Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

SummaryThe impact of inflammation suppressor pathways on Alzheimer’s disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1+Il10−/−). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1+Il10−/− mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1+Il10−/− brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that “rebalancing” innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD

A Comprehensive Study of Short Bursts from SGR 1806-20 and SGR 1900+14 Detected by HETE-2

We present the results of temporal and spectral studies of the short burst (less than a few hundred milliseconds) from the soft gamma repeaters (SGRs) 1806-20 and 1900+14 using the HETE-2 samples. In five years from 2001 to 2005, HETE-2 detected 50 bursts which were localized to SGR 1806-20 and 5 bursts which were localized to SGR 1900+14. Especially SGR 1806-20 was active in 2004, and HETE-2 localized 33 bursts in that year. The cumulative number-intensity distribution of SGR 1806-20 in 2004 is well described by a power law model with an index of -1.1+/-0.6. It is consistent with previous studies but burst data taken in other years clearly give a steeper distribution. This may suggest that more energetic bursts could occur more frequently in periods of greater activity. A power law cumulative number-intensity distribution is also known for earthquakes and solar flares. It may imply analogous triggering mechanisms. Although spectral evolution during bursts with a time scale of > 20 ms is not common in the HETE-2 sample, spectral softening due to the very rapid (< a few milliseconds) energy reinjection and cooling may not be excluded. The spectra of all short bursts are well reproduced by a two blackbody function (2BB) with temperatures ~4 and ~11 keV. From the timing analysis of the SGR 1806-20 data, a time lag of 2.2+/-0.4 ms is found between the 30-100 keV and 2-10 keV radiation bands. This may imply (1) a very rapid spectral softening and energy reinjection, (2) diffused (elongated) emission plasma along the magnetic field lines in pseudo equilibrium with multi-temperatures, or (3) a separate (located at < 700 km) emission region of softer component (say, ~4 keV) which could be reprocessed X-rays by higher energy (> 11 keV) photons from an emission region near the stellar surface.Comment: 50 pages, 14 figures, accepted for publication in PAS

Deep Learning for Automated Experimentation in Scanning Transmission Electron Microscopy

Machine learning (ML) has become critical for post-acquisition data analysis in (scanning) transmission electron microscopy, (S)TEM, imaging and spectroscopy. An emerging trend is the transition to real-time analysis and closed-loop microscope operation. The effective use of ML in electron microscopy now requires the development of strategies for microscopy-centered experiment workflow design and optimization. Here, we discuss the associated challenges with the transition to active ML, including sequential data analysis and out-of-distribution drift effects, the requirements for the edge operation, local and cloud data storage, and theory in the loop operations. Specifically, we discuss the relative contributions of human scientists and ML agents in the ideation, orchestration, and execution of experimental workflows and the need to develop universal hyper languages that can apply across multiple platforms. These considerations will collectively inform the operationalization of ML in next-generation experimentation.Comment: Review Articl

Study of Atmospheric Pollution Scavenging: Twenty-first Progress Report

published or submitted for publicationis peer reviewedOpe

Study of Atmospheric Pollution Scavenging: Twentieth Progress Report

published or submitted for publicationis peer reviewedOpe

Assessing Monkeypox Virus Prevalence in Small Mammals at the Human-Animal Interface in the Democratic Republic of the Congo

During 2012, 2013 and 2015, we collected small mammals within 25 km of the town of Boende in Tshuapa Province, the Democratic Republic of the Congo. The prevalence of monkeypox virus (MPXV) in this area is unknown; however, cases of human infection were previously confirmed near these collection sites. Samples were collected from 353 mammals (rodents, shrews, pangolins, elephant shrews, a potamogale, and a hyrax). Some rodents and shrews were captured from houses where human monkeypox cases have recently been identified, but most were trapped in forests and agricultural areas near villages. Real-time PCR and ELISA were used to assess evidence of MPXV infection and other Orthopoxvirus (OPXV) infections in these small mammals. Seven (2.0%) of these animal samples were found to be anti-orthopoxvirus immunoglobulin G (IgG) antibody positive (six rodents: two Funisciurus spp.; one Graphiurus lorraineus; one Cricetomys emini; one Heliosciurus sp.; one Oenomys hypoxanthus, and one elephant shrew Petrodromus tetradactylus); no individuals were found positive in PCR-based assays. These results suggest that a variety of animals can be infected with OPXVs, and that epidemiology studies and educational campaigns should focus on animals that people are regularly contacting, including larger rodents used as protein sources

NFIL3 Is a Regulator of IL-12 p40 in Macrophages and Mucosal Immunity

Regulation of innate inflammatory responses against the enteric microbiota is essential for the maintenance of intestinal homeostasis. Key participants in innate defenses are macrophages. In these studies, the basic leucine zipper protein, NFIL3, is identified as a regulatory transcription factor in macrophages, controlling IL-12 p40 production induced by bacterial products and the enteric microbiota. Exposure to commensal bacteria and bacterial products induced NFIL3 in cultured macrophages and in vivo. The Il12b promoter has a putative DNA-binding element for NFIL3. Basal and LPS-activated NFIL3 binding to this site was confirmed by chromatin immunoprecipitation. LPS-induced Il12b promoter activity was inhibited by NFIL3 expression and augmented by NFIL3-short hairpin RNA in an Il12b-bacterial artificial chromosome-GFP reporter macrophage line. Il12b inhibition by NFIL3 does not require IL-10 expression, but a C-terminal minimal repression domain is necessary. Furthermore, colonic CD11b+ lamina propria mononuclear cells from Nfil3−/− mice spontaneously expressed Il12b mRNA. Importantly, lower expression of NFIL3 was observed in CD14+ lamina propria mononuclear cells from Crohn’s disease and ulcerative colitis patients compared with control subjects. Likewise, no induction of Nfil3 was observed in colons of colitis-prone Il10−/− mice transitioned from germ-free to a conventional microbiota. In conclusion, these experiments characterize NFIL3 as an Il12b transcriptional inhibitor. Interactions of macrophages with the enteric microbiota induce NFIL3 to limit their inflammatory capacity. Furthermore, altered intestinal NFIL3 expression may have implications for the pathogenesis of experimental and human inflammatory bowel diseases

The LHS 1678 system : two earth-sized transiting planets and an astrometric companion orbiting an M dwarf near the convective boundary at 20 pc

Funding: The MEarth Team gratefully acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering (awarded to D.C.). This material is based upon work supported by the National Science Foundation under grants AST-0807690, AST-1109468, AST-1004488 (Alan T. Waterman Award), and AST-1616624, and upon work supported by the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program. This work is made possible by a grant from the John Templeton Foundation. N. A.-D. acknowledges the support of FONDECYT project 3180063. TD acknowledges support from MIT’s Kavli Institute as a Kavli postdoctoral fellow. KH acknowledges support from STFC grant ST/R000824/1. E.A.G. thanks the LSSTC Data Science Fellowship Program, which is funded by LSSTC, NSF Cybertraining Grant #1829740, the Brinson Foundation, and the Moore Foundation; The material is based upon work supported by NASA under award number 80GSFC21M0002. This work was supported by the lead author’s appointment to the NASA Postdoctoral Program at the Goddard Space Flight Center, administered by Universities Space Research Association under contract with NASAWe present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (VJ = 12.5, Ks = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R⊕ and 0.98 ± 0.06 R⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M⊕ and 1.4 M⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung–Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars.Publisher PDFPeer reviewe

HETE-2 Observations of the X-Ray Flash XRF 040916

A long X-ray flash was detected and localized by the instruments aboard the High Energy Transient Explorer II (HETE-2) at 00:03:30 UT on 2004 September 16. The position was reported to the GRB Coordinates Network (GCN) approximately 2 hours after the burst. This burst consists of two peaks separated by 200 s, with durations of 110 s and 60 s. We have analyzed the energy spectra of the 1st and 2nd peaks observed with the Wide Field X-Ray Monitor (WXM) and the French Gamma Telescope (FREGATE). We discuss the origin of the 2nd peak in terms of flux variabilities and timescales. We find that it is most likely part of the prompt emission, and is explained by the long-acting engine model. This feature is similar to some bright X-ray flares detected in the early afterglow phase of bursts observed by the Swift satellite.Comment: 9 pages, 4 figures, Accepted for publication in PAS

A Giant Planet Candidate Transiting a White Dwarf

Astronomers have discovered thousands of planets outside the solar system, most of which orbit stars that will eventually evolve into red giants and then into white dwarfs. During the red giant phase, any close-orbiting planets will be engulfed by the star, but more distant planets can survive this phase and remain in orbit around the white dwarf. Some white dwarfs show evidence for rocky material floating in their atmospheres, in warm debris disks, or orbiting very closely, which has been interpreted as the debris of rocky planets that were scattered inward and tidally disrupted. Recently, the discovery of a gaseous debris disk with a composition similar to ice giant planets demonstrated that massive planets might also find their way into tight orbits around white dwarfs, but it is unclear whether the planets can survive the journey. So far, the detection of intact planets in close orbits around white dwarfs has remained elusive. Here, we report the discovery of a giant planet candidate transiting the white dwarf WD 1856+534 (TIC 267574918) every 1.4 days. The planet candidate is roughly the same size as Jupiter and is no more than 14 times as massive (with 95% confidence). Other cases of white dwarfs with close brown dwarf or stellar companions are explained as the consequence of common-envelope evolution, wherein the original orbit is enveloped during the red-giant phase and shrinks due to friction. In this case, though, the low mass and relatively long orbital period of the planet candidate make common-envelope evolution less likely. Instead, the WD 1856+534 system seems to demonstrate that giant planets can be scattered into tight orbits without being tidally disrupted, and motivates searches for smaller transiting planets around white dwarfs.Comment: 50 pages, 12 figures, 2 tables. Published in Nature on Sept. 17, 2020. The final authenticated version is available online at: https://www.nature.com/articles/s41586-020-2713-