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 - 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 - Browning, Timothy D 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 -