TY - JOUR AB - Bacteria regulate genes to survive antibiotic stress, but regulation can be far from perfect. When regulation is not optimal, mutations that change gene expression can contribute to antibiotic resistance. It is not systematically understood to what extent natural gene regulation is or is not optimal for distinct antibiotics, and how changes in expression of specific genes quantitatively affect antibiotic resistance. Here we discover a simple quantitative relation between fitness, gene expression, and antibiotic potency, which rationalizes our observation that a multitude of genes and even innate antibiotic defense mechanisms have expression that is critically nonoptimal under antibiotic treatment. First, we developed a pooled-strain drug-diffusion assay and screened Escherichia coli overexpression and knockout libraries, finding that resistance to a range of 31 antibiotics could result from changing expression of a large and functionally diverse set of genes, in a primarily but not exclusively drug-specific manner. Second, by synthetically controlling the expression of single-drug and multidrug resistance genes, we observed that their fitness-expression functions changed dramatically under antibiotic treatment in accordance with a log-sensitivity relation. Thus, because many genes are nonoptimally expressed under antibiotic treatment, many regulatory mutations can contribute to resistance by altering expression and by activating latent defenses. AU - Palmer, Adam AU - Chait, Remy P AU - Kishony, Roy ID - 19 IS - 11 JF - Molecular Biology and Evolution SN - 0737-4038 TI - Nonoptimal gene expression creates latent potential for antibiotic resistance VL - 35 ER - TY - JOUR AB - Lesion and electrode location verification are traditionally done via histological examination of stained brain slices, a time-consuming procedure that requires manual estimation. Here, we describe a simple, straightforward method for quantifying lesions and locating electrodes in the brain that is less laborious and yields more detailed results. Whole brains are stained with osmium tetroxide, embedded in resin, and imaged with a micro-CT scanner. The scans result in 3D digital volumes of the brains with resolutions and virtual section thicknesses dependent on the sample size (12-15 and 5-6 µm per voxel for rat and zebra finch brains, respectively). Surface and deep lesions can be characterized, and single tetrodes, tetrode arrays, electrolytic lesions, and silicon probes can also be localized. Free and proprietary software allows experimenters to examine the sample volume from any plane and segment the volume manually or automatically. Because this method generates whole brain volume, lesions and electrodes can be quantified to a much higher degree than in current methods, which will help standardize comparisons within and across studies. AU - Masís, Javier AU - Mankus, David AU - Wolff, Steffen AU - Guitchounts, Grigori AU - Jösch, Maximilian A AU - Cox, David ID - 6 JF - Journal of visualized experiments TI - A micro-CT-based method for characterising lesions and locating electrodes in small animal brains VL - 141 ER - TY - GEN AB - Dataset for manuscript 'Social network plasticity decreases disease transmission in a eusocial insect' Compared to previous versions: - raw image files added - correction of URLs within README.txt file AU - Stroeymeyt, Nathalie AU - Grasse, Anna V AU - Crespi, Alessandro AU - Mersch, Danielle AU - Cremer, Sylvia AU - Keller, Laurent ID - 13055 TI - Social network plasticity decreases disease transmission in a eusocial insect ER - TY - JOUR AB - Conventional ultra-high sensitivity detectors in the millimeter-wave range are usually cooled as their own thermal noise at room temperature would mask the weak received radiation. The need for cryogenic systems increases the cost and complexity of the instruments, hindering the development of, among others, airborne and space applications. In this work, the nonlinear parametric upconversion of millimeter-wave radiation to the optical domain inside high-quality (Q) lithium niobate whispering-gallery mode (WGM) resonators is proposed for ultra-low noise detection. We experimentally demonstrate coherent upconversion of millimeter-wave signals to a 1550 nm telecom carrier, with a photon conversion efficiency surpassing the state-of-the-art by 2 orders of magnitude. Moreover, a theoretical model shows that the thermal equilibrium of counterpropagating WGMs is broken by overcoupling the millimeter-wave WGM, effectively cooling the upconverted mode and allowing ultra-low noise detection. By theoretically estimating the sensitivity of a correlation radiometer based on the presented scheme, it is found that room-temperature radiometers with better sensitivity than state-of-the-art high-electron-mobility transistor (HEMT)-based radiometers can be designed. This detection paradigm can be used to develop room-temperature instrumentation for radio astronomy, earth observation, planetary missions, and imaging systems. AU - Botello, Gabriel AU - Sedlmeir, Florian AU - Rueda Sanchez, Alfredo R AU - Abdalmalak, Kerlos AU - Brown, Elliott AU - Leuchs, Gerd AU - Preu, Sascha AU - Segovia Vargas, Daniel AU - Strekalov, Dmitry AU - Munoz, Luis AU - Schwefel, Harald ID - 22 IS - 10 JF - Optica SN - 23342536 TI - Sensitivity limits of millimeter-wave photonic radiometers based on efficient electro-optic upconverters VL - 5 ER - TY - JOUR AB - Recently, contract-based design has been proposed as an “orthogonal” approach that complements system design methodologies proposed so far to cope with the complexity of system design. Contract-based design provides a rigorous scaffolding for verification, analysis, abstraction/refinement, and even synthesis. A number of results have been obtained in this domain but a unified treatment of the topic that can help put contract-based design in perspective was missing. This monograph intends to provide such a treatment where contracts are precisely defined and characterized so that they can be used in design methodologies with no ambiguity. In particular, this monograph identifies the essence of complex system design using contracts through a mathematical “meta-theory”, where all the properties of the methodology are derived from a very abstract and generic notion of contract. We show that the meta-theory provides deep and illuminating links with existing contract and interface theories, as well as guidelines for designing new theories. Our study encompasses contracts for both software and systems, with emphasis on the latter. We illustrate the use of contracts with two examples: requirement engineering for a parking garage management, and the development of contracts for timing and scheduling in the context of the Autosar methodology in use in the automotive sector. AU - Benveniste, Albert AU - Nickovic, Dejan AU - Caillaud, Benoît AU - Passerone, Roberto AU - Raclet, Jean Baptiste AU - Reinkemeier, Philipp AU - Sangiovanni-Vincentelli, Alberto AU - Damm, Werner AU - Henzinger, Thomas A AU - Larsen, Kim G. ID - 5677 IS - 2-3 JF - Foundations and Trends in Electronic Design Automation SN - 1551-3939 TI - Contracts for system design VL - 12 ER - TY - JOUR AB - It is shown that two fundamentally different phenomena, the bound states in continuum and the spectral singularity (or time-reversed spectral singularity), can occur simultaneously. This can be achieved in a rectangular core dielectric waveguide with an embedded active (or absorbing) layer. In such a system a two-dimensional bound state in a continuum is created in the plane of a waveguide cross section, and it is emitted or absorbed along the waveguide core. The idea can be used for experimental implementation of a laser or a coherent-perfect-absorber for a photonic bound state that resides in a continuous spectrum. AU - Midya, Bikashkali AU - Konotop, Vladimir ID - 435 IS - 3 JF - Optics Letters TI - Coherent-perfect-absorber and laser for bound states in a continuum VL - 43 ER - TY - JOUR AB - Genome-scale diversity data are increasingly available in a variety of biological systems, and can be used to reconstruct the past evolutionary history of species divergence. However, extracting the full demographic information from these data is not trivial, and requires inferential methods that account for the diversity of coalescent histories throughout the genome. Here, we evaluate the potential and limitations of one such approach. We reexamine a well-known system of mussel sister species, using the joint site frequency spectrum (jSFS) of synonymousmutations computed either fromexome capture or RNA-seq, in an Approximate Bayesian Computation (ABC) framework. We first assess the best sampling strategy (number of: individuals, loci, and bins in the jSFS), and show that model selection is robust to variation in the number of individuals and loci. In contrast, different binning choices when summarizing the jSFS, strongly affect the results: including classes of low and high frequency shared polymorphisms can more effectively reveal recent migration events. We then take advantage of the flexibility of ABC to compare more realistic models of speciation, including variation in migration rates through time (i.e., periodic connectivity) and across genes (i.e., genome-wide heterogeneity in migration rates). We show that these models were consistently selected as the most probable, suggesting that mussels have experienced a complex history of gene flow during divergence and that the species boundary is semi-permeable. Our work provides a comprehensive evaluation of ABC demographic inference in mussels based on the coding jSFS, and supplies guidelines for employing different sequencing techniques and sampling strategies. We emphasize, perhaps surprisingly, that inferences are less limited by the volume of data, than by the way in which they are analyzed. AU - Fraisse, Christelle AU - Roux, Camille AU - Gagnaire, Pierre AU - Romiguier, Jonathan AU - Faivre, Nicolas AU - Welch, John AU - Bierne, Nicolas ID - 139 IS - 7 JF - PeerJ TI - The divergence history of European blue mussel species reconstructed from Approximate Bayesian Computation: The effects of sequencing techniques and sampling strategies VL - 2018 ER - TY - JOUR AB - Secondary contact is the reestablishment of gene flow between sister populations that have diverged. For instance, at the end of the Quaternary glaciations in Europe, secondary contact occurred during the northward expansion of the populations which had found refugia in the southern peninsulas. With the advent of multi-locus markers, secondary contact can be investigated using various molecular signatures including gradients of allele frequency, admixture clines, and local increase of genetic differentiation. We use coalescent simulations to investigate if molecular data provide enough information to distinguish between secondary contact following range expansion and an alternative evolutionary scenario consisting of a barrier to gene flow in an isolation-by-distance model. We find that an excess of linkage disequilibrium and of genetic diversity at the suture zone is a unique signature of secondary contact. We also find that the directionality index ψ, which was proposed to study range expansion, is informative to distinguish between the two hypotheses. However, although evidence for secondary contact is usually conveyed by statistics related to admixture coefficients, we find that they can be confounded by isolation-by-distance. We recommend to account for the spatial repartition of individuals when investigating secondary contact in order to better reflect the complex spatio-temporal evolution of populations and species. AU - Bertl, Johanna AU - Ringbauer, Harald AU - Blum, Michaël ID - 33 IS - 10 JF - PeerJ TI - Can secondary contact following range expansion be distinguished from barriers to gene flow? VL - 2018 ER - TY - JOUR AB - Cell polarity, manifested by the localization of proteins to distinct polar plasma membrane domains, is a key prerequisite of multicellular life. In plants, PIN auxin transporters are prominent polarity markers crucial for a plethora of developmental processes. Cell polarity mechanisms in plants are distinct from other eukaryotes and still largely elusive. In particular, how the cell polarities are propagated and maintained following cell division remains unknown. Plant cytokinesis is orchestrated by the cell plate—a transient centrifugally growing endomembrane compartment ultimately forming the cross wall1. Trafficking of polar membrane proteins is typically redirected to the cell plate, and these will consequently have opposite polarity in at least one of the daughter cells2–5. Here, we provide mechanistic insights into post-cytokinetic re-establishment of cell polarity as manifested by the apical, polar localization of PIN2. We show that the apical domain is defined in a cell-intrinsic manner and that re-establishment of PIN2 localization to this domain requires de novo protein secretion and endocytosis, but not basal-to-apical transcytosis. Furthermore, we identify a PINOID-related kinase WAG1, which phosphorylates PIN2 in vitro6 and is transcriptionally upregulated specifically in dividing cells, as a crucial regulator of post-cytokinetic PIN2 polarity re-establishment. AU - Glanc, Matous AU - Fendrych, Matyas AU - Friml, Jirí ID - 5673 IS - 12 JF - Nature Plants SN - 2055-0278 TI - Mechanistic framework for cell-intrinsic re-establishment of PIN2 polarity after cell division VL - 4 ER - TY - JOUR AB - We consider a class of students learning a language from a teacher. The situation can be interpreted as a group of child learners receiving input from the linguistic environment. The teacher provides sample sentences. The students try to learn the grammar from the teacher. In addition to just listening to the teacher, the students can also communicate with each other. The students hold hypotheses about the grammar and change them if they receive counter evidence. The process stops when all students have converged to the correct grammar. We study how the time to convergence depends on the structure of the classroom by introducing and evaluating various complexity measures. We find that structured communication between students, although potentially introducing confusion, can greatly reduce some of the complexity measures. Our theory can also be interpreted as applying to the scientific process, where nature is the teacher and the scientists are the students. AU - Ibsen-Jensen, Rasmus AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin ID - 198 IS - 140 JF - Journal of the Royal Society Interface TI - Language acquisition with communication between learners VL - 15 ER - TY - JOUR AB - The emergence of syntax during childhood is a remarkable example of how complex correlations unfold in nonlinear ways through development. In particular, rapid transitions seem to occur as children reach the age of two, which seems to separate a two-word, tree-like network of syntactic relations among words from the scale-free graphs associated with the adult, complex grammar. Here, we explore the evolution of syntax networks through language acquisition using the chromatic number, which captures the transition and provides a natural link to standard theories on syntactic structures. The data analysis is compared to a null model of network growth dynamics which is shown to display non-trivial and sensible differences. At a more general level, we observe that the chromatic classes define independent regions of the graph, and thus, can be interpreted as the footprints of incompatibility relations, somewhat as opposed to modularity considerations. AU - Corominas-Murtra, Bernat AU - Fibla, Martí Sànchez AU - Valverde, Sergi AU - Solé, Ricard ID - 5859 IS - 12 JF - Royal Society Open Science SN - 2054-5703 TI - Chromatic transitions in the emergence of syntax networks VL - 5 ER - TY - GEN AB - We study the unique solution $m$ of the Dyson equation \[ -m(z)^{-1} = z - a + S[m(z)] \] on a von Neumann algebra $\mathcal{A}$ with the constraint $\mathrm{Im}\,m\geq 0$. Here, $z$ lies in the complex upper half-plane, $a$ is a self-adjoint element of $\mathcal{A}$ and $S$ is a positivity-preserving linear operator on $\mathcal{A}$. We show that $m$ is the Stieltjes transform of a compactly supported $\mathcal{A}$-valued measure on $\mathbb{R}$. Under suitable assumptions, we establish that this measure has a uniformly $1/3$-H\"{o}lder continuous density with respect to the Lebesgue measure, which is supported on finitely many intervals, called bands. In fact, the density is analytic inside the bands with a square-root growth at the edges and internal cubic root cusps whenever the gap between two bands vanishes. The shape of these singularities is universal and no other singularity may occur. We give a precise asymptotic description of $m$ near the singular points. These asymptotics generalize the analysis at the regular edges given in the companion paper on the Tracy-Widom universality for the edge eigenvalue statistics for correlated random matrices [arXiv:1804.07744] and they play a key role in the proof of the Pearcey universality at the cusp for Wigner-type matrices [arXiv:1809.03971,arXiv:1811.04055]. We also extend the finite dimensional band mass formula from [arXiv:1804.07744] to the von Neumann algebra setting by showing that the spectral mass of the bands is topologically rigid under deformations and we conclude that these masses are quantized in some important cases. AU - Alt, Johannes AU - Erdös, László AU - Krüger, Torben H ID - 6183 T2 - arXiv TI - The Dyson equation with linear self-energy: Spectral bands, edges and cusps ER - TY - GEN AB - We prove that any convex body in the plane can be partitioned into m convex parts of equal areas and perimeters for any integer m≥2; this result was previously known for prime powers m=pk. We also give a higher-dimensional generalization. AU - Akopyan, Arseniy AU - Avvakumov, Sergey AU - Karasev, Roman ID - 75 TI - Convex fair partitions into arbitrary number of pieces ER - TY - JOUR AB - We investigate the free boundary Schur process, a variant of the Schur process introduced by Okounkov and Reshetikhin, where we allow the first and the last partitions to be arbitrary (instead of empty in the original setting). The pfaffian Schur process, previously studied by several authors, is recovered when just one of the boundary partitions is left free. We compute the correlation functions of the process in all generality via the free fermion formalism, which we extend with the thorough treatment of “free boundary states.” For the case of one free boundary, our approach yields a new proof that the process is pfaffian. For the case of two free boundaries, we find that the process is not pfaffian, but a closely related process is. We also study three different applications of the Schur process with one free boundary: fluctuations of symmetrized last passage percolation models, limit shapes and processes for symmetric plane partitions and for plane overpartitions. AU - Betea, Dan AU - Bouttier, Jeremie AU - Nejjar, Peter AU - Vuletic, Mirjana ID - 556 IS - 12 JF - Annales Henri Poincare SN - 1424-0637 TI - The free boundary Schur process and applications I VL - 19 ER - TY - DATA AB - Graph matching problems for large displacement optical flow of RGB-D images. AU - Alhaija, Hassan AU - Sellent, Anita AU - Kondermann, Daniel AU - Rother, Carsten ID - 5573 KW - graph matching KW - quadratic assignment problem< TI - Graph matching problems for GraphFlow – 6D Large Displacement Scene Flow ER - TY - DATA AB - Data on Austrian open access publication output at Emerald from 2013-2017 including data analysis. AU - Villányi, Márton ID - 5577 KW - Publication analysis KW - Bibliography KW - Open Access TI - Emerald Austrian Publications 2013-2017 ER - TY - DATA AB - Data on Austrian open access publication output at IOP from 2012-2015 including data analysis. AU - Villányi, Márton ID - 5578 KW - Publication analysis KW - Bibliography KW - Open Access TI - IOP Austrian Publications 2012-2015 ER - TY - DATA AB - Comparison of Scopus' and publisher's data on Austrian publication output at IOP. AU - Villányi, Márton ID - 5574 KW - Publication analysis KW - Bibliography KW - Open Access TI - Data Check IOP Scopus vs. Publisher ER - TY - THES AB - Consortial subscription contracts regulate the digital access to publications between publishers and scientific libraries. However, since a couple of years the tendency towards a freely accessible publishing (Open Access) intensifies. As a consequence of this trend the contractual relationship between licensor and licensee is gradually changing as well: More and more contracts exercise influence on open access publishing. The present study attempts to compare Austrian examples of consortial licence contracts, which include components of open access. It describes the difference between pure subscription contracts and differing innovative deals including open access components. Thereby it becomes obvious that for the evaluation of this licence contracts new methods are needed. An essential new element of such analyses is the evaluation of the open access publication numbers. So this study tries to carry out such publication analyses for Austrian open access deals focusing on quantitative questions: How does the number of publications evolve? How does the open access share change? Publications reports of the publishers and database queries from Scopus form the data basis. The analysis of the data points out that differing approaches of contracts result in highly divergent results: Particular deals can prioritize a saving in costs or else the increase of the open access rate. It is to be assumed that within the following years further numerous open access deals will be negotiated. The finding of this study shall provide guidance. AU - Villányi, Márton ID - 278 TI - Lizenzverträge mit Open-Access-Komponenten an österreichischen Bibliotheken ER - TY - DATA AB - Script to perform a simple exponential lifetime fit of a ROI on time stacks acquired with a FLIM X16 TCSPC detector (+example data) AU - Hauschild, Robert ID - 5588 KW - FLIM KW - FRET KW - fluorescence lifetime imaging TI - Fluorescence lifetime analysis of FLIM X16 TCSPC data ER - TY - DATA AB - Data on Austrian open access publication output at Taylor&Francis from 2013-2017 including data analysis. AU - Villányi, Márton ID - 5582 KW - Publication analysis KW - Bibliography KW - Open Access TI - Taylor&Francis Austrian Publications 2013-2017 ER - TY - DATA AB - Data on Austrian open access publication output at Springer from 2013-2016 including data analysis. AU - Villányi, Márton ID - 5581 KW - Publication analysis KW - Bibliography KW - Open Access TI - Springer Austrian Publications 2013-2016 ER - TY - DATA AB - Data on Austrian open access publication output at SAGE from 2013-2017 including data analysis. AU - Villányi, Márton ID - 5580 KW - Publication analysis KW - Bibliography KW - Open Access TI - SAGE Austrian Publications 2013-2017 ER - TY - DATA AB - Data on Austrian open access publication output at RSC from 2013-2017 including data analysis. AU - Villányi, Márton ID - 5579 KW - Publication analysis KW - Bibliography KW - Open Access TI - RSC Austrian Publications 2013-2017 ER - TY - DATA AB - Comparison of Scopus' and FWF's data on Austrian publication output at T&F. AU - Villányi, Márton ID - 5576 KW - Publication analysis KW - Bibliography KW - Open Access TI - Data Check T&F Scopus vs. FWF ER - TY - DATA AB - Comparison of Scopus' and FWF's data on Austrian publication output at RSC. AU - Villányi, Márton ID - 5575 KW - Publication analysis KW - Bibliography KW - Open Access TI - Data Check RSC Scopus vs. FWF ER - TY - JOUR AB - Retina is a paradigmatic system for studying sensory encoding: the transformation of light into spiking activity of ganglion cells. The inverse problem, where stimulus is reconstructed from spikes, has received less attention, especially for complex stimuli that should be reconstructed “pixel-by-pixel”. We recorded around a hundred neurons from a dense patch in a rat retina and decoded movies of multiple small randomly-moving discs. We constructed nonlinear (kernelized and neural network) decoders that improved significantly over linear results. An important contribution to this was the ability of nonlinear decoders to reliably separate between neural responses driven by locally fluctuating light signals, and responses at locally constant light driven by spontaneous-like activity. This improvement crucially depended on the precise, non-Poisson temporal structure of individual spike trains, which originated in the spike-history dependence of neural responses. We propose a general principle by which downstream circuitry could discriminate between spontaneous and stimulus-driven activity based solely on higher-order statistical structure in the incoming spike trains. AU - Botella Soler, Vicent AU - Deny, Stephane AU - Martius, Georg S AU - Marre, Olivier AU - Tkacik, Gasper ID - 292 IS - 5 JF - PLoS Computational Biology TI - Nonlinear decoding of a complex movie from the mammalian retina VL - 14 ER - TY - JOUR AB - The MazF toxin sequence-specifically cleaves single-stranded RNA upon various stressful conditions, and it is activated as a part of the mazEF toxin–antitoxin module in Escherichia coli. Although autoregulation of mazEF expression through the MazE antitoxin-dependent transcriptional repression has been biochemically characterized, less is known about post-transcriptional autoregulation, as well as how both of these autoregulatory features affect growth of single cells during conditions that promote MazF production. Here, we demonstrate post-transcriptional autoregulation of mazF expression dynamics by MazF cleaving its own transcript. Single-cell analyses of bacterial populations during ectopic MazF production indicated that two-level autoregulation of mazEF expression influences cell-to-cell growth rate heterogeneity. The increase in growth rate heterogeneity is governed by the MazE antitoxin, and tuned by the MazF-dependent mazF mRNA cleavage. Also, both autoregulatory features grant rapid exit from the stress caused by mazF overexpression. Time-lapse microscopy revealed that MazF-mediated cleavage of mazF mRNA leads to increased temporal variability in length of individual cells during ectopic mazF overexpression, as explained by a stochastic model indicating that mazEF mRNA cleavage underlies temporal fluctuations in MazF levels during stress. AU - Nikolic, Nela AU - Bergmiller, Tobias AU - Vandervelde, Alexandra AU - Albanese, Tanino AU - Gelens, Lendert AU - Moll, Isabella ID - 438 IS - 6 JF - Nucleic Acids Research TI - Autoregulation of mazEF expression underlies growth heterogeneity in bacterial populations VL - 46 ER - TY - JOUR AB - XY systems usually show chromosome-wide compensation of X-linked genes, while in many ZW systems, compensation is restricted to a minority of dosage-sensitive genes. Why such differences arose is still unclear. Here, we combine comparative genomics, transcriptomics and proteomics to obtain a complete overview of the evolution of gene dosage on the Z-chromosome of Schistosoma parasites. We compare the Z-chromosome gene content of African (Schistosoma mansoni and S. haematobium) and Asian (S. japonicum) schistosomes and describe lineage-specific evolutionary strata. We use these to assess gene expression evolution following sex-linkage. The resulting patterns suggest a reduction in expression of Z-linked genes in females, combined with upregulation of the Z in both sexes, in line with the first step of Ohno’s classic model of dosage compensation evolution. Quantitative proteomics suggest that post-transcriptional mechanisms do not play a major role in balancing the expression of Z-linked genes. AU - Picard, Marion A AU - Cosseau, Celine AU - Ferré, Sabrina AU - Quack, Thomas AU - Grevelding, Christoph AU - Couté, Yohann AU - Vicoso, Beatriz ID - 131 JF - eLife TI - Evolution of gene dosage on the Z-chromosome of schistosome parasites VL - 7 ER - TY - DATA AB - This package contains data for the publication "Nonlinear decoding of a complex movie from the mammalian retina" by Deny S. et al, PLOS Comput Biol (2018). The data consists of (i) 91 spike sorted, isolated rat retinal ganglion cells that pass stability and quality criteria, recorded on the multi-electrode array, in response to the presentation of the complex movie with many randomly moving dark discs. The responses are represented as 648000 x 91 binary matrix, where the first index indicates the timebin of duration 12.5 ms, and the second index the neural identity. The matrix entry is 0/1 if the neuron didn't/did spike in the particular time bin. (ii) README file and a graphical illustration of the structure of the experiment, specifying how the 648000 timebins are split into epochs where 1, 2, 4, or 10 discs were displayed, and which stimulus segments are exact repeats or unique ball trajectories. (iii) a 648000 x 400 matrix of luminance traces for each of the 20 x 20 positions ("sites") in the movie frame, with time that is locked to the recorded raster. The luminance traces are produced as described in the manuscript by filtering the raw disc movie with a small gaussian spatial kernel. AU - Deny, Stephane AU - Marre, Olivier AU - Botella-Soler, Vicente AU - Martius, Georg S AU - Tkacik, Gasper ID - 5584 KW - retina KW - decoding KW - regression KW - neural networks KW - complex stimulus TI - Nonlinear decoding of a complex movie from the mammalian retina ER - TY - JOUR AB - Pedigree and sibship reconstruction are important methods in quantifying relationships and fitness of individuals in natural populations. Current methods employ a Markov chain-based algorithm to explore plausible possible pedigrees iteratively. This provides accurate results, but is time-consuming. Here, we develop a method to infer sibship and paternity relationships from half-sibling arrays of known maternity using hierarchical clustering. Given 50 or more unlinked SNP markers and empirically derived error rates, the method performs as well as the widely used package Colony, but is faster by two orders of magnitude. Using simulations, we show that the method performs well across contrasting mating scenarios, even when samples are large. We then apply the method to open-pollinated arrays of the snapdragon Antirrhinum majus and find evidence for a high degree of multiple mating. Although we focus on diploid SNP data, the method does not depend on marker type and as such has broad applications in nonmodel systems. AU - Ellis, Thomas AU - Field, David AU - Barton, Nicholas H ID - 286 IS - 5 JF - Molecular Ecology Resources TI - Efficient inference of paternity and sibship inference given known maternity via hierarchical clustering VL - 18 ER - TY - DATA AB - Input files and scripts from "Evolution of gene dosage on the Z-chromosome of schistosome parasites" by Picard M.A.L., et al (2018). AU - Vicoso, Beatriz ID - 5586 KW - schistosoma KW - Z-chromosome KW - gene expression TI - Input files and scripts from "Evolution of gene dosage on the Z-chromosome of schistosome parasites" by Picard M.A.L., et al (2018) ER - TY - DATA AB - Data and scripts are provided in support of the manuscript "Efficient inference of paternity and sibship inference given known maternity via hierarchical clustering", and the associated Python package FAPS, available from www.github.com/ellisztamas/faps. Simulation scripts cover: 1. Performance under different mating scenarios. 2. Comparison with Colony2. 3. Effect of changing the number of Monte Carlo draws The final script covers the analysis of half-sib arrays from wild-pollinated seed in an Antirrhinum majus hybrid zone. AU - Ellis, Thomas ID - 5583 TI - Data and Python scripts supporting Python package FAPS ER - TY - DATA AB - Nela Nikolic, Tobias Bergmiller, Alexandra Vandervelde, Tanino G. Albanese, Lendert Gelens, and Isabella Moll (2018) “Autoregulation of mazEF expression underlies growth heterogeneity in bacterial populations” Nucleic Acids Research, doi: 10.15479/AT:ISTA:74; microscopy experiments by Tobias Bergmiller; image and data analysis by Nela Nikolic. AU - Bergmiller, Tobias AU - Nikolic, Nela ID - 5569 KW - microscopy KW - microfluidics TI - Time-lapse microscopy data ER - TY - JOUR AB - Which properties of metabolic networks can be derived solely from stoichiometry? Predictive results have been obtained by flux balance analysis (FBA), by postulating that cells set metabolic fluxes to maximize growth rate. Here we consider a generalization of FBA to single-cell level using maximum entropy modeling, which we extend and test experimentally. Specifically, we define for Escherichia coli metabolism a flux distribution that yields the experimental growth rate: the model, containing FBA as a limit, provides a better match to measured fluxes and it makes a wide range of predictions: on flux variability, regulation, and correlations; on the relative importance of stoichiometry vs. optimization; on scaling relations for growth rate distributions. We validate the latter here with single-cell data at different sub-inhibitory antibiotic concentrations. The model quantifies growth optimization as emerging from the interplay of competitive dynamics in the population and regulation of metabolism at the level of single cells. AU - De Martino, Daniele AU - Mc, Andersson Anna AU - Bergmiller, Tobias AU - Guet, Calin C AU - Tkacik, Gasper ID - 161 IS - 1 JF - Nature Communications TI - Statistical mechanics for metabolic networks during steady state growth VL - 9 ER - TY - DATA AB - Supporting material to the article STATISTICAL MECHANICS FOR METABOLIC NETWORKS IN STEADY-STATE GROWTH boundscoli.dat Flux Bounds of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium. polcoli.dat Matrix enconding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium, obtained from the soichiometric matrix by standard linear algebra (reduced row echelon form). ellis.dat Approximate Lowner-John ellipsoid rounding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium obtained with the Lovasz method. point0.dat Center of the approximate Lowner-John ellipsoid rounding the polytope of the E. coli catabolic core model iAF1260 in a glucose limited minimal medium obtained with the Lovasz method. lovasz.cpp This c++ code file receives in input the polytope of the feasible steady states of a metabolic network, (matrix and bounds), and it gives in output an approximate Lowner-John ellipsoid rounding the polytope with the Lovasz method NB inputs are referred by defaults to the catabolic core of the E.Coli network iAF1260. For further details we refer to PLoS ONE 10.4 e0122670 (2015). sampleHRnew.cpp This c++ code file receives in input the polytope of the feasible steady states of a metabolic network, (matrix and bounds), the ellipsoid rounding the polytope, a point inside and it gives in output a max entropy sampling at fixed average growth rate of the steady states by performing an Hit-and-Run Monte Carlo Markov chain. NB inputs are referred by defaults to the catabolic core of the E.Coli network iAF1260. For further details we refer to PLoS ONE 10.4 e0122670 (2015). AU - De Martino, Daniele AU - Tkacik, Gasper ID - 5587 KW - metabolic networks KW - e.coli core KW - maximum entropy KW - monte carlo markov chain sampling KW - ellipsoidal rounding TI - Supporting materials "STATISTICAL MECHANICS FOR METABOLIC NETWORKS IN STEADY-STATE GROWTH" ER - TY - JOUR AB - The t-haplotype, a mouse meiotic driver found on chromosome 17, has been a model for autosomal segregation distortion for close to a century, but several questions remain regarding its biology and evolutionary history. A recently published set of population genomics resources for wild mice includes several individuals heterozygous for the t-haplotype, which we use to characterize this selfish element at the genomic and transcriptomic level. Our results show that large sections of the t-haplotype have been replaced by standard homologous sequences, possibly due to occasional events of recombination, and that this complicates the inference of its history. As expected for a long genomic segment of very low recombination, the t-haplotype carries an excess of fixed nonsynonymous mutations compared to the standard chromosome. This excess is stronger for regions that have not undergone recent recombination, suggesting that occasional gene flow between the t and the standard chromosome may provide a mechanism to regenerate coding sequences that have accumulated deleterious mutations. Finally, we find that t-complex genes with altered expression largely overlap with deleted or amplified regions, and that carrying a t-haplotype alters the testis expression of genes outside of the t-complex, providing new leads into the pathways involved in the biology of this segregation distorter. AU - Kelemen, Réka K AU - Vicoso, Beatriz ID - 542 IS - 1 JF - Genetics TI - Complex history and differentiation patterns of the t-haplotype, a mouse meiotic driver VL - 208 ER - TY - JOUR AB - Because of the intrinsic randomness of the evolutionary process, a mutant with a fitness advantage has some chance to be selected but no certainty. Any experiment that searches for advantageous mutants will lose many of them due to random drift. It is therefore of great interest to find population structures that improve the odds of advantageous mutants. Such structures are called amplifiers of natural selection: they increase the probability that advantageous mutants are selected. Arbitrarily strong amplifiers guarantee the selection of advantageous mutants, even for very small fitness advantage. Despite intensive research over the past decade, arbitrarily strong amplifiers have remained rare. Here we show how to construct a large variety of them. Our amplifiers are so simple that they could be useful in biotechnology, when optimizing biological molecules, or as a diagnostic tool, when searching for faster dividing cells or viruses. They could also occur in natural population structures. AU - Pavlogiannis, Andreas AU - Tkadlec, Josef AU - Chatterjee, Krishnendu AU - Nowak, Martin A. ID - 5751 IS - 1 JF - Communications Biology SN - 2399-3642 TI - Construction of arbitrarily strong amplifiers of natural selection using evolutionary graph theory VL - 1 ER - TY - DATA AB - File S1. Variant Calling Format file of the ingroup: 197 haploid sequences of D. melanogaster from Zambia (Africa) aligned to the D. melanogaster 5.57 reference genome. File S2. Variant Calling Format file of the outgroup: 1 haploid sequence of D. simulans aligned to the D. melanogaster 5.57 reference genome. File S3. Annotations of each transcript in coding regions with SNPeff: Ps (# of synonymous polymorphic sites); Pn (# of non-synonymous polymorphic sites); Ds (# of synonymous divergent sites); Dn (# of non-synonymous divergent sites); DoS; ⍺ MK . All variants were included. File S4. Annotations of each transcript in non-coding regions with SNPeff: Ps (# of synonymous polymorphic sites); Pu (# of UTR polymorphic sites); Ds (# of synonymous divergent sites); Du (# of UTR divergent sites); DoS; ⍺ MK . All variants were included. File S5. Annotations of each transcript in coding regions with SNPGenie: Ps (# of synonymous polymorphic sites); πs (synonymous diversity); Ss_p (total # of synonymous sites in the polymorphism data); Pn (# of non-synonymous polymorphic sites); πn (non-synonymous diversity); Sn_p (total # of non-synonymous sites in the polymorphism data); Ds (# of synonymous divergent sites); ks (synonymous evolutionary rate); Ss_d (total # of synonymous sites in the divergence data); Dn (# of non-synonymous divergent sites); kn (non-synonymous evolutionary rate); Sn_d (total # of non- synonymous sites in the divergence data); DoS; ⍺ MK . All variants were included. File S6. Gene expression values (RPKM summed over all transcripts) for each sample. Values were quantile-normalized across all samples. File S7. Final dataset with all covariates, ⍺ MK , ωA MK and DoS for coding sites, excluding variants below 5% frequency. File S8. Final dataset with all covariates, ⍺ MK , ωA MK and DoS for non-coding sites, excluding variants below 5% frequency. File S9. Final dataset with all covariates, ⍺ EWK , ωA EWK and deleterious SFS for coding sites obtained with the Eyre-Walker and Keightley method on binned data and using all variants. AU - Fraisse, Christelle ID - 5757 KW - (mal)adaptation KW - pleiotropy KW - selective constraint KW - evo-devo KW - gene expression KW - Drosophila melanogaster TI - Supplementary Files for "Pleiotropy modulates the efficacy of selection in Drosophila melanogaster" ER - TY - THES AB - The eigenvalue density of many large random matrices is well approximated by a deterministic measure, the self-consistent density of states. In the present work, we show this behaviour for several classes of random matrices. In fact, we establish that, in each of these classes, the self-consistent density of states approximates the eigenvalue density of the random matrix on all scales slightly above the typical eigenvalue spacing. For large classes of random matrices, the self-consistent density of states exhibits several universal features. We prove that, under suitable assumptions, random Gram matrices and Hermitian random matrices with decaying correlations have a 1/3-Hölder continuous self-consistent density of states ρ on R, which is analytic, where it is positive, and has either a square root edge or a cubic root cusp, where it vanishes. We, thus, extend the validity of the corresponding result for Wigner-type matrices from [4, 5, 7]. We show that ρ is determined as the inverse Stieltjes transform of the normalized trace of the unique solution m(z) to the Dyson equation −m(z) −1 = z − a + S[m(z)] on C N×N with the constraint Im m(z) ≥ 0. Here, z lies in the complex upper half-plane, a is a self-adjoint element of C N×N and S is a positivity-preserving operator on C N×N encoding the first two moments of the random matrix. In order to analyze a possible limit of ρ for N → ∞ and address some applications in free probability theory, we also consider the Dyson equation on infinite dimensional von Neumann algebras. We present two applications to random matrices. We first establish that, under certain assumptions, large random matrices with independent entries have a rotationally symmetric self-consistent density of states which is supported on a centered disk in C. Moreover, it is infinitely often differentiable apart from a jump on the boundary of this disk. Second, we show edge universality at all regular (not necessarily extreme) spectral edges for Hermitian random matrices with decaying correlations. AU - Alt, Johannes ID - 149 SN - 2663-337X TI - Dyson equation and eigenvalue statistics of random matrices ER - TY - JOUR AB - Recently it was shown that a molecule rotating in a quantum solvent can be described in terms of the “angulon” quasiparticle [M. Lemeshko, Phys. Rev. Lett. 118, 095301 (2017)]. Here we extend the angulon theory to the case of molecules possessing an additional spin-1/2 degree of freedom and study the behavior of the system in the presence of a static magnetic field. We show that exchange of angular momentum between the molecule and the solvent can be altered by the field, even though the solvent itself is non-magnetic. In particular, we demonstrate a possibility to control resonant emission of phonons with a given angular momentum using a magnetic field. AU - Rzadkowski, Wojciech AU - Lemeshko, Mikhail ID - 415 IS - 10 JF - The Journal of Chemical Physics TI - Effect of a magnetic field on molecule–solvent angular momentum transfer VL - 148 ER - TY - JOUR AB - The current state of the art in real-time two-dimensional water wave simulation requires developers to choose between efficient Fourier-based methods, which lack interactions with moving obstacles, and finite-difference or finite element methods, which handle environmental interactions but are significantly more expensive. This paper attempts to bridge this long-standing gap between complexity and performance, by proposing a new wave simulation method that can faithfully simulate wave interactions with moving obstacles in real time while simultaneously preserving minute details and accommodating very large simulation domains. Previous methods for simulating 2D water waves directly compute the change in height of the water surface, a strategy which imposes limitations based on the CFL condition (fast moving waves require small time steps) and Nyquist's limit (small wave details require closely-spaced simulation variables). This paper proposes a novel wavelet transformation that discretizes the liquid motion in terms of amplitude-like functions that vary over space, frequency, and direction, effectively generalizing Fourier-based methods to handle local interactions. Because these new variables change much more slowly over space than the original water height function, our change of variables drastically reduces the limitations of the CFL condition and Nyquist limit, allowing us to simulate highly detailed water waves at very large visual resolutions. Our discretization is amenable to fast summation and easy to parallelize. We also present basic extensions like pre-computed wave paths and two-way solid fluid coupling. Finally, we argue that our discretization provides a convenient set of variables for artistic manipulation, which we illustrate with a novel wave-painting interface. AU - Jeschke, Stefan AU - Skrivan, Tomas AU - Mueller Fischer, Matthias AU - Chentanez, Nuttapong AU - Macklin, Miles AU - Wojtan, Christopher J ID - 134 IS - 4 JF - ACM Transactions on Graphics TI - Water surface wavelets VL - 37 ER - TY - JOUR AB - We introduce a diagrammatic Monte Carlo approach to angular momentum properties of quantum many-particle systems possessing a macroscopic number of degrees of freedom. The treatment is based on a diagrammatic expansion that merges the usual Feynman diagrams with the angular momentum diagrams known from atomic and nuclear structure theory, thereby incorporating the non-Abelian algebra inherent to quantum rotations. Our approach is applicable at arbitrary coupling, is free of systematic errors and of finite-size effects, and naturally provides access to the impurity Green function. We exemplify the technique by obtaining an all-coupling solution of the angulon model; however, the method is quite general and can be applied to a broad variety of systems in which particles exchange quantum angular momentum with their many-body environment. AU - Bighin, Giacomo AU - Tscherbul, Timur AU - Lemeshko, Mikhail ID - 6339 IS - 16 JF - Physical Review Letters TI - Diagrammatic Monte Carlo approach to angular momentum in quantum many-particle systems VL - 121 ER - TY - JOUR AB - We introduce a Diagrammatic Monte Carlo (DiagMC) approach to complex molecular impurities with rotational degrees of freedom interacting with a many-particle environment. The treatment is based on the diagrammatic expansion that merges the usual Feynman diagrams with the angular momentum diagrams known from atomic and nuclear structure theory, thereby incorporating the non-Abelian algebra inherent to quantum rotations. Our approach works at arbitrary coupling, is free of systematic errors and of finite size effects, and naturally provides access to the impurity Green function. We exemplify the technique by obtaining an all-coupling solution of the angulon model, however, the method is quite general and can be applied to a broad variety of quantum impurities possessing angular momentum degrees of freedom. AU - Bighin, Giacomo AU - Tscherbul, Timur AU - Lemeshko, Mikhail ID - 417 IS - 16 JF - Physical Review Letters TI - Diagrammatic Monte Carlo approach to rotating molecular impurities VL - 121 ER - TY - JOUR AB - Clathrin-mediated endocytosis (CME) is a cellular trafficking process in which cargoes and lipids are internalized from the plasma membrane into vesicles coated with clathrin and adaptor proteins. CME is essential for many developmental and physiological processes in plants, but its underlying mechanism is not well characterised compared to that in yeast and animal systems. Here, we searched for new factors involved in CME in Arabidopsis thaliana by performing Tandem Affinity Purification of proteins that interact with clathrin light chain, a principal component of the clathrin coat. Among the confirmed interactors, we found two putative homologues of the clathrin-coat uncoating factor auxilin previously described in non-plant systems. Overexpression of AUXILIN-LIKE1 and AUXILIN-LIKE2 in A. thaliana caused an arrest of seedling growth and development. This was concomitant with inhibited endocytosis due to blocking of clathrin recruitment after the initial step of adaptor protein binding to the plasma membrane. By contrast, auxilin-like(1/2) loss-of-function lines did not present endocytosis-related developmental or cellular phenotypes under normal growth conditions. This work contributes to the on-going characterization of the endocytotic machinery in plants and provides a robust tool for conditionally and specifically interfering with CME in A. thaliana. AU - Adamowski, Maciek AU - Narasimhan, Madhumitha AU - Kania, Urszula AU - Glanc, Matous AU - De Jaeger, Geert AU - Friml, Jirí ID - 412 IS - 3 JF - The Plant Cell SN - 1040-4651 TI - A functional study of AUXILIN LIKE1 and 2 two putative clathrin uncoating factors in Arabidopsis VL - 30 ER - TY - JOUR AB - With the advent of optogenetics, it became possible to change the activity of a targeted population of neurons in a temporally controlled manner. To combine the advantages of 60-channel in vivo tetrode recording and laser-based optogenetics, we have developed a closed-loop recording system that allows for the actual electrophysiological signal to be used as a trigger for the laser light mediating the optogenetic intervention. We have optimized the weight, size, and shape of the corresponding implant to make it compatible with the size, force, and movements of a behaving mouse, and we have shown that the system can efficiently block sharp wave ripple (SWR) events using those events themselves as a trigger. To demonstrate the full potential of the optogenetic recording system we present a pilot study addressing the contribution of SWR events to learning in a complex behavioral task. AU - Rangel Guerrero, Dámaris K AU - Donnett, James G. AU - Csicsvari, Jozsef L AU - Kovács, Krisztián ID - 5914 IS - 4 JF - eNeuro TI - Tetrode recording from the hippocampus of behaving mice coupled with four-point-irradiation closed-loop optogenetics: A technique to study the contribution of Hippocampal SWR events to learning VL - 5 ER - TY - JOUR AB - During metastasis, malignant cells escape the primary tumor, intravasate lymphatic vessels, and reach draining sentinel lymph nodes before they colonize distant organs via the blood circulation. Although lymph node metastasis in cancer patients correlates with poor prognosis, evidence is lacking as to whether and how tumor cells enter the bloodstream via lymph nodes. To investigate this question, we delivered carcinoma cells into the lymph nodes of mice by microinfusing the cells into afferent lymphatic vessels. We found that tumor cells rapidly infiltrated the lymph node parenchyma, invaded blood vessels, and seeded lung metastases without involvement of the thoracic duct. These results suggest that the lymph node blood vessels can serve as an exit route for systemic dissemination of cancer cells in experimental mouse models. Whether this form of tumor cell spreading occurs in cancer patients remains to be determined. AU - Brown, Markus AU - Assen, Frank P AU - Leithner, Alexander F AU - Abe, Jun AU - Schachner, Helga AU - Asfour, Gabriele AU - Bagó Horváth, Zsuzsanna AU - Stein, Jens AU - Uhrin, Pavel AU - Sixt, Michael K AU - Kerjaschki, Dontscho ID - 402 IS - 6382 JF - Science TI - Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice VL - 359 ER - TY - THES AB - Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. AU - Tarlungeanu, Dora-Clara ID - 395 SN - 2663-337X TI - The branched chain amino acids in autism spectrum disorders ER - TY - THES AB - Asymmetries have long been known about in the central nervous system. From gross anatomical differences, such as the presence of the parapineal organ in only one hemisphere of the developing zebrafish, to more subtle differences in activity between both hemispheres, as seen in freely roaming animals or human participants under PET and fMRI imaging analysis. The presence of asymmetries has been demonstrated to have huge behavioural implications, with their disruption often leading to the generation of neurological disorders, memory problems, changes in personality, and in an organism's health and well-being. For my Ph.D. work I aimed to tackle two important avenues of research. The first being the process of input-side dependency in the hippocampus, with the goal of finding a key gene responsible for its development (Gene X). The second project was to do with experience-induced laterality formation in the hippocampus. Specifically, how laterality in the synapse density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental enrichment. Through unilateral tracer injections into the CA3, I was able to selectively measure the properties of synapses within the CA1 and investigate how they differed based upon which hemisphere the presynaptic neurone originated. Having found the existence of a previously unreported reversed (left-isomerism) i.v. mutant, through morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate a key gene responsible for the process of left or right determination of inputs to the CA1 s.r.. This work relates to the previous finding of input-side dependent asymmetry in the wild-type rodent, where the origin of the projecting neurone to the CA1 will determine the morphology of a synapse, to a greater degree than the hemisphere in which the projection terminates. Using left- and right-isomerism i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like (Evl) as a potential target for Gene X. In relation to this topic, I also highlight my work in the recently published paper of how knockout of PirB can lead to a lack of input-side dependency in the murine hippocampus. For the second question, I show that the environmental enrichment paradigm will lead to an asymmetry in the synapse densities in the hippocampus of mice. I also highlight that the nature of the enrichment is of less consequence than the process of enrichment itself. I demonstrate that the CA3 region will dramatically alter its projection targets, in relation to environmental stimulation, with the asymmetry in synaptic density, caused by enrichment, relying heavily on commissural fibres. I also highlight the vital importance of input-side dependent asymmetry, as a necessary component of experience-dependent laterality formation in the CA1 s.r.. However, my results suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism also at play. Upon further investigation, I highlight the significant, and highly important, finding that the changes seen in the CA1 s.r. were predominantly caused through projections from the left-CA3, with the right-CA3 having less involvement in this mechanism. AU - Case, Matthew J ID - 51 SN - 2663-337X TI - From the left to the right: A tale of asymmetries, environments, and hippocampal development ER - TY - THES AB - Genomic imprinting is an epigenetic process that leads to parent of origin-specific gene expression in a subset of genes. Imprinted genes are essential for brain development, and deregulation of imprinting is associated with neurodevelopmental diseases and the pathogenesis of psychiatric disorders. However, the cell-type specificity of imprinting at single cell resolution, and how imprinting and thus gene dosage regulates neuronal circuit assembly is still largely unknown. Here, MADM (Mosaic Analysis with Double Markers) technology was employed to assess genomic imprinting at single cell level. By visualizing MADM-induced uniparental disomies (UPDs) in distinct colors at single cell level in genetic mosaic animals, this experimental paradigm provides a unique quantitative platform to systematically assay the UPD-mediated imbalances in imprinted gene expression at unprecedented resolution. An experimental pipeline based on FACS, RNA-seq and bioinformatics analysis was established and applied to systematically map cell-type-specific ‘imprintomes’ in the mouse brain. The results revealed that parental-specific expression of imprinted genes per se is rarely cell-type-specific even at the individual cell level. Conversely, when we extended the comparison to downstream responses resulting from imbalanced imprinted gene expression, we discovered an unexpectedly high degree of cell-type specificity. Furthermore, we determined a novel function of genomic imprinting in cortical astrocyte production and in olfactory bulb (OB) granule cell generation. These results suggest important functional implication of genomic imprinting for generating cell-type diversity in the brain. In addition, MADM provides a powerful tool to study candidate genes by concomitant genetic manipulation and fluorescent labelling of single cells. MADM-based candidate gene approach was utilized to identify potential imprinted genes involved in the generation of cortical astrocytes and OB granule cells. We investigated p57Kip2, a maternally expressed gene and known cell cycle regulator. Although we found that p57Kip2 does not play a role in these processes, we detected an unexpected function of the paternal allele previously thought to be silent. Finally, we took advantage of a key property of MADM which is to allow unambiguous investigation of environmental impact on single cells. The experimental pipeline based on FACS and RNA-seq analysis of MADM-labeled cells was established to probe the functional differences of single cell loss of gene function compared to global loss of function on a transcriptional level. With this method, both common and distinct responses were isolated due to cell-autonomous and non-autonomous effects acting on genotypically identical cells. As a result, transcriptional changes were identified which result solely from the surrounding environment. Using the MADM technology to study genomic imprinting at single cell resolution, we have identified cell-type-specific gene expression, novel gene function and the impact of environment on single cell transcriptomes. Together, these provide important insights to the understanding of mechanisms regulating cell-type specificity and thus diversity in the brain. AU - Laukoter, Susanne ID - 10 SN - 2663-337X TI - Role of genomic imprinting in cerebral cortex development ER -