TY - CHAP AB - Experimental studies have demonstrated that environmental variation can create genotype‐environment interactions (GEIs) in the traits involved in sexual selection. Understanding the genetic architecture of phenotype across environments will require statistical tests that can describe both changes in genetic variance and covariance across environments. This chapter outlines the theoretical framework for the processes of sexual selection in the wild, identifying key parameters in wild systems, and highlighting the potential effects of the environment. It describes the proposed approaches for the estimation of these key parameters in a quantitative genetic framework within naturally occurring pedigreed populations. The chapter provides a worked example for a range of analysis methods. It aims to provide an overview of the analytical methods that can be used to model GEIs for traits involved in sexual selection in naturally occurring pedigreed populations. AU - Robinson, Matthew Richard AU - Qvarnström, Anna ED - Hunt, John ED - Hosken, David ID - 7743 SN - 9780470671795 T2 - Genotype-by-Environment Interactions and Sexual Selection TI - Influence of the environment on the genetic architecture of traits involved in sexual selection within wild populations ER - TY - JOUR AU - Robinson, Matthew Richard AU - Wray, Naomi R. AU - Visscher, Peter M. ID - 7744 IS - 4 JF - Trends in Genetics SN - 0168-9525 TI - Explaining additional genetic variation in complex traits VL - 30 ER - TY - JOUR AB - We investigate the vibrational modes of quasi-two-dimensional disordered colloidal packings of hard colloidal spheres with short-range attractions as a function of packing fraction. Certain properties of the vibrational density of states (vDOS) are shown to correlate with the density and structure of the samples (i.e., in sparsely versus densely packed samples). Specifically, a crossover from dense glassy to sparse gel-like states is suggested by an excess of phonon modes at low frequency and by a variation in the slope of the vDOS with frequency at low frequency. This change in phonon mode distribution is demonstrated to arise largely from localized vibrations that involve individual and/or small clusters of particles with few local bonds. Conventional order parameters and void statistics did not exhibit obvious gel-glass signatures as a function of volume fraction. These mode behaviors and accompanying structural insights offer a potentially new set of indicators for identification of glass-gel transitions and for assignment of gel-like versus glass-like character to a disordered solid material. AU - Lohr, Matthew A. AU - Still, Tim AU - Ganti, Raman AU - Gratale, Matthew D. AU - Davidson, Zoey S. AU - Aptowicz, Kevin B. AU - Goodrich, Carl Peter AU - Sussman, Daniel M. AU - Yodh, A. G. ID - 7768 IS - 6 JF - Physical Review E SN - 1539-3755 TI - Vibrational and structural signatures of the crossover between dense glassy and sparse gel-like attractive colloidal packings VL - 90 ER - TY - JOUR AB - In their Letter, Schreck, Bertrand, O'Hern and Shattuck [Phys. Rev. Lett. 107, 078301 (2011)] study nonlinearities in jammed particulate systems that arise when contacts are altered. They conclude that there is "no harmonic regime in the large system limit for all compressions" and "at jamming onset for any system size." Their argument rests on the claim that for finite-range repulsive potentials, of the form used in studies of jamming, the breaking or forming of a single contact is sufficient to destroy the linear regime. We dispute these conclusions and argue that linear response is both justified and essential for understanding the nature of the jammed solid. AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Nagel, Sidney R. ID - 7771 IS - 4 JF - Physical Review Letters SN - 0031-9007 TI - Comment on “Repulsive contact interactions make jammed particulate systems inherently nonharmonic” VL - 112 ER - TY - JOUR AB - Particle tracking and displacement covariance matrix techniques are employed to investigate the phonon dispersion relations of two-dimensional colloidal glasses composed of soft, thermoresponsive microgel particles whose temperature-sensitive size permits in situ variation of particle packing fraction. Bulk, B, and shear, G, moduli of the colloidal glasses are extracted from the dispersion relations as a function of packing fraction, and variation of the ratio G/B with packing fraction is found to agree quantitatively with predictions for jammed packings of frictional soft particles. In addition, G and B individually agree with numerical predictions for frictional particles. This remarkable level of agreement enabled us to extract an energy scale for the interparticle interaction from the individual elastic constants and to derive an approximate estimate for the interparticle friction coefficient. AU - Still, Tim AU - Goodrich, Carl Peter AU - Chen, Ke AU - Yunker, Peter J. AU - Schoenholz, Samuel AU - Liu, Andrea J. AU - Yodh, A. G. ID - 7772 IS - 1 JF - Physical Review E SN - 1539-3755 TI - Phonon dispersion and elastic moduli of two-dimensional disordered colloidal packings of soft particles with frictional interactions VL - 89 ER - TY - JOUR AB - For more than a century, physicists have described real solids in terms of perturbations about perfect crystalline order1. Such an approach takes us only so far: a glass, another ubiquitous form of rigid matter, cannot be described in any meaningful sense as a defected crystal2. Is there an opposite extreme to a crystal—a solid with complete disorder—that forms an alternative starting point for understanding real materials? Here, we argue that the solid comprising particles with finite-ranged interactions at the jamming transition3,4,5 constitutes such a limit. It has been shown that the physics associated with this transition can be extended to interactions that are long ranged6. We demonstrate that jamming physics is not restricted to amorphous systems, but dominates the behaviour of solids with surprisingly high order. Just as the free-electron and tight-binding models represent two idealized cases from which to understand electronic structure1, we identify two extreme limits of mechanical behaviour. Thus, the physics of jamming can be set side by side with the physics of crystals to provide an organizing structure for understanding the mechanical properties of solids over the entire spectrum of disorder. AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Nagel, Sidney R. ID - 7773 IS - 8 JF - Nature Physics SN - 1745-2473 TI - Solids between the mechanical extremes of order and disorder VL - 10 ER - TY - JOUR AB - Athermal packings of soft repulsive spheres exhibit a sharp jamming transition in the thermodynamic limit. Upon further compression, various structural and mechanical properties display clean power-law behavior over many decades in pressure. As with any phase transition, the rounding of such behavior in finite systems close to the transition plays an important role in understanding the nature of the transition itself. The situation for jamming is surprisingly rich: the assumption that jammed packings are isotropic is only strictly true in the large-size limit, and finite-size has a profound effect on the very meaning of jamming. Here, we provide a comprehensive numerical study of finite-size effects in sphere packings above the jamming transition, focusing on stability as well as the scaling of the contact number and the elastic response. AU - Goodrich, Carl Peter AU - Dagois-Bohy, Simon AU - Tighe, Brian P. AU - van Hecke, Martin AU - Liu, Andrea J. AU - Nagel, Sidney R. ID - 7769 IS - 2 JF - Physical Review E SN - 1539-3755 TI - Jamming in finite systems: Stability, anisotropy, fluctuations, and scaling VL - 90 ER - TY - JOUR AB - Packings of frictionless athermal particles that interact only when they overlap experience a jamming transition as a function of packing density. Such packings provide the foundation for the theory of jamming. This theory rests on the observation that, despite the multitude of disordered configurations, the mechanical response to linear order depends only on the distance to the transition. We investigate the validity and utility of such measurements that invoke the harmonic approximation and show that, despite particles coming in and out of contact, there is a well-defined linear regime in the thermodynamic limit. AU - Goodrich, Carl Peter AU - Liu, Andrea J. AU - Nagel, Sidney R. ID - 7770 IS - 2 JF - Physical Review E SN - 1539-3755 TI - Contact nonlinearities and linear response in jammed particulate packings VL - 90 ER - TY - JOUR AB - Most excitatory inputs in the mammalian brain are made on dendritic spines, rather than on dendritic shafts. Spines compartmentalize calcium, and this biochemical isolation can underlie input-specific synaptic plasticity, providing a raison d'etre for spines. However, recent results indicate that the spine can experience a membrane potential different from that in the parent dendrite, as though the spine neck electrically isolated the spine. Here we use two-photon calcium imaging of mouse neocortical pyramidal neurons to analyze the correlation between the morphologies of spines activated under minimal synaptic stimulation and the excitatory postsynaptic potentials they generate. We find that excitatory postsynaptic potential amplitudes are inversely correlated with spine neck lengths. Furthermore, a spike timing-dependent plasticity protocol, in which two-photon glutamate uncaging over a spine is paired with postsynaptic spikes, produces rapid shrinkage of the spine neck and concomitant increases in the amplitude of the evoked spine potentials. Using numerical simulations, we explore the parameter regimes for the spine neck resistance and synaptic conductance changes necessary to explain our observations. Our data, directly correlating synaptic and morphological plasticity, imply that long-necked spines have small or negligible somatic voltage contributions, but that, upon synaptic stimulation paired with postsynaptic activity, they can shorten their necks and increase synaptic efficacy, thus changing the input/output gain of pyramidal neurons. AU - Araya, R. AU - Vogels, Tim P AU - Yuste, R. ID - 8021 IS - 28 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - Activity-dependent dendritic spine neck changes are correlated with synaptic strength VL - 111 ER - TY - JOUR AB - Uniform random sparse network architectures are ubiquitous in computational neuroscience, but the implicit hypothesis that they are a good representation of real neuronal networks has been met with skepticism. Here we used two experimental data sets, a study of triplet connectivity statistics and a data set measuring neuronal responses to channelrhodopsin stimuli, to evaluate the fidelity of thousands of model networks. Network architectures comprised three neuron types (excitatory, fast spiking, and nonfast spiking inhibitory) and were created from a set of rules that govern the statistics of the resulting connection types. In a high-dimensional parameter scan, we varied the degree distributions (i.e., how many cells each neuron connects with) and the synaptic weight correlations of synapses from or onto the same neuron. These variations converted initially uniform random and homogeneously connected networks, in which every neuron sent and received equal numbers of synapses with equal synaptic strength distributions, to highly heterogeneous networks in which the number of synapses per neuron, as well as average synaptic strength of synapses from or to a neuron were variable. By evaluating the impact of each variable on the network structure and dynamics, and their similarity to the experimental data, we could falsify the uniform random sparse connectivity hypothesis for 7 of 36 connectivity parameters, but we also confirmed the hypothesis in 8 cases. Twenty-one parameters had no substantial impact on the results of the test protocols we used. AU - Tomm, Christian AU - Avermann, Michael AU - Petersen, Carl AU - Gerstner, Wulfram AU - Vogels, Tim P ID - 8023 IS - 8 JF - Journal of Neurophysiology SN - 0022-3077 TI - Connection-type-specific biases make uniform random network models consistent with cortical recordings VL - 112 ER - TY - JOUR AB - Populations of neurons in motor cortex engage in complex transient dynamics of large amplitude during the execution of limb movements. Traditional network models with stochastically assigned synapses cannot reproduce this behavior. Here we introduce a class of cortical architectures with strong and random excitatory recurrence that is stabilized by intricate, fine-tuned inhibition, optimized from a control theory perspective. Such networks transiently amplify specific activity states and can be used to reliably execute multidimensional movement patterns. Similar to the experimental observations, these transients must be preceded by a steady-state initialization phase from which the network relaxes back into the background state by way of complex internal dynamics. In our networks, excitation and inhibition are as tightly balanced as recently reported in experiments across several brain areas, suggesting inhibitory control of complex excitatory recurrence as a generic organizational principle in cortex. AU - Hennequin, Guillaume AU - Vogels, Tim P AU - Gerstner, Wulfram ID - 8022 IS - 6 JF - Neuron SN - 0896-6273 TI - Optimal control of transient dynamics in balanced networks supports generation of complex movements VL - 82 ER - TY - JOUR AB - The assembly of HIV-1 is mediated by oligomerization of the major structural polyprotein, Gag, into a hexameric protein lattice at the plasma membrane of the infected cell. This leads to budding and release of progeny immature virus particles. Subsequent proteolytic cleavage of Gag triggers rearrangement of the particles to form mature infectious virions. Obtaining a structural model of the assembled lattice of Gag within immature virus particles is necessary to understand the interactions that mediate assembly of HIV-1 particles in the infected cell, and to describe the substrate that is subsequently cleaved by the viral protease. An 8-Å resolution structure of an immature virus-like tubular array assembled from a Gag-derived protein of the related retrovirus Mason-Pfizer monkey virus (M-PMV) has previously been reported, and a model for the arrangement of the HIV-1 capsid (CA) domains has been generated based on homology to this structure. Here we have assembled tubular arrays of a HIV-1 Gag-derived protein with an immature-like arrangement of the C-terminal CA domains and have solved their structure by using hybrid cryo-EM and tomography analysis. The structure reveals the arrangement of the C-terminal domain of CA within an immature-like HIV-1 Gag lattice, and provides, to our knowledge, the first high-resolution view of the region immediately downstream of CA, which is essential for assembly, and is significantly different from the respective region in M-PMV. Our results reveal a hollow column of density for this region in HIV-1 that is compatible with the presence of a six-helix bundle at this position. AU - Bharata, Tanmay A AU - Menendez, Luis R AU - Hagena, Wim J AU - Luxd, Vanda AU - Igonete, Sebastien AU - Schorba, Martin AU - Florian Schur AU - Kraüsslich, Hans Georg AU - Briggsa, John A ID - 809 IS - 22 JF - PNAS TI - Cryo electron microscopy of tubular arrays of HIV-1 Gag resolves structures essential for immature virus assembly VL - 111 ER - TY - JOUR AB - Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuximab in human clinical oncology, we present here a “caninized” version of this antibody, can225IgG, for comparative oncology studies. Variable region genes of 225, the murine precursor of cetuximab, were fused with canine constant heavy gamma and kappa chain genes, respectively, and transfected into Chinese hamster ovary (CHO) DUKX-B11 cells. Of note, 480 clones were screened and the best clones were selected according to productivity and highest specificity in EGFR-coated ELISA. Upon purification with Protein G, the recombinant cetuximab-like canine IgG was tested for integrity, correct assembly, and functionality. Specific binding to the surface of EGFR-overexpressing cells was assessed by flow cytometry and immunofluorescence; moreover, binding to canine mammary tissue was demonstrated by immunohistochemistry. In cell viability and proliferation assays, incubation with can225IgG led to significant tumor cell growth inhibition. Moreover, this antibody mediated significant tumor cell killing via phagocytosis in vitro. We thus present here, for the first time, the generation of a canine IgG antibody and its hypothetical structure. On the basis of its cetuximab-like binding site, on the one hand, and the expression of a 91% homologous EGFR molecule in canine cancer, on the other hand, this antibody may be a promising research compound to establish passive immunotherapy in dog patients with cancer. AU - Singer, J. AU - Fazekas, Judit AU - Wang, W. AU - Weichselbaumer, M. AU - Matz, M. AU - Mader, A. AU - Steinfellner, W. AU - Meitz, S. AU - Mechtcheriakova, D. AU - Sobanov, Y. AU - Willmann, M. AU - Stockner, T. AU - Spillner, E. AU - Kunert, R. AU - Jensen-Jarolim, E. ID - 8244 IS - 7 JF - Molecular Cancer Therapeutics SN - 1535-7163 TI - Generation of a canine anti-EGFR (ErbB-1) antibody for passive immunotherapy in dog cancer patients VL - 13 ER - TY - JOUR AB - Nuclear magnetic resonance (NMR) is a powerful tool for observing the motion of biomolecules at the atomic level. One technique, the analysis of relaxation dispersion phenomenon, is highly suited for studying the kinetics and thermodynamics of biological processes. Built on top of the relax computational environment for NMR dynamics is a new dispersion analysis designed to be comprehensive, accurate and easy-to-use. The software supports more models, both numeric and analytic, than current solutions. An automated protocol, available for scripting and driving the graphical user interface (GUI), is designed to simplify the analysis of dispersion data for NMR spectroscopists. Decreases in optimization time are granted by parallelization for running on computer clusters and by skipping an initial grid search by using parameters from one solution as the starting point for another —using analytic model results for the numeric models, taking advantage of model nesting, and using averaged non-clustered results for the clustered analysis. AU - Morin, Sébastien AU - Linnet, Troels E AU - Lescanne, Mathilde AU - Schanda, Paul AU - Thompson, Gary S AU - Tollinger, Martin AU - Teilum, Kaare AU - Gagné, Stéphane AU - Marion, Dominique AU - Griesinger, Christian AU - Blackledge, Martin AU - d’Auvergne, Edward J ID - 8459 IS - 15 JF - Bioinformatics KW - Statistics and Probability KW - Computational Theory and Mathematics KW - Biochemistry KW - Molecular Biology KW - Computational Mathematics KW - Computer Science Applications SN - 1367-4803 TI - Relax: The analysis of biomolecular kinetics and thermodynamics using NMR relaxation dispersion data VL - 30 ER - TY - JOUR AB - The maintenance of bacterial cell shape and integrity is largely attributed to peptidoglycan, a highly cross-linked biopolymer. The transpeptidases that perform this cross-linking are important targets for antibiotics. Despite this biomedical importance, to date no structure of a protein in complex with an intact bacterial peptidoglycan has been resolved, primarily due to the large size and flexibility of peptidoglycan sacculi. Here we use solid-state NMR spectroscopy to derive for the first time an atomic model of an l,d-transpeptidase from Bacillus subtilis bound to its natural substrate, the intact B. subtilis peptidoglycan. Importantly, the model obtained from protein chemical shift perturbation data shows that both domains—the catalytic domain as well as the proposed peptidoglycan recognition domain—are important for the interaction and reveals a novel binding motif that involves residues outside of the classical enzymatic pocket. Experiments on mutants and truncated protein constructs independently confirm the binding site and the implication of both domains. Through measurements of dipolar-coupling derived order parameters of bond motion we show that protein binding reduces the flexibility of peptidoglycan. This first report of an atomic model of a protein–peptidoglycan complex paves the way for the design of new antibiotic drugs targeting l,d-transpeptidases. The strategy developed here can be extended to the study of a large variety of enzymes involved in peptidoglycan morphogenesis. AU - Schanda, Paul AU - Triboulet, Sébastien AU - Laguri, Cédric AU - Bougault, Catherine M. AU - Ayala, Isabel AU - Callon, Morgane AU - Arthur, Michel AU - Simorre, Jean-Pierre ID - 8458 IS - 51 JF - Journal of the American Chemical Society SN - 0002-7863 TI - Atomic model of a cell-wall cross-linking enzyme in complex with an intact bacterial peptidoglycan VL - 136 ER - TY - JOUR AB - The function of proteins depends on their ability to sample a variety of states differing in structure and free energy. Deciphering how the various thermally accessible conformations are connected, and understanding their structures and relative energies is crucial in rationalizing protein function. Many biomolecular reactions take place within microseconds to milliseconds, and this timescale is therefore of central functional importance. Here we show that R1ρ relaxation dispersion experiments in magic‐angle‐spinning solid‐state NMR spectroscopy make it possible to investigate the thermodynamics and kinetics of such exchange process, and gain insight into structural features of short‐lived states. AU - Ma, Peixiang AU - Haller, Jens D. AU - Zajakala, Jérémy AU - Macek, Pavel AU - Sivertsen, Astrid C. AU - Willbold, Dieter AU - Boisbouvier, Jérôme AU - Schanda, Paul ID - 8460 IS - 17 JF - Angewandte Chemie International Edition SN - 1433-7851 TI - Probing transient conformational states of proteins by solid-state R1ρ relaxation-dispersion NMR spectroscopy VL - 53 ER - TY - JOUR AB - In this paper, we study small perturbations of a class of non-convex integrable Hamiltonians with two degrees of freedom, and we prove a result of diffusion for an open and dense set of perturbations, with an optimal time of diffusion which grows linearly with respect to the inverse of the size of the perturbation. AU - Bounemoura, Abed AU - Kaloshin, Vadim ID - 8501 IS - 2 JF - Moscow Mathematical Journal KW - General Mathematics SN - 1609-3321 TI - Generic fast diffusion for a class of non-convex Hamiltonians with two degrees of freedom VL - 14 ER - TY - JOUR AB - The main model studied in this paper is a lattice of pendula with a nearest‐neighbor coupling. If the coupling is weak, then the system is near‐integrable and KAM tori fill most of the phase space. For all KAM trajectories the energy of each pendulum stays within a narrow band for all time. Still, we show that for an arbitrarily weak coupling of a certain localized type, the neighboring pendula can exchange energy. In fact, the energy can be transferred between the pendula in any prescribed way. AU - Kaloshin, Vadim AU - Levi, Mark AU - Saprykina, Maria ID - 8500 IS - 5 JF - Communications on Pure and Applied Mathematics KW - Applied Mathematics KW - General Mathematics SN - 0010-3640 TI - Arnol′d diffusion in a pendulum lattice VL - 67 ER - TY - JOUR AB - Rapid divergence of gene copies after duplication is thought to determine the fate of the copies and evolution of novel protein functions. However, data on howlong the gene copies continue to experience an elevated rate of evolution remain scarce. Standard theory of gene duplications based on some level of genetic redundancy of gene copies predicts that the period of accelerated evolutionmust end relatively quickly. Using a maximum-likelihood approach we estimate preduplication, initial postduplication, and recent postduplication rates of evolution that occurred in themammalian lineage.Wefind that both gene copies experience a similar in magnitude acceleration in their rate of evolution. The copy located in the original genomic position typically returns to the preduplication rates of evolution in a short period of time. The burst of faster evolution of the copy that is located in a new genomic position typically lasts longer. Furthermore, the fast-evolving copies on average continue to evolve faster than the preduplication rates far longer than predicted by standard theory of gene duplications.We hypothesize that the prolonged elevated rates of evolution are determined by functional properties that were acquired during, or soon after, the gene duplication event. AU - Rosello, Oriol P AU - Fyodor Kondrashov ID - 852 IS - 8 JF - Genome Biology and Evolution TI - Long-Term asymmetrical acceleration of protein evolution after gene duplication VL - 6 ER - TY - JOUR AB - The emergence of new genes throughout evolution requires rewiring and extension of regulatory networks. However, the molecular details of how the transcriptional regulation of new gene copies evolves remain largely unexplored. Here we show how duplication of a transcription factor gene allowed the emergence of two independent regulatory circuits. Interestingly, the ancestral transcription factor was promiscuous and could bind different motifs in its target promoters. After duplication, one paralogue evolved increased binding specificity so that it only binds one type of motif, whereas the other copy evolved a decreased activity so that it only activates promoters that contain multiple binding sites. Interestingly, only a few mutations in both the DNA-binding domains and in the promoter binding sites were required to gradually disentangle the two networks. These results reveal how duplication of a promiscuous transcription factor followed by concerted cis and trans mutations allows expansion of a regulatory network. AU - Pougach, Ksenia S AU - Voet, Arnout R AU - Fyodor Kondrashov AU - Voordeckers, Karin AU - Christiaens, Joaquin F AU - Baying, Bianka AU - Bénès, Vladimı́r AU - Sakai, Ryo AU - Aerts, Jan A AU - Zhu, Bo AU - Van Dijck, Patrick AU - Verstrepen, Kevin J ID - 856 JF - Nature Communications TI - Duplication of a promiscuous transcription factor drives the emergence of a new regulatory network VL - 5 ER - TY - JOUR AB - The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores (comb jellies) have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes, and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well recognized in ctenophores, many bilaterian neuron-specific genes and genes of 'classical' neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals. AU - Moroz, Leonid L AU - Kocot, Kevin M AU - Citarella, Mathew R AU - Dosung, Sohn AU - Norekian, Tigran P AU - Povolotskaya, Inna AU - Grigorenko, Anastasia P AU - Dailey, Christopher A AU - Berezikov, Eugene AU - Buckley, Katherine M AU - Ptitsyn, Andrey A AU - Reshetov, Denis A AU - Mukherjee, Krishanu AU - Moroz, Tatiana P AU - Bobkova, Yelena V AU - Yu, Fahong AU - Kapitonov, Vladimir V AU - Jurka, Jerzy W AU - Bobkov, Yuriy V AU - Swore, Joshua J AU - Girardo, David O AU - Fodor, Alexander AU - Gusev, Fedor E AU - Sanford, Rachel S AU - Bruders, Rebecca AU - Kittler, Ellen L AU - Mills, Claudia E AU - Rast, Jonathan P AU - Derelle, Romain AU - Solovyev, Victor AU - Fyodor Kondrashov AU - Swalla, Billie J AU - Sweedler, Jonathan V AU - Rogaev, Evgeny I AU - Halanych, Kenneth M AU - Kohn, Andrea B ID - 863 IS - 7503 JF - Nature TI - The ctenophore genome and the evolutionary origins of neural systems VL - 510 ER - TY - JOUR AB - Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt-FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and β-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers. AU - Koval, Alexey V AU - Vlasov, Peter K AU - Shichkova, Polina AU - Khunderyakova, S AU - Markov, Yury AU - Panchenko, J AU - Volodina, A AU - Fyodor Kondrashov AU - Katanaev, Vladimir L ID - 865 IS - 4 JF - Biochemical Pharmacology TI - Anti leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling VL - 87 ER - TY - JOUR AB - The morphological stability of biological tubes is crucial for the efficient circulation of fluids and gases. Failure of this stability causes irregularly shaped tubes found in multiple pathological conditions. Here, we report that Drosophila mutants of the ESCRT III component Shrub/Vps32 exhibit a strikingly elongated sinusoidal tube phenotype. This is caused by excessive apical membrane synthesis accompanied by the ectopic accumulation and overactivation of Crumbs in swollen endosomes. Furthermore, we demonstrate that the apical extracellular matrix (aECM) of the tracheal tube is a viscoelastic material coupled with the apical membrane. We present a simple mechanical model in which aECM elasticity, apical membrane growth, and their interaction are three vital parameters determining the stability of biological tubes. Our findings demonstrate a mechanical role for the extracellular matrix and suggest that the interaction of the apical membrane and an elastic aECM determines the final morphology of biological tubes independent of cell shape. AU - Dong, Bo AU - Hannezo, Edouard B AU - Hayashi, Shigeo ID - 925 IS - 4 JF - Cell Reports TI - Balance between apical membrane growth and luminal matrix resistance determines epithelial tubule shape VL - 7 ER - TY - JOUR AB - Morphogenesis during embryo development requires the coordination of mechanical forces to generate the macroscopic shapes of organs. We propose a minimal theoretical model, based on cell adhesion and actomyosin contractility, which describes the various shapes of epithelial cells and the bending and buckling of epithelial sheets, as well as the relative stability of cellular tubes and spheres. We show that, to understand these processes, a full 3D description of the cells is needed, but that simple scaling laws can still be derived. The morphologies observed in vivo can be understood as stable points of mechanical equations and the transitions between them are either continuous or discontinuous. We then focus on epithelial sheet bending, a ubiquitous morphogenetic process. We calculate the curvature of an epithelium as a function of actin belt tension as well as of cell-cell and and cell-substrate tension. The model allows for a comparison of the relative stabilities of spherical or cylindrical cellular structures (acini or tubes). Finally, we propose a unique type of buckling instability of epithelia, driven by a flattening of individual cell shapes, and discuss experimental tests to verify our predictions. AU - Hannezo, Edouard B AU - Prost, Jacques AU - Joanny, Jean ID - 927 IS - 1 JF - PNAS TI - Theory of epithelial sheet morphology in three dimensions VL - 111 ER - TY - JOUR AB - Transposons are selfish genetic sequences that can increase their copy number and inflict substantial damage on their hosts. To combat these genomic parasites, plants have evolved multiple pathways to identify and silence transposons by methylating their DNA. Plants have also evolved mechanisms to limit the collateral damage from the antitransposon machinery. In this review, we examine recent developments that have elucidated many of the molecular workings of these pathways. We also highlight the evidence that the methylation and demethylation pathways interact, indicating that plants have a highly sophisticated, integrated system of transposon defense that has an important role in the regulation of gene expression. AU - Kim, M. Yvonne AU - Zilberman, Daniel ID - 9519 IS - 5 JF - Trends in Plant Science SN - 1360-1385 TI - DNA methylation as a system of plant genomic immunity VL - 19 ER - TY - JOUR AB - Multielectron spin qubits are demonstrated, and performance examined by comparing coherent exchange oscillations in coupled single-electron and multielectron quantum dots, measured in the same device. Fast (>1 GHz) exchange oscillations with a quality factor Q∼15 are found for the multielectron case, compared to Q∼2 for the single-electron case, the latter consistent with experiments in the literature. A model of dephasing that includes voltage and hyperfine noise is developed that is in good agreement with both single- and multielectron data, though in both cases additional exchange-independent dephasing is needed to obtain quantitative agreement across a broad parameter range. AU - Higginbotham, Andrew P AU - Kuemmeth, Ferdinand AU - Hanson, Micah AU - Gossard, Arthur AU - Marcus, Charles ID - 96 IS - 2 JF - APS Physics, Physical Review Letters TI - Coherent operations and screening in multielectron spin qubits VL - 112 ER - TY - JOUR AB - Let d≥3 be a fixed integer. We give an asympotic formula for the expected number of spanning trees in a uniformly random d-regular graph with n vertices. (The asymptotics are as n→∞, restricted to even n if d is odd.) We also obtain the asymptotic distribution of the number of spanning trees in a uniformly random cubic graph, and conjecture that the corresponding result holds for arbitrary (fixed) d. Numerical evidence is presented which supports our conjecture. AU - Greenhill, Catherine AU - Kwan, Matthew Alan AU - Wind, David ID - 9594 IS - 1 JF - The Electronic Journal of Combinatorics TI - On the number of spanning trees in random regular graphs VL - 21 ER - TY - JOUR AB - Correlative microscopy incorporates the specificity of fluorescent protein labeling into high-resolution electron micrographs. Several approaches exist for correlative microscopy, most of which have used the green fluorescent protein (GFP) as the label for light microscopy. Here we use chemical tagging and synthetic fluorophores instead, in order to achieve protein-specific labeling, and to perform multicolor imaging. We show that synthetic fluorophores preserve their post-embedding fluorescence in the presence of uranyl acetate. Post-embedding fluorescence is of such quality that the specimen can be prepared with identical protocols for scanning electron microscopy (SEM) and transmission electron microscopy (TEM); this is particularly valuable when singular or otherwise difficult samples are examined. We show that synthetic fluorophores give bright, well-resolved signals in super-resolution light microscopy, enabling us to superimpose light microscopic images with a precision of up to 25 nm in the x–y plane on electron micrographs. To exemplify the preservation quality of our new method we visualize the molecular arrangement of cadherins in adherens junctions of mouse epithelial cells. AU - Perkovic, Mario AU - Kunz, Michael AU - Endesfelder, Ulrike AU - Bunse, Stefanie AU - Wigge, Christoph AU - Yu, Zhou AU - Hodirnau, Victor-Valentin AU - Scheffer, Margot P. AU - Seybert, Anja AU - Malkusch, Sebastian AU - Schuman, Erin M. AU - Heilemann, Mike AU - Frangakis, Achilleas S. ID - 9655 IS - 2 JF - Journal of Structural Biology SN - 1047-8477 TI - Correlative light- and electron microscopy with chemical tags VL - 186 ER - TY - JOUR AB - It is well known that ultrasonic vibration can soften metals, and this phenomenon has been widely exploited in industrial applications concerning metal forming and bonding. Recent experiments show that the simultaneous application of oscillatory stresses from audible to ultrasonic frequency ranges can lead to not only softening but also significant dislocation annihilation and subgrain formation in metal samples from the nano- to macro-size range. These findings indicate that the existing understanding of ultrasound softening – that the vibrations either impose additional stress waves to augment the quasi-static applied load, or cause heating of the metal, whereas the metal’s intrinsic deformation resistance or mechanism remains unaltered – is far from complete. To understand the softening and the associated enhanced subgrain formation and dislocation annihilation, a new simulator based on the dynamics of dislocation-density functions is employed. This new simulator considers the flux, production and annihilation, as well as the Taylor and elastic interactions between dislocation densities. Softening during vibrations as well as enhanced cell formation is predicted. The simulations reveal the main mechanism for subcell formation under oscillatory loadings to be the enhanced elimination of statistically stored dislocations (SSDs) by the oscillatory stress, leaving behind geometrically necessary dislocations with low Schmid factors which then form the subgrain walls. The oscillatory stress helps the depletion of the SSDs, because the chance for them to meet up and annihilate is increased with reversals of dislocation motions. This is the first simulation effort to successfully predict the cell formation phenomenon under vibratory loadings. AU - Cheng, Bingqing AU - Leung, H.S. AU - Ngan, A.H.W. ID - 9686 IS - 16-18 JF - Philosophical Magazine SN - 1478-6435 TI - Strength of metals under vibrations – dislocation-density-function dynamics simulations VL - 95 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 - GEN 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 - 9747 TI - Data from: Role of sex and migration in adaptation to sink environments ER - TY - JOUR AB - We propose a method for detecting many-body localization (MBL) in disordered spin systems. The method involves pulsed coherent spin manipulations that probe the dephasing of a given spin due to its entanglement with a set of distant spins. It allows one to distinguish the MBL phase from a noninteracting localized phase and a delocalized phase. In particular, we show that for a properly chosen pulse sequence the MBL phase exhibits a characteristic power-law decay reflecting its slow growth of entanglement. We find that this power-law decay is robust with respect to thermal and disorder averaging, provide numerical simulations supporting our results, and discuss possible experimental realizations in solid-state and cold-atom systems. AU - Maksym Serbyn AU - Knap, Michael J AU - Gopalakrishnan, Sarang AU - Papić, Zlatko AU - Yao, Norman Y AU - Laumann, Chris R AU - Abanin, Dmitry A AU - Lukin, Mikhail D AU - Demler, Eugene A ID - 977 IS - 14 JF - Physical Review Letters TI - Interferometric probes of many-body localization VL - 113 ER - TY - JOUR AB - Many-body localized (MBL) systems are characterized by the absence of transport and thermalization and, therefore, cannot be described by conventional statistical mechanics. In this paper, using analytic arguments and numerical simulations, we study the behavior of local observables in an isolated MBL system following a quantum quench. For the case of a global quench, we find that the local observables reach stationary, highly nonthermal values at long times as a result of slow dephasing characteristic of the MBL phase. These stationary values retain the local memory of the initial state due to the existence of local integrals of motion in the MBL phase. The temporal fluctuations around stationary values exhibit universal power-law decay in time, with an exponent set by the localization length and the diagonal entropy of the initial state. Such a power-law decay holds for any local observable and is related to the logarithmic in time growth of entanglement in the MBL phase. This behavior distinguishes the MBL phase from both the Anderson insulator (where no stationary state is reached) and from the ergodic phase (where relaxation is expected to be exponential). For the case of a local quench, we also find a power-law approach of local observables to their stationary values when the system is prepared in a mixed state. Quench protocols considered in this paper can be naturally implemented in systems of ultracold atoms in disordered optical lattices, and the behavior of local observables provides a direct experimental signature of many-body localization. AU - Maksym Serbyn AU - Papić, Zlatko AU - Abanin, Dmitry A ID - 980 IS - 17 JF - Physical Review B - Condensed Matter and Materials Physics TI - Quantum quenches in the many-body localized phase VL - 90 ER - TY - JOUR AB - Relaxation and dephasing of hole spins are measured in a gate-defined Ge/Si nanowire double quantum dot using a fast pulsed-gate method and dispersive readout. An inhomogeneous dephasing time T2* ∼ 0.18 μs exceeds corresponding measurements in III-V semiconductors by more than an order of magnitude, as expected for predominately nuclear-spin-free materials. Dephasing is observed to be exponential in time, indicating the presence of a broadband noise source, rather than Gaussian, previously seen in systems with nuclear-spin-dominated dephasing. AU - Higginbotham, Andrew P AU - Larsen, Thorvald AU - Yao, Jun AU - Yan, Hao AU - Lieber, Charles AU - Marcus, Charles AU - Kuemmeth, Ferdinand ID - 98 IS - 6 JF - Nano Letters TI - Hole spin coherence in a Ge/Si heterostructure nanowire VL - 14 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 - GEN AB - Detailed description of the experimental prodedures, data analyses and additional statistical analyses of the results. AU - Wolf, Stephan AU - Mcmahon, Dino AU - Lim, Ka AU - Pull, Christopher AU - Clark, Suzanne AU - Paxton, Robert AU - Osborne, Juliet ID - 9888 TI - Supporting information ER - TY - JOUR AB - Recombination between double-stranded DNA molecules is a key genetic process which occurs in a wide variety of organisms. Usually, crossing-over (CO) occurs during meiosis between genotypes with 98.0-99.9% sequence identity, because within-population nucleotide diversity only rarely exceeds 2%. However, some species are hypervariable and it is unclear how CO can occur between genotypes with less than 90% sequence identity. Here, we study CO in Schizophyllum commune, a hypervariable cosmopolitan basidiomycete mushroom, a frequently encountered decayer of woody substrates. We crossed two haploid individuals, from the United States and from Russia, and obtained genome sequences for their 17 offspring. The average genetic distance between the parents was 14%, making it possible to study CO at very high resolution. We found reduced levels of linkage disequilibrium between loci flanking the CO sites indicating that they are mostly confined to hotspots of recombination. Furthermore, CO events preferentially occurred in regions under stronger negative selection, in particular within exons that showed reduced levels of nucleotide diversity. Apparently, in hypervariable species CO must avoid regions of higher divergence between the recombining genomes due to limitations imposed by the mismatch repair system, with regions under strong negative selection providing the opportunity for recombination. These patterns are opposite to those observed in a number of less variable species indicating that population genomics of hypervariable species may reveal novel biological phenomena. AU - Seplyarskiy, Vladimir B AU - Logacheva, Maria D AU - Penin, Aleksey A AU - Baranová, Maria A AU - Leushkin, Evgeny V AU - Demidenko, Natalia V AU - Klepikova, Anna V AU - Fyodor Kondrashov AU - Kondrashov, Alexey S AU - James, Timothy Y ID - 845 IS - 11 JF - Molecular Biology and Evolution TI - Crossing-over in a hypervariable species preferentially occurs in regions of high local similarity VL - 31 ER - TY - JOUR AB - The study of molecular evolution is important because it reveals how protein functions emerge and evolve. Recently, several types of studies indicated that substitutions in molecular evolution occur in a compensatory manner, whereby the occurrence of a substitution depends on the amino acid residues at other sites. However, a molecular or structural basis behind the compensation often remains obscure. Here, we review studies on the interface of structural biology and molecular evolution that revealed novel aspects of compensatory evolution. In many cases structural studies benefit from evolutionary data while structural data often add a functional dimension to the study of molecular evolution. AU - Ivankov, Dmitry N AU - Finkelstein, Alexei V AU - Fyodor Kondrashov ID - 892 IS - 1 JF - Current Opinion in Structural Biology TI - A structural perspective of compensatory evolution VL - 26 ER - TY - JOUR AB - Self-propelled particles can exhibit surprising non-equilibrium behaviors, and how they interact with obstacles or boundaries remains an important open problem. Here we show that chemically propelled micro-rods can be captured, with little change in their speed, into close orbits around solid spheres resting on or near a horizontal plane. We show that this interaction between sphere and particle is short-range, occurring even for spheres smaller than the particle length, and for a variety of sphere materials. We consider a simple model, based on lubrication theory, of a force- and torque-free swimmer driven by a surface slip (the phoretic propulsion mechanism) and moving near a solid surface. The model demonstrates capture, or movement towards the surface, and yields speeds independent of distance. This study reveals the crucial aspects of activity–driven interactions of self-propelled particles with passive objects, and brings into question the use of colloidal tracers as probes of active matter. AU - Takagi, Daisuke AU - Palacci, Jérémie A AU - Braunschweig, Adam B. AU - Shelley, Michael J. AU - Zhang, Jun ID - 9050 IS - 11 JF - Soft Matter KW - General Chemistry KW - Condensed Matter Physics SN - 1744-683X TI - Hydrodynamic capture of microswimmers into sphere-bound orbits VL - 10 ER - TY - JOUR AB - Light-activated self-propelled colloids are synthesized and their active motion is studied using optical microscopy. We propose a versatile route using different photoactive materials, and demonstrate a multiwavelength activation and propulsion. Thanks to the photoelectrochemical properties of two semiconductor materials (α-Fe2O3 and TiO2), a light with an energy higher than the bandgap triggers the reaction of decomposition of hydrogen peroxide and produces a chemical cloud around the particle. It induces a phoretic attraction with neighbouring colloids as well as an osmotic self-propulsion of the particle on the substrate. We use these mechanisms to form colloidal cargos as well as self-propelled particles where the light-activated component is embedded into a dielectric sphere. The particles are self-propelled along a direction otherwise randomized by thermal fluctuations, and exhibit a persistent random walk. For sufficient surface density, the particles spontaneously form ‘living crystals’ which are mobile, break apart and reform. Steering the particle with an external magnetic field, we show that the formation of the dense phase results from the collisions heads-on of the particles. This effect is intrinsically non-equilibrium and a novel principle of organization for systems without detailed balance. Engineering families of particles self-propelled by different wavelength demonstrate a good understanding of both the physics and the chemistry behind the system and points to a general route for designing new families of self-propelled particles. AU - Palacci, Jérémie A AU - Sacanna, S. AU - Kim, S.-H. AU - Yi, G.-R. AU - Pine, D. J. AU - Chaikin, P. M. ID - 9166 IS - 2029 JF - Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences KW - General Engineering KW - General Physics and Astronomy KW - General Mathematics SN - 1364-503X TI - Light-activated self-propelled colloids VL - 372 ER - TY - JOUR AB - The regulation of cell growth in animal tissues is a question of critical importance: most tissues contain different types of cells in interconversion and the fraction of each type has to be controlled in a precise way, by mechanisms that remain unclear. Here, we provide a theoretical framework for the homeostasis of stem-cell-containing epithelial tissues using mechanical equations, which describe the size of the tissue and kinetic equations, which describe the interconversions of the cell populations. We show that several features, such as the evolution of stem cell fractions during intestinal development, the shape of a developing intestinal wall, as well as the increase in the proliferative compartment in cancer initiation, can be studied and understood from generic modelling which does not rely on a particular regulatory mechanism. Finally, inspired by recent experiments, we propose a model where cell division rates are regulated by the mechanical stresses in the epithelial sheet. We show that pressure-controlled growth can, in addition to the previous features, also explain with few parameters the formation of stem cell compartments as well as the morphologies observed when a colonic crypt becomes cancerous. We also discuss optimal strategies of wound healing, in connection with experiments on the cornea. AU - Hannezo, Edouard B AU - Prost, Jacques AU - Joanny, Jean ID - 926 IS - 93 JF - Journal of the Royal Society Interface TI - Growth homeostatic regulation and stem cell dynamics in tissues VL - 11 ER - TY - JOUR AB - Dnmt1 epigenetically propagates symmetrical CG methylation in many eukaryotes. Their genomes are typically depleted of CG dinucleotides because of imperfect repair of deaminated methylcytosines. Here, we extensively survey diverse species lacking Dnmt1 and show that, surprisingly, symmetrical CG methylation is nonetheless frequently present and catalyzed by a different DNA methyltransferase family, Dnmt5. Numerous Dnmt5-containing organisms that diverged more than a billion years ago exhibit clustered methylation, specifically in nucleosome linkers. Clustered methylation occurs at unprecedented densities and directly disfavors nucleosomes, contributing to nucleosome positioning between clusters. Dense methylation is enabled by a regime of genomic sequence evolution that enriches CG dinucleotides and drives the highest CG frequencies known. Species with linker methylation have small, transcriptionally active nuclei that approach the physical limits of chromatin compaction. These features constitute a previously unappreciated genome architecture, in which dense methylation influences nucleosome positions, likely facilitating nuclear processes under extreme spatial constraints. AU - Huff, Jason T. AU - Zilberman, Daniel ID - 9458 IS - 6 JF - Cell SN - 0092-8674 TI - Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes VL - 156 ER - TY - JOUR AB - Centromeres mediate chromosome segregation and are defined by the centromere-specific histone H3 variant (CenH3)/centromere protein A (CENP-A). Removal of CenH3 from centromeres is a general property of terminally differentiated cells, and the persistence of CenH3 increases the risk of diseases such as cancer. However, active mechanisms of centromere disassembly are unknown. Nondividing Arabidopsis pollen vegetative cells, which transport engulfed sperm by extended tip growth, undergo loss of CenH3; centromeric heterochromatin decondensation; and bulk activation of silent rRNA genes, accompanied by their translocation into the nucleolus. Here, we show that these processes are blocked by mutations in the evolutionarily conserved AAA-ATPase molecular chaperone, CDC48A, homologous to yeast Cdc48 and human p97 proteins, both of which are implicated in ubiquitin/small ubiquitin-like modifier (SUMO)-targeted protein degradation. We demonstrate that CDC48A physically associates with its heterodimeric cofactor UFD1-NPL4, known to bind ubiquitin and SUMO, as well as with SUMO1-modified CenH3 and mutations in NPL4 phenocopy cdc48a mutations. In WT vegetative cell nuclei, genetically unlinked ribosomal DNA (rDNA) loci are uniquely clustered together within the nucleolus and all major rRNA gene variants, including those rDNA variants silenced in leaves, are transcribed. In cdc48a mutant vegetative cell nuclei, however, these rDNA loci frequently colocalized with condensed centromeric heterochromatin at the external periphery of the nucleolus. Our results indicate that the CDC48ANPL4 complex actively removes sumoylated CenH3 from centromeres and disrupts centromeric heterochromatin to release bulk rRNA genes into the nucleolus for ribosome production, which fuels single nucleus-driven pollen tube growth and is essential for plant reproduction. AU - Mérai, Zsuzsanna AU - Chumak, Nina AU - García-Aguilar, Marcelina AU - Hsieh, Tzung-Fu AU - Nishimura, Toshiro AU - Schoft, Vera K. AU - Bindics, János AU - Ślusarz, Lucyna AU - Arnoux, Stéphanie AU - Opravil, Susanne AU - Mechtler, Karl AU - Zilberman, Daniel AU - Fischer, Robert L. AU - Tamaru, Hisashi ID - 9479 IS - 45 JF - Proceedings of the National Academy of Sciences SN - 0027-8424 TI - The AAA-ATPase molecular chaperone Cdc48/p97 disassembles sumoylated centromeres, decondenses heterochromatin, and activates ribosomal RNA genes VL - 111 ER - TY - JOUR AB - Fractionation of isotopes among distinct molecules or phases is a quantum effect which is often exploited to obtain insights on reaction mechanisms, biochemical, geochemical, and atmospheric phenomena. Accurate evaluation of isotope ratios in atomistic simulations is challenging, because one needs to perform a thermodynamic integration with respect to the isotope mass, along with time-consuming path integral calculations. By re-formulating the problem as a particle exchange in the ring polymer partition function, we derive new estimators giving direct access to the differential partitioning of isotopes, which can simplify the calculations by avoiding thermodynamic integration. We demonstrate the efficiency of these estimators by applying them to investigate the isotope fractionation ratios in the gas-phase Zundel cation, and in a few simple hydrocarbons. AU - Cheng, Bingqing AU - Ceriotti, Michele ID - 9662 IS - 24 JF - The Journal of Chemical Physics SN - 0021-9606 TI - Direct path integral estimators for isotope fractionation ratios VL - 141 ER - TY - JOUR AB - The distribution of Coulomb blockade peak heights as a function of magnetic field is investigated experimentally in a Ge-Si nanowire quantum dot. Strong spin-orbit coupling in this hole-gas system leads to antilocalization of Coulomb blockade peaks, consistent with theory. In particular, the peak height distribution has its maximum away from zero at zero magnetic field, with an average that decreases with increasing field. Magnetoconductance in the open-wire regime places a bound on the spin-orbit length (lso < 20 nm), consistent with values extracted in the Coulomb blockade regime (lso < 25 nm). AU - Higginbotham, Andrew P AU - Kuemmeth, Ferdinand AU - Larsen, Thorvald AU - Fitzpatrick, Mattias AU - Yao, Jun AU - Yan, Hao AU - Lieber, Charles AU - Marcus, Charles ID - 97 IS - 21 JF - APS Physics, Physical Review Letters TI - Antilocalization of coulomb blockade in a Ge/Si nanowire VL - 112 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 - GEN AU - Lovrics, Anna AU - Gao, Yu AU - Juhász, Bianka AU - Bock, István AU - Byrne, Helen M. AU - Dinnyés, András AU - Kovács, Krisztián ID - 9722 TI - Transition probability between TF expression states when Dbx2 inhibits Nkx2.2 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 - 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 SN - 0340-5443 TI - Increased grooming after repeated brood care provides sanitary benefits in a clonal ant VL - 68 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 - GEN AB - The fitness effects of symbionts on their hosts can be context-dependent, with usually benign symbionts causing detrimental effects when their hosts are stressed, or typically parasitic symbionts providing protection towards their hosts (e.g. against pathogen infection). Here, we studied the novel association between the invasive garden ant Lasius neglectus and its fungal ectosymbiont Laboulbenia formicarum for potential costs and benefits. We tested ants with different Laboulbenia levels for their survival and immunity under resource limitation and exposure to the obligate killing entomopathogen Metarhizium brunneum. While survival of L. neglectus workers under starvation was significantly decreased with increasing Laboulbenia levels, host survival under Metarhizium exposure increased with higher levels of the ectosymbiont, suggesting a symbiont-mediated anti-pathogen protection, which seems to be driven mechanistically by both improved sanitary behaviours and an upregulated immune system. Ants with high Laboulbenia levels showed significantly longer self-grooming and elevated expression of immune genes relevant for wound repair and antifungal responses (β-1,3-glucan binding protein, Prophenoloxidase), compared with ants carrying low Laboulbenia levels. This suggests that the ectosymbiont Laboulbenia formicarum weakens its ant host by either direct resource exploitation or the costs of an upregulated behavioural and immunological response, which, however, provides a prophylactic protection upon later exposure to pathogens. AU - Konrad, Matthias AU - Grasse, Anna V AU - Tragust, Simon AU - Cremer, Sylvia ID - 9740 TI - Data from: Anti-pathogen protection versus survival costs mediated by an ectosymbiont in an ant host ER - TY - GEN 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 - 9741 TI - Data from: Selection history and epistatic interactions impact dynamics of adaptation to novel environmental stresses ER - TY - GEN AU - Chatterjee, Krishnendu AU - Pavlogiannis, Andreas AU - Adlam, Ben AU - Novak, Martin ID - 9739 TI - Detailed proofs for “The time scale of evolutionary innovation” ER - TY - JOUR AB - Short-read sequencing technologies have in principle made it feasible to draw detailed inferences about the recent history of any organism. In practice, however, this remains challenging due to the difficulty of genome assembly in most organisms and the lack of statistical methods powerful enough to discriminate between recent, nonequilibrium histories. We address both the assembly and inference challenges. We develop a bioinformatic pipeline for generating outgroup-rooted alignments of orthologous sequence blocks from de novo low-coverage short-read data for a small number of genomes, and show how such sequence blocks can be used to fit explicit models of population divergence and admixture in a likelihood framework. To illustrate our approach, we reconstruct the Pleistocene history of an oak-feeding insect (the oak gallwasp Biorhiza pallida), which, in common with many other taxa, was restricted during Pleistocene ice ages to a longitudinal series of southern refugia spanning the Western Palaearctic. Our analysis of sequence blocks sampled from a single genome from each of three major glacial refugia reveals support for an unexpected history dominated by recent admixture. Despite the fact that 80% of the genome is affected by admixture during the last glacial cycle, we are able to infer the deeper divergence history of these populations. These inferences are robust to variation in block length, mutation model and the sampling location of individual genomes within refugia. This combination of de novo assembly and numerical likelihood calculation provides a powerful framework for estimating recent population history that can be applied to any organism without the need for prior genetic resources. AU - Hearn, Jack AU - Stone, Graham AU - Bunnefeld, Lynsey AU - Nicholls, James AU - Barton, Nicholas H AU - Lohse, Konrad ID - 2170 IS - 1 JF - Molecular Ecology TI - Likelihood-based inference of population history from low-coverage de novo genome assemblies VL - 23 ER - TY - GEN AB - Background: The brood of ants and other social insects is highly susceptible to pathogens, particularly those that penetrate the soft larval and pupal cuticle. We here test whether the presence of a pupal cocoon, which occurs in some ant species but not in others, affects the sanitary brood care and fungal infection patterns after exposure to the entomopathogenic fungus Metarhizium brunneum. We use a) a comparative approach analysing four species with either naked or cocooned pupae and b) a within-species analysis of a single ant species, in which both pupal types co-exist in the same colony. Results: We found that the presence of a cocoon did not compromise fungal pathogen detection by the ants and that species with cocooned pupae increased brood grooming after pathogen exposure. All tested ant species further removed brood from their nests, which was predominantly expressed towards larvae and naked pupae treated with the live fungal pathogen. In contrast, cocooned pupae exposed to live fungus were not removed at higher rates than cocooned pupae exposed to dead fungus or a sham control. Consistent with this, exposure to the live fungus caused high numbers of infections and fungal outgrowth in larvae and naked pupae, but not in cocooned pupae. Moreover, the ants consistently removed the brood prior to fungal outgrowth, ensuring a clean brood chamber. Conclusion: Our study suggests that the pupal cocoon has a protective effect against fungal infection, causing an adaptive change in sanitary behaviours by the ants. It further demonstrates that brood removal - originally described for honeybees as “hygienic behaviour” – is a widespread sanitary behaviour in ants, which likely has important implications on disease dynamics in social insect colonies. AU - Tragust, Simon AU - Ugelvig, Line V AU - Chapuisat, Michel AU - Heinze, Jürgen AU - Cremer, Sylvia ID - 9753 TI - Data from: Pupal cocoons affect sanitary brood care and limit fungal infections in ant colonies ER - TY - GEN AB - Redundancies and correlations in the responses of sensory neurons may seem to waste neural resources, but they can also carry cues about structured stimuli and may help the brain to correct for response errors. To investigate the effect of stimulus structure on redundancy in retina, we measured simultaneous responses from populations of retinal ganglion cells presented with natural and artificial stimuli that varied greatly in correlation structure; these stimuli and recordings are publicly available online. Responding to spatio-temporally structured stimuli such as natural movies, pairs of ganglion cells were modestly more correlated than in response to white noise checkerboards, but they were much less correlated than predicted by a non-adapting functional model of retinal response. Meanwhile, responding to stimuli with purely spatial correlations, pairs of ganglion cells showed increased correlations consistent with a static, non-adapting receptive field and nonlinearity. We found that in response to spatio-temporally correlated stimuli, ganglion cells had faster temporal kernels and tended to have stronger surrounds. These properties of individual cells, along with gain changes that opposed changes in effective contrast at the ganglion cell input, largely explained the pattern of pairwise correlations across stimuli where receptive field measurements were possible. AU - Simmons, Kristina AU - Prentice, Jason AU - Tkačik, Gašper AU - Homann, Jan AU - Yee, Heather AU - Palmer, Stephanie AU - Nelson, Philip AU - Balasubramanian, Vijay ID - 9752 TI - Data from: Transformation of stimulus correlations by the retina ER - TY - JOUR AB - The newly discovered topological crystalline insulators feature a complex band structure involving multiple Dirac cones, and are potentially highly tunable by external electric field, temperature or strain. Theoretically, it has been predicted that the various Dirac cones, which are offset in energy and momentum, might harbour vastly different orbital character. However, their orbital texture, which is of immense importance in determining a variety of a materialâ €™ s properties remains elusive. Here, we unveil the orbital texture of Pb 1â ̂'x Sn x Se, a prototypical topological crystalline insulator. By using Fourier-transform scanning tunnelling spectroscopy we measure the interference patterns produced by the scattering of surface-state electrons. We discover that the intensity and energy dependences of the Fourier transforms show distinct characteristics, which can be directly attributed to orbital effects. Our experiments reveal a complex band topology involving two Lifshitz transitions and establish the orbital nature of the Dirac bands, which could provide an alternative pathway towards future quantum applications. AU - Zeljkovic, Ilija AU - Okada, Yoshinori AU - Huang, Chengyi AU - Sankar, Raman AU - Walkup, Daniel AU - Zhou, Wenwen AU - Maksym Serbyn AU - Chou, Fangcheng AU - Tsai, Wei-Feng AU - Lin, Hsin AU - Bansil, Arun AU - Fu, Liang AU - Hasan, Md Z AU - Madhavan, Vidya ID - 978 IS - 8 JF - Nature Physics TI - Mapping the unconventional orbital texture in topological crystalline insulators VL - 10 ER - TY - JOUR AB - In the recently discovered topological crystalline insulators SnTe and Pb1-xSnx(Te, Se), crystal symmetry and electronic topology intertwine to create topological surface states with many interesting features including Lifshitz transition, Van-Hove singularity, and fermion mass generation. These surface states are protected by mirror symmetry with respect to the (110) plane. In this work we present a comprehensive study of the effects of different mirror-symmetry-breaking perturbations on the (001) surface band structure. Pristine (001) surface states have four branches of Dirac fermions at low energy. We show that ferroelectric-type structural distortion generates a mass and gaps out some or all of these Dirac points, while strain shifts Dirac points in the Brillouin zone. An in-plane magnetic field leaves the surface state gapless, but introduces asymmetry between Dirac points. Finally, an out-of-plane magnetic field leads to discrete Landau levels. We show that the Landau level spectrum has an unusual pattern of degeneracy and interesting features due to the unique underlying band structure. This suggests that Landau level spectroscopy can detect and distinguish between different mechanisms of symmetry breaking in topological crystalline insulators. AU - Maksym Serbyn AU - Fu, Liang ID - 979 IS - 3 JF - Physical Review B - Condensed Matter and Materials Physics TI - Symmetry breaking and Landau quantization in topological crystalline insulators VL - 90 ER - TY - JOUR AB - Gene duplication is important in evolution, because it provides new raw material for evolutionary adaptations. Several existing hypotheses about the causes of duplicate retention and diversification differ in their emphasis on gene dosage, subfunctionalization, and neofunctionalization. Little experimental data exist on the relative importance of gene expression changes and changes in coding regions for the evolution of duplicate genes. Furthermore, we do not know how strongly the environment could affect this importance. To address these questions, we performed evolution experiments with the TEM-1 beta lactamase gene in Escherichia coli to study the initial stages of duplicate gene evolution in the laboratory. We mimicked tandem duplication by inserting two copies of the TEM-1 gene on the same plasmid. We then subjected these copies to repeated cycles of mutagenesis and selection in various environments that contained antibiotics in different combinations and concentrations. Our experiments showed that gene dosage is the most important factor in the initial stages of duplicate gene evolution, and overshadows the importance of point mutations in the coding region. AU - Dhar, Riddhiman AU - Bergmiller, Tobias AU - Wagner, Andreas ID - 9931 IS - 6 JF - Evolution SN - 0014-3820 TI - Increased gene dosage plays a predominant role in the initial stages of evolution of duplicate TEM-1 beta lactamase genes VL - 68 ER - TY - GEN AB - Gene duplication is important in evolution, because it provides new raw material for evolutionary adaptations. Several existing hypotheses about the causes of duplicate retention and diversification differ in their emphasis on gene dosage, sub-functionalization, and neo-functionalization. Little experimental data exists on the relative importance of gene expression changes and changes in coding regions for the evolution of duplicate genes. Furthermore, we do not know how strongly the environment could affect this importance. To address these questions, we performed evolution experiments with the TEM-1 beta lactamase gene in E. coli to study the initial stages of duplicate gene evolution in the laboratory. We mimicked tandem duplication by inserting two copies of the TEM-1 gene on the same plasmid. We then subjected these copies to repeated cycles of mutagenesis and selection in various environments that contained antibiotics in different combinations and concentrations. Our experiments showed that gene dosage is the most important factor in the initial stages of duplicate gene evolution, and overshadows the importance of point mutations in the coding region. AU - Dhar, Riddhiman AU - Bergmiller, Tobias AU - Wagner, Andreas ID - 9932 TI - Data from: Increased gene dosage plays a predominant role in the initial stages of evolution of duplicate TEM-1 beta lactamase genes ER - TY - JOUR AB - The performance of glaciohydrological models which simulate catchment response to climate variability depends to a large degree on the data used to force the models. The forcing data become increasingly important in high-elevation, glacierized catchments where the interplay between extreme topography, climate, and the cryosphere is complex. It is challenging to generate a reliable forcing data set that captures this spatial heterogeneity. In this paper, we analyze the results of a 1 year field campaign focusing on air temperature and precipitation observations in the Langtang valley in the Nepalese Himalayas. We use the observed time series to characterize both temperature lapse rates (LRs) and precipitation gradients (PGs). We study their spatial and temporal variability, and we attempt to identify possible controlling factors. We show that very clear LRs exist in the valley and that there are strong seasonal differences related to the water vapor content in the atmosphere. Results also show that the LRs are generally shallower than the commonly used environmental lapse rates. The analysis of the precipitation observations reveals that there is great variability in precipitation over short horizontal distances. A uniform valley wide PG cannot be established, and several scale-dependent mechanisms may explain our observations. We complete our analysis by showing the impact of the observed LRs and PGs on the outputs of the TOPKAPI-ETH glaciohydrological model. We conclude that LRs and PGs have a very large impact on the water balance composition and that short-term monitoring campaigns have the potential to improve model quality considerably. AU - Immerzeel, W. W. AU - Petersen, L. AU - Ragettli, S. AU - Pellicciotti, Francesca ID - 12637 IS - 3 JF - Water Resources Research KW - Water Science and Technology SN - 0043-1397 TI - The importance of observed gradients of air temperature and precipitation for modeling runoff from a glacierized watershed in the Nepalese Himalayas VL - 50 ER - TY - JOUR AB - Himalayan glacier tongues are commonly debris covered and they are an important source of melt water. However, they remain relatively unstudied because of the inaccessibility of the terrain and the difficulties in field work caused by the thick debris mantles. Observations of debris-covered glaciers are therefore scarce and airborne remote sensing may bridge the gap between scarce field observations and coarse resolution space-borne remote sensing. In this study we deploy an Unmanned Aerial Vehicle (UAV) before and after the melt and monsoon season (May and October 2013) over the debris-covered tongue of the Lirung Glacier in Nepal. Based on stereo-imaging and the structure for motion algorithm we derive highly detailed ortho-mosaics and digital elevation models (DEMs), which we geometrically correct using differential GPS observations collected in the field. Based on DEM differencing and manual feature tracking we derive the mass loss and the surface velocity of the glacier at a high spatial accuracy. On average, mass loss is limited and the surface velocity is very small. However, the spatial variability of melt rates is very high, and ice cliffs and supra-glacial ponds show mass losses that can be an order of magnitude higher than the average. We suggest that future research should focus on the interaction between supra-glacial ponds, ice cliffs and englacial hydrology to further understand the dynamics of debris-covered glaciers. Finally, we conclude that UAV deployment has large potential in glaciology and it may revolutionize methods currently applied in studying glacier surface features. AU - Immerzeel, W.W. AU - Kraaijenbrink, P.D.A. AU - Shea, J.M. AU - Shrestha, A.B. AU - Pellicciotti, Francesca AU - Bierkens, M.F.P. AU - de Jong, S.M. ID - 12636 IS - 7 JF - Remote Sensing of Environment KW - Computers in Earth Sciences KW - Geology KW - Soil Science SN - 0034-4257 TI - High-resolution monitoring of Himalayan glacier dynamics using unmanned aerial vehicles VL - 150 ER - TY - JOUR AB - Switzerland is one of the countries with some of the longest and best glaciological data sets. Its glaciers and their changes in response to climate have been extensively investigated, and the number and quality of related studies are notable. However, a comprehensive review of glacier changes and their impact on the hydrology of glacierised catchments for Switzerland is missing and we use the opportunity provided by the EU-FP7 ACQWA project to review the current state of knowledge about past changes and future projections. We examine the type of models that have been applied to infer glacier evolution and identify knowledge gaps that should be addressed in future research in addition to those indicated in previous publications. Common characteristics in long-term series of projected future glacier runoff are an initial peak followed by a decline, associated with shifts in seasonality, earlier melt onset and reduced summer runoff. However, the quantitative predictions are difficult to compare, as studies differ in terms of model structure, calibration strategies, input data, temporal and spatial resolution as well as future scenarios used for impact studies. We identify two sources of uncertainties among those emerging from recent research, and use simulations over four glaciers to: i) quantify the importance of the correct extrapolation of air temperature, and ii) point at the key role played by debris cover in modulating glacier response. AU - Pellicciotti, Francesca AU - Carenzo, M. AU - Bordoy, R. AU - Stoffel, M. ID - 12635 JF - Science of The Total Environment KW - Pollution KW - Waste Management and Disposal KW - Environmental Chemistry KW - Environmental Engineering SN - 0048-9697 TI - Changes in glaciers in the Swiss Alps and impact on basin hydrology: Current state of the art and future research VL - 493 ER - TY - JOUR AB - We investigate the performance of five glacier melt models over a multi-decadal period in order to assess their ability to model future glacier response. The models range from a simple degree-day model, based solely on air temperature, to more-sophisticated models, including the full shortwave radiation balance. In addition to the empirical models, the performance of a physically based energy-balance (EB) model is examined. The melt models are coupled to an accumulation and a surface evolution model and applied in a distributed manner to Rhonegletscher, Switzerland, over the period 1929–2012 at hourly resolution. For calibration, seasonal mass-balance measurements (2006–12) are used. Decadal ice volume changes for six periods in the years 1929–2012 serve for model validation. Over the period 2006–12, there are almost no differences in performance between the models, except for EB, which is less consistent with observations, likely due to lack of meteorological in situ data. However, simulations over the long term (1929–2012) reveal that models which include a separate term for shortwave radiation agree best with the observed ice volume changes, indicating that their melt relationships are robust in time and thus suitable for long-term modelling, in contrast to more empirical approaches that are oversensitive to temperature fluctuations. AU - Gabbi, Jeannette AU - Carenzo, Marco AU - Pellicciotti, Francesca AU - Bauder, Andreas AU - Funk, Martin ID - 12632 IS - 224 JF - Journal of Glaciology KW - Earth-Surface Processes SN - 0022-1430 TI - A comparison of empirical and physically based glacier surface melt models for long-term simulations of glacier response VL - 60 ER - TY - JOUR AB - Glaciers in the Andes of Chile seem to be shrinking and possibly loosing mass, but the number and types of studies conducted, constrained mainly by data availability, are not sufficient to provide a synopsis of glacier changes for the past or future or explain in an explicit way causes of the observed changes. In this paper, we provide a systematic review of changes in glaciers for the entire country, followed by a discussion of the studies that have provided evidence of such changes. We identify a missing type of work in distributed, physically-oriented modelling studies that are needed to bridge the gap between the numerous remote sensing studies and the specific, point scale works focused on process understanding. We use an advanced mass balance model applied to one of the best monitored glaciers in the region to investigate four main research issues that should be addressed in modelling studies for a sound assessment of glacier changes: 1) the use of physically-based models of glacier ablation (energy balance models) versus more empirical models (enhanced temperature index approaches); 2) the importance of the correct extrapolation of air temperature forcing on glaciers and in high elevation areas and the large uncertainty in model outputs associated with it; 3) the role played by snow gravitational redistribution; and 4) the uncertainty associated with future climate scenarios. We quantify differences in model outputs associated with each of these choices, and conclude with suggestions for future work directions. AU - Pellicciotti, Francesca AU - Ragettli, S. AU - Carenzo, M. AU - McPhee, J. ID - 12634 JF - Science of The Total Environment KW - Pollution KW - Waste Management and Disposal KW - Environmental Chemistry KW - Environmental Engineering SN - 0048-9697 TI - Changes of glaciers in the Andes of Chile and priorities for future work VL - 493 ER - TY - JOUR AB - Nature has long inspired scientists with its seemingly unlimited ability to harness solar energy and to utilize it to drive various physiological processes. With the help of man-made molecular photoswitches, we now have the potential to outperform natural systems in many ways, with the ultimate goal of fabricating multifunctional materials that operate at different light wavelengths. An important challenge in developing light-controlled artificial molecular machines lies in attaining a detailed understanding of the photoisomerization-coupled conformational changes that occur in macromolecules and molecular assemblies. In this issue of ACS Nano, Bléger, Rabe, and co-workers use force microscopy to provide interesting insights into the behavior of individual photoresponsive molecules and to identify contraction, extension, and crawling events accompanying light-induced isomerization. AU - Kundu, Pintu K. AU - Klajn, Rafal ID - 13399 IS - 12 JF - ACS Nano KW - General Physics and Astronomy KW - General Engineering KW - General Materials Science SN - 1936-0851 TI - Watching single molecules move in response to light VL - 8 ER - TY - JOUR AB - Nanoporous frameworks are polymeric materials built from rigid molecules, which give rise to their nanoporous structures with applications in gas sorption and storage, catalysis and others. Conceptually new applications could emerge, should these beneficial properties be manipulated by external stimuli in a reversible manner. One approach to render nanoporous frameworks responsive to external signals would be to immobilize molecular switches within their nanopores. Although the majority of molecular switches require conformational freedom to isomerize, and switching in the solid state is prohibited, the nanopores may provide enough room for the switches to efficiently isomerize. Here we describe two families of nanoporous materials incorporating the spiropyran molecular switch. These materials exhibit a variety of interesting properties, including reversible photochromism and acidochromism under solvent-free conditions, light-controlled capture and release of metal ions, as well reversible chromism induced by solvation/desolvation. AU - Kundu, Pintu K. AU - Olsen, Gregory L. AU - Kiss, Vladimir AU - Klajn, Rafal ID - 13402 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry KW - Multidisciplinary TI - Nanoporous frameworks exhibiting multiple stimuli responsiveness VL - 5 ER - TY - JOUR AB - Organizing inorganic nanocrystals into complex architectures is challenging and typically relies on preexisting templates, such as properly folded DNA or polypeptide chains. We found that under carefully controlled conditions, cubic nanocrystals of magnetite self-assemble into arrays of helical superstructures in a template-free manner with >99% yield. Computer simulations revealed that the formation of helices is determined by the interplay of van der Waals and magnetic dipole-dipole interactions, Zeeman coupling, and entropic forces and can be attributed to spontaneous formation of chiral nanocube clusters. Neighboring helices within their densely packed ensembles tended to adopt the same handedness in order to maximize packing, thus revealing a novel mechanism of symmetry breaking and chirality amplification. AU - Singh, Gurvinder AU - Chan, Henry AU - Baskin, Artem AU - Gelman, Elijah AU - Repnin, Nikita AU - Král, Petr AU - Klajn, Rafal ID - 13400 IS - 6201 JF - Science KW - Multidisciplinary SN - 0036-8075 TI - Self-assembly of magnetite nanocubes into helical superstructures VL - 345 ER - TY - JOUR AB - In the past few years, spiropyran has emerged as the molecule-of-choice for the construction of novel dynamic materials. This unique molecular switch undergoes structural isomerisation in response to a variety of orthogonal stimuli, e.g. light, temperature, metal ions, redox potential, and mechanical stress. Incorporation of this switch onto macromolecular supports or inorganic scaffolds allows for the creation of robust dynamic materials. This review discusses the synthesis, switching conditions, and use of dynamic materials in which spiropyran has been attached to the surfaces of polymers, biomacromolecules, inorganic nanoparticles, as well as solid surfaces. The resulting materials show fascinating properties whereby the state of the switch intimately affects a multitude of useful properties of the support. The utility of the spiropyran switch will undoubtedly endow these materials with far-reaching applications in the near future. AU - Klajn, Rafal ID - 13404 IS - 1 JF - Chemical Society Reviews KW - General Chemistry SN - 0306-0012 TI - Spiropyran-based dynamic materials VL - 43 ER - TY - JOUR AB - A compound combining the features of a molecular rotor and a photoswitch was synthesized and was shown to exist as three diastereomers, which interconvert via a reversible cyclic reaction scheme. Each of the three diastereomers was isolated, and by following the equilibration kinetics, activation barriers for all reactions were calculated. The results indicate that the properties of molecular switches depend heavily on their immediate chemical environment. The conclusions are important in the context of designing new switchable molecules and materials. AU - Kundu, Pintu K. AU - Lerner, Avishai AU - Kučanda, Kristina AU - Leitus, Gregory AU - Klajn, Rafal ID - 13401 IS - 32 JF - Journal of the American Chemical Society KW - Colloid and Surface Chemistry KW - Biochemistry KW - General Chemistry KW - Catalysis SN - 0002-7863 TI - Cyclic kinetics during thermal equilibration of an axially chiral bis-spiropyran VL - 136 ER - TY - JOUR AB - We show that bimolecular reactions between species confined to the surfaces of nanoparticles can be manipulated by the nature of the linker, as well as by the curvature of the underlying particles. AU - Zdobinsky, Tino AU - Sankar Maiti, Pradipta AU - Klajn, Rafal ID - 13403 IS - 7 JF - Journal of the American Chemical Society KW - Colloid and Surface Chemistry KW - Biochemistry KW - General Chemistry KW - Catalysis SN - 0002-7863 TI - Support curvature and conformational freedom control chemical reactivity of immobilized species VL - 136 ER - TY - JOUR AB - The sensitivities of high-harmonic generation (HHG) and strong-field ionization (SFI) to coupled electronic and nuclear dynamics are studied, using the nitric oxide (NO) molecule as an example. A coherent superposition of electronic and rotational states of NO is prepared by impulsive stimulated Raman scattering and probed by simultaneous detection of HHG and SFI yields. We observe a fourfold higher sensitivity of high-harmonic generation to electronic dynamics and attribute it to the presence of inelastic quantum paths connecting coherently related electronic states [Kraus et al., Phys. Rev. Lett.111, 243005 (2013)]. Whereas different harmonic orders display very different sensitivities to rotational or electronic dynamics, strong-field ionization is found to be most sensitive to electronic motion. We introduce a general theoretical formalism for high-harmonic generation from coupled nuclear-electronic wave packets. We show that the unequal sensitivities of different harmonic orders to electronic or rotational dynamics result from the angle dependence of the photorecombination matrix elements which encode several autoionizing and shape resonances in the photoionization continuum of NO. We further study the dependence of rotational and electronic coherences on the intensity of the excitation pulse and support the observations with calculations. AU - Baykusheva, Denitsa Rangelova AU - Kraus, Peter M. AU - Zhang, Song Bin AU - Rohringer, Nina AU - Wörner, Hans Jakob ID - 14018 JF - Faraday Discussions KW - Physical and Theoretical Chemistry SN - 1359-6640 TI - The sensitivities of high-harmonic generation and strong-field ionization to coupled electronic and nuclear dynamics VL - 171 ER - TY - JOUR AB - The cyclopropene radical cation (c-C3H₄⁺) is an important but poorly characterized three-membered-ring hydrocarbon. We report on a measurement of the high-resolution photoelectron and photoionization spectra of cyclopropene and several deuterated isotopomers, from which we have determined the rovibrational energy level structure of the X⁺ (2)B2 ground electronic state of c-C3H₄⁺ at low energies for the first time. The synthesis of the partially deuterated isotopomers always resulted in mixtures of several isotopomers, differing in their number of D atoms and in the location of these atoms, so that the photoelectron spectra of deuterated samples are superpositions of the spectra of several isotopomers. The rotationally resolved spectra indicate a C(2v)-symmetric R0 structure for the ground electronic state of c-C3H₄⁺. Two vibrational modes of c-C3H₄⁺ are found to have vibrational wave numbers below 300 cm(-1), which is surprising for such a small cyclic hydrocarbon. The analysis of the isotopic shifts of the vibrational levels enabled the assignment of the lowest-frequency mode (fundamental wave number of ≈110 cm(-1) in c-C3H₄⁺) to the CH2 torsional mode (ν₈⁺, A2 symmetry) and of the second-lowest-frequency mode (≈210 cm(-1) in c-C3H₄⁺) to a mode combining a CH out-of-plane with a CH2 rocking motion (ν₁₅⁺, B2 symmetry). The potential energy along the CH2 torsional coordinate is flat near the equilibrium structure and leads to a pronounced anharmonicity. AU - Vasilatou, K. AU - Michaud, J. M. AU - Baykusheva, Denitsa Rangelova AU - Grassi, G. AU - Merkt, F. ID - 14019 IS - 6 JF - The Journal of Chemical Physics KW - Physical and Theoretical Chemistry KW - General Physics and Astronomy SN - 0021-9606 TI - The cyclopropene radical cation: Rovibrational level structure at low energies from high-resolution photoelectron spectra VL - 141 ER - TY - JOUR AB - We present the detailed analysis of a new two-pulse orientation scheme that achieves macroscopic field-free orientation at the high particle densities required for attosecond and high-harmonic spectroscopies (Kraus et al 2013 arXiv:1311.3923). Carbon monoxide molecules are oriented by combining one-colour and delayed two-colour non-resonant femtosecond laser pulses. High-harmonic generation is used to probe the oriented wave-packet dynamics and reveals that a very high degree of orientation (Nup/Ntotal = 0.73–0.82) is achieved. We further extend this approach to orienting carbonyl sulphide molecules. We show that the present two-pulse scheme selectively enhances orientation created by the hyperpolarizability interaction whereas the ionization-depletion mechanism plays no role. We further control and optimize orientation through the delay between the one- and two-colour pump pulses. Finally, we demonstrate a complementary encoding of electronic-structure features, such as shape resonances, in the even- and odd-harmonic spectrum. The achieved progress makes two-pulse field-free orientation an attractive tool for a broad class of time-resolved measurements. AU - Kraus, P M AU - Baykusheva, Denitsa Rangelova AU - Wörner, H J ID - 14021 IS - 12 JF - Journal of Physics B: Atomic, Molecular and Optical Physics KW - Condensed Matter Physics KW - Atomic and Molecular Physics KW - and Optics SN - 0953-4075 TI - Two-pulse orientation dynamics and high-harmonic spectroscopy of strongly-oriented molecules VL - 47 ER - TY - JOUR AB - We report the observation of macroscopic field-free orientation, i.e., more than 73% of CO molecules pointing in the same direction. This is achieved through an all-optical scheme operating at high particle densities (>10(17)  cm(-3)) that combines one-color (ω) and two-color (ω+2ω) nonresonant femtosecond laser pulses. We show that the achieved orientation solely relies on the hyperpolarizability interaction as opposed to an ionization-depletion mechanism, thus, opening a wide range of applications. The achieved strong orientation enables us to reveal the molecular-frame anisotropies of the photorecombination amplitudes and phases caused by a shape resonance. The resonance appears as a local maximum in the even-harmonic emission around 28 eV. In contrast, the odd-harmonic emission is suppressed in this spectral region through the combined effects of an asymmetric photorecombination phase and a subcycle Stark effect, generic for polar molecules, that we experimentally identify. AU - Kraus, P. M. AU - Baykusheva, Denitsa Rangelova AU - Wörner, H. J. ID - 14020 IS - 2 JF - Physical Review Letters KW - General Physics and Astronomy SN - 0031-9007 TI - Two-pulse field-free orientation reveals anisotropy of molecular shape resonance VL - 113 ER - TY - JOUR AB - Energy games belong to a class of turn-based two-player infinite-duration games played on a weighted directed graph. It is one of the rare and intriguing combinatorial problems that lie in NP∩co-NP, but are not known to be in P. The existence of polynomial-time algorithms has been a major open problem for decades and apart from pseudopolynomial algorithms there is no algorithm that solves any non-trivial subclass in polynomial time. In this paper, we give several results based on the weight structures of the graph. First, we identify a notion of penalty and present a polynomial-time algorithm when the penalty is large. Our algorithm is the first polynomial-time algorithm on a large class of weighted graphs. It includes several worst-case instances on which previous algorithms, such as value iteration and random facet algorithms, require at least sub-exponential time. Our main technique is developing the first non-trivial approximation algorithm and showing how to convert it to an exact algorithm. Moreover, we show that in a practical case in verification where weights are clustered around a constant number of values, the energy game problem can be solved in polynomial time. We also show that the problem is still as hard as in general when the clique-width is bounded or the graph is strongly ergodic, suggesting that restricting the graph structure does not necessarily help. AU - Chatterjee, Krishnendu AU - Henzinger, Monika H AU - Krinninger, Sebastian AU - Nanongkai, Danupon ID - 535 IS - 3 JF - Algorithmica TI - Polynomial-time algorithms for energy games with special weight structures VL - 70 ER - TY - CONF AB - We propose a method for visualizing two-dimensional symmetric positive definite tensor fields using the Heat Kernel Signature (HKS). The HKS is derived from the heat kernel and was originally introduced as an isometry invariant shape signature. Each positive definite tensor field defines a Riemannian manifold by considering the tensor field as a Riemannian metric. On this Riemmanian manifold we can apply the definition of the HKS. The resulting scalar quantity is used for the visualization of tensor fields. The HKS is closely related to the Gaussian curvature of the Riemannian manifold and the time parameter of the heat kernel allows a multiscale analysis in a natural way. In this way, the HKS represents field related scale space properties, enabling a level of detail analysis of tensor fields. This makes the HKS an interesting new scalar quantity for tensor fields, which differs significantly from usual tensor invariants like the trace or the determinant. A method for visualization and a numerical realization of the HKS for tensor fields is proposed in this chapter. To validate the approach we apply it to some illustrating simple examples as isolated critical points and to a medical diffusion tensor data set. AU - Zobel, Valentin AU - Reininghaus, Jan AU - Hotz, Ingrid ID - 10886 SN - 1612-3786 T2 - Topological Methods in Data Analysis and Visualization III TI - Visualization of two-dimensional symmetric positive definite tensor fields using the heat kernel signature ER - TY - CHAP AB - Mechanically coupled cells can generate forces driving cell and tissue morphogenesis during development. Visualization and measuring of these forces is of major importance to better understand the complexity of the biomechanic processes that shape cells and tissues. Here, we describe how UV laser ablation can be utilized to quantitatively assess mechanical tension in different tissues of the developing zebrafish and in cultures of primary germ layer progenitor cells ex vivo. AU - Smutny, Michael AU - Behrndt, Martin AU - Campinho, Pedro AU - Ruprecht, Verena AU - Heisenberg, Carl-Philipp J ED - Nelson, Celeste ID - 6178 SN - 1064-3745 T2 - Tissue Morphogenesis TI - UV laser ablation to measure cell and tissue-generated forces in the zebrafish embryo in vivo and ex vivo VL - 1189 ER - TY - JOUR AB - We review recent progress towards a rigorous understanding of the excitation spectrum of bosonic quantum many-body systems. In particular, we explain how one can rigorously establish the predictions resulting from the Bogoliubov approximation in the mean field limit. The latter predicts that the spectrum is made up of elementary excitations, whose energy behaves linearly in the momentum for small momentum. This property is crucial for the superfluid behavior of the system. We also discuss a list of open problems in this field. AU - Seiringer, Robert ID - 10814 JF - Jahresbericht der Deutschen Mathematiker-Vereinigung KW - General Medicine SN - 0012-0456 TI - The excitation spectrum for Bose fluids with weak interactions VL - 116 ER - TY - CHAP AB - The Morse-Smale complex can be either explicitly or implicitly represented. Depending on the type of representation, the simplification of the Morse-Smale complex works differently. In the explicit representation, the Morse-Smale complex is directly simplified by explicitly reconnecting the critical points during the simplification. In the implicit representation, on the other hand, the Morse-Smale complex is given by a combinatorial gradient field. In this setting, the simplification changes the combinatorial flow, which yields an indirect simplification of the Morse-Smale complex. The topological complexity of the Morse-Smale complex is reduced in both representations. However, the simplifications generally yield different results. In this chapter, we emphasize properties of the two representations that cause these differences. We also provide a complexity analysis of the two schemes with respect to running time and memory consumption. AU - Günther, David AU - Reininghaus, Jan AU - Seidel, Hans-Peter AU - Weinkauf, Tino ED - Bremer, Peer-Timo ED - Hotz, Ingrid ED - Pascucci, Valerio ED - Peikert, Ronald ID - 10817 SN - 1612-3786 T2 - Topological Methods in Data Analysis and Visualization III. TI - Notes on the simplification of the Morse-Smale complex ER - TY - THES AB - In this thesis I studied various individual and social immune defences employed by the invasive garden ant Lasius neglectus mostly against entomopathogenic fungi. The first two chapters of this thesis address the phenomenon of 'social immunisation'. Social immunisation, that is the immunological protection of group members due to social contact to a pathogen-exposed nestmate, has been described in various social insect species against different types of pathogens. However, in the case of entomopathogenic fungi it has, so far, only been demonstrated that social immunisation exists at all. Its underlying mechanisms r any other properties were, however, unknown. In the first chapter of this thesis I identified the mechanistic basis of social immunisation in L. neglectus against the entomopathogenous fungus Metarhizium. I could show that nestmates of a pathogen-exposed individual contract low-level infections due to social interactions. These low-level infections are, however, non-lethal and cause an active stimulation of the immune system, which protects the nestmates upon subsequent pathogen encounters. In the second chapter of this thesis I investigated the specificity and colony level effects of social immunisation. I demonstrated that the protection conferred by social immunisation is highly specific, protecting ants only against the same pathogen strain. In addition, depending on the respective context, social immunisation may even cause fitness costs. I further showed that social immunisation crucially affects sanitary behaviour and disease dynamics within ant groups. In the third chapter of this thesis I studied the effects of the ectosymbiotic fungus Laboulbenia formicarum on its host L. neglectus. Although Laboulbeniales are the largest order of insect-parasitic fungi, research concerning host fitness consequence is sparse. I showed that highly Laboulbenia-infected ants sustain fitness costs under resource limitation, however, gain fitness benefits when exposed to an entomopathogenus fungus. These effects are probably cause by a prophylactic upregulation of behavioural as well as physiological immune defences in highly infected ants. AU - Konrad, Matthias ID - 1395 SN - 2663-337X TI - Immune defences in ants: Effects of social immunisation and a fungal ectosymbiont in the ant Lasius neglectus ER - TY - THES AB - Phosphatidylinositol (Ptdlns) is a structural phospholipid that can be phosphorylated into various lipid signaling molecules, designated polyphosphoinositides (PPIs). The reversible phosphorylation of PPIs on the 3, 4, or 5 position of inositol is performed by a set of organelle-specific kinases and phosphatases, and the characteristic head groups make these molecules ideal for regulating biological processes in time and space. In yeast and mammals, Ptdlns3P and Ptdlns(3,5)P2 play crucial roles in trafficking toward the lytic compartments, whereas the role in plants is not yet fully understood. Here we identified the role of a land plant-specific subgroup of PPI phosphatases, the suppressor of actin 2 (SAC2) to SAC5, during vauolar trafficking and morphogenesis in Arabidopsis thaliana. SAC2-SAC5 localize to the tonoplast along with Ptdlns3P, the presumable product of their activity. in SAC gain- and loss-of-function mutants, the levels of Ptdlns monophosphates and bisphosphates were changed, with opposite effects on the morphology of storage and lytic vacuoles, and the trafficking toward the vacuoles was defective. Moreover, multiple sac knockout mutants had an increased number of smaller storage and lytic vacuoles, whereas extralarge vacuoles were observed in the overexpression lines, correlating with various growth and developmental defects. The fragmented vacuolar phenotype of sac mutants could be mimicked by treating wild-type seedlings with Ptdlns(3,5)P2, corroborating that this PPI is important for vacuole morphology. Taken together, these results provide evidence that PPIs, together with their metabolic enzymes SAC2-SAC5, are crucial for vacuolar trafficking and for vacuolar morphology and function in plants. AU - Marhavá, Petra ID - 1402 SN - 2663-337X TI - Molecular mechanisms of patterning and subcellular trafficking in Arabidopsis thaliana ER - TY - JOUR AB - Motivated by applications in biology, we present an algorithm for estimating the length of tube-like shapes in 3-dimensional Euclidean space. In a first step, we combine the tube formula of Weyl with integral geometric methods to obtain an integral representation of the length, which we approximate using a variant of the Koksma-Hlawka Theorem. In a second step, we use tools from computational topology to decrease the dependence on small perturbations of the shape. We present computational experiments that shed light on the stability and the convergence rate of our algorithm. AU - Edelsbrunner, Herbert AU - Pausinger, Florian ID - 2255 IS - 1 JF - Journal of Mathematical Imaging and Vision SN - 09249907 TI - Stable length estimates of tube-like shapes VL - 50 ER - TY - CONF AB - Motivated by topological Tverberg-type problems, we consider multiple (double, triple, and higher multiplicity) selfintersection points of maps from finite simplicial complexes (compact polyhedra) into ℝd and study conditions under which such multiple points can be eliminated. The most classical case is that of embeddings (i.e., maps without double points) of a κ-dimensional complex K into ℝ2κ. For this problem, the work of van Kampen, Shapiro, and Wu provides an efficiently testable necessary condition for embeddability (namely, vanishing of the van Kampen ob-struction). For κ ≥ 3, the condition is also sufficient, and yields a polynomial-time algorithm for deciding embeddability: One starts with an arbitrary map f : K→ℝ2κ, which generically has finitely many double points; if k ≥ 3 and if the obstruction vanishes then one can successively remove these double points by local modifications of the map f. One of the main tools is the famous Whitney trick that permits eliminating pairs of double points of opposite intersection sign. We are interested in generalizing this approach to intersection points of higher multiplicity. We call a point y 2 ℝd an r-fold Tverberg point of a map f : Kκ →ℝd if y lies in the intersection f(σ1)∩. ∩f(σr) of the images of r pairwise disjoint simplices of K. The analogue of (non-)embeddability that we study is the problem Tverbergκ r→d: Given a κ-dimensional complex K, does it satisfy a Tverberg-type theorem with parameters r and d, i.e., does every map f : K κ → ℝd have an r-fold Tverberg point? Here, we show that for fixed r, κ and d of the form d = rm and k = (r-1)m, m ≥ 3, there is a polynomial-time algorithm for deciding this (based on the vanishing of a cohomological obstruction, as in the case of embeddings). Our main tool is an r-fold analogue of the Whitney trick: Given r pairwise disjoint simplices of K such that the intersection of their images contains two r-fold Tverberg points y+ and y- of opposite intersection sign, we can eliminate y+ and y- by a local isotopy of f. In a subsequent paper, we plan to develop this further and present a generalization of the classical Haeiger-Weber Theorem (which yields a necessary and sufficient condition for embeddability of κ-complexes into ℝd for a wider range of dimensions) to intersection points of higher multiplicity. AU - Mabillard, Isaac AU - Wagner, Uli ID - 2159 T2 - Proceedings of the Annual Symposium on Computational Geometry TI - Eliminating Tverberg points, I. An analogue of the Whitney trick ER - TY - JOUR AB - Understanding the evolution of dispersal is essential for understanding and predicting the dynamics of natural populations. Two main factors are known to influence dispersal evolution: spatio-temporal variation in the environment and relatedness between individuals. However, the relation between these factors is still poorly understood, and they are usually treated separately. In this article, I present a theoretical framework that contains and connects effects of both environmental variation and relatedness, and reproduces and extends their known features. Spatial habitat variation selects for balanced dispersal strategies, whereby the population is kept at an ideal free distribution. Within this class of dispersal strategies, I explain how increased dispersal is promoted by perturbations to the dispersal type frequencies. An explicit formula shows the magnitude of the selective advantage of increased dispersal in terms of the spatial variability in the frequencies of the different dispersal strategies present. These variances are capable of capturing various sources of stochasticity and hence establish a common scale for their effects on the evolution of dispersal. The results furthermore indicate an alternative approach to identifying effects of relatedness on dispersal evolution. AU - Novak, Sebastian ID - 2023 IS - 24 JF - Ecology and Evolution TI - Habitat heterogeneities versus spatial type frequency variances as driving forces of dispersal evolution VL - 4 ER - TY - CONF AB - While fixing concurrency bugs, program repair algorithms may introduce new concurrency bugs. We present an algorithm that avoids such regressions. The solution space is given by a set of program transformations we consider in the repair process. These include reordering of instructions within a thread and inserting atomic sections. The new algorithm learns a constraint on the space of candidate solutions, from both positive examples (error-free traces) and counterexamples (error traces). From each counterexample, the algorithm learns a constraint necessary to remove the errors. From each positive examples, it learns a constraint that is necessary in order to prevent the repair from turning the trace into an error trace. We implemented the algorithm and evaluated it on simplified Linux device drivers with known bugs. AU - Cerny, Pavol AU - Henzinger, Thomas A AU - Radhakrishna, Arjun AU - Ryzhyk, Leonid AU - Tarrach, Thorsten ID - 2218 SN - 978-331908866-2 TI - Regression-free synthesis for concurrency VL - 8559 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 - 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 - 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 - 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 - Kupffer's vesicle (KV) is the zebrafish organ of laterality, patterning the embryo along its left-right (LR) axis. Regional differences in cell shape within the lumen-lining KV epithelium are essential for its LR patterning function. However, the processes by which KV cells acquire their characteristic shapes are largely unknown. Here, we show that the notochord induces regional differences in cell shape within KV by triggering extracellular matrix (ECM) accumulation adjacent to anterior-dorsal (AD) regions of KV. This localized ECM deposition restricts apical expansion of lumen-lining epithelial cells in AD regions of KV during lumen growth. Our study provides mechanistic insight into the processes by which KV translates global embryonic patterning into regional cell shape differences required for its LR symmetry-breaking function. AU - Compagnon, Julien AU - Barone, Vanessa AU - Rajshekar, Srivarsha AU - Kottmeier, Rita AU - Pranjic-Ferscha, Kornelija AU - Behrndt, Martin AU - Heisenberg, Carl-Philipp J ID - 1912 IS - 6 JF - Developmental Cell TI - The notochord breaks bilateral symmetry by controlling cell shapes in the Zebrafish laterality organ VL - 31 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 - 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 - CONF AB - PHAT is a C++ library for the computation of persistent homology by matrix reduction. We aim for a simple generic design that decouples algorithms from data structures without sacrificing efficiency or user-friendliness. This makes PHAT a versatile platform for experimenting with algorithmic ideas and comparing them to state of the art implementations. AU - Bauer, Ulrich AU - Kerber, Michael AU - Reininghaus, Jan AU - Wagner, Hubert ID - 10894 SN - 0302-9743 T2 - ICMS 2014: International Congress on Mathematical Software TI - PHAT – Persistent Homology Algorithms Toolbox VL - 8592 ER - TY - GEN AB - Simulation is an attractive alternative for language inclusion for automata as it is an under-approximation of language inclusion, but usually has much lower complexity. For non-deterministic automata, while language inclusion is PSPACE-complete, simulation can be computed in polynomial time. Simulation has also been extended in two orthogonal directions, namely, (1) fair simulation, for simulation over specified set of infinite runs; and (2) quantitative simulation, for simulation between weighted automata. Again, while fair trace inclusion is PSPACE-complete, fair simulation can be computed in polynomial time. For weighted automata, the (quantitative) language inclusion problem is undecidable for mean-payoff automata and the decidability is open for discounted-sum automata, whereas the (quantitative) simulation reduce to mean-payoff games and discounted-sum games, which admit pseudo-polynomial time algorithms. In this work, we study (quantitative) simulation for weighted automata with Büchi acceptance conditions, i.e., we generalize fair simulation from non-weighted automata to weighted automata. We show that imposing Büchi acceptance conditions on weighted automata changes many fundamental properties of the simulation games. For example, whereas for mean-payoff and discounted-sum games, the players do not need memory to play optimally; we show in contrast that for simulation games with Büchi acceptance conditions, (i) for mean-payoff objectives, optimal strategies for both players require infinite memory in general, and (ii) for discounted-sum objectives, optimal strategies need not exist for both players. While the simulation games with Büchi acceptance conditions are more complicated (e.g., due to infinite-memory requirements for mean-payoff objectives) as compared to their counterpart without Büchi acceptance conditions, we still present pseudo-polynomial time algorithms to solve simulation games with Büchi acceptance conditions for both weighted mean-payoff and weighted discounted-sum automata. AU - Chatterjee, Krishnendu AU - Henzinger, Thomas A AU - Otop, Jan AU - Velner, Yaron ID - 5428 SN - 2664-1690 TI - Quantitative fair simulation games ER - TY - JOUR AU - Cremer, Sylvia ID - 1887 JF - Zoologie TI - Gemeinsame Krankheitsabwehr in Ameisengesellschaften ER - TY - JOUR AB - The cerebral cortex, the seat of our cognitive abilities, is composed of an intricate network of billions of excitatory projection and inhibitory interneurons. Postmitotic cortical neurons are generated by a diverse set of neural stem cell progenitors within dedicated zones and defined periods of neurogenesis during embryonic development. Disruptions in neurogenesis can lead to alterations in the neuronal cytoarchitecture, which is thought to represent a major underlying cause for several neurological disorders, including microcephaly, autism and epilepsy. Although a number of signaling pathways regulating neurogenesis have been described, the precise cellular and molecular mechanisms regulating the functional neural stem cell properties in cortical neurogenesis remain unclear. Here, we discuss the most up-to-date strategies to monitor the fundamental mechanistic parameters of neuronal progenitor proliferation, and recent advances deciphering the logic and dynamics of neurogenesis. AU - Postiglione, Maria P AU - Hippenmeyer, Simon ID - 2175 IS - 3 JF - Future Neurology SN - 1479-6708 TI - Monitoring neurogenesis in the cerebral cortex: an update VL - 9 ER - TY - JOUR AB - Deposits of phosphorylated tau protein and convergence of pathology in the hippocampus are the hallmarks of neurodegenerative tauopathies. Thus we aimed to evaluate whether regional and cellular vulnerability patterns in the hippocampus distinguish tauopathies or are influenced by their concomitant presence. Methods: We created a heat map of phospho-tau (AT8) immunoreactivity patterns in 24 hippocampal subregions/layers in individuals with Alzheimer's disease (AD)-related neurofibrillary degeneration (n = 40), Pick's disease (n = 8), progressive supranuclear palsy (n = 7), corticobasal degeneration (n = 6), argyrophilic grain disease (AGD, n = 18), globular glial tauopathy (n = 5), and tau-astrogliopathy of the elderly (n = 10). AT8 immunoreactivity patterns were compared by mathematical analysis. Results: Our study reveals disease-specific hot spots and regional selective vulnerability for these disorders. The pattern of hippocampal AD-related tau pathology is strongly influenced by concomitant AGD. Mathematical analysis reveals that hippocampal involvement in primary tauopathies is distinguishable from early-stage AD-related neurofibrillary degeneration. Conclusion: Our data demonstrate disease-specific AT8 immunoreactivity patterns and hot spots in the hippocampus even in tauopathies, which primarily do not affect the hippocampus. These hot spots can be shifted to other regions by the co-occurrence of tauopathies like AGD. Our observations support the notion that globular glial tauopathies and tau-astrogliopathy of the elderly are distinct entities. AU - Milenković, Ivan AU - Petrov, Tatjana AU - Kovács, Gábor ID - 1913 IS - 5-6 JF - Dementia and Geriatric Cognitive Disorders SN - 1420-8008 TI - Patterns of hippocampal tau pathology differentiate neurodegenerative dementias VL - 38 ER - TY - CONF AB - The Wigner-Dyson-Gaudin-Mehta conjecture asserts that the local eigenvalue statistics of large real and complex Hermitian matrices with independent, identically distributed entries are universal in a sense that they depend only on the symmetry class of the matrix and otherwise are independent of the details of the distribution. We present the recent solution to this half-century old conjecture. We explain how stochastic tools, such as the Dyson Brownian motion, and PDE ideas, such as De Giorgi-Nash-Moser regularity theory, were combined in the solution. We also show related results for log-gases that represent a universal model for strongly correlated systems. Finally, in the spirit of Wigner’s original vision, we discuss the extensions of these universality results to more realistic physical systems such as random band matrices. AU - Erdös, László ID - 1507 T2 - Proceedings of the International Congress of Mathematicians TI - Random matrices, log-gases and Hölder regularity VL - 3 ER - TY - CONF AB - Many questions concerning models in quantum mechanics require a detailed analysis of the spectrum of the corresponding Hamiltonian, a linear operator on a suitable Hilbert space. Of particular relevance for an understanding of the low-temperature properties of a system is the structure of the excitation spectrum, which is the part of the spectrum close to the spectral bottom. We present recent progress on this question for bosonic many-body quantum systems with weak two-body interactions. Such system are currently of great interest, due to their experimental realization in ultra-cold atomic gases. We investigate the accuracy of the Bogoliubov approximations, which predicts that the low-energy spectrum is made up of sums of elementary excitations, with linear dispersion law at low momentum. The latter property is crucial for the superfluid behavior the system. AU - Seiringer, Robert ID - 8044 SN - 9788961058063 T2 - Proceeding of the International Congress of Mathematicans TI - Structure of the excitation spectrum for many-body quantum systems VL - 3 ER -