The present paper is the culmination of a series aimed at contributing to the understanding of the kinematic structures of the solar neighborhood (SN), explaining the origin of the Local Arm, and ...relating the moving groups with the spiral-arms resonances in the disk. With a model for the Galactic potential, with the Sun inside the spiral corotation resonance (CR), we integrate the 2D orbits of test particles distributed in birthplaces along the main spiral arms, the Local Arm, and in the axisymmetric disk. A comparison of the resulting U-V plane of the SN with that provided by Gaia DR2 confirms our previous conclusion that the moving groups of Coma Berenices, Pleiades, and Hyades are associated with the CR, and that the Hercules stream is formed by the bulk of high-order inner Lindblad resonances. The kinematic structures result from stellar orbits trapped by the spiral resonances in a timespan of ∼1 Gyr, indicating the long-lived nature of the spiral structure and challenging recent arguments in favor of short-lived structures originated from incomplete phase mixing in the Galactic disk. As a byproduct, our simulations give some insight into the birthplaces of the stars presently located in the SN; the majority of stars of the main moving groups and the Hercules stream were likely born in the Local Arm, while stars of the Sirius group possibly originated from the outer segment of the Sagittarius-Carina arm. We also propose the spiral resonances as the dynamical origin for the diagonal ridges in the Galactic distribution of rotation velocities.
Interactions between surfaces and particles in aqueous suspension are usually limited to distances smaller than 1 μm. However, in a range of studies from different disciplines, repulsion of particles ...has been observed over distances of up to hundreds of micrometers, in the absence of any additional external fields. Although a range of hypotheses have been suggested to account for such behavior, the physical mechanisms responsible for the phenomenon still remain unclear. To identify and isolate these mechanisms, we perform detailed experiments on a well-defined experimental system, using a setup that minimizes the effects of gravity and convection. Our experiments clearly indicate that the observed long-range repulsion is driven by a combination of ion exchange, ion diffusion, and diffusiophoresis. We develop a simple model that accounts for our data; this description is expected to be directly applicable to a wide range of systems exhibiting similar long-range forces.
Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of ...systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as a source of hepcidin that is induced by microbial stimulation in mice, prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Collectively, these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.
The aim of this Letter is to contribute to the understanding of the stellar velocity distribution in the solar neighborhood (SN). We propose that the structures on the U-V planes, known as the moving ...groups, can be mainly explained by the spiral arms perturbations. The applied model of the Galactic disk and spiral arms, with the parameters defined by observational data and with pattern speed p = 28.0 km s−1 kpc−1, is the same that allowed us to explain the origin of the Local Arm and the Sun's orbit trapped inside the corotation resonance (CR). We show that the U-V picture of the SN consists of the main component, associated with the CR, and the inner and outer structures, which we could associate with the Hercules and Sirius streams, respectively. The Coma-Berenices and Hyades-Pleiades groups, and the Sun itself, belong to the main part. The substructures of Hercules are formed mainly by the nearby 8/1, 12/1, and even 6/1 inner Lindblad resonances, while Sirius is shaped by the bulk of overlapping outer Lindblad resonances, −8/1, −12/1, −16/1, which are stuck to the CR. This richness in resonances only exists near corotation, which should be of the spiral arms, not of the Galactic bar, whose stable corotation zone is far away from the Sun. The model's predictions of the velocity distribution match qualitatively and quantitatively the distribution provided by Gaia data release 2.
The Local Arm of the Milky Way, a short spiral feature near the Sun whose existence has been known for decades, was recently observed in detail with different tracers. Many efforts have been ...dedicated to elaborate plausible hypotheses concerning the origin of the main spiral arms of the Galaxy; however, up to now, no specific mechanism for the origin of the Local Arm has been proposed. Here we explain, for the first time, the Local Arm as an outcome of the spiral corotation resonance, which traps arm tracers and the Sun inside it. We show that the majority of maser sources belonging to the Local Arm, together with the Sun, evolve inside the corotation resonance, never crossing the main spiral arms but instead oscillating in the region between them. This peculiar behavior of the Sun could have numerous consequences for our understanding of the local kinematics of stars, the Galactic Habitable Zone, and the solar system evolution.
Lysine 9 of histone 3 (H3K9) can be mono-, di-, or trimethylated, inducing distinct effects on gene expression and chromatin compaction. H3K9 methylation can be mediated by several histone ...methyltransferases (HKMTs) that possess mono-, di-, or trimethylation activities. Here we provide evidence that a subset of each of the main H3K9 HKMTs, G9a/KMT1C, GLP/KMT1D, SETDB1/KMT1E, and Suv39h1/KMT1A, coexist in the same megacomplex. Moreover, in
Suv39h or
G9a null cells, the remaining HKMTs are destabilized at the protein level, indicating that the integrity of these HKMTs is interdependent. The four HKMTs are recruited to major satellite repeats, a known Suv39h1 genomic target, but also to multiple G9a target genes. Moreover, we report a functional cooperation between the four H3K9 HKMTs in the regulation of known G9a target genes. Altogether, our data identify a H3K9 methylation multimeric complex.
► Four H3K9 HKMTs (G9a, GLP, SETDB1, and Suv39h1) interact to form a megacomplex ► Deletion of either
Suv39h or
G9a destabilizes the other HKMTs at the protein level ► The H3K9 HKMTs are recruited to major satellite repeats, known Suv39h1 target loci ► The four HKMTs are recruited to multiple G9a target genes
Defective systemic and local iron metabolism correlates with cardiac disorders. Hepcidin, a master iron sensor, actively tunes iron trafficking. We hypothesized that hepcidin could play a key role to ...locally regulate cardiac homeostasis after acute myocardial infarction.
Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with acute myocardial infarction.
We found that the expression of hepcidin was elevated after acute myocardial infarction and the specific deletion of hepcidin in cardiomyocytes failed to improve cardiac repair and function. However, transplantation of bone marrow-derived cells from hepcidin-deficient mice ( Hamp
) or from mice with specific deletion of hepcidin in myeloid cells (LysM
/ Hamp
) improved cardiac function. This effect was associated with a robust reduction in the infarct size and tissue fibrosis in addition to favoring cardiomyocyte renewal. Macrophages lacking hepcidin promoted cardiomyocyte proliferation in a prototypic model of apical resection-induced cardiac regeneration in neonatal mice. Interleukin (IL)-6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45
/CD11b
/F4/80
/CD64
/MHCII
/chemokine (C-C motif) receptor 2 (CCR2)
inflammatory macrophages and fostered signal transducer and activator of transcription factor-3 (STAT3) phosphorylation, an instrumental step in the release of IL-4 and IL-13. The combined genetic suppression of hepcidin and IL-4/IL-13 in macrophages failed to improve cardiac function in both adult and neonatal injured hearts.
Hepcidin refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways.
A spectral survey of methyl acetylene (CH3CCH) was conducted toward the hot molecular core/outflow G331.512-0.103. Our APEX observations allowed the detection of 41 uncontaminated rotational lines of ...CH3CCH in the frequency range between 172 and 356 GHz. Through an analysis under the local thermodynamic equilibrium assumption, by means of rotational diagrams, we determined Texc = 50 ± 1 K, N(CH3CCH) = (7.5 ± 0.4) × 1015 cm2, XCH3CCH/H2 ≈ (0.8–2.8) × 10−8, and XCH3CCH/CH3OH ≈ 0.42 ± 0.05 for an extended emitting region (∼10″). The relative intensities of the K = 2 and K = 3 lines within a given K-ladder are strongly negatively correlated to the transitions’ upper J quantum number (r = −0.84). Pure rotational spectra of CH3CCH were simulated at different temperatures, in order to interpret this observation. The results indicate that the emission is characterized by a nonnegligible temperature gradient with upper and lower limits of ∼45 and ∼60 K, respectively. Moreover, the line widths and peak velocities show an overall strong correlation with their rest frequencies, suggesting that the warmer gas is also associated with stronger turbulence effects. The K = 0 transitions present a slightly different kinematic signature than the remaining lines, indicating that they might be tracing a different gas component. We speculate that this component is characterized by lower temperatures and therefore larger sizes. Moreover, we predict and discuss the temporal evolution of the CH3CCH abundance using a two-stage zero-dimensional model of the source constructed with the three-phase Nautilus gas-grain code.
Objective
Host–microbial interactions are central in health and disease. Monosodium urate monohydrate (MSU) crystals cause gout by activating the NLRP3 inflammasome, leading to interleukin‐1β (IL‐1β) ...production and neutrophil recruitment. This study was undertaken to investigate the relevance of gut microbiota, acetate, and the metabolite‐sensing receptor GPR43 in regulating inflammation in a murine model of gout.
Methods
Gout was induced by the injection of MSU crystals into the knee joints of mice. Macrophages from the various animals were stimulated to determine inflammasome activation and production of reactive oxygen species (ROS).
Results
Injection of MSU crystals caused joint inflammation, as seen by neutrophil influx, hypernociception, and production of IL‐1β and CXCL1. These parameters were greatly decreased in germ‐free mice, mice treated with antibiotics, and GPR‐43–deficient mice. Recolonization or administration of acetate to germ‐free mice restored inflammation in response to injection of MSU crystals. In vitro, macrophages produced ROS and assembled the inflammasome when stimulated with MSU. Macrophages from germ‐free animals produced little ROS, and there was little inflammasome assembly. Similar results were observed in macrophages from GPR‐43–deficient mice. Treatment of germ‐free mice with acetate restored in vitro responsiveness of macrophages to MSU crystals.
Conclusion
In the absence of microbiota, there is decreased production of short‐chain fatty acids that are necessary for adequate inflammasome assembly and IL‐1β production in a manner that is at least partially dependent on GPR43. These results clearly show that the commensal microbiota shapes the host's ability to respond to an inflammasome‐dependent acute inflammatory stimulus outside the gut.
Background Patient Derived Organoids (PDOs) emerged as the best technology to develop ex vivo tumor avatars. Whether drug testing on PDOs to identify efficient therapies will bring clinical utility ...by improving patient survival remains unclear. To test this hypothesis in the frame of clinical trials, PDO technology faces three main challenges to be implemented in routine clinical practices: i) generating PDOs with a limited amount of tumor material; ii) testing a wide panel of anti-cancer drugs; and iii) obtaining results within a time frame compatible with patient disease management. We aimed to address these challenges in a prospective study in patients with colorectal cancer (CRC). Methods Fresh surgical or core needle biopsies were obtained from patients with CRC. PDOs were established and challenged with a panel of 25 FDA-approved anti-cancer drugs (chemotherapies and targeted therapies) to establish a scoring method ('chemogram') identifying in vitro responders. The results were analyzed at the scale of the cohort and individual patients when the follow-up data were available. Results A total of 25 PDOs were successfully established, harboring 94% concordance with the genomic profile of the tumor they were derived from. The take-on rate for PDOs derived from core needle biopsies was 61.5%. A chemogram was obtained with a 6-week median turnaround time (range, 4-10 weeks). At least one hit (mean 6.16) was identified for 92% of the PDOs. The number of hits was inversely correlated to disease metastatic dissemination and the number of lines of treatment the patient received. The chemograms were compared to clinical data obtained from 8 patients and proved to be predictive of their response with 75% sensitivity and specificity. Conclusions We show that PDO-based drug tests can be achieved in the frame of routine clinical practice. The chemogram could provide clinicians with a decision-making tool to tailor patient treatment. Thus, PDO-based functional precision oncology should now be tested in interventional trials assessing its clinical utility for patients who do not harbor activable genomic alterations or have developed resistance to standard of care treatments. Keywords: Organoids, Precision medicine, Colorectal cancer, Chemogram
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