Glia-Pinealocyte Network: The Paracrine Modulation of Melatonin Synthesis by Tumor Necrosis Factor (TNF)

The pineal gland, a circumventricular organ, plays an integrative role in defense responses. The injury-induced suppression of the pineal gland hormone, melatonin, which is triggered by darkness, allows the mounting of innate immune responses. We have previously shown that cultured pineal glands, which express toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1), produce TNF when challenged with lipopolysaccharide (LPS). Here our aim was to evaluate which cells present in the pineal gland, astrocytes, microglia or pinealocytes produced TNF, in order to understand the interaction between pineal activity, melatonin production and immune function. Cultured pineal glands or pinealocytes were stimulated with LPS. TNF content was measured using an enzyme-linked immunosorbent assay. TLR4 and TNFR1 expression were analyzed by confocal microscopy. Microglial morphology was analyzed by immunohistochemistry. In the present study, we show that although the main cell types of the pineal gland (pinealocytes, astrocytes and microglia) express TLR4, the production of TNF induced by LPS is mediated by microglia. This effect is due to activation of the nuclear factor kappa B (NF-kB) pathway. In addition, we observed that LPS activates microglia and modulates the expression of TNFR1 in pinealocytes. As TNF has been shown to amplify and prolong inflammatory responses, its production by pineal microglia suggests a glia-pinealocyte network that regulates melatonin output. The current study demonstrates the molecular and cellular basis for understanding how melatonin synthesis is regulated during an innate immune response, thus our results reinforce the role of the pineal gland as sensor of immune status

Data-driven modeling of electron recoil nucleation in PICO C3F8 bubble chambers

[EN] The primary advantage of moderately superheated bubble chamber detectors is their simultaneous sensitivity to nuclear recoils from weakly interacting massive particle (WIMP) dark matter and insensitivity to electron recoil backgrounds. A comprehensive analysis of PICO gamma calibration data demonstrates for the first time that electron recoils in C3F8 scale in accordance with a new nucleation mechanism, rather than one driven by a hot spike as previously supposed. Using this semiempirical model, bubble chamber nucleation thresholds may be tuned to be sensitive to lower energy nuclear recoils while maintaining excellent electron recoil rejection. The PICO-40L detector will exploit this model to achieve thermodynamic thresholds as low as 2.8 keV while being dominated by single-scatter events from coherent elastic neutrino-nucleus scattering of solar neutrinos. In one year of operation, PICO-401, can improve existing leading limits from PICO on spin-dependent WIMP-proton coupling by nearly an order of magnitude for WIMP masses greater than 3 GeV c(-2) and will have the ability to surpass all existing non-xenon bounds on spin-independent WIMP-nucleon coupling for WIMP masses from 3 to 40 GeV c(-2).The PICO Collaboration wishes to thank SNOLAB and its staff for support through underground space, logistical and technical services. SNOLAB operations are supported by the Canada Foundation for Innovation and the Province of Ontario Ministry of Research and Innovation, with underground access provided by Vale at the Creighton mine site. We wish to acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. We acknowledge the support from National Science Foundation (NSF) (Grants No. 0919526, No. 1506337, No. 1242637, No. 1205987, and No. 1806722). We acknowledge that this work is supported by the U.S. Department of Energy (DOE) Office of Science, Office of High Energy Physics (under Award No. DE-SC-0012161), by DGAPA-UNAM (PAPIIT No. IA100118) and Consejo Nacional de Ciencia y Tecnología (CONACyT, M¿exico, Grants No. 252167 and No. A1-S-8960), by the Department of Atomic Energy (DAE), Government of India, under the Centre for AstroParticle Physics II project (CAPP-II) at the Saha Institute of Nuclear Physics (SINP), European Regional Development Fund¿Project ¿Engineering Applications of Microworld Physics¿ (Project No. CZ.02.1.01/0.0/0.0/ 16_019/0000766), and the Spanish Ministerio de Ciencia, Innovación y Universidades (Red Consolider MultiDark, Grant No. FPA2017-90566-REDC). This work is partially supported by the Kavli Institute for Cosmological Physics at the University of Chicago through NSF Grant No. 1125897, and an endowment from the Kavli Foundation and its founder Fred Kavli. We also wish to acknowledge the support from Fermi National Accelerator Laboratory under Contract No. DE-AC02-07CH11359, and Pacific Northwest National Laboratory, which is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05- 76RL01830. We also thank Compute Canada [75] and the Center for Advanced Computing, ACENET, Calcul Qu¿ebec, Compute Ontario, and WestGrid for computational support.Amole, C.; Ardid Ramírez, M.; Arnquist, I.; Asner, DM.; Baxter, D.; Behnke, E.; Bressler, M.... (2019). Data-driven modeling of electron recoil nucleation in PICO C3F8 bubble chambers. Physical Review D: covering particles, fields, gravitation, and cosmology. 100(8):1-18. https://doi.org/10.1103/PhysRevD.100.082006S1181008Amole, C., Ardid, M., Arnquist, I. J., Asner, D. M., Baxter, D., Behnke, E., … Chen, C. J. (2019). Dark matter search results from the complete exposure of the PICO-60 C3F8 bubble chamber. Physical Review D, 100(2). doi:10.1103/physrevd.100.022001Agnese, R., Anderson, A. J., Aramaki, T., Arnquist, I., Baker, W., Barker, D., … Bowles, M. A. (2017). Projected sensitivity of the SuperCDMS SNOLAB experiment. Physical Review D, 95(8). doi:10.1103/physrevd.95.082002Amaudruz, P.-A., Baldwin, M., Batygov, M., Beltran, B., Bina, C. E., Bishop, D., … Broerman, B. (2018). First Results from the DEAP-3600 Dark Matter Search with Argon at SNOLAB. Physical Review Letters, 121(7). doi:10.1103/physrevlett.121.071801Arnaud, Q., Asner, D., Bard, J.-P., Brossard, A., Cai, B., Chapellier, M., … Zampaolo, M. (2018). First results from the NEWS-G direct dark matter search experiment at the LSM. Astroparticle Physics, 97, 54-62. doi:10.1016/j.astropartphys.2017.10.009Aguilar-Arevalo, A., Amidei, D., Bertou, X., Butner, M., Cancelo, G., … Castañeda Vázquez, A. (2016). Search for low-mass WIMPs in a 0.6 kg day exposure of the DAMIC experiment at SNOLAB. Physical Review D, 94(8). doi:10.1103/physrevd.94.082006Aalseth, C. E., Acerbi, F., Agnes, P., Albuquerque, I. F. M., Alexander, T., Alici, A., … Ardito, R. (2018). DarkSide-20k: A 20 tonne two-phase LAr TPC for direct dark matter detection at LNGS. The European Physical Journal Plus, 133(3). doi:10.1140/epjp/i2018-11973-4Jungman, G., Kamionkowski, M., & Griest, K. (1996). Supersymmetric dark matter. Physics Reports, 267(5-6), 195-373. doi:10.1016/0370-1573(95)00058-5Bertone, G., Hooper, D., & Silk, J. (2005). Particle dark matter: evidence, candidates and constraints. Physics Reports, 405(5-6), 279-390. doi:10.1016/j.physrep.2004.08.031Feng, J. L. (2010). Dark Matter Candidates from Particle Physics and Methods of Detection. Annual Review of Astronomy and Astrophysics, 48(1), 495-545. doi:10.1146/annurev-astro-082708-101659Duncan, F., Noble, A. J., & Sinclair, D. (2010). The Construction and Anticipated Science of SNOLAB. Annual Review of Nuclear and Particle Science, 60(1), 163-180. doi:10.1146/annurev.nucl.012809.104513Behnke, E., Behnke, J., Brice, S. J., Broemmelsiek, D., Collar, J. I., … Conner, A. (2012). First dark matter search results from a 4-kgCF3Ibubble chamber operated in a deep underground site. Physical Review D, 86(5). doi:10.1103/physrevd.86.052001Behnke, E., Behnke, J., Brice, S. J., Broemmelsiek, D., Collar, J. I., … Conner, A. (2014). Erratum: First dark matter search results from a 4-kgCF3Ibubble chamber operated in a deep underground site [Phys. Rev. D86, 052001 (2012)]. Physical Review D, 90(7). doi:10.1103/physrevd.90.079902Aubin, F., Auger, M., Genest, M.-H., Giroux, G., Gornea, R., Faust, R., … Storey, C. (2008). Discrimination of nuclear recoils from alpha particles with superheated liquids. New Journal of Physics, 10(10), 103017. doi:10.1088/1367-2630/10/10/103017Zacek, V. (1994). Search for dark matter with moderately superheated liquids. Il Nuovo Cimento A, 107(2), 291-298. doi:10.1007/bf02781560Amole, C., Ardid, M., Asner, D. M., Baxter, D., Behnke, E., Bhattacharjee, P., … Broemmelsiek, D. (2016). Dark matter search results from the PICO-60CF3Ibubble chamber. Physical Review D, 93(5). doi:10.1103/physrevd.93.052014Amole, C., Ardid, M., Arnquist, I. J., Asner, D. M., Baxter, D., Behnke, E., … Campion, P. (2017). Dark Matter Search Results from the PICO−60 C3F8 Bubble Chamber. Physical Review Letters, 118(25). doi:10.1103/physrevlett.118.251301Amole, C., Ardid, M., Arnquist, I. J., Asner, D. M., Baxter, D., Behnke, E., … Brice, S. J. (2016). Improved dark matter search results from PICO-2L Run 2. Physical Review D, 93(6). doi:10.1103/physrevd.93.061101Amole, C., Ardid, M., Asner, D. M., Baxter, D., Behnke, E., Bhattacharjee, P., … Broemmelsiek, D. (2015). Dark Matter Search Results from the PICO-2LC3F8Bubble Chamber. Physical Review Letters, 114(23). doi:10.1103/physrevlett.114.231302Hasert, F. J., Faissner, H., Krenz, W., Von Krogh, J., Lanske, D., Morfin, J., … Lemonne, J. (1973). Search for elastic muon-neutrino electron scattering. Physics Letters B, 46(1), 121-124. doi:10.1016/0370-2693(73)90494-2Hasert, F. J., Kabe, S., Krenz, W., Von Krogh, J., Lanske, D., Morfin, J., … Sacton, J. (1973). Observation of neutrino-like interactions without muon or electron in the gargamelle neutrino experiment. Physics Letters B, 46(1), 138-140. doi:10.1016/0370-2693(73)90499-1Behnke, E., Benjamin, T., Brice, S. J., Broemmelsiek, D., Collar, J. I., … Cooper, P. S. (2013). Direct measurement of the bubble-nucleation energy threshold in aCF3Ibubble chamber. Physical Review D, 88(2). doi:10.1103/physrevd.88.021101Tenner, A. G. (1963). Nucleation in bubble chambers. Nuclear Instruments and Methods, 22, 1-42. doi:10.1016/0029-554x(63)90224-6Kozynets, T., Fallows, S., & Krauss, C. B. (2019). Modeling emission of acoustic energy during bubble expansion in PICO bubble chambers. Physical Review D, 100(5). doi:10.1103/physrevd.100.052001Seitz, F. (1958). On the Theory of the Bubble Chamber. Physics of Fluids, 1(1), 2. doi:10.1063/1.1724333Behnke, E., Collar, J. I., Cooper, P. S., Crum, K., Crisler, M., Hu, M., … Tschirhart, R. (2008). Spin-Dependent WIMP Limits from a Bubble Chamber. Science, 319(5865), 933-936. doi:10.1126/science.1149999Barnabé-Heider, M., Di Marco, M., Doane, P., Genest, M.-H., Gornea, R., Guénette, R., … Noulty, R. (2005). Response of superheated droplet detectors of the PICASSO dark matter search experiment. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 555(1-2), 184-204. doi:10.1016/j.nima.2005.09.015Ziegler, J. F., Ziegler, M. D., & Biersack, J. P. (2010). SRIM – The stopping and range of ions in matter (2010). Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms, 268(11-12), 1818-1823. doi:10.1016/j.nimb.2010.02.091Bressler, M., Campion, P., Cushman, V. S., Morrese, A., Wagner, J. M., Zerbo, S., … Dahl, C. E. (2019). A buffer-free concept bubble chamber for PICO dark matter searches. Journal of Instrumentation, 14(08), P08019-P08019. doi:10.1088/1748-0221/14/08/p08019Agostinelli, S., Allison, J., Amako, K., Apostolakis, J., Araujo, H., Arce, P., … Barrand, G. (2003). Geant4—a simulation toolkit. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 506(3), 250-303. doi:10.1016/s0168-9002(03)01368-8Pozzi, S. A., Padovani, E., & Marseguerra, M. (2003). MCNP-PoliMi: a Monte-Carlo code for correlation measurements. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 513(3), 550-558. doi:10.1016/j.nima.2003.06.012Archambault, S., Aubin, F., Auger, M., Beleshi, M., Behnke, E., … Behnke, J. (2011). New insights into particle detection with superheated liquids. New Journal of Physics, 13(4), 043006. doi:10.1088/1367-2630/13/4/043006Glaser, D. A. (1954). Progress report on the development of bubble chambers. Il Nuovo Cimento, 11(S2), 361-368. doi:10.1007/bf02781098Fabian, B. N., Place, R. L., Riley, W. A., Sims, W. H., & Kenney, V. P. (1963). Density of Particle Tracks in the Hydrogen Bubble Chamber. Review of Scientific Instruments, 34(5), 484-495. doi:10.1063/1.1718415Willis, W. J., Fowler, E. C., & Rahm, D. C. (1957). Bubble Density in a Propane Bubble Chamber. Physical Review, 108(4), 1046-1047. doi:10.1103/physrev.108.1046Hahn, B., & Hugentobler, E. (1960). Relativistic increase in bubble density in a CBrF3 bubble chamber. Il Nuovo Cimento, 17(6), 983-985. doi:10.1007/bf02732145Brown, J. L., Glaser, D. A., & Perl, M. L. (1956). Liquid Xenon Bubble Chamber. Physical Review, 102(2), 586-587. doi:10.1103/physrev.102.586Baxter, D., Chen, C. J., Crisler, M., Cwiok, T., Dahl, C. E., Grimsted, A., … Zhang, J. (2017). First Demonstration of a Scintillating Xenon Bubble Chamber for Detecting Dark Matter and Coherent Elastic Neutrino-Nucleus Scattering. Physical Review Letters, 118(23). doi:10.1103/physrevlett.118.231301Durup, J., & Platzman, R. L. (1961). Role of the Auger effect in the displacement of atoms in solids by ionizing radiation. Discussions of the Faraday Society, 31, 156. doi:10.1039/df9613100156Schönfeld, E., & Janßen, H. (2000). Calculation of emission probabilities of X-rays and Auger electrons emitted in radioactive disintegration processes. Applied Radiation and Isotopes, 52(3), 595-600. doi:10.1016/s0969-8043(99)00216-xStrigari, L. E. (2009). Neutrino coherent scattering rates at direct dark matter detectors. New Journal of Physics, 11(10), 105011. doi:10.1088/1367-2630/11/10/105011Lewin, J. D., & Smith, P. F. (1996). Review of mathematics, numerical factors, and corrections for dark matter experiments based on elastic nuclear recoil. Astroparticle Physics, 6(1), 87-112. doi:10.1016/s0927-6505(96)00047-3Fitzpatrick, A. L., Haxton, W., Katz, E., Lubbers, N., & Xu, Y. (2013). The effective field theory of dark matter direct detection. Journal of Cosmology and Astroparticle Physics, 2013(02), 004-004. doi:10.1088/1475-7516/2013/02/004Anand, N., Fitzpatrick, A. L., & Haxton, W. C. (2014). Weakly interacting massive particle-nucleus elastic scattering response. Physical Review C, 89(6). doi:10.1103/physrevc.89.065501Gresham, M. I., & Zurek, K. M. (2014). Effect of nuclear response functions in dark matter direct detection. Physical Review D, 89(12). doi:10.1103/physrevd.89.123521Gluscevic, V., Gresham, M. I., McDermott, S. D., Peter, A. H. G., & Zurek, K. M. (2015). Identifying the theory of dark matter with direct detection. Journal of Cosmology and Astroparticle Physics, 2015(12), 057-057. doi:10.1088/1475-7516/2015/12/057Aprile, E., Aalbers, J., Agostini, F., Alfonsi, M., Althueser, L., Amaro, F. D., … Baudis, L. (2019). Constraining the Spin-Dependent WIMP-Nucleon Cross Sections with XENON1T. Physical Review Letters, 122(14). doi:10.1103/physrevlett.122.141301Akerib, D. S., Alsum, S., Araújo, H. M., Bai, X., Bailey, A. J., Balajthy, J., … Biesiadzinski, T. P. (2017). Limits on Spin-Dependent WIMP-Nucleon Cross Section Obtained from the Complete LUX Exposure. Physical Review Letters, 118(25). doi:10.1103/physrevlett.118.251302Fu, C., Cui, X., Zhou, X., Chen, X., Chen, Y., … Fang, D. (2017). Spin-Dependent Weakly-Interacting-Massive-Particle–Nucleon Cross Section Limits from First Data of PandaX-II Experiment. Physical Review Letters, 118(7). doi:10.1103/physrevlett.118.071301Behnke, E., Besnier, M., Bhattacharjee, P., Dai, X., Das, M., Davour, A., … Zacek, V. (2017). Final results of the PICASSO dark matter search experiment. Astroparticle Physics, 90, 85-92. doi:10.1016/j.astropartphys.2017.02.005Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2017). Search for annihilating dark matter in the Sun with 3 years of IceCube data. The European Physical Journal C, 77(3). doi:10.1140/epjc/s10052-017-4689-9Choi, K., Abe, K., Haga, Y., Hayato, Y., Iyogi, K., Kameda, J., … Nakahata, M. (2015). Search for Neutrinos from Annihilation of Captured Low-Mass Dark Matter Particles in the Sun by Super-Kamiokande. Physical Review Letters, 114(14). doi:10.1103/physrevlett.114.141301Ruppin, F., Billard, J., Figueroa-Feliciano, E., & Strigari, L. (2014). Complementarity of dark matter detectors in light of the neutrino background. Physical Review D, 90(8). doi:10.1103/physrevd.90.083510Felizardo, M., Girard, T. A., Morlat, T., Fernandes, A. C., Ramos, A. R., Marques, J. G., … Marques, R. (2014). The SIMPLE Phase II dark matter search. Physical Review D, 89(7). doi:10.1103/physrevd.89.072013Adrián-Martínez, S., Albert, A., André, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2016). Limits on dark matter annihilation in the sun using the ANTARES neutrino telescope. Physics Letters B, 759, 69-74. doi:10.1016/j.physletb.2016.05.019Adrián-Martínez, S., Albert, A., André, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2016). A search for Secluded Dark Matter in the Sun with the ANTARES neutrino telescope. Journal of Cosmology and Astroparticle Physics, 2016(05), 016-016. doi:10.1088/1475-7516/2016/05/016Aprile, E., Aalbers, J., Agostini, F., Alfonsi, M., Althueser, L., Amaro, F. D., … Bauermeister, B. (2018). Dark Matter Search Results from a One Ton-Year Exposure of XENON1T. Physical Review Letters, 121(11). doi:10.1103/physrevlett.121.111302Akerib, D. S., Alsum, S., Araújo, H. M., Bai, X., Bailey, A. J., Balajthy, J., … Biesiadzinski, T. P. (2017). Results from a Search for Dark Matter in the Complete LUX Exposure. Physical Review Letters, 118(2). doi:10.1103/physrevlett.118.021303Agnes, P., Albuquerque, I. F. M., Alexander, T., Alton, A. K., Araujo, G. R., Asner, D. M., … Batignani, G. (2018). Low-Mass Dark Matter Search with the DarkSide-50 Experiment. Physical Review Letters, 121(8). doi:10.1103/physrevlett.121.081307Agnes, P., Albuquerque, I. F. M., Alexander, T., Alton, A. K., Araujo, G. R., Ave, M., … Biery, K. (2018). DarkSide-50 532-day dark matter search with low-radioactivity argon. Physical Review D, 98(10). doi:10.1103/physrevd.98.102006Agnese, R., Anderson, A. J., Aralis, T., Aramaki, T., Arnquist, I. J., Baker, W., … Bauer, D. A. (2018). Low-mass dark matter search with CDMSlite. Physical Review D, 97(2). doi:10.1103/physrevd.97.022002Agnese, R., Aramaki, T., Arnquist, I. J., Baker, W., Balakishiyeva, D., Banik, S., … Binder, T. (2018). Results from the Super Cryogenic Dark Matter Search Experiment at Soudan. Physical Review Letters, 120(6). doi:10.1103/physrevlett.120.061802Hehn, L., Armengaud, E., Arnaud, Q., Augier, C., Benoît, A., Bergé, L., … Yakushev, E. (2016). Improved EDELWEISS-III sensitivity for low-mass WIMPs using a profile likelihood approach. The European Physical Journal C, 76(10). doi:10.1140/epjc/s10052-016-4388-yTolman, R. C. (1949). The Effect of Droplet Size on Surface Tension. The Journal of Chemical Physics, 17(3), 333-337. doi:10.1063/1.1747247Kirkwood, J. G., & Buff, F. P. (1949). The Statistical Mechanical Theory of Surface Tension. The Journal of Chemical Physics, 17(3), 338-343. doi:10.1063/1.1747248Xue, Y.-Q., Yang, X.-C., Cui, Z.-X., & Lai, W.-P. (2010). The Effect of Microdroplet Size on the Surface Tension and Tolman Length. The Journal of Physical Chemistry B, 115(1), 109-112. doi:10.1021/jp108431

International lower limb collaborative (INTELLECT) study: a multicentre, international retrospective audit of lower extremity open fractures

Trauma remains a major cause of mortality and disability across the world1, with a higher burden in developing nations2. Open lower extremity injuries are devastating events from a physical3, mental health4, and socioeconomic5 standpoint. The potential sequelae, including risk of chronic infection and amputation, can lead to delayed recovery and major disability6. This international study aimed to describe global disparities, timely intervention, guideline-directed care, and economic aspects of open lower limb injuries

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration

We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior

First Sagittarius A* Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole in the Center of the Milky Way

We present the first Event Horizon Telescope (EHT) observations of Sagittarius A* (Sgr A*), the Galactic center source associated with a supermassive black hole. These observations were conducted in 2017 using a global interferometric array of eight telescopes operating at a wavelength of lambda = 1.3 mm. The EHT data resolve a compact emission region with intrahour variability. A variety of imaging and modeling analyses all support an image that is dominated by a bright, thick ring with a diameter of 51.8 +/- 2.3 mu as (68% credible interval). The ring has modest azimuthal brightness asymmetry and a comparatively dim interior. Using a large suite of numerical simulations, we demonstrate that the EHT images of Sgr A* are consistent with the expected appearance of a Kerr black hole with mass similar to 4 x 10(6) M (circle dot), which is inferred to exist at this location based on previous infrared observations of individual stellar orbits, as well as maser proper-motion studies. Our model comparisons disfavor scenarios where the black hole is viewed at high inclination (i > 50 degrees), as well as nonspinning black holes and those with retrograde accretion disks. Our results provide direct evidence for the presence of a supermassive black hole at the center of the Milky Way, and for the first time we connect the predictions from dynamical measurements of stellar orbits on scales of 10(3)-10(5) gravitational radii to event-horizon-scale images and variability. Furthermore, a comparison with the EHT results for the supermassive black hole M87* shows consistency with the predictions of general relativity spanning over three orders of magnitude in central mass

編集後記

Adopting the Standard Halo Model (SHM) of an isotropic Maxwellian velocity distribution for dark matter (DM) particles in the Galaxy, the most stringent current constraints on their spin-dependent scattering cross-section with nucleons come from the IceCube neutrino observatory and the PICO-60 C$_3$F$_8$ superheated bubble chamber experiments. The former is sensitive to high energy neutrinos from the self-annihilation of DM particles captured in the Sun, while the latter looks for nuclear recoil events from DM scattering off nucleons. Although slower DM particles are more likely to be captured by the Sun, the faster ones are more likely to be detected by PICO. Recent N-body simulations suggest significant deviations from the SHM for the smooth halo component of the DM, while observations hint at a dominant fraction of the local DM being in substructures. We use the method of Ferrer et al. (2015) to exploit the complementarity between the two approaches and derive conservative constraints on DM-nucleon scattering. Our results constrain $\sigma_{\mathrm{SD}} \lesssim 3 \times 10^{-39} \mathrm{cm}^2$ (6 $\times 10^{-38} \mathrm{cm}^2$) at $\gtrsim 90\%$ C.L. for a DM particle of mass 1~TeV annihilating into $\tau^+ \tau^-$ ($b\bar{b}$) with a local density of $\rho_{\mathrm{DM}} = 0.3~\mathrm{ GeV/cm}^3$. The constraints scale inversely with $\rho_{\mathrm{DM}}$ and are independent of the DM velocity distribution.Comment: 9 pages, 3 figures, 1 table. To appear in Eur.Phys.J.