TY - JOUR AB - Like many developing tissues, the vertebrate neural tube is patterned by antiparallel morphogen gradients. To understand how these inputs are interpreted, we measured morphogen signaling and target gene expression in mouse embryos and chick ex vivo assays. From these data, we derived and validated a characteristic decoding map that relates morphogen input to the positional identity of neural progenitors. Analysis of the observed responses indicates that the underlying interpretation strategy minimizes patterning errors in response to the joint input of noisy opposing gradients. We reverse-engineered a transcriptional network that provides a mechanistic basis for the observed cell fate decisions and accounts for the precision and dynamics of pattern formation. Together, our data link opposing gradient dynamics in a growing tissue to precise pattern formation. AU - Zagórski, Marcin P AU - Tabata, Yoji AU - Brandenberg, Nathalie AU - Lutolf, Matthias AU - Tkacik, Gasper AU - Bollenbach, Tobias AU - Briscoe, James AU - Kicheva, Anna ID - 943 IS - 6345 JF - Science SN - 00368075 TI - Decoding of position in the developing neural tube from antiparallel morphogen gradients VL - 356 ER - TY - JOUR AB - The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms. AU - Beattie, Robert J AU - Postiglione, Maria P AU - Burnett, Laura AU - Laukoter, Susanne AU - Streicher, Carmen AU - Pauler, Florian AU - Xiao, Guanxi AU - Klezovitch, Olga AU - Vasioukhin, Valeri AU - Ghashghaei, Troy AU - Hippenmeyer, Simon ID - 944 IS - 3 JF - Neuron SN - 08966273 TI - Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells VL - 94 ER - TY - CONF AB - A notable class of techniques for automatic program repair is known as semantics-based. Such techniques, e.g., Angelix, infer semantic specifications via symbolic execution, and then use program synthesis to construct new code that satisfies those inferred specifications. However, the obtained specifications are naturally incomplete, leaving the synthesis engine with a difficult task of synthesizing a general solution from a sparse space of many possible solutions that are consistent with the provided specifications but that do not necessarily generalize. We present S3, a new repair synthesis engine that leverages programming-by-examples methodology to synthesize high-quality bug repairs. The novelty in S3 that allows it to tackle the sparse search space to create more general repairs is three-fold: (1) A systematic way to customize and constrain the syntactic search space via a domain-specific language, (2) An efficient enumeration-based search strategy over the constrained search space, and (3) A number of ranking features based on measures of the syntactic and semantic distances between candidate solutions and the original buggy program. We compare S3’s repair effectiveness with state-of-the-art synthesis engines Angelix, Enumerative, and CVC4. S3 can successfully and correctly fix at least three times more bugs than the best baseline on datasets of 52 bugs in small programs, and 100 bugs in real-world large programs. AU - Le, Xuan AU - Chu, Duc Hiep AU - Lo, David AU - Le Goues, Claire AU - Visser, Willem ID - 942 SN - 978-145035105-8 TI - S3: Syntax- and semantic-guided repair synthesis via programming by examples VL - F130154 ER - TY - JOUR AB - We reveal the existence of continuous families of guided single-mode solitons in planar waveguides with weakly nonlinear active core and absorbing boundaries. Stable propagation of TE and TM-polarized solitons is accompanied by attenuation of all other modes, i.e., the waveguide features properties of conservative and dissipative systems. If the linear spectrum of the waveguide possesses exceptional points, which occurs in the case of TM polarization, an originally focusing (defocusing) material nonlinearity may become effectively defocusing (focusing). This occurs due to the geometric phase of the carried eigenmode when the surface impedance encircles the exceptional point. In its turn, the change of the effective nonlinearity ensures the existence of dark (bright) solitons in spite of focusing (defocusing) Kerr nonlinearity of the core. The existence of an exceptional point can also result in anomalous enhancement of the effective nonlinearity. In terms of practical applications, the nonlinearity of the reported waveguide can be manipulated by controlling the properties of the absorbing cladding. AU - Midya, Bikashkali AU - Konotop, Vladimir ID - 939 IS - 3 JF - Physical Review Letters SN - 00319007 TI - Waveguides with absorbing boundaries: Nonlinearity controlled by an exceptional point and solitons VL - 119 ER - TY - GEN AB - Egg laying rates and infection loads of C. obscurior queens AU - Giehr, Julia AU - Grasse, Anna V AU - Cremer, Sylvia AU - Heinze, Jürgen AU - Schrempf, Alexandra ID - 9853 TI - Raw data from ant queens increase their reproductive efforts after pathogen infection ER - TY - JOUR AB - Polymicrobial infections constitute small ecosystems that accommodate several bacterial species. Commonly, these bacteria are investigated in isolation. However, it is unknown to what extent the isolates interact and whether their interactions alter bacterial growth and ecosystem resilience in the presence and absence of antibiotics. We quantified the complete ecological interaction network for 72 bacterial isolates collected from 23 individuals diagnosed with polymicrobial urinary tract infections and found that most interactions cluster based on evolutionary relatedness. Statistical network analysis revealed that competitive and cooperative reciprocal interactions are enriched in the global network, while cooperative interactions are depleted in the individual host community networks. A population dynamics model parameterized by our measurements suggests that interactions restrict community stability, explaining the observed species diversity of these communities. We further show that the clinical isolates frequently protect each other from clinically relevant antibiotics. Together, these results highlight that ecological interactions are crucial for the growth and survival of bacteria in polymicrobial infection communities and affect their assembly and resilience. AU - De Vos, Marjon AU - Zagórski, Marcin P AU - Mcnally, Alan AU - Bollenbach, Mark Tobias ID - 822 IS - 40 JF - PNAS SN - 00278424 TI - Interaction networks, ecological stability, and collective antibiotic tolerance in polymicrobial infections VL - 114 ER - TY - CONF AB - We present an efficient algorithm to compute Euler characteristic curves of gray scale images of arbitrary dimension. In various applications the Euler characteristic curve is used as a descriptor of an image. Our algorithm is the first streaming algorithm for Euler characteristic curves. The usage of streaming removes the necessity to store the entire image in RAM. Experiments show that our implementation handles terabyte scale images on commodity hardware. Due to lock-free parallelism, it scales well with the number of processor cores. Additionally, we put the concept of the Euler characteristic curve in the wider context of computational topology. In particular, we explain the connection with persistence diagrams. AU - Heiss, Teresa AU - Wagner, Hubert ED - Felsberg, Michael ED - Heyden, Anders ED - Krüger, Norbert ID - 833 SN - 03029743 TI - Streaming algorithm for Euler characteristic curves of multidimensional images VL - 10424 ER - TY - JOUR AB - During corticogenesis, distinct classes of neurons are born from progenitor cells located in the ventricular and subventricular zones, from where they migrate towards the pial surface to assemble into highly organized layer-specific circuits. However, the precise and coordinated transcriptional network activity defining neuronal identity is still not understood. Here, we show that genetic depletion of the basic helix-loop-helix (bHLH) transcription factor E2A splice variant E47 increased the number of Tbr1-positive deep layer and Satb2-positive upper layer neurons at E14.5, while depletion of the alternatively spliced E12 variant did not affect layer-specific neurogenesis. While ChIP-Seq identified a big overlap for E12- and E47-specific binding sites in embryonic NSCs, including sites at the cyclin-dependent kinase inhibitor (CDKI) Cdkn1c gene locus, RNA-Seq revealed a unique transcriptional regulation by each splice variant. E47 activated the expression of the CDKI Cdkn1c through binding to a distal enhancer. Finally, overexpression of E47 in embryonic NSCs in vitro impaired neurite outgrowth and E47 overexpression in vivo by in utero electroporation disturbed proper layer-specific neurogenesis and upregulated p57(KIP2) expression. Overall, this study identified E2A target genes in embryonic NSCs and demonstrates that E47 regulates neuronal differentiation via p57(KIP2). AU - Pfurr, Sabrina AU - Chu, Yu AU - Bohrer, Christian AU - Greulich, Franziska AU - Beattie, Robert J AU - Mammadzada, Könül AU - Hils, Miriam AU - Arnold, Sebastian AU - Taylor, Verdon AU - Schachtrup, Kristina AU - Uhlenhaut, N Henriette AU - Schachtrup, Christian ID - 805 JF - Development TI - The E2A splice variant E47 regulates the differentiation of projection neurons via p57(KIP2) during cortical development VL - 144 ER - TY - JOUR AB - Thermal and many-body localized phases are separated by a dynamical phase transition of a new kind. We analyze the distribution of off-diagonal matrix elements of local operators across this transition in two different models of disordered spin chains. We show that the behavior of matrix elements can be used to characterize the breakdown of thermalization and to extract the many-body Thouless energy. We find that upon increasing the disorder strength the system enters a critical region around the many-body localization transition. The properties of the system in this region are: (i) the Thouless energy becomes smaller than the level spacing, (ii) the matrix elements show critical dependence on the energy difference, and (iii) the matrix elements, viewed as amplitudes of a fictitious wave function, exhibit strong multifractality. This critical region decreases with the system size, which we interpret as evidence for a diverging correlation length at the many-body localization transition. Our findings show that the correlation length becomes larger than the accessible system sizes in a broad range of disorder strength values and shed light on the critical behavior near the many-body localization transition. AU - Serbyn, Maksym AU - Zlatko, Papic AU - Abanin, Dmitry ID - 834 IS - 10 JF - Physical Review B - Condensed Matter and Materials Physics SN - 24699950 TI - Thouless energy and multifractality across the many-body localization transition VL - 96 ER - TY - JOUR AB - The resolution of a linear system with positive integer variables is a basic yet difficult computational problem with many applications. We consider sparse uncorrelated random systems parametrised by the density c and the ratio α=N/M between number of variables N and number of constraints M. By means of ensemble calculations we show that the space of feasible solutions endows a Van-Der-Waals phase diagram in the plane (c, α). We give numerical evidence that the associated computational problems become more difficult across the critical point and in particular in the coexistence region. AU - Colabrese, Simona AU - De Martino, Daniele AU - Leuzzi, Luca AU - Marinari, Enzo ID - 823 IS - 9 JF - Journal of Statistical Mechanics: Theory and Experiment SN - 17425468 TI - Phase transitions in integer linear problems VL - 2017 ER -