Cyclic Nucleotide-Specific Optogenetics Highlights Compartmentalization of the Sperm Flagellum into cAMP Microdomains.

Inside the female genital tract, mammalian sperm undergo a maturation process called capacitation, which primes the sperm to navigate across the oviduct and fertilize the egg. Sperm capacitation and motility are controlled by 3′,5′-cyclic adenosine monophosphate (cAMP). Here, we show that optogenetics, the control of cellular signaling by genetically encoded light-activated proteins, allows to manipulate cAMP dynamics in sperm flagella and, thereby, sperm capacitation and motility by light. To this end, we used sperm that express the light-activated phosphodiesterase LAPD or the photo-activated adenylate cyclase bPAC. The control of cAMP by LAPD or bPAC combined with pharmacological interventions provides spatiotemporal precision and allows to probe the physiological function of cAMP compartmentalization in mammalian sperm

Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope

[EN] The Hamamatsu R12199-02 3-inch photomultiplier tube is the photodetector chosen for the first phase of the KM3NeT neutrino telescope. About 7000 photomultipliers have been characterised for dark count rate, timing spread and spurious pulses. The quantum eÿciency, the gain and the peak-to-valley ratio have also been measured for a sub-sample in order to determine parameter values needed as input to numerical simulations of the detector.The authors acknowledge the financial support of the funding agencies: Agence Nationale de la Recherche (contract ANR-15-CE31-0020), Centre National de la Recherche Scientifique (CNRS), 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), France; 'Helmholtz Alliance for Astroparticle Physics' funded by the Initiative and Networking Fund of the Helmholtz Association, Germany; The General Secretariat of Research and Technology (GSRT), Greece; Istituto Nazionale di Fisica Nucleare (INFN), Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR), Italy; Agence de l'Oriental and CNRST, Morocco; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; National Authority for Scientific Research (ANCS), Romania; 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.Aiello, S.; Akrame, SE.; Ameli, F.; Anassontzis, EG.; Andre, M.; Androulakis, G.; Anghinolfi, M.... (2018). Characterisation of the Hamamatsu photomultipliers for the KM3NeT Neutrino Telescope. Journal of Instrumentation. 13:1-17. https://doi.org/10.1088/1748-0221/13/05/P05035S11713Adrián-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:10.1088/0954-3899/43/8/084001Adrián-Martínez, S., Ageron, M., Aharonian, F., Aiello, S., Albert, A., Ameli, F., … Anvar, S. (2014). Deep sea tests of a prototype of the KM3NeT digital optical module. The European Physical Journal C, 74(9). doi:10.1140/epjc/s10052-014-3056-3Adrián-Martínez, S., Ageron, M., Aharonian, F., Aiello, S., Albert, A., Ameli, F., … Anton, G. (2016). The prototype detection unit of the KM3NeT detector. The European Physical Journal C, 76(2). doi:10.1140/epjc/s10052-015-3868-9Herold, B., Kalekin, O., & Reubelt, J. (2011). PMT characterisation for the KM3NeT project. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 639(1), 70-72. doi:10.1016/j.nima.2010.09.018Timmer, P., Heine, E., & Peek, H. (2010). Very low power, high voltage base for a Photo Multiplier Tube for the KM3NeT deep sea neutrino telescope. Journal of Instrumentation, 5(12), C12049-C12049. doi:10.1088/1748-0221/5/12/c12049Mollo, C. M., Bozza, C., Chiarusi, T., Costa, M., Capua, F. D., Kulikovskiy, V., … Vivolo, D. (2016). A new instrument for high statistics measurement of photomultiplier characteristics. Journal of Instrumentation, 11(08), T08002-T08002. doi:10.1088/1748-0221/11/08/t08002Adrián-Martínez, S., Ageron, M., Aiello, S., Albert, A., Ameli, F., Anassontzis, E. G., … Anton, G. (2016). A method to stabilise the performance of negatively fed KM3NeT photomultipliers. Journal of Instrumentation, 11(12), P12014-P12014. doi:10.1088/1748-0221/11/12/p12014Lubsandorzhiev, B. K., Vasiliev, R. V., Vyatchin, Y. E., & Shaibonov, B. A. J. (2006). Photoelectron backscattering in vacuum phototubes. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 567(1), 12-16. doi:10.1016/j.nima.2006.05.04

Dependence of atmospheric muon flux on seawater depth measured with the first KM3NeT detection units: The KM3NeT Collaboration

KM3NeT is a research infrastructure located in the Mediterranean Sea, that will consist of two deep-sea Cherenkov neutrino detectors. With one detector (ARCA), the KM3NeT Collaboration aims at identifying and studying TeV–PeV astrophysical neutrino sources. With the other detector (ORCA), the neutrino mass ordering will be determined by studying GeV-scale atmospheric neutrino oscillations. The first KM3NeT detection units were deployed at the Italian and French sites between 2015 and 2017. In this paper, a description of the detector is presented, together with a summary of the procedures used to calibrate the detector in-situ. Finally, the measurement of the atmospheric muon flux between 2232–3386 m seawater depth is obtained

Sensitivity of the KM3NeT/ARCA neutrino telescope to point-like neutrino sources

Instrumentatio

The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone

PURPOSE: To evaluate the role of cytochrome 450 2D6 (CYP2D6) and ABCB1 variants on plasma risperidone concentrations and treatment response in 83 drug-naive patients experiencing a first episode of psychosis. ----- METHODS: All patients were treated with risperidone for 8 weeks. The CYP2D6 genotyping was performed by allele-specific PCR-restriction fragment length polymorphism analysis (for alleles *3,*4,*6) and long-distance PCR (for duplications and allele *5), while real-time PCR analysis was used for the ABCB1 G2677T/A and C3435T variants. Plasma concentrations of risperidone and 9-OH risperidone were measured by high-performance liquid chromatography. ----- RESULTS: The number of patients with the CYP2D6 wild type (wt)/wt, wt/mutation (mut) and mut/mut genotype was 43, 32 and 8, respectively. The number of patients with the ABCB1 2677G/G, G/T and T/T variants was 29, 42 and 12, respectively; those with the 3435CC, C/T and T/T variants was 25, 37 and 21, respectively. The CYP2D6 genotype had a strong effect on the steady-state dose-corrected plasma levels (C/D) of risperidone, its 9-OH metabolite and the active moiety, while the ABCB1 2677 T/T and 3435 T/T genotypes has similarly strong effects on the active moiety C/D. The CYP2D6 poor metabolizers had a significantly higher risperidone C/D and active moiety C/D and lower 9-OH risperidone C/D. The ABCB1 3435 T allele and the ABCB1 2667 T-3435 T haplotype carriers were more frequent among subjects without extrapyramidal syndromes. Patients showed significant improvements in positive and general symptoms, but not in negative symptoms. These changes were not related to variations in genetic and drug concentration data. ----- CONCLUSION: Our findings suggest that CYP2D6 and ABCB1 G2677T and C3435T may be useful determinants of risperidone plasma concentrations, but the clinical implications of these associations in relation to treatment response and side-effects remain unclear