TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection

Introduction: Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%–40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required. Methods: It is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl−) channel modulators to investigate their role during the HRSV life-cycle. Results: We demonstrate the requirement for TMEM16A, a calcium-activated Cl− channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01. Discussion: These findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics

Lowering the radioactivity of the photomultiplier tubes for the XENON1T dark matter experiment

The low-background, VUV-sensitive 3-inch diameter photomultiplier tube R11410 has been developed by Hamamatsu for dark matter direct detection experiments using liquid xenon as the target material. We present the results from the joint effort between the XENON collaboration and the Hamamatsu company to produce a highly radio-pure photosensor (version R11410-21) for the XENON1T dark matter experiment. After introducing the photosensor and its components, we show the methods and results of the radioactive contamination measurements of the individual materials employed in the photomultiplier production. We then discuss the adopted strategies to reduce the radioactivity of the various PMT versions. Finally, we detail the results from screening 216 tubes with ultra-low background germanium detectors, as well as their implications for the expected electronic and nuclear recoil background of the XENON1T experiment.Comment: 10 pages, 5 figure

Search for Event Rate Modulation in XENON100 Electronic Recoil Data

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an un-binned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1 sigma for all periods suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8 sigma, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of WIMPs to electrons is excluded at 4.8 sigma.Comment: 6 pages, 4 figure

Removing krypton from xenon by cryogenic distillation to the ppq level

The XENON1T experiment aims for the direct detection of dark matter in a cryostat filled with 3.3 tons of liquid xenon. In order to achieve the desired sensitivity, the background induced by radioactive decays inside the detector has to be sufficiently low. One major contributor is the $\beta$-emitter $^{85}$Kr which is an intrinsic contamination of the xenon. For the XENON1T experiment a concentration of natural krypton in xenon $\rm{^{nat}}$Kr/Xe < 200 ppq (parts per quadrillion, 1 ppq = 10$^{-15}$ mol/mol) is required. In this work, the design of a novel cryogenic distillation column using the common McCabe-Thiele approach is described. The system demonstrated a krypton reduction factor of 6.4$\cdot$10$^5$ with thermodynamic stability at process speeds above 3 kg/h. The resulting concentration of $\rm{^{nat}}$Kr/Xe < 26 ppq is the lowest ever achieved, almost one order of magnitude below the requirements for XENON1T and even sufficient for future dark matter experiments using liquid xenon, such as XENONnT and DARWIN

Search for Two-Neutrino Double Electron Capture of 124^{124}Xe with XENON100

Two-neutrino double electron capture is a rare nuclear decay where two electrons are simultaneously captured from the atomic shell. For $^{124}$Xe this process has not yet been observed and its detection would provide a new reference for nuclear matrix element calculations. We have conducted a search for two-neutrino double electron capture from the K-shell of $^{124}$Xe using 7636 kg$\cdot$d of data from the XENON100 dark matter detector. Using a Bayesian analysis we observed no significant excess above background, leading to a lower 90 % credibility limit on the half-life $T_{1/2}>6.5\times10^{20}$ yr. We also evaluated the sensitivity of the XENON1T experiment, which is currently being commissioned, and find a sensitivity of $T_{1/2}>6.1\times10^{22}$ yr after an exposure of 2 t$\cdot$yr.Comment: 6 pages, 4 figure

Radio Astronomy

Contains table of contents for Section 4 and reports on ten research projects.National Science Foundation Grant AST 90-22501Alfred P. Sloan FellowshipDavid and Lucile Packard Fellowship Award for Science and EngineeringNational Aeronautics and Space AdministrationNational Science Foundation Presidential Young Investigator AwardNational Aeronautics and Space Administration Grant NAGW-2310MIT Lincoln Laboratory Agreement BX-4975National Aeronautics and Space Administration/Goddard Space Flight Center Contract NAS 5-31276MIT Leaders for Manufacturing Progra

Radio Astronomy

Contains table of contents for Section 4 and reports on ten research projects.National Science Foundation Grant AST 90-22501National Aeronautics and Space Administration Grant NAGW 1386National Science Foundation Presidential Young Investigator AwardDavid and Lucile Packard Fellowship for Science and EngineeringNational Aeronautics and Space Administration Grant NAGW-2310MIT Lincoln LaboratorySM Systems and Research CorporationNational Aeronautics and Space Administration/Goddard Space Flight Center Contract NAS 5-30791National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAG 5-10MIT Leaders for Manufacturing Progra

Radio Astronomy

Contains table of contents for Section 4 and reports on nine research projects.National Science Foundation Grant AST 88-19848National Science Foundation Grant AST 90-22501Alfred P. Sloan FellowshipNational Science Foundation Presidential Young Investigator AwardNational Aeronautics and Space Administration Grant NAGW-2310David and Lucile Packard FellowshipSM Systems and Research CorporationNational Aeronautics and Space Administration/Goddard Space Flight Center Contract NAS 5-30791National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAG5-10Leaders for Manufacturing Progra

Non-stationary covariance function modelling in 2D least-squares collocation

Standard least-squares collocation (LSC) assumes 2D stationarity and 3D isotropy, and relies on a covariance function to account for spatial dependence in the ob-served data. However, the assumption that the spatial dependence is constant through-out the region of interest may sometimes be violated. Assuming a stationary covariance structure can result in over-smoothing of, e.g., the gravity field in mountains and under-smoothing in great plains. We introduce the kernel convolution method from spatial statistics for non-stationary covariance structures, and demonstrate its advantage fordealing with non-stationarity in geodetic data. We then compared stationary and non-stationary covariance functions in 2D LSC to the empirical example of gravity anomaly interpolation near the Darling Fault, Western Australia, where the field is anisotropic and non-stationary. The results with non-stationary covariance functions are better than standard LSC in terms of formal errors and cross-validation against data not used in the interpolation, demonstrating that the use of non-stationary covariance functions can improve upon standard (stationary) LSC