Sperm whale long-range echolocation sounds revealed by ANTARES, a deep-sea neutrino telescope

[EN] Despite dedicated research has been carried out to adequately map the distribution of the sperm whale in the Mediterranean Sea, unlike other regions of the world, the species population status is still presently uncertain. The analysis of two years of continuous acoustic data provided by the ANTARES neutrino telescope revealed the year-round presence of sperm whales in the Ligurian Sea, probably associated with the availability of cephalopods in the region. The presence of the Ligurian Sea sperm whales was demonstrated through the real-time analysis of audio data streamed from a cabled-to- shore deep-sea observatory that allowed the hourly tracking of their long-range echolocation behaviour on the Internet. Interestingly, the same acoustic analysis indicated that the occurrence of surface shipping noise would apparently not condition the foraging behaviour of the sperm whale in the area, since shipping noise was almost always present when sperm whales were acoustically detected. The continuous presence of the sperm whale in the region confirms the ecological value of the Ligurian sea and the importance of ANTARES to help monitoring its ecosystemsThe authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a lenergie atomique et aux energies alternatives (CEA), la Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Istituto Nazionale di Fisica Nucleare (INFN), Italy; Stichting voor Fundamenteel Onderzoek der Materie (FOM), Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; National Authority for Scientific Research (ANCS), Romania; Ministerio de Economia y Competitividad (MINECO), Prometeo and Grisolia programs of Generalitat Valenciana and MultiDark, Spain; Agence de l'Oriental and CNRST, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilitiesAndre, M.; Caballé, A.; Van Der Schaar, M.; Solsona, A.; Houégnigan, L.; Zaugg, S.; Sanchez, AM.... (2017). Sperm whale long-range echolocation sounds revealed by ANTARES, a deep-sea neutrino telescope. Scientific Reports. 7:1-12. https://doi.org/10.1038/srep45517S1127Aguilar, J. A. et al. ANTARES: the first undersea neutrino telescope. Nucl Inst and Met Phys Res A. 656, 11–38 (2011a).Aguilar, J. A. et al. AMADEUS - The Acoustic Neutrino Detection Test System of the ANTARES Deep-Sea Neutrino Telescope -. Nucl Inst and Met Phys Res A. 626–627, 128–143 (2011b).Ruhl, H. et al. Societal need for improved understanding of climate change, anthropogenic impacts, and geo-hazard warning drive development of ocean observatories in European Seas. Prog Oceanog. 91, 1–33 (2011).Tamburini, C. et al. Deep-sea bioluminescence blooms after dense water formation at the ocean surface. PLoS One. 8(7), e67523. doi: 10.1371/journal.pone.0067523 (2013).Van Haren, H. et al. Acoustic and optical variations during rapid downward motion episodes in the deep North Western Mediterranean. Deep Sea Res I. 58, 875–884 (2011).Van der Graaf, A. J. et al. European Marine Strategy Framework Directive - Good Environmental Status (MSFD GES): Report of the Technical Subgroup on Underwater noise and other forms of energy (2012).Hatch, L. T., Clark, C. W., Van Parijs, S. M., Frankel, A. S. & Ponirakis, D. W. Quantifying Loss of Acoustic Communication Space for Right Whales in and around a U.S. National Marine Sanctuary. Conserv Biol. 26, 983–994 (2012).André, M. et al. Low-frequency sounds induce acoustic trauma in cephalopods. Front. Ecol. Environ. 9, 489–493 (2011).Solé, M. et al. Does exposure to noise from human activities compromise sensory information from cephalopod statocysts? Deep Sea Res. II. 95, 160–181 (2013).Solé, M. et al. Ultrastructural damage of Loligo vulgaris and Illex coindetii statocysts after low frequency sound exposure. PLoS One 8(10), e78825. doi: 10.1371/journal.pone.0078825 (2013).André, M. et al. Listening to the Deep: Live monitoring of ocean noise and cetacean acoustic signals. Mar Pollut Bull. 63, 18–26 (2011).Whitehead, H. Sperm whales: social evolution in the ocean(The University of Chicago Press, Chicaho, 2003).Mohl, B., Wahlberg, M., Madsen, P. T., Heerfordt, A. & Lund, A. The monopulsed nature of sperm whale clicks. J Acous Soc Am. 114, 1143–1154 (2003).André, M., Johansson, T., Delory, E. & van der Schaar, M. Foraging on squid: the sperm whale mid-range sonar. Jour Mar Biol Assoc. 87, 59–67 (2007).Madsen, P., Wahlberg, M. & Møhl, B. Male sperm whale (Physeter macrocephalus) acoustics in a high-latitude habitat: implications for echolocation and communication. Behav Ecol Sociobiol. 53, 31, doi: 10.1007/s00265-002-0548-1 (2002).Gannier, A., Drouot, V. & Goold, J. C. Distribution and relative abundance of sperm whales in the Mediterranean Sea . Mar Ecol Prog Ser. 243, 281–293 (2000).Drouot, V., Gannier, A. & Gould, J. C. Summer social distribution of sperm whales in the Mediterranean Sea. J Mar Biol Ass. 84, 675–680 (2004).Pavan, G. et al. G. Short Term and Long Term Bioacoustic Monitoring of the Marine Environment. Results from NEMO ONDE Experiment and Way Ahead in Computational bioacoustics for assessing biodiversity . Proceedings of the International Expert meeting on IT-based detection of bioacoustical patterns(ed. Frommolt, K. H., Rolf Bardeli, R. & Clausen, M. ) 7–14 (Federal Agency for Nature Conservation, Bonn, 2008).Frantzis, A. et al. Sperm whale presence off South-West Crete, Eastern Mediterranean Sea in Proc. 13th Ann. Conf. ECS. 214–217 (Eur Res Cet, Valencia, 1999).Notarbartolo-Di-Sciara, G. Sperm whales, Physeter macrocephalus, in the Mediterranean Sea: a summary of status, threats, and conservation recommendations. Aquatic Conserv. Mar. Freshw. Ecosyst. 24, 4–10. doi: 10.1002/aqc.2409 (2014).Pace, D. S., Mussi, B., Gordon, J. C. D. & Würtz, M. Ecology, Behaviour and Conservation of Sperm Whale in the Mediterranean Sea in Aquatic Conserv . Mar. Freshw. Ecosyst. 24 (ed. Wiley, J. ) 1–118 (Wiley Online library, 2014).Rendell, L. E. & Frantzis, A. Mediterranean sperm whales, Physeter macrocephalus: the precarious state of a lost tribe In Medit. Mar. Mam. Ecol. Cons. 75 (ed. Notarbartolo di Sciara, G., Podestà, M. P. & Curry, B. E. ) 37–74, doi: 10.1016/bs.amb.2016.08.001 (Advances in Marine Biology, Academic Press/Elsevier, 2016).Di Natale, A. & Notarbartolo di Sciara, G. A review of the passive fishing nets and trap fisheries in the Mediterranean Sea and of the cetacean bycatch In Gillnets and cetaceans(ed. Perrin, W. F., Donovan, G. 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PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

Time-dependent search for neutrino emission from X-ray binaries with the ANTARES telescope

[EN] ANTARES is currently the largest neutrino telescope operating in the Northern Hemisphere, aiming at the detection of high-energy neutrinos from astrophysical sources. Neutrino telescopes constantly monitor at least one complete hemisphere of the sky, and are thus well-suited to detect neutrinos produced in transient astrophysical sources. A time-dependent search has been applied to a list of 33 X-ray binaries undergoing high flaring activities in satellite data (RXTE/ASM, MAXI and Swift/BAT) and during hardness transi-tion states in the 2008 2012 period. The background originating from interactions of charged cosmic rays in the Earth s atmosphere is drastically reduced by requiring a directional and temporal coincidence with astrophysical phenomena. The results of this search are presented together with comparisons between the neutrino flux upper limits and the neutrino flux predictions from astrophysical models. The neutrino flux upper limits resulting from this search limit the jet parameter space for some astrophysical models.The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'energie atomique et aux energies alternatives (CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11-IDEX-0005-02), Labex OCEVU (ANR-11-LABX-0060) and the A* MIDEX project (ANR-11-IDEX-0001-02), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Istituto Nazionale di Fisica Nucleare (INFN), Italy; Stichting voor Fundamenteel Onderzoek der Materie (FOM), Nederlandse organisatie voor Weten-schappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; National Authority for Scientific Research (ANCS), Romania; Ministerio de Economia y Competitividad (MINECO): Plan Estatal de Investigacion (refs. FPA2015-65150-C3-1-P, -2-P and -3-P, (MINECO/FEDER)), Severo Ochoa Centre of Excellence and MultiDark Consolider (MINECO), and Prometeo and Grisolia programs (Generalitat Valenciana), Spain; Agence de l'Oriental and CNRST, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilitiesAlbert, A.; Andre, M.; Anton, G.; Ardid Ramírez, M.; Aubert, J.; Avgitas, T.; Baret, B.... (2017). Time-dependent search for neutrino emission from X-ray binaries with the ANTARES telescope. JOURNAL OF COSMOLOGY AND ASTROPARTICLE PHYSICS. 4(19):1-23. https://doi.org/10.1088/1475-7516/2017/04/019S123419Vila, G. S., Romero, G. E., & Casco, N. A. (2012). An inhomogeneous lepto-hadronic model for the radiation of relativistic jets. Astronomy & Astrophysics, 538, A97. doi:10.1051/0004-6361/201118106Pepe, C., Vila, G. S., & Romero, G. E. (2015). Lepto-hadronic model for the broadband emission of Cygnus X-1. Astronomy & Astrophysics, 584, A95. doi:10.1051/0004-6361/201527156Blandford, R. D., & Payne, D. G. (1982). Hydromagnetic flows from accretion discs and the production of radio jets. Monthly Notices of the Royal Astronomical Society, 199(4), 883-903. doi:10.1093/mnras/199.4.883Trigo, M. D., Miller-Jones, J. C. A., Migliari, S., Broderick, J. W., & Tzioumis, T. (2013). Baryons in the relativistic jets of the stellar-mass black-hole candidate 4U 1630-47. Nature, 504(7479), 260-262. doi:10.1038/nature12672Heinz, S. (2006). Composition, Collimation, Contamination: The Jet of Cygnus X‐1. The Astrophysical Journal, 636(1), 316-322. doi:10.1086/497954Levinson, A., & Waxman, E. (2001). Probing Microquasars with TeV Neutrinos. Physical Review Letters, 87(17). doi:10.1103/physrevlett.87.171101Sahakyan, N., Piano, G., & Tavani, M. (2013). HADRONIC GAMMA-RAY AND NEUTRINO EMISSION FROM CYGNUS X-3. The Astrophysical Journal, 780(1), 29. doi:10.1088/0004-637x/780/1/29Adrián-Martínez, S., Albert, A., Al Samarai, I., André, M., Anghinolfi, M., Anton, G., … Aubert, J.-J. (2013). Search for muon neutrinos from gamma-ray bursts with the ANTARES neutrino telescope using 2008 to 2011 data. Astronomy & Astrophysics, 559, A9. doi:10.1051/0004-6361/201322169Adrián-Martínez, S., Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., … Barrios, J. (2014). A search for time dependent neutrino emission from microquasars with the ANTARES telescope. Journal of High Energy Astrophysics, 3-4, 9-17. doi:10.1016/j.jheap.2014.06.002Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Arguelles, C. (2015). SEARCHES FOR TIME-DEPENDENT NEUTRINO SOURCES WITH ICECUBE DATA FROM 2008 TO 2012. The Astrophysical Journal, 807(1), 46. doi:10.1088/0004-637x/807/1/46Remillard, R. A., & McClintock, J. E. (2006). X-Ray Properties of Black-Hole Binaries. 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The first resolved imaging of milliarcsecond-scale jets in Circinus X-1. Monthly Notices of the Royal Astronomical Society: Letters, 419(1), L49-L53. doi:10.1111/j.1745-3933.2011.01176.xSguera, V., Romero, G. E., Bazzano, A., Masetti, N., Bird, A. J., & Bassani, L. (2009). DISSECTING THE REGION OF 3EG J1837-0423 AND HESS J1841-055 WITHINTEGRAL. The Astrophysical Journal, 697(2), 1194-1205. doi:10.1088/0004-637x/697/2/1194García, F., Aguilera, D. N., & Romero, G. E. (2014). Exploring jet-launching conditions for supergiant fast X-ray transients. Astronomy & Astrophysics, 565, A122. doi:10.1051/0004-6361/201323157Giovannelli, F., & Graziati, L. S. (1992). A 0535 + 26/HDE 245770: A typical X-ray/Be system. Space Science Reviews, 59(1-2), 1-81. doi:10.1007/bf01262537Anchordoqui, L. A., Torres, D. F., McCauley, T. P., Romero, G. E., & Aharonian, F. A. (2003). Neutrinos from Accreting Neutron Stars. The Astrophysical Journal, 589(1), 481-486. doi:10.1086/374551Scargle, J. D. (1981). Studies in astronomical time series analysis. I - Modeling random processes in the time domain. The Astrophysical Journal Supplement Series, 45, 1. doi:10.1086/190706Scargle, J. D. (1998). Studies in Astronomical Time Series Analysis. V. Bayesian Blocks, a New Method to Analyze Structure in Photon Counting Data. The Astrophysical Journal, 504(1), 405-418. doi:10.1086/306064Scargle, J. D., Norris, J. P., Jackson, B., & Chiang, J. (2013). STUDIES IN ASTRONOMICAL TIME SERIES ANALYSIS. VI. BAYESIAN BLOCK REPRESENTATIONS. The Astrophysical Journal, 764(2), 167. doi:10.1088/0004-637x/764/2/167collaboration, T. A. (2015). Search for muon-neutrino emission from GeV and TeV gamma-ray flaring blazars using five years of data of the ANTARES telescope. Journal of Cosmology and Astroparticle Physics, 2015(12), 014-014. doi:10.1088/1475-7516/2015/12/014Kappes, A., Hinton, J., Stegmann, C., & Aharonian, F. A. (2007). Potential Neutrino Signals from Galactic γ‐Ray Sources. The Astrophysical Journal, 656(2), 870-878. doi:10.1086/508936Outline of a Theory of Statistical Estimation Based on the Classical Theory of Probability. (1937). Philosophical Transactions of the Royal Society of London. Series A, Mathematical and Physical Sciences, 236(767), 333-380. doi:10.1098/rsta.1937.0005Romero, G. E., & Vila, G. S. (2008). The proton low-mass microquasar: high-energy emission. Astronomy & Astrophysics, 485(3), 623-631. doi:10.1051/0004-6361:200809563Reynoso, M. M., Romero, G. E., & Christiansen, H. R. (2008). Production of gamma rays and neutrinos in the dark jets of the microquasar SS433. Monthly Notices of the Royal Astronomical Society, 387(4), 1745-1754. doi:10.1111/j.1365-2966.2008.13364.xReynoso, M. M., & Romero, G. E. (2008). Magnetic field effects on neutrino production in microquasars. Astronomy & Astrophysics, 493(1), 1-11. doi:10.1051/0004-6361:200811004Bednarek, W. (2005). TeV Neutrinos from Microquasars in Compact Massive Binaries. The Astrophysical Journal, 631(1), 466-470. doi:10.1086/432411Romero, G. E., Vieyro, F. L., & Vila, G. S. (2010). Non-thermal processes around accreting galactic black holes. Astronomy and Astrophysics, 519, A109. doi:10.1051/0004-6361/200913663Miller-Jones, J. C. A., Fender, R. P., & Nakar, E. (2006). Opening angles, Lorentz factors and confinement of X-ray binary jets. Monthly Notices of the Royal Astronomical Society, 367(4), 1432-1440. doi:10.1111/j.1365-2966.2006.10092.xBlandford, R. D., & Konigl, A. (1979). Relativistic jets as compact radio sources. The Astrophysical Journal, 232, 34. doi:10.1086/157262Zhang, J. F., Feng, Y. G., Lei, M. C., Tang, Y. Y., & Tian, Y. P. (2010). High-energy neutrino emission from low-mass microquasars. Monthly Notices of the Royal Astronomical Society, 407(4), 2468-2474. doi:10.1111/j.1365-2966.2010.17072.xHeinz, S., Burton, M., Braiding, C., Brandt, W. N., Jonker, P. G., Sell, P., … Schulz, N. S. (2015). LORD OF THE RINGS: A KINEMATIC DISTANCE TO CIRCINUS X-1 FROM A GIANT X-RAY LIGHT ECHO. The Astrophysical Journal, 806(2), 265. doi:10.1088/0004-637x/806/2/265Bednarek, W. (2009). TeV neutrinos from accreting x-ray pulsars. Physical Review D, 79(12). doi:10.1103/physrevd.79.123010Adrián-Martínez, S., Ageron, M., Aharonian, F., Aiello, S., Albert, A., Ameli, F., … Anghinolfi, M. (2016). Letter of intent for KM3NeT 2.0. Journal of Physics G: Nuclear and Particle Physics, 43(8), 084001. doi:10.1088/0954-3899/43/8/084001Russell, D. M., Markoff, S., Casella, P., Cantrell, A. G., Chatterjee, R., Fender, R. P., … Shahbaz, T. (2012). Jet spectral breaks in black hole X-ray binaries. Monthly Notices of the Royal Astronomical Society, 429(1), 815-832. doi:10.1093/mnras/sts377Stirling, A. M., Spencer, R. E., de La Force, C. J., Garrett, M. A., Fender, R. P., & Ogley, R. N. (2001). A relativistic jet from Cygnus X-1 in the low/hard X-ray state. Monthly Notices of the Royal Astronomical Society, 327(4), 1273-1278. doi:10.1046/j.1365-8711.2001.04821.xCorbel, S., Kaaret, P., Fender, R. P., Tzioumis, A. K., Tomsick, J. A., & Orosz, J. A. (2005). Discovery of X‐Ray Jets in the Microquasar H1743−322. The Astrophysical Journal, 632(1), 504-513. doi:10.1086/432499Paragi, Z., van der Horst, A. J., Belloni, T., Miller-Jones, J. C. A., Linford, J., Taylor, G., … Wijers, R. A. M. J. (2013). VLBI observations of the shortest orbital period black hole binary, MAXI J1659−152. Monthly Notices of the Royal Astronomical Society, 432(2), 1319-1329. doi:10.1093/mnras/stt545Mainzer, A., Masiero, J., Grav, T., Bauer, J., Tholen, D. J., McMillan, R. S., … Maleszewski, C. (2011). NEOWISE STUDIES OF ASTEROIDS WITH SLOAN PHOTOMETRY: PRELIMINARY RESULTS. The Astrophysical Journal, 745(1), 7. doi:10.1088/0004-637x/745/1/

Event reconstruction for KM3NeT/ORCA using convolutional neural networks

The KM3NeT research infrastructure is currently under construction at two locations in the Mediterranean Sea. The KM3NeT/ORCA water-Cherenkov neutrino detector off the French coast will instrument several megatons of seawater with photosensors. Its main objective is the determination of the neutrino mass ordering. This work aims at demonstrating the general applicability of deep convolutional neural networks to neutrino telescopes, using simulated datasets for the KM3NeT/ORCA detector as an example. To this end, the networks are employed to achieve reconstruction and classification tasks that constitute an alternative to the analysis pipeline presented for KM3NeT/ORCA in the KM3NeT Letter of Intent. They are used to infer event reconstruction estimates for the energy, the direction, and the interaction point of incident neutrinos. The spatial distribution of Cherenkov light generated by charged particles induced in neutrino interactions is classified as shower- or track-like, and the main background processes associated with the detection of atmospheric neutrinos are recognized. Performance comparisons to machine-learning classification and maximum-likelihood reconstruction algorithms previously developed for KM3NeT/ORCA are provided. It is shown that this application of deep convolutional neural networks to simulated datasets for a large-volume neutrino telescope yields competitive reconstruction results and performance improvements with respect to classical approaches

Event reconstruction for KM3NeT/ORCA using convolutional neural networks

The KM3NeT research infrastructure is currently under construction at two locations in the Mediterranean Sea. The KM3NeT/ORCA water-Cherenkov neutrino de tector off the French coast will instrument several megatons of seawater with photosensors. Its main objective is the determination of the neutrino mass ordering. This work aims at demonstrating the general applicability of deep convolutional neural networks to neutrino telescopes, using simulated datasets for the KM3NeT/ORCA detector as an example. To this end, the networks are employed to achieve reconstruction and classification tasks that constitute an alternative to the analysis pipeline presented for KM3NeT/ORCA in the KM3NeT Letter of Intent. They are used to infer event reconstruction estimates for the energy, the direction, and the interaction point of incident neutrinos. The spatial distribution of Cherenkov light generated by charged particles induced in neutrino interactions is classified as shower-or track-like, and the main background processes associated with the detection of atmospheric neutrinos are recognized. Performance comparisons to machine-learning classification and maximum-likelihood reconstruction algorithms previously developed for KM3NeT/ORCA are provided. It is shown that this application of deep convolutional neural networks to simulated datasets for a large-volume neutrino telescope yields competitive reconstruction results and performance improvements with respect to classical approaches

Molecular Components and Functions of the Endocannabinoid System in Mouse Prefrontal Cortex

Background. Cannabinoids have deleterious effects on prefrontal cortex (PFC)-mediated functions and multiple evidences link the endogenous cannabinoid (endocannabinoid) system, cannabis use and schizophrenia, a disease in which PFC functions are altered. Nonetheless, the molecular composition and the physiological functions of the endocannabinoid system in the PFC are unknown. Methodology/Principal Findings. Here, using electron microscopy we found that key proteins involved in endocannabinoid signaling are expressed in layers V/VI of the mouse prelimbic area of the PFC: presynaptic cannabinoid CB1 receptors (CB1R) faced postsynaptic mGluR5 while diacylglycerol lipase alpha (DGL-alpha), the enzyme generating the endocannabinoid 2-arachidonoyl-glycerol (2-AG) was expressed in the same dendritic processes as mGluR5. Activation of presynaptic CB1R strongly inhibited evoked excitatory post-synaptic currents. Prolonged synaptic stimulation at 10Hz induced a profound long-term depression (LTD) of layers V/VI excitatory inputs. The endocannabinoid -LTD was presynaptically expressed and depended on the activation of postsynaptic mGluR5, phospholipase C and a rise in postsynaptic Ca2+ as predicted from the localization of the different components of the endocannabinoid system. Blocking the degradation of 2-AG (with URB 602) but not of anandamide (with URB 597) converted subthreshold tetanus to LTD-inducing ones. Moreover, inhibiting the synthesis of 2-AG with Tetrahydrolipstatin, blocked endocannabinoid-mediated LTD. All together, our data show that 2-AG mediates LTD at these synapses. Conclusions/Significance. Our data show that the endocannabinoid -retrograde signaling plays a prominent role in long-term synaptic plasticity at the excitatory synapses of the PFC. Alterations of endocannabinoid -mediated synaptic plasticity may participate to the etiology of PFC-related pathologies

Overexpression of the Cytokine BAFF and Autoimmunity Risk

$\textbf{BACKGROUND}$: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. $\textbf{METHODS}$: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. $\textbf{RESULTS}$: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. $\textbf{CONCLUSIONS}$: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).Supported by grants (2011/R/13 and 2015/R/09, to Dr. Cucca) from the Italian Foundation for Multiple Sclerosis; contracts (N01-AG-1-2109 and HHSN271201100005C, to Dr. Cucca) from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); a grant (FaReBio2011 “Farmaci e Reti Biotecnologiche di Qualità,” to Dr. Cucca) from the Italian Ministry of Economy and Finance; a grant (633964, to Dr. Cucca) from the Horizon 2020 Research and Innovation Program of the European Union; a grant (U1301.2015/AI.1157.BE Prat. 2015-1651, to Dr. Cucca) from Fondazione di Sardegna; grants (“Centro per la ricerca di nuovi farmaci per malattie rare, trascurate e della povertà” and “Progetto collezione di composti chimici ed attività di screening,” to Dr. Cucca) from Ministero dell’Istruzione, dell’Università e della Ricerca; grants (HG005581, HG005552, HG006513, and HG007022, to Dr. Abecasis) from the National Human Genome Research Institute; a grant (9-2011-253, to Dr. Todd) from JDRF; a grant (091157, to Dr. Todd) from the Wellcome Trust; a grant (to Dr. Todd) from the National Institute for Health Research (NIHR); and the NIHR Cambridge Biomedical Research Centre. Dr. Idda was a recipient of a Master and Back fellowship from the Autonomous Region of Sardinia

Unleashing e-commerce’s potential an exploratory study about companies’ drivers and barriers to purchase it-related products and services online

Inetum-Realdolmen has helped companies navigate through the challenges of the digital world for over 14 years, by offering a wide range of IT-related products and delivering strategic, operational and tactical solutions. The company is part of the Inetum Group, who aims to conquer new markets and to continue building a culture of positive digital flow for all stakeholders. This resulted in a consolidated turnover of more than €2.219 billion worldwide in 2021. Now, Inetum-Realdolmen is innovating its way of doing business, and with the growing importance of e-commerce activities, the company has set high ambitions for its online channels. By developing an online solution that creates a new unified point of entry to their products, services and people for all clients, it aims at generating €1 billion in revenue by 2027 through e-commerce. Similar to the B2C market, B2B clients are now starting to demand customer centricity and the omnichannel trend is finding its way to more and more companies. THis change in consumer expectations means that the online unified point of entry will have to connect with the client base as a whole, while still engaging with each user in a personal way. The company will also have to find a way to, in addition to their current product web shops: the Cloudstore and Rstore, offer their service range online. Therefore, Inetum-Realdolmen is aiming to align the new solution with its clients preferences and find the right strategy to market the solution. Purpose: The current research seeks to discover how Inetum-Realdolmen can optimise its current web shops and expand the online portfolio with projects, professional services and managed services, to create a one-stop shop. It helps clarify which steps within the purchase process are better done using self-service technologies and provides examples of tools that can be implemented to guide clients when buying online. It also explains the feasibility of expanding the offering portfolio with services and suggests how the company can start its go-to-market strategy. Methodology: Fourteen exploratory customer interviews were conducted to understand clients’ preferences towards self-service technologies and human interaction. Both clients that already used Inetum-Realdolmen’s online solutions and clients that avoid using them were asked to map their current purchase processes, explain their experience with Inetum-Realdolmen’s web shops and elaborate on their need for human interaction. In addition, the clients were asked to state their preferences for bundling and mobile solutions to discover implementation strategies. To complete the findings retrieved from the interviews, the research team also analysed Inetum-Realdolmen’s 3 C’s (Company, Customer and Competitors) and explored future B2B sales trends. Lastly, the feasibility and strategies to market the online solutions were analysed based on internal interviews and the scalability was assessed through two exploratory interviews with teams from the Inetum Group in Spain. Findings: From the interviews, it was retrieved that although some of the processes for product and managed services are similar and thus could be standardised, the process of buying professional services and projects can be very complex and specific. Therefore, clients preferred self-service technologies while buying products or managed services as it would help them save time, but required human interaction when looking for projects or professional services due to the need for advice and coordination when specifying the service. Nevertheless, clients also mentioned there was room for technologies that would enhance their experience before and after the specification step in those cases too. When it came to the current online solutions, comparing them with B2C e-commerce web shops resulted in clients stating it lacked intuitiveness and user friendliness. The web shop was mostly used for lower volume purchases and to look up products. Non-users of the web shops clarified that they preferred direct contact with sales persons as it would give them a higher bargaining power and added a personal touch. Clients from the public sector also mentioned working through the web shop would mean they had to process the order twice, which generated more workload for them. From the interviews, it was also retrieved that clients had mixed feelings about bundling offers. Although some clients acknowledged that discounts and correctly putting offerings together brought value when Inetum-Realdolmen combined hardware, licences and services, most clients needed to maintain IT products with different inventory durations or wanted to do added services in-house and were therefore not convinced. For mobile usage, in the interviews it became clear that purchasing products in a B2B context through a mobile phone was not yet done by clients from Inetum-Realdolmen, and is not something they are eager to do. The only way a mobile solution could still bring value was by assisting them in approving and following up on orders. However, many clients were assessed to have a rigid mentality that resisted certain technological changes. In combination with the fact that most of them did belong to Generation X or Y, not being in favour of a mobile application was put into perspective. It also stressed the importance of knowing the technological readiness of the client base when going to the market with a new solution. Recommendations: In response to the findings from the client interviews, cost-benefit analysis, market research, future B2B sales trends and the company’s vision, the following actions are suggested: Grow the Customer Experience Portal to serve as a single point of entry to the Cloudstore, Rstore and a newly developed Service Store; and implement a renewed design with easier access to all offers while providing features like a centralised Admin Centre, Support Centre and Monitoring options. Limit the development of a mobile application of the Portal to a tool that allows clients to follow-up on their orders and use it as a stepping stone to future mobile extensions. This way, creating the one-stop solution will not only potentially increase the amount of business done through e-commerce, but it will also drive clients more towards self-servicing their administrative requests; which will allow account managers and customer success managers of Inetum-Realdolmen to focus on more strategic tasks. Use the client feedback and proposals to transform the current Rstore into a consumer-centric web shop. Regarding this point, Inetum-Realdolmen should improve the product information section in the store with less technical explanations and the addition of reviews. Additionally, it should add a chat-bot/box feature to the web shop to automatically answer simple questions and help clients solve more complex problems in person. Furthermore, a bundle page where customers can view and buy combined offers of hardware, licences and managed services with discounts should also be included. With its new design and features, the Rstore should serve as the part of the Portal all clients’ hardware products are bought through. Develop a Service Store that at the same time covers the online purchasing of managed services and lists and informs about all specifications of professional services and projects offered. In addition, add simple e-commerce tools like search filters and extensions, expert profiles and automatic scheduling to the web shop to help clients navigate through the different services and solutions. This will result in clients not only having a clear view on the full service range, but also having the opportunity to easily start the purchase process online in a self-service way. Reorganise the role account managers now have within the company by freeing up time that is spent on administrative workload and redirect their focus to strategic assistance and client onboarding. This way you make sure the e-commerce strategy can be an integral part of the overall sales strategy rather than as a separate business. Analyse if the company possesses not only the design skills but also the technical skills to develop the Service Store in-house as it is the most flexible option without any dependencies on third-parties nor commissions. The same vendor that was used to develop the Rstore should also be used to incorporate the new features as it will bring cost savings and a higher client satisfaction. In addition, bundles should be implemented as cross selling and upselling opportunities will outweigh the overall lower price. Direct new traffic to the Customer Experience Portal by focusing on SEO and SEA, and convince existing customers of the benefits the portal provides by communicating, for example, the time saving it will create and the availability of customer support. For scalability, reach out to other countries with insights and a tangible solution of the Customer Experience Portal. Additionally, communicate it as a powerful tool that combines the 3 web shops for clients and helps employees focus on strategic tasks by lowering administrative workload. By doing so, the portal should get all the chances of not only being adopted by clients but also being implemented in other countries.Inetum-Realdolme

A mindfulness-based intervention for breast cancer patients with cognitive impairment after chemotherapy: Study protocol of a three-group randomized controlled trial.

Background: Mindfulness has been applied to improve cancer care by enhancing psychological well-being. However, little is known about its impact on cognitive impairment experienced by cancer patients after chemotherapy. Mindfulness may be relevant in tackling cognitive impairment by decreasing emotional distress and fatigue, by decreasing inflammation, and by strengthening functional brain connectivity. The aim of the present study protocol is to evaluate the efficacy and mechanisms of a mindfulness-based intervention to reduce cognitive impairment in breast cancer patients after chemotherapy. Methods/design: The present study is a three-arm, parallel-group, randomized controlled trial with assessments at baseline, 1 to 3 weeks after the intervention and at 3 months’ follow-up. One hundred and twenty breast cancer patients who ended treatment a minimum of 6 months and a maximum of 5 years before, and who have cognitive complaints, will be enrolled. They will be randomized into one of the following three study arms: (1) a mindfulnessbased intervention group (n = 40), (2) an active control condition based on physical training (n = 40), or (3) a treatment as usual (TAU) control group (n = 40). Both the mindfulness-based intervention and the active control condition consist of four group sessions (3 h for the mindfulness condition and 2 h for the physical training) spread over 8 weeks. The primary outcomes will be cognitive symptoms as measured by the Cognitive Failure Questionnaire and changes in functional brain connectivity in the attention network. Secondary outcomes will be (1) levels of emotional distress, fatigue, mindfulness, quality of life; (2) neurocognitive tests; (3) structural and functional brain changes using MR imaging and (4) measures of inflammation. Discussion: The study will examine the impact of a mindfulness-based intervention on cognitive impairment in breast cancer patients. If the findings of this study confirm the effectiveness of a mindfulness-based program to reduce cognitive impairment, it will be possible to improve quality of life for ex-cancer patients. We will inform health care providers about the potential use of a mindfulness-based intervention as a non-pharmaceutical, lowthreshold mental health intervention to improve cognitive impairment after cancer.status: Published onlin