TY - JOUR
AB - To reveal the full potential of human pluripotent stem cells, new methods for rapid, site-specific genomic engineering are needed. Here, we describe a system for precise genetic modification of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We identified a novel human locus, H11, located in a safe, intergenic, transcriptionally active region of chromosome 22, as the recipient site, to provide robust, ubiquitous expression of inserted genes. Recipient cell lines were established by site-specific placement of a ‘landing pad’ cassette carrying attP sites for phiC31 and Bxb1 integrases at the H11 locus by spontaneous or TALEN-assisted homologous recombination. Dual integrase cassette exchange (DICE) mediated by phiC31 and Bxb1 integrases was used to insert genes of interest flanked by phiC31 and Bxb1 attB sites at the H11 locus, replacing the landing pad. This system provided complete control over content, direction and copy number of inserted genes, with a specificity of 100%. A series of genes, including mCherry and various combinations of the neural transcription factors LMX1a, FOXA2 and OTX2, were inserted in recipient cell lines derived from H9 ESC, as well as iPSC lines derived from a Parkinson’s disease patient and a normal sibling control. The DICE system offers rapid, efficient and precise gene insertion in ESC and iPSC and is particularly well suited for repeated modifications of the same locus.
AU - Zhu, Fangfang
AU - Gamboa, Matthew
AU - Farruggio, Alfonso
AU - Hippenmeyer, Simon
AU - Tasic, Bosiljka
AU - Schüle, Birgitt
AU - Chen Tsai, Yanru
AU - Calos, Michele
ID - 2261
IS - 5
JF - Nucleic Acids Research
TI - DICE, an efficient system for iterative genomic editing in human pluripotent stem cells
VL - 42
ER -
TY - CHAP
AB - Coordinated migration of newly-born neurons to their target territories is essential for correct neuronal circuit assembly in the developing brain. Although a cohort of signaling pathways has been implicated in the regulation of cortical projection neuron migration, the precise molecular mechanisms and how a balanced interplay of cell-autonomous and non-autonomous functions of candidate signaling molecules controls the discrete steps in the migration process, are just being revealed. In this chapter, I will focally review recent advances that improved our understanding of the cell-autonomous and possible cell-nonautonomous functions of the evolutionarily conserved LIS1/NDEL1-complex in regulating the sequential steps of cortical projection neuron migration. I will then elaborate on the emerging concept that the Reelin signaling pathway, acts exactly at precise stages in the course of cortical projection neuron migration. Lastly, I will discuss how finely tuned transcriptional programs and downstream effectors govern particular aspects in driving radial migration at discrete stages and how they regulate the precise positioning of cortical projection neurons in the developing cerebral cortex.
AU - Hippenmeyer, Simon
ED - Nguyen, Laurent
ID - 2265
T2 - Cellular and Molecular Control of Neuronal Migration
TI - Molecular pathways controlling the sequential steps of cortical projection neuron migration
VL - 800
ER -
TY - CONF
AB - Energies with high-order non-submodular interactions have been shown to be very useful in vision due to their high modeling power. Optimization of such energies, however, is generally NP-hard. A naive approach that works for small problem instances is exhaustive search, that is, enumeration of all possible labelings of the underlying graph. We propose a general minimization approach for large graphs based on enumeration of labelings of certain small patches.
This partial enumeration technique reduces complex high-order energy formulations to pairwise Constraint Satisfaction Problems with unary costs (uCSP), which can be efficiently solved using standard methods like TRW-S. Our approach outperforms a number of existing state-of-the-art algorithms on well known difficult problems (e.g. curvature regularization, stereo, deconvolution); it gives near global minimum and better speed.
Our main application of interest is curvature regularization. In the context of segmentation, our partial enumeration technique allows to evaluate curvature directly on small patches using a novel integral geometry approach.
AU - Olsson, Carl
AU - Ulen, Johannes
AU - Boykov, Yuri
AU - Kolmogorov, Vladimir
ID - 2275
TI - Partial enumeration and curvature regularization
ER -
TY - JOUR
AB - We consider two-dimensional Bose-Einstein condensates with attractive interaction, described by the Gross-Pitaevskii functional. Minimizers of this functional exist only if the interaction strength a satisfies {Mathematical expression}, where Q is the unique positive radial solution of {Mathematical expression} in {Mathematical expression}. We present a detailed analysis of the behavior of minimizers as a approaches a*, where all the mass concentrates at a global minimum of the trapping potential.
AU - Guo, Yujin
AU - Seiringer, Robert
ID - 2281
IS - 2
JF - Letters in Mathematical Physics
TI - On the mass concentration for Bose-Einstein condensates with attractive interactions
VL - 104
ER -
TY - JOUR
AB - GABAergic inhibitory interneurons control fundamental aspects of neuronal network function. Their functional roles are assumed to be defined by the identity of their input synapses, the architecture of their dendritic tree, the passive and active membrane properties and finally the nature of their postsynaptic targets. Indeed, interneurons display a high degree of morphological and physiological heterogeneity. However, whether their morphological and physiological characteristics are correlated and whether interneuron diversity can be described by a continuum of GABAergic cell types or by distinct classes has remained unclear. Here we perform a detailed morphological and physiological characterization of GABAergic cells in the dentate gyrus, the input region of the hippocampus. To achieve an unbiased and efficient sampling and classification we used knock-in mice expressing the enhanced green fluorescent protein (eGFP) in glutamate decarboxylase 67 (GAD67)-positive neurons and performed cluster analysis. We identified five interneuron classes, each of them characterized by a distinct set of anatomical and physiological parameters. Cross-correlation analysis further revealed a direct relation between morphological and physiological properties indicating that dentate gyrus interneurons fall into functionally distinct classes which may differentially control neuronal network activity.
AU - Hosp, Jonas
AU - Strüber, Michael
AU - Yanagawa, Yuchio
AU - Obata, Kunihiko
AU - Vida, Imre
AU - Jonas, Peter M
AU - Bartos, Marlene
ID - 2285
IS - 2
JF - Hippocampus
TI - Morpho-physiological criteria divide dentate gyrus interneurons into classes
VL - 23
ER -
TY - JOUR
AB - Two definitions of the effective mass of a particle interacting with a quantum field, such as a polaron, are considered and shown to be equal in models similar to the Fröhlich polaron model. These are: 1. the mass defined by the low momentum energy E(P)≈E(0)+P2/2 M of the translation invariant system constrained to have momentum P and 2. the mass M of a simple particle in an arbitrary slowly varying external potential, V, described by the nonrelativistic Schrödinger equation, whose ground state energy equals that of the combined particle/field system in a bound state in the same V.
AU - Lieb, Élliott
AU - Seiringer, Robert
ID - 2407
IS - 1-2
JF - Journal of Statistical Physics
TI - Equivalence of two definitions of the effective mass of a polaron
VL - 154
ER -
TY - JOUR
AB - For any pencil of conics or higher-dimensional quadrics over ℚ, with all degenerate fibres defined over ℚ, we show that the Brauer–Manin obstruction controls weak approximation. The proof is based on the Hasse principle and weak approximation for some special intersections of quadrics over ℚ, which is a consequence of recent advances in additive combinatorics.
AU - Timothy Browning
AU - Matthiesen, Lilian
AU - Skorobogatov, Alexei N
ID - 248
IS - 1
JF - Annals of Mathematics
TI - Rational points on pencils of conics and quadrics with many degenerate fibres
VL - 180
ER -
TY - JOUR
AB - A version of the Hardy-Littlewood circle method is developed for number fields K/ℚ and is used to show that nonsingular projective cubic hypersurfaces over K always have a K-rational point when they have dimension at least 8.
AU - Timothy Browning
AU - Vishe, Pankaj
ID - 249
IS - 10
JF - Duke Mathematical Journal
TI - Cubic hypersurfaces and a version of the circle method for number fields
VL - 163
ER -
TY - JOUR
AB - For any number field k, upper bounds are established for the number of k-rational points of bounded height on non-singular del Pezzo surfaces defined over k, which are equipped with suitable conic bundle structures over k.
AU - Timothy Browning
AU - Jones, Michael S
ID - 252
IS - 3
JF - Acta Arithmetica
TI - Counting rational points on del Pezzo surfaces with a conic bundle structure
VL - 163
ER -
TY - JOUR
AB - A new "polynomial sieve" is presented and used to show that almost all integers have at most one representation as a sum of two values of a given polynomial of degree at least 3.
AU - Timothy Browning
ID - 254
IS - 7
JF - International Mathematics Research Notices
TI - The polynomial sieve and equal sums of like polynomials
VL - 2015
ER -
TY - JOUR
AB - We investigate the Hasse principle for complete intersections cut out by a quadric hypersurface and a cubic hypersurface defined over the rational numbers.
AU - Timothy Browning
AU - Dietmann, Rainer
AU - Heath-Brown, Roger
ID - 255
IS - 4
JF - Journal of the Institute of Mathematics of Jussieu
TI - Rational points on intersections of cubic and quadric hypersurfaces
VL - 14
ER -
TY - JOUR
AB - We prove the universality of the β-ensembles with convex analytic potentials and for any β >
0, i.e. we show that the spacing distributions of log-gases at any inverse temperature β coincide with those of the Gaussian β-ensembles.
AU - Erdös, László
AU - Bourgade, Paul
AU - Yau, Horng
ID - 2699
IS - 6
JF - Duke Mathematical Journal
TI - Universality of general β-ensembles
VL - 163
ER -
TY - JOUR
AB - Multi-dimensional mean-payoff and energy games provide the mathematical foundation for the quantitative study of reactive systems, and play a central role in the emerging quantitative theory of verification and synthesis. In this work, we study the strategy synthesis problem for games with such multi-dimensional objectives along with a parity condition, a canonical way to express ω ω -regular conditions. While in general, the winning strategies in such games may require infinite memory, for synthesis the most relevant problem is the construction of a finite-memory winning strategy (if one exists). Our main contributions are as follows. First, we show a tight exponential bound (matching upper and lower bounds) on the memory required for finite-memory winning strategies in both multi-dimensional mean-payoff and energy games along with parity objectives. This significantly improves the triple exponential upper bound for multi energy games (without parity) that could be derived from results in literature for games on vector addition systems with states. Second, we present an optimal symbolic and incremental algorithm to compute a finite-memory winning strategy (if one exists) in such games. Finally, we give a complete characterization of when finite memory of strategies can be traded off for randomness. In particular, we show that for one-dimension mean-payoff parity games, randomized memoryless strategies are as powerful as their pure finite-memory counterparts.
AU - Chatterjee, Krishnendu
AU - Randour, Mickael
AU - Raskin, Jean
ID - 2716
IS - 3-4
JF - Acta Informatica
TI - Strategy synthesis for multi-dimensional quantitative objectives
VL - 51
ER -
TY - JOUR
AB - A robust combiner for hash functions takes two candidate implementations and constructs a hash function which is secure as long as at least one of the candidates is secure. So far, hash function combiners only aim at preserving a single property such as collision-resistance or pseudorandomness. However, when hash functions are used in protocols like TLS they are often required to provide several properties simultaneously. We therefore put forward the notion of robust multi-property combiners and elaborate on different definitions for such combiners. We then propose a combiner that provably preserves (target) collision-resistance, pseudorandomness, and being a secure message authentication code. This combiner satisfies the strongest notion we propose, which requires that the combined function satisfies every security property which is satisfied by at least one of the underlying hash function. If the underlying hash functions have output length n, the combiner has output length 2 n. This basically matches a known lower bound for black-box combiners for collision-resistance only, thus the other properties can be achieved without penalizing the length of the hash values. We then propose a combiner which also preserves the property of being indifferentiable from a random oracle, slightly increasing the output length to 2 n+ω(log n). Moreover, we show how to augment our constructions in order to make them also robust for the one-wayness property, but in this case require an a priory upper bound on the input length.
AU - Fischlin, Marc
AU - Lehmann, Anja
AU - Pietrzak, Krzysztof Z
ID - 2852
IS - 3
JF - Journal of Cryptology
TI - Robust multi-property combiners for hash functions
VL - 27
ER -
TY - CONF
AB - Persistent homology is a recent grandchild of homology that has found use in
science and engineering as well as in mathematics. This paper surveys the method as well
as the applications, neglecting completeness in favor of highlighting ideas and directions.
AU - Edelsbrunner, Herbert
AU - Morozovy, Dmitriy
ID - 2905
TI - Persistent homology: Theory and practice
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 - 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 - 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 - 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 -
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 -