Meaning in life in emerging adulthood: a person-oriented approach

The present study investigated naturally occurring profiles based on two dimensions of meaning in life: Presence of Meaning and Search for Meaning. Cluster analysis was used to examine meaning-in-life profiles, and subsequent analyses identified different patterns in psychosocial functioning for each profile. A sample of 8,492 American emerging adults (72.5% women) from 30 colleges and universities completed measures on meaning in life, and positive and negative psychosocial functioning. Results provided support for five meaningful yet distinguishable profiles. A strong generalizability of the cluster solution was found across age, and partial generalizability was found across gender and ethnicity. Furthermore, the five profiles showed specific patterns in relation to positive and negative psychosocial functioning. Specifically, respondents with profiles high on Presence of Meaning showed the most adaptive psychosocial functioning, whereas respondents with profiles where meaning was largely absent showed maladaptive psychosocial functioning. The present study provided additional evidence for prior research concerning the complex relationship between Presence of Meaning and Search for Meaning, and their relation with psychosocial functioning. Our results offer a partial clarification of the nature of the Search for Meaning process by distinguishing between adaptive and maladaptive searching for meaning in life

A Simple Artificial Life Model Explains Irrational Behavior in Human Decision-Making

Although praised for their rationality, humans often make poor decisions, even in simple situations. In the repeated binary choice experiment, an individual has to choose repeatedly between the same two alternatives, where a reward is assigned to one of them with fixed probability. The optimal strategy is to perseverate with choosing the alternative with the best expected return. Whereas many species perseverate, humans tend to match the frequencies of their choices to the frequencies of the alternatives, a sub-optimal strategy known as probability matching. Our goal was to find the primary cognitive constraints under which a set of simple evolutionary rules can lead to such contrasting behaviors. We simulated the evolution of artificial populations, wherein the fitness of each animat (artificial animal) depended on its ability to predict the next element of a sequence made up of a repeating binary string of varying size. When the string was short relative to the animats’ neural capacity, they could learn it and correctly predict the next element of the sequence. When it was long, they could not learn it, turning to the next best option: to perseverate. Animats from the last generation then performed the task of predicting the next element of a non-periodical binary sequence. We found that, whereas animats with smaller neural capacity kept perseverating with the best alternative as before, animats with larger neural capacity, which had previously been able to learn the pattern of repeating strings, adopted probability matching, being outperformed by the perseverating animats. Our results demonstrate how the ability to make predictions in an environment endowed with regular patterns may lead to probability matching under less structured conditions. They point to probability matching as a likely by-product of adaptive cognitive strategies that were crucial in human evolution, but may lead to sub-optimal performances in other environments

Reduced Expression of IFIH1 Is Protective for Type 1 Diabetes

IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response. IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function. Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala. This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala946, may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles. We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-β stimulated peripheral blood mononuclear cells (overall p = 0.012). In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D-associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1). We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1. These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D

B Lymphocyte intestinal homing in inflammatory bowel disease

<p>Abstract</p> <p>Background</p> <p>Inflammatory bowel disease (IBD) is thought to be due to an abnormal interaction between the host immune system and commensal microflora. Within the intestinal immune system, B cells produce physiologically natural antibodies but pathologically atypical anti-neutrophil antibodies (xANCAs) are frequently observed in patients with IBD. The objective is to investigate the localisation of immunoglobulin-producing cells (IPCs) in samples of inflamed intestinal tissue taken from patients with IBD, and their possible relationship with clinical features.</p> <p>Methods</p> <p>The IPCs in small intestinal, colonic and rectal biopsy specimens of patients with IBD were analysed by means of immunofluorescence using polyclonal rabbit anti-human Ig and goat anti-human IgM. The B cell phenotype of the IPC-positive samples was assessed using monoclonal antibodies specific for CD79, CD20, CD23, CD21, CD5, λ and κ chains. Statistical correlations were sought between the histological findings and clinical expression.</p> <p>Results</p> <p>The study involved 96 patients (64 with ulcerative colitis and 32 with Crohn's disease). Two different patterns of B lymphocyte infiltrates were found in the intestinal tissue: one was characterised by a strong to moderate stromal localisation of small IgM⁺/CD79⁺/CD20^-/CD21^-/CD23^-/CD5^±IPCs (42.7% of cases); in the other (57.3%) no such small IPCs were detected in stromal or epithelial tissues. <it>IPCs </it>were significantly less frequent in the patients with Crohn's disease than in those with ulcerative colitis (p = 0.004).</p> <p>Conclusion</p> <p>Our findings suggest that different immunopathogenetic pathways underlie chronic intestinal inflammation with different clinical expressions. The presence of small B lymphocytes resembling B-1 cells also seemed to be negatively associated with Crohn's disease. It can therefore be inferred that the gut contains an alternative population of B cells that have a regulatory function.</p

Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation

Background: We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson’s disease (PD) and multiple system atrophy (MSA). The objective of this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case. Results: All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state. Conclusions: Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication

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

Rotavirus NSP1 Inhibits NFκB Activation by Inducing Proteasome-Dependent Degradation of β-TrCP: A Novel Mechanism of IFN Antagonism

Mechanisms by which viruses counter innate host defense responses generally involve inhibition of one or more components of the interferon (IFN) system. Multiple steps in the induction and amplification of IFN signaling are targeted for inhibition by viral proteins, and many of the IFN antagonists have direct or indirect effects on activation of latent cytoplasmic transcription factors. Rotavirus nonstructural protein NSP1 blocks transcription of type I IFNα/β by inducing proteasome-dependent degradation of IFN-regulatory factors 3 (IRF3), IRF5, and IRF7. In this study, we show that rotavirus NSP1 also inhibits activation of NFκB and does so by a novel mechanism. Proteasome-mediated degradation of inhibitor of κB (IκBα) is required for NFκB activation. Phosphorylated IκBα is a substrate for polyubiquitination by a multisubunit E3 ubiquitin ligase complex, Skp1/Cul1/F-box, in which the F-box substrate recognition protein is β-transducin repeat containing protein (β-TrCP). The data presented show that phosphorylated IκBα is stable in rotavirus-infected cells because infection induces proteasome-dependent degradation of β-TrCP. NSP1 expressed in isolation in transiently transfected cells is sufficient to induce this effect. Targeted degradation of an F-box protein of an E3 ligase complex with a prominent role in modulation of innate immune signaling and cell proliferation pathways is a unique mechanism of IFN antagonism and defines a second strategy of immune evasion used by rotaviruses

Innate Sensing of HIV-Infected Cells

Cell-free HIV-1 virions are poor stimulators of type I interferon (IFN) production. We examined here how HIV-infected cells are recognized by plasmacytoid dendritic cells (pDCs) and by other cells. We show that infected lymphocytes are more potent inducers of IFN than virions. There are target cell-type differences in the recognition of infected lymphocytes. In primary pDCs and pDC-like cells, recognition occurs in large part through TLR7, as demonstrated by the use of inhibitors and by TLR7 silencing. Donor cells expressing replication-defective viruses, carrying mutated reverse transcriptase, integrase or nucleocapsid proteins induced IFN production by target cells as potently as wild-type virus. In contrast, Env-deleted or fusion defective HIV-1 mutants were less efficient, suggesting that in addition to TLR7, cytoplasmic cellular sensors may also mediate sensing of infected cells. Furthermore, in a model of TLR7-negative cells, we demonstrate that the IRF3 pathway, through a process requiring access of incoming viral material to the cytoplasm, allows sensing of HIV-infected lymphocytes. Therefore, detection of HIV-infected lymphocytes occurs through both endosomal and cytoplasmic pathways. Characterization of the mechanisms of innate recognition of HIV-infected cells allows a better understanding of the pathogenic and exacerbated immunologic events associated with HIV infection

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches