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Annunziata, Ida ; van de Vlekkert, Diantha ; Wolf, Elmar ; Finkelstein, David ; Neale, Geoffrey ; Machado, Eda ; Mosca, Rosario ; Campos, Yvan ; Tillman, Heather ; Roussel, Martine F. ; Weesner, Jason Andrew ; Fremuth, Leigh Ellen ; Qiu, Xiaohui ; Han, Min-Joon ; Grosveld, Gerard C. ; d'Azzo, Alessandra
Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
Al-Zaben, Naim ; Medyukhina, Anna ; Dietrich, Stefanie ; Marolda, Alessandra ; Hünniger, Kerstin ; Kurzai, Oliver ; Figge, Marc Thilo
Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.
Albrecht, Franziska ; Mueller, Karsten ; Ballarini, Tommaso ; Lampe, Leonie ; Diehl-Schmid, Janine ; Fassbender, Klaus ; Fliessbach, Klaus ; Jahn, Holger ; Jech, Robert ; Kassubek, Jan ; Kornhuber, Johannes ; Landwehrmeyer, Bernhard ; Lauer, Martin ; Ludolph, Albert C. ; Lyros, Epameinondas ; Prudlo, Johannes ; Schneider, Anja ; Synofzik, Matthis ; Wiltfang, Jens ; Danek, Adrian ; Otto, Markus ; Schroeter, Matthias L.
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes.
Albert, A. ; André, M. ; Anghinolfi, M. ; Anton, G. ; Ardid, M. ; Aubert, J.-J. ; Aublin, J. ; Avgitas, T. ; Baret, B. ; Barrios-Martít, J. ; Basa, S. ; Belhorma, B. ; Bertin, V. ; Biagi, S. ; Bormuth, R. ; Boumaaza, J ; Bourret, S. ; Bouwhuis, M. C. ; Brânzas, H. ; Bruijn, R. ; Brunner, J. ; Busto, J. ; Capone, A. ; Caramete, L. ; Carr, J. ; Celli, S. ; Chabab, M. ; Cherkaoui El Moursli, R. ; Chiarusi, T. ; Circella, M. ; Coelho, J. A. B. ; Coleiro, A. ; Colomer, M ; Coniglione, R. ; Costantini, H. ; Coyle, P. ; Creusot, A. ; Díaz, A. F. ; Deschamps, A. ; Distefano, C. ; Di Palma, I. ; Domi, A. ; Donzaud, C. ; Dornic, D. ; Drouhin, D. ; Eberl, T. ; El Bojaddaini, I. ; El Khayati, N. ; Elsässer, D. ; Enzenhöfer, A. ; Ettahiri, A. ; Fassi, F. ; Felis, I. ; Fermani, P. ; Ferrara, G. ; Fusco, L. A. ; Gay, P. ; Glotin, H. ; Grégoire, T. ; Gracia Ruiz, R. ; Graf, K. ; Hallmann, S. ; van Haren, H. ; Heijboer, A. J. ; Hello, Y. ; Hernández-Rey, J. J. ; Hößl, J. ; Hofestädt, J. ; Illuminati, G. ; de Jong, M. ; Jongen, M. ; Kadler, M. ; Kalekin, O. ; Katz, U. ; Khan-Chowdhury, N. R. ; Kouchner, A. ; Kreter, M. ; Kreykenbohm, I. ; Kulikovskiy, V. ; Lachaud, C. ; Lahmann, R. ; Lefèvre, D. ; Leonora, E. ; Levi, G. ; Lotze, M. ; Loucatos, S. ; Marcelin, M. ; Margiotta, A. ; Marinelli, A. ; Martínez-Mora, J. A. ; Mele, R. ; Melis, K. ; Migliozzi, P. ; Moussa, A. ; Navas, S. ; Nezri, E. ; Nuñez, A. ; Organokov, M. ; Pavalas, G. E. ; Pellegrino, C. ; Piattelli, P. ; Popa, V. ; Pradier, T. ; Quinn, L. ; Racca, C. ; Randazzo, N. ; Riccobene, G. ; Sánchez-Losa, A. ; Saldaña, M. ; Salvadori, I. ; Samtleben, D. F. E. ; Sanguineti, M. ; Sapienza, P. ; Schüssler, F. ; Spurio, M. ; Stolarczyk, Th. ; Taiuti, M. ; Tayalati, Y. ; Trovato, A. ; Vallage, B. ; Van Elewyck, V. ; Versari, F. ; Vivolo, D. ; Wilms, J. ; Zaborov, D. ; Zornoza, J. D. ; Zúñiga, J.
One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.
The ANTARES neutrino telescope has an energy threshold of a few tens of GeV. This allows to study the phenomenon of atmospheric muon neutrino disappearance due to neutrino oscillations. In a similar way, constraints on the 3+1 neutrino model, which foresees the existence of one sterile neutrino, can be inferred. Using data collected by the ANTARES neutrino telescope from 2007 to 2016, a new measurement of m 2 and (23) has been performed which is consistent with world best-fit values and constraints on the 3+1 neutrino model have been derived.
Alacevich, Massimo ; Carloni Calame, Carlo M. ; Chiesa, Mauro ; Montagna, Guido ; Nicrosini, Oreste ; Piccinini, Fulvio
We consider the process of muon-electron elastic scattering, which has been proposed as an ideal framework to measure the running of the electromagnetic coupling constant at space-like momenta and determine the leading-order hadronic contribution to the muon g-2 (MUonE experiment). We compute the next-to-leading (NLO) contributions due to QED and purely weak corrections and implement them into a fully differential Monte Carlo event generator, which is available for first experimental studies. We show representative phenomenological results of interest for the MUonE experiment and examine in detail the impact of the various sources of radiative corrections under different selection criteria, in order to study the dependence of the NLO contributions on the applied cuts. The study represents the first step towards the realisation of a high-precision Monte Carlo code necessary for data analysis.
The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells
(2019)
Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.
KM3NeT will be a network of deep-sea neutrino telescopes in the Mediterranean Sea. The KM3NeT/ARCA detector, to be installed at the Capo Passero site (Italy), is optimised for the detection of high-energy neutrinos of cosmic origin. Thanks to its geographical location on the Northern hemisphere, KM3NeT/ARCA can observe upgoing neutrinos from most of the Galactic Plane, including the Galactic Centre. Given its effective area and excellent pointing resolution, KM3NeT/ARCA will measure or significantly constrain the neutrino flux from potential astrophysical neutrino sources. At the same time, it will test flux predictions based on gamma-ray measurements and the assumption that the gamma-ray flux is of hadronic origin. Assuming this scenario, discovery potentials and sensitivities for a selected list of Galactic sources and to generic point sources with an E-2 spectrum are presented. These spectra are assumed to be time independent. The results indicate that an observation with 3 sigma significance is possible in about six years of operation for the most intense sources, such as Supernovae Remnants RX J1713.7-3946 and Vela Jr. If no signal will be found during this time, the fraction of the gamma-ray flux coming from hadronic processes can be constrained to be below 50% for these two objects. (C) 2019 The Authors. Published by Elsevier B.V.
Abt, Raimond ; Erdmenger, Johanna ; Gerbershagen, Marius ; Melby-Thompson, Charles M. ; Northe, Christian
We consider the computation of volumes contained in a spatial slice of AdS(3) in terms of observables in a dual CFT. Our main tool is kinematic space, defined either from the bulk perspective as the space of oriented bulk geodesics, or from the CFT perspective as the space of entangling intervals. We give an explicit formula for the volume of a general region in a spatial slice of AdS(3) as an integral over kinematic space. For the region lying below a geodesic, we show how to write this volume purely in terms of entangling entropies in the dual CFT. This expression is perhaps most interesting in light of the complexity = volume proposal, which posits that complexity of holographic quantum states is computed by bulk volumes. An extension of this idea proposes that the holographic subregion complexity of an interval, defined as the volume under its Ryu-Takayanagi surface, is a measure of the complexity of the corresponding reduced density matrix. If this is true, our results give an explicit relationship between entanglement and subregion complexity in CFT, at least in the vacuum. We further extend many of our results to conical defect and BTZ black hole geometries.