Roles of bHLH Transcription Factors Neurod1, Neurod2 and Neurod6 in Cerebral Cortex Development and Commissure Formation.

Basische Helix-Loop-Helix (bHLH)-Proteine bilden eine diverse Gruppe evolutionär gut konservierter Transkriptionsfaktoren. Viele transaktivierende bHLH-Proteine werden zelltyp- oder gewebespezifisch exprimiert und fungieren als wichtige Schlüsselregulatoren zellulärer Determinations- und Differenzierungsprozesse. Die eng verwandten neuronalen bHLH-Gene Neurod1, Neurod2 und Neurod6 werden in differenzierenden Pyramidenneuronen des sich entwickelnden zerebralen Kortex exprimiert und stehen schon lange im Verdacht, deren Reifung zu steuern. In der Vergangenheit wurde jedes der drei Gene in Mäusen inaktiviert. Untersuchungen an den einfach-defizienten Tieren konnten jedoch keine wichtigen Funktionen in embryonalen Pyramidenneuronen identifizieren. Da die Aminosäuresequenzen und die Expressionsmuster der Faktoren sehr ähnlich sind, wurde angenommen, dass sie sich redundante Funktionalität teilen. Um dies zu überprüfen, habe ich Neurod2/6-doppel-defiziente Tiere gezüchtet und unter besonderer Berücksichtigung der Differenzierung von Pyramidenneuronen und der Konnektivität des zerebralen Kortex analysiert: Die Experimente zeigen, dass Neurod2 und Neurod6 tatsächlich mehrere bisher unbekannte gemeinsame Funktionen haben, wobei jeder Faktor für den Verlust des jeweils anderen kompensieren kann. Zumindest eines der beiden Gene ist notwendig für (1) die Kontrolle der radialen Migration eines Teils der Pyramidenneurone, (2) die frühe Regionalisierung des zerebralen Kortex und (3) die Bildung kortikaler Projektionen vom Neokortex zum Striatum, zum Thalamus und zur kontralateralen Hemisphäre. Callosale Axone bilden in Neurod2/6-doppel-defizienten Mäusen Faserbündel die tangential in den medialen Kortex einwachsen, aber noch vor Erreichen des ipsilateralen Cingulums und vor dem Kontakt mit der Mittellinie stoppen und defaszikulieren. Es resultiert eine neue Variante der callosalen Agenesie, die nahelegt, dass es bisher nicht identifizierte Wachstumssignale im medialen Kortex gibt. Die Expression von Neurod1, welche sich normalerweise auf die Subventrikularzone beschränkt, persistiert in radial migrierenden Pyramidenneuronen der Intermediärzone und der Kortikalplatte von Neurod2/6-doppel-defizienten Mäusen. Diese ektopische Neurod1-Expression kann dort den Verlust von Neurod2 und Neurod6 kompensieren. In einem weiteren Schritt habe ich konditionale Neurod1/2/6-tripel-defiziente Mäuse gezüchtet. In diesen Tieren wird das Neurod1-Gen durch selektive genetische Rekombination in all jenen Zellen, die über Neurod6-Promoteraktivität verfügen, irreversibel entfernt: Wie erwartet, teilt sich Neurod1 weitere gemeinsame Funktionen mit Neurod2 und Neurod6. Zumindest eines der drei Gene ist notwendig für die Differenzierung hippokampaler Pyramidenzellen und die Hemmung des programmierten Zelltods der unreifen Neuronen des Cornu Ammonis. Während die gemeinsame Inaktivierung von Neurod1/2/6 zur Aplasie des Hippocampus führt, überlebt ein Großteil der neokortikalen Pyramidenzellen. Die terminale neuronale Differenzierung ist jedoch auch im Neokortex gestört und die neokortikale Konnektivität sehr stark reduziert. Diese Arbeit zeigt, dass die Transkriptionsfaktoren der NeuroD-Familie gemeinsam die Differenzierung, das Überleben, die Migration und das axonale Wachstum von pyramidalen Neuronen des sich entwickelnden zerebralen Kortex steuern. Während der Embryonalentwicklung ergeben sich folgende, teils überschneidende Funktionen der NeuroD-Gene: Die Differenzierung und das Überleben von hippocampalen Körnerzellen ist abhängig von Neurod1. Die frühen Schritte der Differenzierung von hippocampalen Pyramidenneuronen und deren Überleben sind eine Funktion von wahlweise Neurod1, Neurod2 oder Neurod6. Spätere neuronale Differenzierungsschritte, die Regionalisierung des Neokortex und das gezielte Wachstum wichtiger neokortikaler Faserzüge basieren auf Funktionen von Neurod2 oder Neurod6, aber nicht von Neurod1. Der postnatale Umbau des somatosensorischen Kortex und die funktionale Integration thalamischer Afferenzen wurden bereits als strikt Neurod2-abhängig beschrieben

Chasing cosmic tau neutrinos in the abyss

In this work the reconstruction of a tau neutrino signal in the KM3NeT detector is discussed. Tau neutrinos leave a two shower signature in the detector, which is a unique signature among all neutrino interactions. By identifying and reconstructing these tau signatures the KM3NeT detector will be able to distinguish all three neutrino flavors. In addition, cosmic tau neutrinos suffer significantly less from atmospheric backgrounds, makign them ideal messengers for cosmic events. The presented reconstruction is the first tau reconstruction for the KM3NeT detector and resulted in a total expected observation rate of half a tau event per year for one unit of the KM3NeT detector.Theoretical Physic

Coordinately Co-opted Multiple Transposable Elements Constitute an Enhancer for wnt5a Expression in the Mammalian Secondary Palate

Acquisition of cis-regulatory elements is a major driving force of evolution, and there are several examples of developmental enhancers derived from transposable elements (TEs). However, it remains unclear whether one enhancer element could have been produced via cooperation among multiple, yet distinct, TEs during evolution. Here we show that an evolutionarily conserved genomic region named AS3_9 comprises three TEs (AmnSINE1, X6b_DNA and MER117), inserted side-by-side, and functions as a distal enhancer for wnt5a expression during morphogenesis of the mammalian secondary palate. Functional analysis of each TE revealed step-by-step retroposition/transposition and co-option together with acquisition of a binding site for Msx1 for its full enhancer function during mammalian evolution. The present study provides a new perspective suggesting that a huge variety of TEs, in combination, could have accelerated the diversity of cis-regulatory elements involved in morphological evolution

Adhesion dynamics in the neocortex determine the start of migration and the post-migratory orientation of neurons.

peer reviewedThe neocortex is stereotypically organized into layers of excitatory neurons arranged in a precise parallel orientation. Here we show that dynamic adhesion both preceding and following radial migration is essential for this organization. Neuronal adhesion is regulated by the Mowat-Wilson syndrome-associated transcription factor Zeb2 (Sip1/Zfhx1b) through direct repression of independent adhesion pathways controlled by Neuropilin-1 (Nrp1) and Cadherin-6 (Cdh6). We reveal that to initiate radial migration, neurons must first suppress adhesion to the extracellular matrix. Zeb2 regulates the multipolar stage by transcriptional repression of Nrp1 and thereby downstream inhibition of integrin signaling. Upon completion of migration, neurons undergo an orientation process that is independent of migration. The parallel organization of neurons within the neocortex is controlled by Cdh6 through atypical regulation of integrin signaling via its RGD motif. Our data shed light on the mechanisms that regulate initiation of radial migration and the postmigratory orientation of neurons during neocortical development

Классификация экзонов генов человека с использованием алгоритмов автоматического выбора атрибутов экзонов

Volkov AV, Yatskov NN, Grinev VV Classification of exons of human genes using algorithms for automatic selection of exon attributesСекция 2. МЕТОДЫ И ТЕХНОЛОГИИ МАТЕМАТИЧЕСКОГО И ИМИТАЦИОННОГО МОДЕЛИРОВАНИЯ СИСТЕ

Optical forces through guided light deflections

Optical trapping and manipulation typically relies on shaping focused light to control the optical force, usually on spherical objects. However, one can also shape the object to control the light deflection arising from the light-matter interaction and, hence, achieve desired optomechanical effects. In this work we look into the object shaping aspect and its potential for controlled optical manipulation. Using a simple bent waveguide as example, our numerical simulations show that the guided deflection of light efficiently converts incident light momentum into optical force with one order-of-magnitude improvement in the efficiency factor relative to a microbead, which is comparable to the improvement expected from orthogonal deflection with a perfect mirror. This improvement is illustrated in proof-of-principle experiments demonstrating the optical manipulation of two-photon polymerized waveguides. Results show that the force on the waveguide exceeds the combined forces on spherical trapping handles. Furthermore, it shows that static illumination can exert a constant force on a moving structure, unlike the position-dependent forces from harmonic potentials in conventional trapping. © 2013 Optical Society of America

Search for muon-neutrino emission from GeV and TeV gamma-ray flaring blazars using five years of data of the ANTARES telescope

The ANTARES telescope is well-suited for detecting astrophysical transient neutrino sources as it can observe a full hemisphere of the sky at all times with a high duty cycle. The background due to atmospheric particles can be drastically reduced, and the point-source sensitivity improved, by selecting a narrow time window around possible neutrino production periods. Blazars, being radio-loud active galactic nuclei with their jets pointing almost directly towards the observer, are particularly attractive potential neutrino point sources, since they are among the most likely sources of the very high-energy cosmic rays. Neutrinos and gamma rays may be produced in hadronic interactions with the surrounding medium. Moreover, blazars generally show high time variability in their light curves at different wavelengths and on various time scales. This paper presents a time-dependent analysis applied to a selection of flaring gamma-ray blazars observed by the FERMI/LAT experiment and by TeV Cherenkov telescopes using five years of ANTARES data taken from 2008 to 2012. The results are compatible with fluctuations of the background. Upper limits on the neutrino fluence have been produced and compared to the measured gamma-ray spectral energy distribution.Comment: 27 pages, 16 figure

All-sky Search for High-Energy Neutrinos from Gravitational Wave Event GW170104 with the ANTARES Neutrino Telescope

Advanced LIGO detected a significant gravitational wave signal (GW170104) originating from the coalescence of two black holes during the second observation run on January 4$^{\textrm{th}}$, 2017. An all-sky high-energy neutrino follow-up search has been made using data from the ANTARES neutrino telescope, including both upgoing and downgoing events in two separate analyses. No neutrino candidates were found within $\pm500$ s around the GW event time nor any time clustering of events over an extended time window of $\pm3$ months. The non-detection is used to constrain isotropic-equivalent high-energy neutrino emission from GW170104 to less than $\sim4\times 10^{54}$ erg for a $E^{-2}$ spectrum

The Antares Collaboration : Contributions to the 34th International Cosmic Ray Conference (ICRC 2015, The Hague)

The ANTARES detector, completed in 2008, is the largest neutrino telescope in the Northern hemisphere. Located at a depth of 2.5 km in the Mediterranean Sea, 40 km off the Toulon shore, its main goal is the search for astrophysical high energy neutrinos. In this paper we collect the 21 contributions of the ANTARES collaboration to the 34th International Cosmic Ray Conference (ICRC 2015). The scientific output is very rich and the contributions included in these proceedings cover the main physics results, ranging from steady point sources, diffuse searches, multi-messenger analyses to exotic physics