Molnár, Elek
AU - Shigemoto, Ryuichi
ID - 2064
IS - 18
JF - Journal of Comparative Neurology
TI - Target- and input-dependent organization of AMPA and NMDA receptors in synaptic connections of the cochlear nucleus
VL - 522
ER -
TY - CONF
AB - Spinning tops and yo-yos have long fascinated cultures around the world with their unexpected, graceful motions that seemingly elude gravity. We present an algorithm to generate designs for spinning objects by optimizing rotational dynamics properties. As input, the user provides a solid 3D model and a desired axis of rotation. Our approach then modifies the mass distribution such that the principal directions of the moment of inertia align with the target rotation frame. We augment the model by creating voids inside its volume, with interior fill represented by an adaptive multi-resolution vox-elization. The discrete voxel fill values are optimized using a continuous, nonlinear formulation. Further, we optimize for rotational stability by maximizing the dominant principal moment. We extend our technique to incorporate deformation and multiple materials for cases where internal voids alone are insufficient. Our method is well-suited for a variety of 3D printed models, ranging from characters to abstract shapes. We demonstrate tops and yo-yos that spin surprisingly stably despite their asymmetric appearance.
AU - Bac̈her, Moritz
AU - Whiting, Emily
AU - Bernd Bickel
AU - Sorkine-Hornung, Olga
ID - 2080
IS - 4
TI - Spin-It: Optimizing moment of inertia for spinnable objects
VL - 33
ER -
TY - CONF
AB - We propose an interactive, optimization-in-the-loop tool for designing inflatable structures. Given a target shape, the user draws a network of seams defining desired segment boundaries in 3D. Our method computes optimally-shaped flat panels for the segments, such that the inflated structure is as close as possible to the target while satisfying the desired seam positions. Our approach is underpinned by physics-based pattern optimization, accurate coarse-scale simulation using tension field theory, and a specialized constraint-optimization method. Our system is fast enough to warrant interactive exploration of different seam layouts, including internal connections, and their effects on the inflated shape. We demonstrate the resulting design process on a varied set of simulation examples, some of which we have fabricated, demonstrating excellent agreement with the design intent.
AU - Skouras, Mélina
AU - Thomaszewski, Bernhard
AU - Kaufmann, Peter
AU - Garg, Akash
AU - Bickel, Bernd
AU - Grinspun, Eitan
AU - Gross, Markus
ID - 2081
IS - 4
TI - Designing inflatable structures
VL - 33
ER -
TY - CONF
AB - NMAC is a mode of operation which turns a fixed input-length keyed hash function f into a variable input-length function. A practical single-key variant of NMAC called HMAC is a very popular and widely deployed message authentication code (MAC). Security proofs and attacks for NMAC can typically be lifted to HMAC. NMAC was introduced by Bellare, Canetti and Krawczyk [Crypto'96], who proved it to be a secure pseudorandom function (PRF), and thus also a MAC, assuming that (1) f is a PRF and (2) the function we get when cascading f is weakly collision-resistant. Unfortunately, HMAC is typically instantiated with cryptographic hash functions like MD5 or SHA-1 for which (2) has been found to be wrong. To restore the provable guarantees for NMAC, Bellare [Crypto'06] showed its security based solely on the assumption that f is a PRF, albeit via a non-uniform reduction. - Our first contribution is a simpler and uniform proof for this fact: If f is an ε-secure PRF (against q queries) and a δ-non-adaptively secure PRF (against q queries), then NMAC f is an (ε+ℓqδ)-secure PRF against q queries of length at most ℓ blocks each. - We then show that this ε+ℓqδ bound is basically tight. For the most interesting case where ℓqδ ≥ ε we prove this by constructing an f for which an attack with advantage ℓqδ exists. This also violates the bound O(ℓε) on the PRF-security of NMAC recently claimed by Koblitz and Menezes. - Finally, we analyze the PRF-security of a modification of NMAC called NI [An and Bellare, Crypto'99] that differs mainly by using a compression function with an additional keying input. This avoids the constant rekeying on multi-block messages in NMAC and allows for a security proof starting by the standard switch from a PRF to a random function, followed by an information-theoretic analysis. We carry out such an analysis, obtaining a tight ℓq2/2 c bound for this step, improving over the trivial bound of ℓ2q2/2c. The proof borrows combinatorial techniques originally developed for proving the security of CBC-MAC [Bellare et al., Crypto'05].
AU - Gazi, Peter
AU - Pietrzak, Krzysztof Z
AU - Rybar, Michal
ED - Garay, Juan
ED - Gennaro, Rosario
ID - 2082
IS - 1
TI - The exact PRF-security of NMAC and HMAC
VL - 8616
ER -
TY - JOUR
AB - Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment.
AU - Lagator, Mato
AU - Morgan, Andrew
AU - Neve, Paul
AU - Colegrave, Nick
ID - 2083
IS - 8
JF - Evolution
TI - Role of sex and migration in adaptation to sink environments
VL - 68
ER -
TY - JOUR
AB - Receptor tyrosine kinases (RTKs) are a large family of cell surface receptors that sense growth factors and hormones and regulate a variety of cell behaviours in health and disease. Contactless activation of RTKs with spatial and temporal precision is currently not feasible. Here, we generated RTKs that are insensitive to endogenous ligands but can be selectively activated by low-intensity blue light. We screened light-oxygen-voltage (LOV)-sensing domains for their ability to activate RTKs by light-activated dimerization. Incorporation of LOV domains found in aureochrome photoreceptors of stramenopiles resulted in robust activation of the fibroblast growth factor receptor 1 (FGFR1), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET). In human cancer and endothelial cells, light induced cellular signalling with spatial and temporal precision. Furthermore, light faithfully mimicked complex mitogenic and morphogenic cell behaviour induced by growth factors. RTKs under optical control (Opto-RTKs) provide a powerful optogenetic approach to actuate cellular signals and manipulate cell behaviour.
AU - Grusch, Michael
AU - Schelch, Karin
AU - Riedler, Robert
AU - Gschaider-Reichhart, Eva
AU - Differ, Christopher
AU - Berger, Walter
AU - Inglés Prieto, Álvaro
AU - Janovjak, Harald L
ID - 2084
IS - 15
JF - EMBO Journal
TI - Spatio-temporally precise activation of engineered receptor tyrosine kinases by light
VL - 33
ER -
TY - JOUR
AB - Pathogens may gain a fitness advantage through manipulation of the behaviour of their hosts. Likewise, host behavioural changes can be a defence mechanism, counteracting the impact of pathogens on host fitness. We apply harmonic radar technology to characterize the impact of an emerging pathogen - Nosema ceranae (Microsporidia) - on honeybee (Apis mellifera) flight and orientation performance in the field. Honeybees are the most important commercial pollinators. Emerging diseases have been proposed to play a prominent role in colony decline, partly through sub-lethal behavioural manipulation of their hosts. We found that homing success was significantly reduced in diseased (65.8%) versus healthy foragers (92.5%). Although lost bees had significantly reduced continuous flight times and prolonged resting times, other flight characteristics and navigational abilities showed no significant difference between infected and non-infected bees. Our results suggest that infected bees express normal flight characteristics but are constrained in their homing ability, potentially compromising the colony by reducing its resource inputs, but also counteracting the intra-colony spread of infection. We provide the first high-resolution analysis of sub-lethal effects of an emerging disease on insect flight behaviour. The potential causes and the implications for both host and parasite are discussed.
AU - Wolf, Stephan
AU - Mcmahon, Dino
AU - Lim, Ka
AU - Pull, Christopher
AU - Clark, Suzanne
AU - Paxton, Robert
AU - Osborne, Juliet
ID - 2086
IS - 8
JF - PLoS One
TI - So near and yet so far: Harmonic radar reveals reduced homing ability of Nosema infected honeybees
VL - 9
ER -
TY - JOUR
AB - The facial performance of an individual is inherently rich in subtle deformation and timing details. Although these subtleties make the performance realistic and compelling, they often elude both motion capture and hand animation. We present a technique for adding fine-scale details and expressiveness to low-resolution art-directed facial performances, such as those created manually using a rig, via marker-based capture, by fitting a morphable model to a video, or through Kinect reconstruction using recent faceshift technology. We employ a high-resolution facial performance capture system to acquire a representative performance of an individual in which he or she explores the full range of facial expressiveness. From the captured data, our system extracts an expressiveness model that encodes subtle spatial and temporal deformation details specific to that particular individual. Once this model has been built, these details can be transferred to low-resolution art-directed performances. We demonstrate results on various forms of input; after our enhancement, the resulting animations exhibit the same nuances and fine spatial details as the captured performance, with optional temporal enhancement to match the dynamics of the actor. Finally, we show that our technique outperforms the current state-of-the-art in example-based facial animation.
AU - Bermano, Amit H
AU - Bradley, Derek J
AU - Beeler, Thabo
AU - Zund, Fabio
AU - Nowrouzezahrai, Derek
AU - Baran, Ilya
AU - Sorkine-Hornung, Olga
AU - Pfister, Hanspeter
AU - Sumner, Robert W
AU - Bernd Bickel
AU - Groß, Markus S
ID - 2115
IS - 2
JF - ACM Transactions on Graphics
TI - Facial performance enhancement using dynamic shape space analysis
VL - 33
ER -
TY - JOUR
AB - We study approximations to a class of vector-valued equations of Burgers type driven by a multiplicative space-time white noise. A solution theory for this class of equations has been developed recently in Probability Theory Related Fields by Hairer and Weber. The key idea was to use the theory of controlled rough paths to give definitions of weak/mild solutions and to set up a Picard iteration argument. In this article the limiting behavior of a rather large class of (spatial) approximations to these equations is studied. These approximations are shown to converge and convergence rates are given, but the limit may depend on the particular choice of approximation. This effect is a spatial analogue to the Itô-Stratonovich correction in the theory of stochastic ordinary differential equations, where it is well known that different approximation schemes may converge to different solutions.
AU - Hairer, Martin M
AU - Jan Maas
AU - Weber, Hendrik
ID - 2131
IS - 5
JF - Communications on Pure and Applied Mathematics
TI - Approximating Rough Stochastic PDEs
VL - 67
ER -
TY - JOUR
AB - We consider discrete porous medium equations of the form ∂tρt=Δϕ(ρt), where Δ is the generator of a reversible continuous time Markov chain on a finite set χ, and ϕ is an increasing function. We show that these equations arise as gradient flows of certain entropy functionals with respect to suitable non-local transportation metrics. This may be seen as a discrete analogue of the Wasserstein gradient flow structure for porous medium equations in ℝn discovered by Otto. We present a one-dimensional counterexample to geodesic convexity and discuss Gromov-Hausdorff convergence to the Wasserstein metric.
AU - Erbar, Matthias
AU - Jan Maas
ID - 2132
IS - 4
JF - Discrete and Continuous Dynamical Systems- Series A
TI - Gradient flow structures for discrete porous medium equations
VL - 34
ER -
TY - JOUR
AB - Let ℭ denote the Clifford algebra over ℝ𝑛, which is the von Neumann algebra generated by n self-adjoint operators Q j , j = 1,…,n satisfying the canonical anticommutation relations, Q i Q j + Q j Q i = 2δ ij I, and let τ denote the normalized trace on ℭ. This algebra arises in quantum mechanics as the algebra of observables generated by n fermionic degrees of freedom. Let 𝔓 denote the set of all positive operators 𝜌∈ℭ such that τ(ρ) = 1; these are the non-commutative analogs of probability densities in the non-commutative probability space (ℭ,𝜏). The fermionic Fokker–Planck equation is a quantum-mechanical analog of the classical Fokker–Planck equation with which it has much in common, such as the same optimal hypercontractivity properties. In this paper we construct a Riemannian metric on 𝔓 that we show to be a natural analog of the classical 2-Wasserstein metric, and we show that, in analogy with the classical case, the fermionic Fokker–Planck equation is gradient flow in this metric for the relative entropy with respect to the ground state. We derive a number of consequences of this, such as a sharp Talagrand inequality for this metric, and we prove a number of results pertaining to this metric. Several open problems are raised.
AU - Carlen, Eric
AU - Maas, Jan
ID - 2133
IS - 3
JF - Communications in Mathematical Physics
TI - An analog of the 2-Wasserstein metric in non-commutative probability under which the fermionic Fokker-Planck equation is gradient flow for the entropy
VL - 331
ER -
TY - JOUR
AB - We propose a technique for engineering momentum-dependent dissipation in Bose-Einstein condensates with non-local interactions. The scheme relies on the use of momentum-dependent dark-states in close analogy to velocity-selective coherent population trapping. During the short-time dissipative dynamics, the system is driven into a particular finite-momentum phonon mode, which in real space corresponds to an ordered structure with non-local density-density correlations. Dissipation-induced ordering can be observed and studied in present-day experiments using cold atoms with dipole-dipole or off-resonant Rydberg interactions. Due to its dissipative nature, the ordering does not require artificial breaking of translational symmetry by an opticallattice or harmonic trap. This opens up a perspective of direct cooling of quantum gases into strongly-interacting phases.
AU - Otterbach, Johannes
AU - Lemeshko, Mikhail
ID - 2140
IS - 7
JF - Physical Review Letters
TI - Dissipative preparation of spatial order in Rydberg-dressed Bose-Einstein condensates
VL - 113
ER -
TY - JOUR
AB - The computation of the winning set for Büchi objectives in alternating games on graphs is a central problem in computer-aided verification with a large number of applications. The long-standing best known upper bound for solving the problem is Õ(n ⋅ m), where n is the number of vertices and m is the number of edges in the graph. We are the first to break the Õ(n ⋅ m) boundary by presenting a new technique that reduces the running time to O(n2). This bound also leads to O(n2)-time algorithms for computing the set of almost-sure winning vertices for Büchi objectives (1) in alternating games with probabilistic transitions (improving an earlier bound of Õ(n ⋅ m)), (2) in concurrent graph games with constant actions (improving an earlier bound of O(n3)), and (3) in Markov decision processes (improving for m>n4/3 an earlier bound of O(m ⋅ √m)). We then show how to maintain the winning set for Büchi objectives in alternating games under a sequence of edge insertions or a sequence of edge deletions in O(n) amortized time per operation. Our algorithms are the first dynamic algorithms for this problem. We then consider another core graph theoretic problem in verification of probabilistic systems, namely computing the maximal end-component decomposition of a graph. We present two improved static algorithms for the maximal end-component decomposition problem. Our first algorithm is an O(m ⋅ √m)-time algorithm, and our second algorithm is an O(n2)-time algorithm which is obtained using the same technique as for alternating Büchi games. Thus, we obtain an O(min &lcu;m ⋅ √m,n2})-time algorithm improving the long-standing O(n ⋅ m) time bound. Finally, we show how to maintain the maximal end-component decomposition of a graph under a sequence of edge insertions or a sequence of edge deletions in O(n) amortized time per edge deletion, and O(m) worst-case time per edge insertion. Again, our algorithms are the first dynamic algorithms for this problem.
AU - Chatterjee, Krishnendu
AU - Henzinger, Monika
ID - 2141
IS - 3
JF - Journal of the ACM
TI - Efficient and dynamic algorithms for alternating Büchi games and maximal end-component decomposition
VL - 61
ER -
TY - CONF
AB - We define a simple, explicit map sending a morphism f : M → N of pointwise finite dimensional persistence modules to a matching between the barcodes of M and N. Our main result is that, in a precise sense, the quality of this matching is tightly controlled by the lengths of the longest intervals in the barcodes of ker f and coker f . As an immediate corollary, we obtain a new proof of the algebraic stability theorem for persistence barcodes [5, 9], a fundamental result in the theory of persistent homology. In contrast to previous proofs, ours shows explicitly how a δ-interleaving morphism between two persistence modules induces a δ-matching between the barcodes of the two modules. Our main result also specializes to a structure theorem for submodules and quotients of persistence modules. Copyright is held by the owner/author(s).
AU - Bauer, Ulrich
AU - Lesnick, Michael
ID - 2153
T2 - Proceedings of the Annual Symposium on Computational Geometry
TI - Induced matchings of barcodes and the algebraic stability of persistence
ER -
TY - JOUR
AB - A result of Boros and Füredi (d = 2) and of Bárány (arbitrary d) asserts that for every d there exists cd > 0 such that for every n-point set P ⊂ ℝd, some point of ℝd is covered by at least (Formula presented.) of the d-simplices spanned by the points of P. The largest possible value of cd has been the subject of ongoing research. Recently Gromov improved the existing lower bounds considerably by introducing a new, topological proof method. We provide an exposition of the combinatorial component of Gromov's approach, in terms accessible to combinatorialists and discrete geometers, and we investigate the limits of his method. In particular, we give tighter bounds on the cofilling profiles for the (n - 1)-simplex. These bounds yield a minor improvement over Gromov's lower bounds on cd for large d, but they also show that the room for further improvement through the cofilling profiles alone is quite small. We also prove a slightly better lower bound for c3 by an approach using an additional structure besides the cofilling profiles. We formulate a combinatorial extremal problem whose solution might perhaps lead to a tight lower bound for cd.
AU - Matoušek, Jiří
AU - Wagner, Uli
ID - 2154
IS - 1
JF - Discrete & Computational Geometry
TI - On Gromov's method of selecting heavily covered points
VL - 52
ER -
TY - CONF
AB - Given a finite set of points in Rn and a positive radius, we study the Čech, Delaunay-Čech, alpha, and wrap complexes as instances of a generalized discrete Morse theory. We prove that the latter three complexes are simple-homotopy equivalent. Our results have applications in topological data analysis and in the reconstruction of shapes from sampled data. Copyright is held by the owner/author(s).
AU - Bauer, Ulrich
AU - Edelsbrunner, Herbert
ID - 2155
T2 - Proceedings of the Annual Symposium on Computational Geometry
TI - The morse theory of Čech and Delaunay filtrations
ER -
TY - CONF
AB - We propose a metric for Reeb graphs, called the functional distortion distance. Under this distance, the Reeb graph is stable against small changes of input functions. At the same time, it remains discriminative at differentiating input functions. In particular, the main result is that the functional distortion distance between two Reeb graphs is bounded from below by the bottleneck distance between both the ordinary and extended persistence diagrams for appropriate dimensions. As an application of our results, we analyze a natural simplification scheme for Reeb graphs, and show that persistent features in Reeb graph remains persistent under simplification. Understanding the stability of important features of the Reeb graph under simplification is an interesting problem on its own right, and critical to the practical usage of Reeb graphs. Copyright is held by the owner/author(s).
AU - Bauer, Ulrich
AU - Ge, Xiaoyin
AU - Wang, Yusu
ID - 2156
T2 - Proceedings of the Annual Symposium on Computational Geometry
TI - Measuring distance between Reeb graphs
ER -
TY - CONF
AB - We show that the following algorithmic problem is decidable: given a 2-dimensional simplicial complex, can it be embedded (topologically, or equivalently, piecewise linearly) in ℝ3? By a known reduction, it suffices to decide the embeddability of a given triangulated 3-manifold X into the 3-sphere S3. The main step, which allows us to simplify X and recurse, is in proving that if X can be embedded in S3, then there is also an embedding in which X has a short meridian, i.e., an essential curve in the boundary of X bounding a disk in S3 nX with length bounded by a computable function of the number of tetrahedra of X.
AU - Matoušek, Jiří
AU - Sedgwick, Eric
AU - Tancer, Martin
AU - Wagner, Uli
ID - 2157
T2 - Proceedings of the Annual Symposium on Computational Geometry
TI - Embeddability in the 3 sphere is decidable
ER -
TY - JOUR
AB - Directional guidance of migrating cells is relatively well explored in the reductionist setting of cell culture experiments. Here spatial gradients of chemical cues as well as gradients of mechanical substrate characteristics prove sufficient to attract single cells as well as their collectives. How such gradients present and act in the context of an organism is far less clear. Here we review recent advances in understanding how guidance cues emerge and operate in the physiological context.
AU - Majumdar, Ritankar
AU - Sixt, Michael K
AU - Parent, Carole
ID - 2158
IS - 1
JF - Current Opinion in Cell Biology
TI - New paradigms in the establishment and maintenance of gradients during directed cell migration
VL - 30
ER -
TY - CONF
AB - Transfer learning has received a lot of attention in the machine learning community over the last years, and several effective algorithms have been developed. However, relatively little is known about their theoretical properties, especially in the setting of lifelong learning, where the goal is to transfer information to tasks for which no data have been observed so far. In this work we study lifelong learning from a theoretical perspective. Our main result is a PAC-Bayesian generalization bound that offers a unified view on existing paradigms for transfer learning, such as the transfer of parameters or the transfer of low-dimensional representations. We also use the bound to derive two principled lifelong learning algorithms, and we show that these yield results comparable with existing methods.
AU - Pentina, Anastasia
AU - Lampert, Christoph
ED - Xing, Eric
ED - Jebara, Tony
ID - 2160
TI - A PAC-Bayesian bound for Lifelong Learning
VL - 32
ER -
TY - JOUR
AB - Repeated pathogen exposure is a common threat in colonies of social insects, posing selection pressures on colony members to respond with improved disease-defense performance. We here tested whether experience gained by repeated tending of low-level fungus-exposed (Metarhizium robertsii) larvae may alter the performance of sanitary brood care in the clonal ant, Platythyrea punctata. We trained ants individually over nine consecutive trials to either sham-treated or fungus-exposed larvae. We then compared the larval grooming behavior of naive and trained ants and measured how effectively they removed infectious fungal conidiospores from the fungus-exposed larvae. We found that the ants changed the duration of larval grooming in response to both, larval treatment and their level of experience: (1) sham-treated larvae received longer grooming than the fungus-exposed larvae and (2) trained ants performed less self-grooming but longer larval grooming than naive ants, which was true for both, ants trained to fungus-exposed and also to sham-treated larvae. Ants that groomed the fungus-exposed larvae for longer periods removed a higher number of fungal conidiospores from the surface of the fungus-exposed larvae. As experienced ants performed longer larval grooming, they were more effective in fungal removal, thus making them better caretakers under pathogen attack of the colony. By studying this clonal ant, we can thus conclude that even in the absence of genetic variation between colony members, differences in experience levels of brood care may affect performance of sanitary brood care in social insects.
AU - Westhus, Claudia
AU - Ugelvig, Line V
AU - Tourdot, Edouard
AU - Heinze, Jürgen
AU - Doums, Claudie
AU - Cremer, Sylvia
ID - 2161
IS - 10
JF - Behavioral Ecology and Sociobiology
TI - Increased grooming after repeated brood care provides sanitary benefits in a clonal ant
VL - 68
ER -
TY - CONF
AB - We study two-player (zero-sum) concurrent mean-payoff games played on a finite-state graph. We focus on the important sub-class of ergodic games where all states are visited infinitely often with probability 1. The algorithmic study of ergodic games was initiated in a seminal work of Hoffman and Karp in 1966, but all basic complexity questions have remained unresolved. Our main results for ergodic games are as follows: We establish (1) an optimal exponential bound on the patience of stationary strategies (where patience of a distribution is the inverse of the smallest positive probability and represents a complexity measure of a stationary strategy); (2) the approximation problem lies in FNP; (3) the approximation problem is at least as hard as the decision problem for simple stochastic games (for which NP ∩ coNP is the long-standing best known bound). We present a variant of the strategy-iteration algorithm by Hoffman and Karp; show that both our algorithm and the classical value-iteration algorithm can approximate the value in exponential time; and identify a subclass where the value-iteration algorithm is a FPTAS. We also show that the exact value can be expressed in the existential theory of the reals, and establish square-root sum hardness for a related class of games.
AU - Chatterjee, Krishnendu
AU - Ibsen-Jensen, Rasmus
ID - 2162
IS - Part 2
TI - The complexity of ergodic mean payoff games
VL - 8573
ER -
TY - CONF
AB - We consider multi-player graph games with partial-observation and parity objective. While the decision problem for three-player games with a coalition of the first and second players against the third player is undecidable in general, we present a decidability result for partial-observation games where the first and third player are in a coalition against the second player, thus where the second player is adversarial but weaker due to partial-observation. We establish tight complexity bounds in the case where player 1 is less informed than player 2, namely 2-EXPTIME-completeness for parity objectives. The symmetric case of player 1 more informed than player 2 is much more complicated, and we show that already in the case where player 1 has perfect observation, memory of size non-elementary is necessary in general for reachability objectives, and the problem is decidable for safety and reachability objectives. From our results we derive new complexity results for partial-observation stochastic games.
AU - Chatterjee, Krishnendu
AU - Doyen, Laurent
ID - 2163
IS - Part 2
T2 - Lecture Notes in Computer Science
TI - Games with a weak adversary
VL - 8573
ER -
TY - JOUR
AB - Neuronal ectopia, such as granule cell dispersion (GCD) in temporal lobe epilepsy (TLE), has been assumed to result from a migration defect during development. Indeed, recent studies reported that aberrant migration of neonatal-generated dentate granule cells (GCs) increased the risk to develop epilepsy later in life. On the contrary, in the present study, we show that fully differentiated GCs become motile following the induction of epileptiform activity, resulting in GCD. Hippocampal slice cultures from transgenic mice expressing green fluorescent protein in differentiated, but not in newly generated GCs, were incubated with the glutamate receptor agonist kainate (KA), which induced GC burst activity and GCD. Using real-time microscopy, we observed that KA-exposed, differentiated GCs translocated their cell bodies and changed their dendritic organization. As found in human TLE, KA application was associated with decreased expression of the extracellular matrix protein Reelin, particularly in hilar interneurons. Together these findings suggest that KA-induced motility of differentiated GCs contributes to the development of GCD and establish slice cultures as a model to study neuronal changes induced by epileptiform activity.
AU - Chai, Xuejun
AU - Münzner, Gert
AU - Zhao, Shanting
AU - Tinnes, Stefanie
AU - Kowalski, Janina
AU - Häussler, Ute
AU - Young, Christina
AU - Haas, Carola
AU - Frotscher, Michael
ID - 2164
IS - 8
JF - Cerebral Cortex
TI - Epilepsy-induced motility of differentiated neurons
VL - 24
ER -
TY - JOUR
AB - In machine learning, the domain adaptation problem arrives when the test (tar-get) and the train (source) data are generated from different distributions. A key applied issue is thus the design of algorithms able to generalize on a new distribution, for which we have no label information. We focus on learning classification models defined as a weighted majority vote over a set of real-valued functions. In this context, Germain et al. (2013) have shown that a measure of disagreement between these functions is crucial to control. The core of this measure is a theoretical bound—the C-bound (Lacasse et al., 2007)—which involves the disagreement and leads to a well performing majority vote learn-ing algorithm in usual non-adaptative supervised setting: MinCq. In this work,we propose a framework to extend MinCq to a domain adaptation scenario.This procedure takes advantage of the recent perturbed variation divergence between distributions proposed by Harel and Mannor (2012). Justified by a theoretical bound on the target risk of the vote, we provide to MinCq a tar-get sample labeled thanks to a perturbed variation-based self-labeling focused on the regions where the source and target marginals appear similar. We also study the influence of our self-labeling, from which we deduce an original process for tuning the hyperparameters. Finally, our framework called PV-MinCq shows very promising results on a rotation and translation synthetic problem.
AU - Morvant, Emilie
ID - 2165
JF - Pattern Recognition Letters
TI - Domain Adaptation of Weighted Majority Votes via Perturbed Variation-Based Self-Labeling
VL - 51
ER -
TY - CONF
AB - Model-based testing is a promising technology for black-box software and hardware testing, in which test cases are generated automatically from high-level specifications. Nowadays, systems typically consist of multiple interacting components and, due to their complexity, testing presents a considerable portion of the effort and cost in the design process. Exploiting the compositional structure of system specifications can considerably reduce the effort in model-based testing. Moreover, inferring properties about the system from testing its individual components allows the designer to reduce the amount of integration testing. In this paper, we study compositional properties of the ioco-testing theory. We propose a new approach to composition and hiding operations, inspired by contract-based design and interface theories. These operations preserve behaviors that are compatible under composition and hiding, and prune away incompatible ones. The resulting specification characterizes the input sequences for which the unit testing of components is sufficient to infer the correctness of component integration without the need for further tests. We provide a methodology that uses these results to minimize integration testing effort, but also to detect potential weaknesses in specifications. While we focus on asynchronous models and the ioco conformance relation, the resulting methodology can be applied to a broader class of systems.
AU - Daca, Przemyslaw
AU - Henzinger, Thomas A
AU - Krenn, Willibald
AU - Nickovic, Dejan
ID - 2167
SN - 2159-4848
T2 - IEEE 7th International Conference on Software Testing, Verification and Validation
TI - Compositional specifications for IOCO testing
ER -