Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation.

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aβ and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aβ oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aβ oligomerization and disaggregated preformed Aβ oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aβ fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aβ-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aβ-induced release of sTREM2, which blocks Aβ aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aβ aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.European Unio

ExoClock Project. III. 450 New Exoplanet Ephemerides from Ground and Space Observations

The ExoClock project has been created to increase the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates, in order to produce a consistent catalog of reliable and precise ephemerides. This work presents a homogenous catalog of updated ephemerides for 450 planets, generated by the integration of ∼18,000 data points from multiple sources. These sources include observations from ground-based telescopes (the ExoClock network and the Exoplanet Transit Database), midtime values from the literature, and light curves from space telescopes (Kepler, K2, and TESS). With all the above, we manage to collect observations for half of the postdiscovery years (median), with data that have a median uncertainty less than 1 minute. In comparison with the literature, the ephemerides generated by the project are more precise and less biased. More than 40% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95%), and also the identification of missing data. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (transit-timing variations) for a sample of 19 planets. All the products, data, and codes used in this work are open and accessible to the wider scientific community

ExoClock Project III: 450 new exoplanet ephemerides from ground and space observations

The ExoClock project has been created with the aim of increasing the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates over an extended period, in order to produce a consistent catalogue of reliable and precise ephemerides. This work presents a homogenous catalogue of updated ephemerides for 450 planets, generated by the integration of $\sim$18000 data points from multiple sources. These sources include observations from ground-based telescopes (ExoClock network and ETD), mid-time values from the literature and light-curves from space telescopes (Kepler/K2 and TESS). With all the above, we manage to collect observations for half of the post-discovery years (median), with data that have a median uncertainty less than one minute. In comparison with literature, the ephemerides generated by the project are more precise and less biased. More than 40\% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95\%), and also the identification of missing data. The dedicated ExoClock network effectively supports this task by contributing additional observations when a gap in the data is identified. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (TTVs - Transit Timing Variations) for a sample of 19 planets. All products, data, and codes used in this work are open and accessible to the wider scientific community.Comment: Recommended for publication to ApJS (reviewer's comments implemented). Main body: 13 pages, total: 77 pages, 7 figures, 7 tables. Data available at http://doi.org/10.17605/OSF.IO/P298

ExoClock Project. III. 450 New Exoplanet Ephemerides from Ground and Space Observations

The ExoClock project has been created to increase the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates, in order to produce a consistent catalog of reliable and precise ephemerides. This work presents a homogenous catalog of updated ephemerides for 450 planets, generated by the integration of ∼18,000 data points from multiple sources. These sources include observations from ground-based telescopes (the ExoClock network and the Exoplanet Transit Database), midtime values from the literature, and light curves from space telescopes (Kepler, K2, and TESS). With all the above, we manage to collect observations for half of the postdiscovery years (median), with data that have a median uncertainty less than 1 minute. In comparison with the literature, the ephemerides generated by the project are more precise and less biased. More than 40% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95%), and also the identification of missing data. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (transit-timing variations) for a sample of 19 planets. All the products, data, and codes used in this work are open and accessible to the wider scientific community

Targeting cancer cell CCR2 enhances synergistic immune surveillance in breast cancer

High expression of the C-C chemokine receptor type 2 (CCR2) in tumor samples and serum correlates with poor prognosis in human breast cancer, which has sparked interest in targeting the CCR2 pathway for therapeutic benefit. Importantly, a human CCR2 inhibitor (PF-04136309) has been investigated in clinical trials, and is currently being studied in a phase 1b/2 trial for pancreatic cancer (NCT02732938). Previous studies have focused on the protumor effects of CCR2 signaling in inflammatory monocytes. However, CCR2 is also expressed in breast cancer cells, but its potential function in cancer cells is poorly understood. To determine the specific roles of CCR2 in cancer and host cells, respectively, we established an orthotopic breast cancer mouse model by injecting primary cancer cells from MMTV-PyMT; Ccr2+/+ or MMTV-PyMT; Ccr2-/- mice into the mammary glands of wide-type or Ccr2 null hosts. In this cancer model, deleting Ccr2 in host cells, including monocytes, did not alter tumor growth. However, when tumor cells had lost Ccr2, immune surveillance was much more efficient, with greater infiltration and expansion of cytotoxic CD8+ T cell lymphocytes (CTLs) that efficiently recognized and destroyed the cancer cells, resulting in significant inhibition of tumor growth. Consistently, the delayed tumor growth of Ccr2 null cancer cells was fully reversed when these same cancer cells were transplanted into athymic (immunodeficient) mice. The reduced growth of tumors derived from Ccr2-/- cancer cells was associated with upregulation of IFN-γ response genes and genes involved in MHC class I presentation, as well as decreased expression of checkpoint inhibitor PD-L1 in cancer cells. Finally, greater infiltration of CD103+ dendritic cells (DCs) in Ccr2-/- tumor microenvironment also contributed to increased CTL function by cross presentation. Taken together, our results show that CCR2-expressing breast cancer cells orchestrated global changes in the infiltration of CTLs and DCs, leading to effective immune suppression. This suggests that CCR2 may be an immunotherapeutic target in breast cancer