@article{538, abstract = {Optogenetik und Photopharmakologie ermöglichen präzise räumliche und zeitliche Kontrolle von Proteinwechselwirkung und -funktion in Zellen und Tieren. Optogenetische Methoden, die auf grünes Licht ansprechen und zum Trennen von Proteinkomplexen geeignet sind, sind nichtweitläufig verfügbar, würden jedoch mehrfarbige Experimente zur Beantwortung von biologischen Fragestellungen ermöglichen. Hier demonstrieren wir die Verwendung von Cobalamin(Vitamin B12)-bindenden Domänen von bakteriellen CarH-Transkriptionsfaktoren zur Grünlicht-induzierten Dissoziation von Rezeptoren. Fusioniert mit dem Fibroblasten-W achstumsfaktor-Rezeptor 1 führten diese im Dunkeln in kultivierten Zellen zu Signalaktivität durch Oligomerisierung, welche durch Beleuchten umgehend aufgehoben wurde. In Zebrafischembryonen, die einen derartigen Rezeptor exprimieren, ermöglichte grünes Licht die Kontrolle über abnormale Signalaktivität während der Embryonalentwicklung. }, author = {Kainrath, Stephanie and Stadler, Manuela and Gschaider-Reichhart, Eva and Distel, Martin and Janovjak, Harald L}, journal = {Angewandte Chemie}, number = {16}, pages = {4679 -- 4682}, publisher = {Wiley}, title = {{Grünlicht-induzierte Rezeptorinaktivierung durch Cobalamin-bindende Domänen}}, doi = {10.1002/ange.201611998}, volume = {129}, year = {2017}, } @article{256, abstract = {We show that a non-singular integral form of degree d is soluble over the integers if and only if it is soluble over ℝ and over ℚp for all primes p, provided that the form has at least (d - 1/2 √d)2d variables. This improves on a longstanding result of Birch.}, author = {Browning, Timothy D and Prendiville, Sean}, issn = {0075-4102}, journal = {Journal fur die Reine und Angewandte Mathematik}, number = {731}, pages = {122}, publisher = {Walter de Gruyter}, title = {{Improvements in Birch's theorem on forms in many variables}}, doi = {10.1515/crelle-2014-0122}, volume = {2017}, year = {2017}, } @article{265, abstract = {We establish the dimension and irreducibility of the moduli space of rational curves (of fixed degree) on arbitrary smooth hypersurfaces of sufficiently low degree. A spreading out argument reduces the problem to hypersurfaces defined over finite fields of large cardinality, which can then be tackled using a function field version of the Hardy-Littlewood circle method, in which particular care is taken to ensure uniformity in the size of the underlying finite field.}, author = {Browning, Timothy D and Vishe, Pankaj}, issn = {1944-7833}, journal = {Geometric Methods in Algebra and Number Theory}, number = {7}, pages = {1657 -- 1675}, publisher = { Mathematical Sciences Publishers}, title = {{Rational curves on smooth hypersurfaces of low degree}}, doi = {10.2140/ant.2017.11.1657}, volume = {11}, year = {2017}, } @article{266, abstract = {We generalise Birch's seminal work on forms in many variables to handle a system of forms in which the degrees need not all be the same. This allows us to prove the Hasse principle, weak approximation, and the Manin-Peyre conjecture for a smooth and geometrically integral variety X Pm, provided only that its dimension is large enough in terms of its degree.}, author = {Browning, Timothy D and Heath Brown, Roger}, journal = {Journal of the European Mathematical Society}, number = {2}, pages = {357 -- 394}, publisher = {European Mathematical Society Publishing House}, title = {{Forms in many variables and differing degrees}}, doi = {10.4171/JEMS/668}, volume = {19}, year = {2017}, } @article{267, abstract = {Building on recent work of Bhargava, Elkies and Schnidman and of Kriz and Li, we produce infinitely many smooth cubic surfaces defined over the field of rational numbers that contain rational points.}, author = {Browning, Timothy D}, issn = {0025-5793}, journal = {Mathematika}, number = {3}, pages = {818 -- 839}, publisher = {Cambridge University Press}, title = {{Many cubic surfaces contain rational points}}, doi = {10.1112/S0025579317000195}, volume = {63}, year = {2017}, } @article{268, abstract = {We show that any subset of the squares of positive relative upper density contains nontrivial solutions to a translation-invariant linear equation in five or more variables, with explicit quantitative bounds. As a consequence, we establish the partition regularity of any diagonal quadric in five or more variables whose coefficients sum to zero. Unlike previous approaches, which are limited to equations in seven or more variables, we employ transference technology of Green to import bounds from the linear setting.}, author = {Browning, Timothy D and Prendiville, Sean}, issn = {1073-7928}, journal = {International Mathematics Research Notices}, number = {7}, pages = {2219 -- 2248}, publisher = {Oxford University Press}, title = {{A transference approach to a Roth-type theorem in the squares}}, doi = {10.1093/imrn/rnw096}, volume = {2017}, year = {2017}, } @article{269, abstract = {We investigate Fano varieties defined over a number field that contain subvarieties whose number of rational points of bounded height is comparable to the total number on the variety.}, author = {Browning, Timothy D and Loughran, Daniel}, journal = {Mathematische Zeitschrift}, number = {3-4}, pages = {1249 -- 1267}, publisher = {Springer}, title = {{Varieties with too many rational points}}, doi = {10.1007/s00209-016-1746-2}, volume = {285}, year = {2017}, } @article{270, abstract = {Given a symmetric variety Y defined over Q and a non-zero polynomial with integer coefficients, we use techniques from homogeneous dynamics to establish conditions under which the polynomial can be made r-free for a Zariski dense set of integral points on Y . We also establish an asymptotic counting formula for this set. In the special case that Y is a quadric hypersurface, we give explicit bounds on the size of r by combining the argument with a uniform upper bound for the density of integral points on general affine quadrics defined over Q.}, author = {Browning, Timothy D and Gorodnik, Alexander}, issn = {0024-6115}, journal = {Proceedings of the London Mathematical Society}, number = {6}, pages = {1044 -- 1080}, publisher = {Wiley}, title = {{Power-free values of polynomials on symmetric varieties}}, doi = {10.1112/plms.12030}, volume = {114}, year = {2017}, } @article{272, abstract = {Given a number field K/Q and a polynomial P ε Q [t], all of whose roots are Q, let X be the variety defined by the equation NK (x) = P (t). Combining additive combinatiorics with descent we show that the Brauer-Manin obstruction is the only obstruction to the Hesse principle and weak approximation on any smooth and projective model of X.}, author = {Browning, Timothy D and Matthiesen, Lilian}, journal = {Annales Scientifiques de l'Ecole Normale Superieure}, number = {6}, pages = {1383 -- 1446}, publisher = {Societe Mathematique de France}, title = {{Norm forms for arbitrary number fields as products of linear polynomials}}, doi = {10.24033/asens.2348}, volume = {50}, year = {2017}, } @inproceedings{274, abstract = {We consider the problem of estimating the partition function Z(β)=∑xexp(−β(H(x)) of a Gibbs distribution with a Hamilton H(⋅), or more precisely the logarithm of the ratio q=lnZ(0)/Z(β). It has been recently shown how to approximate q with high probability assuming the existence of an oracle that produces samples from the Gibbs distribution for a given parameter value in [0,β]. The current best known approach due to Huber [9] uses O(qlnn⋅[lnq+lnlnn+ε−2]) oracle calls on average where ε is the desired accuracy of approximation and H(⋅) is assumed to lie in {0}∪[1,n]. We improve the complexity to O(qlnn⋅ε−2) oracle calls. We also show that the same complexity can be achieved if exact oracles are replaced with approximate sampling oracles that are within O(ε2qlnn) variation distance from exact oracles. Finally, we prove a lower bound of Ω(q⋅ε−2) oracle calls under a natural model of computation.}, author = {Kolmogorov, Vladimir}, booktitle = {Proceedings of the 31st Conference On Learning Theory}, pages = {228--249}, publisher = {ML Research Press}, title = {{A faster approximation algorithm for the Gibbs partition function}}, volume = {75}, year = {2017}, } @inproceedings{313, abstract = {Tunneling of a particle through a potential barrier remains one of the most remarkable quantum phenomena. Owing to advances in laser technology, electric fields comparable to those electrons experience in atoms are readily generated and open opportunities to dynamically investigate the process of electron tunneling through the potential barrier formed by the superposition of both laser and atomic fields. Attosecond-time and angstrom-space resolution of the strong laser-field technique allow to address fundamental questions related to tunneling, which are still open and debated: Which time is spent under the barrier and what momentum is picked up by the particle in the meantime? In this combined experimental and theoretical study we demonstrate that for strong-field ionization the leading quantum mechanical Wigner treatment for the time resolved description of tunneling is valid. We achieve a high sensitivity on the tunneling barrier and unambiguously isolate its effects by performing a differential study of two systems with almost identical tunneling geometry. Moreover, working with a low frequency laser, we essentially limit the non-adiabaticity of the process as a major source of uncertainty. The agreement between experiment and theory implies two substantial corrections with respect to the widely employed quasiclassical treatment: In addition to a non-vanishing longitudinal momentum along the laser field-direction we provide clear evidence for a non-zero tunneling time delay. This addresses also the fundamental question how the transition occurs from the tunnel barrier to free space classical evolution of the ejected electron.}, author = {Camus, Nicolas and Yakaboylu, Enderalp and Fechner, Lutz and Klaiber, Michael and Laux, Martin and Mi, Yonghao and Hatsagortsyan, Karen and Pfeifer, Thomas and Keitel, Cristoph and Moshammer, Robert}, issn = {17426588}, location = {Kazan, Russian Federation}, number = {1}, publisher = {American Physical Society}, title = {{Experimental evidence for Wigner's tunneling time}}, doi = {10.1088/1742-6596/999/1/012004}, volume = {999}, year = {2017}, } @article{1085, abstract = {Sex chromosomes evolve once recombination is halted between a homologous pair of chromosomes. The dominant model of sex chromosome evolution posits that recombination is suppressed between emerging X and Y chromosomes in order to resolve sexual conflict. Here we test this model using whole genome and transcriptome resequencing data in the guppy, a model for sexual selection with many Y-linked colour traits. We show that although the nascent Y chromosome encompasses nearly half of the linkage group, there has been no perceptible degradation of Y chromosome gene content or activity. Using replicate wild populations with differing levels of sexually antagonistic selection for colour, we also show that sexual selection leads to greater expansion of the non-recombining region and increased Y chromosome divergence. These results provide empirical support for longstanding models of sex chromosome catalysis, and suggest an important role for sexual selection and sexual conflict in genome evolution.}, author = {Wright, Alison and Darolti, Iulia and Bloch, Natasha and Oostra, Vicencio and Sandkam, Benjamin and Buechel, Séverine and Kolm, Niclas and Breden, Felix and Vicoso, Beatriz and Mank, Judith}, issn = {20411723}, journal = {Nature Communications}, publisher = {Nature Publishing Group}, title = {{Convergent recombination suppression suggests role of sexual selection in guppy sex chromosome formation}}, doi = {10.1038/ncomms14251}, volume = {8}, year = {2017}, } @article{1086, abstract = {Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant (Lasius niger), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V1b receptors, but inhibited the human V1aR. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V1aR-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V1aR over the other three subtypes, OTR, V1bR and V2R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes.}, author = {Di Giglio, Maria and Muttenthaler, Markus and Harpsøe, Kasper and Liutkeviciute, Zita and Keov, Peter and Eder, Thomas and Rattei, Thomas and Arrowsmith, Sarah and Wray, Susan and Marek, Ales and Elbert, Tomas and Alewood, Paul and Gloriam, David and Gruber, Christian}, journal = {Scientific Reports}, pages = {41002}, publisher = {Nature Publishing Group}, title = {{Development of a human vasopressin V1a-receptor antagonist from an evolutionary-related insect neuropeptide}}, doi = {10.1038/srep41002}, volume = {7}, year = {2017}, } @article{1087, abstract = {Using extensive direct numerical simulations, the dynamics of laminar-turbulent fronts in pipe flow is investigated for Reynolds numbers between and 5500. We here investigate the physical distinction between the fronts of weak and strong slugs both by analysing the turbulent kinetic energy budget and by comparing the downstream front motion to the advection speed of bulk turbulent structures. Our study shows that weak downstream fronts travel slower than turbulent structures in the bulk and correspond to decaying turbulence at the front. At the downstream front speed becomes faster than the advection speed, marking the onset of strong fronts. In contrast to weak fronts, turbulent eddies are generated at strong fronts by feeding on the downstream laminar flow. Our study also suggests that temporal fluctuations of production and dissipation at the downstream laminar-turbulent front drive the dynamical switches between the two types of front observed up to.}, author = {Song, Baofang and Barkley, Dwight and Hof, Björn and Avila, Marc}, issn = {00221120}, journal = {Journal of Fluid Mechanics}, pages = {1045 -- 1059}, publisher = {Cambridge University Press}, title = {{Speed and structure of turbulent fronts in pipe flow}}, doi = {10.1017/jfm.2017.14}, volume = {813}, year = {2017}, } @article{1089, abstract = {We discuss properties of distributions that are multivariate totally positive of order two (MTP2) related to conditional independence. In particular, we show that any independence model generated by an MTP2 distribution is a compositional semigraphoid which is upward-stable and singleton-transitive. In addition, we prove that any MTP2 distribution satisfying an appropriate support condition is faithful to its concentration graph. Finally, we analyze factorization properties of MTP2 distributions and discuss ways of constructing MTP2 distributions; in particular we give conditions on the log-linear parameters of a discrete distribution which ensure MTP2 and characterize conditional Gaussian distributions which satisfy MTP2.}, author = {Fallat, Shaun and Lauritzen, Steffen and Sadeghi, Kayvan and Uhler, Caroline and Wermuth, Nanny and Zwiernik, Piotr}, issn = {00905364}, journal = {Annals of Statistics}, number = {3}, pages = {1152 -- 1184}, publisher = {Institute of Mathematical Statistics}, title = {{Total positivity in Markov structures}}, doi = {10.1214/16-AOS1478}, volume = {45}, year = {2017}, } @article{1104, abstract = {In the early visual system, cells of the same type perform the same computation in different places of the visual field. How these cells code together a complex visual scene is unclear. A common assumption is that cells of a single-type extract a single-stimulus feature to form a feature map, but this has rarely been observed directly. Using large-scale recordings in the rat retina, we show that a homogeneous population of fast OFF ganglion cells simultaneously encodes two radically different features of a visual scene. Cells close to a moving object code quasilinearly for its position, while distant cells remain largely invariant to the object's position and, instead, respond nonlinearly to changes in the object's speed. We develop a quantitative model that accounts for this effect and identify a disinhibitory circuit that mediates it. Ganglion cells of a single type thus do not code for one, but two features simultaneously. This richer, flexible neural map might also be present in other sensory systems.}, author = {Deny, Stephane and Ferrari, Ulisse and Mace, Emilie and Yger, Pierre and Caplette, Romain and Picaud, Serge and Tkacik, Gasper and Marre, Olivier}, issn = {20411723}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{Multiplexed computations in retinal ganglion cells of a single type}}, doi = {10.1038/s41467-017-02159-y}, volume = {8}, year = {2017}, } @article{11065, abstract = {Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.}, author = {Buchwalter, Abigail and HETZER, Martin W}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry}, publisher = {Springer Nature}, title = {{Nucleolar expansion and elevated protein translation in premature aging}}, doi = {10.1038/s41467-017-00322-z}, volume = {8}, year = {2017}, } @article{11066, abstract = {Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.}, author = {Franks, Tobias M. and McCloskey, Asako and Shokhirev, Maxim Nikolaievich and Benner, Chris and Rathore, Annie and HETZER, Martin W}, issn = {0890-9369}, journal = {Genes & Development}, keywords = {Developmental Biology, Genetics}, number = {22}, pages = {2222--2234}, publisher = {Cold Spring Harbor Laboratory}, title = {{Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells}}, doi = {10.1101/gad.306753.117}, volume = {31}, year = {2017}, } @article{11067, abstract = {Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.}, author = {Toda, Tomohisa and Hsu, Jonathan Y. and Linker, Sara B. and Hu, Lauren and Schafer, Simon T. and Mertens, Jerome and Jacinto, Filipe V. and HETZER, Martin W and Gage, Fred H.}, issn = {1934-5909}, journal = {Cell Stem Cell}, keywords = {Cell Biology, Genetics, Molecular Medicine}, number = {5}, pages = {618--634.e7}, publisher = {Elsevier}, title = {{Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells}}, doi = {10.1016/j.stem.2017.08.012}, volume = {21}, year = {2017}, } @article{1107, abstract = {The generation, migration, and differentiation of neurons requires the functional integrity of the microtubule cytoskeleton. Mutations in the tubulin gene family are known to cause various neurological diseases including lissencephaly, ocular motor disorders, polymicrogyria and amyotrophic lateral sclerosis. We have previously reported that mutations in TUBB5 cause microcephaly that is accompanied by severe intellectual impairment and motor delay. Here we present the characterization of a Tubb5 mouse model that allows for the conditional expression of the pathogenic E401K mutation. Homozygous knockin animals exhibit a severe reduction in brain size and in body weight. These animals do not show any significant impairment in general activity, anxiety, or in the acoustic startle response, however, present with notable defects in motor coordination. When assessed on the static rod apparatus mice took longer to orient and often lost their balance completely. Interestingly, mutant animals also showed defects in prepulse inhibition, a phenotype associated with sensorimotor gating and considered an endophenotype for schizophrenia. This study provides insight into the behavioral consequences of tubulin gene mutations.}, author = {Breuss, Martin and Hansen, Andi H and Landler, Lukas and Keays, David}, issn = {01664328}, journal = {Behavioural Brain Research}, pages = {47 -- 55}, publisher = {Elsevier}, title = {{Brain specific knockin of the pathogenic Tubb5 E401K allele causes defects in motor coordination and prepulse inhibition}}, doi = {10.1016/j.bbr.2017.01.029}, volume = {323}, year = {2017}, }