The mass-luminosity relation for late-type stars has long been a critical tool for estimating stellar masses. However, there is growing need for both a higher-precision relation and a better ...understanding of systematic effects (e.g., metallicity). Here we present an empirical relationship between and M* spanning 0.075 M < M* < 0.70 M . The relation is derived from 62 nearby binaries, whose orbits we determine using a combination of Keck/NIRC2 imaging, archival adaptive optics data, and literature astrometry. From their orbital parameters, we determine the total mass of each system, with a precision better than 1% in the best cases. We use these total masses, in combination with resolved KS magnitudes and system parallaxes, to calibrate the -M* relation. The resulting posteriors can be used to determine masses of single stars with a precision of 2%-3%, which we confirm by testing the relation on stars with individual dynamical masses from the literature. The precision is limited by scatter around the best-fit relation beyond measured M* uncertainties, perhaps driven by intrinsic variation in the -M* relation or underestimated uncertainties in the input parallaxes. We find that the effect of Fe/H on the -M* relation is likely negligible for metallicities in the solar neighborhood (0.0% 2.2% change in mass per dex change in Fe/H). This weak effect is consistent with predictions from the Dartmouth Stellar Evolution Database, but inconsistent with those from MESA Isochrones and Stellar Tracks (at 5 ). A sample of binaries with a wider range of abundances will be required to discern the importance of metallicity in extreme populations (e.g., in the Galactic halo or thick disk).
Fibrosis contributes to ~45% of deaths in western countries. In chronic liver disease, fibrosis is a major factor determining outcomes, but efficient antifibrotic therapies are lacking. Although ...platelet-derived growth factor and transforming growth factor-β constitute key fibrogenic mediators, they do not account for the well-established link between cell death and fibrosis in the liver. Here, we hypothesized that damage-associated molecular patterns (DAMPs) may link epithelial cell death to fibrogenesis in the injured liver. DAMP receptor screening identified purinergic receptor P2Y14 among several candidates as highly enriched in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Conversely, P2Y14 ligands uridine 5'-diphosphate (UDP)-glucose and UDP-galactose were enriched in hepatocytes and were released upon different modes of cell death. Accordingly, ligand-receptor interaction analysis that combined proteomic and single-cell RNA sequencing data revealed P2Y14 ligands and P2Y14 receptor as a link between dying cells and HSCs, respectively. Treatment with P2Y14 ligands or coculture with dying hepatocytes promoted HSC activation in a P2Y14-dependent manner. P2Y14 ligands activated extracellular signal-regulated kinase (ERK) and Yes-associated protein (YAP) signaling in HSCs, resulting in ERK-dependent HSC activation. Global and HSC-selective P2Y14 deficiency attenuated liver fibrosis in multiple mouse models of liver injury. Functional expression of P2Y14 was confirmed in healthy and diseased human liver and human HSCs. In conclusion, P2Y14 ligands and their receptor constitute a profibrogenic DAMP pathway that directly links cell death to fibrogenesis.
Abstract
The atmospheres and accretion disks of planetary-mass and substellar companions provide an unprecedented look into planet and moon formation processes, most notably the frequency and ...lifetime of circumplanetary disks. In our ongoing effort to leverage the extraordinary sensitivity of the Spitzer/Infrared Array Camera (IRAC) at 3.6, 4.5, 5.8, and 8.0
μ
m to study wide planetary-mass and substellar companions near the diffraction limit, we present point-spread function fitting photometry of archival Spitzer/IRAC images for nine stars (G0 to M4+M7) in nearby star-forming regions or stellar associations that host companions at separations of
ρ
= 1.″17–12.″33. We detect all system primaries in all four IRAC channels and recover eight low-mass companions in at least one IRAC channel for our sample, five of which have not been resolved previously in IRAC images. We measure nonphotospheric 3.6–8.0 colors for four of the system companions (DH Tau B, 2M0441 B, SR 12 c, and ROXs 42B b), confirming or discovering the presence of circumstellar or circum(sub)stellar disks. We detect fluxes consistent with photospheric emission for four other companions (AB Pic b, CHXR 73 b, 1RXS J1609 b, and HD 203030 b) that are unlikely to host disks. Combined with past detections of accretion or disk indicators, we determine the global disk frequency of young (<15 Myr) wide companions with masses near the deuterium-burning limit to be 56% ± 12%.
Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) ...phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.
HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.
Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients’ outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.
This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH.
Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.
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•Hepatobiliary cells are associated with poor outcomes in patients with ArLD.•Hepatobiliary cells express pathways related to inflammation and stemness.•Cxcr4 drives hepatocyte dedifferentiation in chronic liver injury.•Cxcr4 overexpression in hepatocytes promotes hepatocyte dedifferentiation and injury progression.•Genetic deletion or pharmacological inhibition of Cxcr4 reverts hepatocyte dedifferentiation.
Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we ...identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response.
The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion.
In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion.
Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response.
Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease.
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•Advanced chronic liver diseases are characterized by the presence of ductular reaction-associated neutrophils.•Ductular reaction-associated neutrophils are long-lasting and immobilized to biliary epithelial cells.•Neutrophils recruited to the liver adopt an altered phenotype and function.•Neutrophils mediate biliary cell proliferation contributing to the maladaptive wound-healing response.
Direct imaging surveys have discovered wide-orbit planetary-mass companions that challenge existing models of both star and planet formation, but their demographics remain poorly sampled. We have ...developed an automated binary companion point-spread function (PSF) fitting pipeline to take advantage of Spitzer's infrared sensitivity to planetary-mass objects and circum(sub)stellar disks, measuring photometry across the four Infrared Array Camera (IRAC) channels of 3.6, 4.5, 5.8, and 8.0 m. We present PSF fitting photometry of archival Spitzer/IRAC images for 11 young, low-mass (M ∼ 0.044-0.88 M ; K3.5-M7.5) members of three nearby star-forming regions (Chameleon, Taurus, and Upper Scorpius; d ∼ 150 pc; τ ∼ 1-10 Myr) that host confirmed or candidate faint companions at = 1 68-7 31. We recover all system primaries, six confirmed, and two candidate low-mass companions in our sample. We also measure nonphotospheric 3.6-8.0 colors for three of the system primaries, four of the confirmed companions, and one candidate companion, signifying the presence of circumstellar or circum(sub)stellar disks. We furthermore report the confirmation of a = 4 66 (540 au) companion to SCH06 J0359+2009 which was previously identified as a candidate via imaging over five years ago, but was not studied further. Based on its brightness (M3.6 = 8.53 mag), we infer the companion mass to be M = 20 5 MJup given the primary's model-derived age of 10 Myr. Our framework is sensitive to companions with masses less than 10 MJup at separations of = 300 au in nearby star-forming regions, opening up a new regime of parameter space that has yet to be studied in detail, discovering planetary-mass companions in their birth environments and revealing their circum(sub)stellar disks.
Young exoplanets are snapshots of the planetary evolution process. Planets that orbit stars in young associations are particularly important because the age of the planetary system is well ...constrained. We present the discovery of a transiting planet larger than Neptune but smaller than Saturn in the 45 Myr Tucana-Horologium young moving group. The host star is a visual binary, and our follow-up observations demonstrate that the planet orbits the G6V primary component, DS Tuc A (HD 222259A, TIC 410214986). We first identified transits using photometry from the Transiting Exoplanet Survey Satellite (TESS; alerted as TOI 200.01). We validated the planet and improved the stellar parameters using a suite of new and archival data, including spectra from Southern Astrophysical Research/Goodman, South African Extremely Large Telescope/High Resolution Spectrograph and Las Cumbres Observatories/Network of Robotic Echelle Spectrographs; transit photometry from Spitzer; and deep adaptive optics imaging from Gemini/Gemini Planet Imager. No additional stellar or planetary signals are seen in the data. We measured the planetary parameters by simultaneously modeling the photometry with a transit model and a Gaussian process to account for stellar variability. We determined that the planetary radius is 5.70 0.17 R⊕ and that the orbital period is 8.1 days. The inclination angles of the host star's spin axis, the planet's orbital axis, and the visual binary's orbital axis are aligned within 15° to within the uncertainties of the relevant data. DS Tuc Ab is bright enough (V = 8.5) for detailed characterization using radial velocities and transmission spectroscopy.
Genetic evidence suggests that indole-3-butyric acid (IBA) is converted to the active auxin indole-3-acetic acid (IAA) by removal of two side-chain methylene units in a process similar to fatty acid ...beta-oxidation. Previous studies implicate peroxisomes as the site of IBA metabolism, although the enzymes that act in this process are still being identified. Here, we describe two IBA-response mutants, ibr1 and ibr10. Like the previously described ibr3 mutant, which disrupts a putative peroxisomal acyl-CoA oxidase/dehydrogenase, ibr1 and ibr10 display normal IAA responses and defective IBA responses. These defects include reduced root elongation inhibition, decreased lateral root initiation, and reduced IBA-responsive gene expression. However, peroxisomal energy-generating pathways necessary during early seedling development are unaffected in the mutants. Positional cloning of the genes responsible for the mutant defects reveals that IBR1 encodes a member of the short-chain dehydrogenase/reductase family and that IBR10 resembles enoyl-CoA hydratases/isomerases. Both enzymes contain C-terminal peroxisomal-targeting signals, consistent with IBA metabolism occurring in peroxisomes. We present a model in which IBR3, IBR10, and IBR1 may act sequentially in peroxisomal IBA beta-oxidation to IAA.
Hepatic stellate cells (HSCs) are non-parenchymal cells with a mesenchymal origin involved in vitamin A storage and extracellular matrix (ECM) homeostasis. In response to injury, HSCs activate and ...acquire myofibroblastic features, participating in the wound healing response. Upon chronic liver injury, HSCs become the main contributors to ECM deposition and to the progression of fibrosis. Due to their relevant roles in liver function and pathophysiology, it is of utmost importance to develop means to obtain HSCs for liver disease modeling and drug development. Here, we describe a directed differentiation protocol from human pluripotent stem cells (hPSCs) to obtain functional HSCs (PSC-HSCs). The procedure is based on the subsequent addition of growth factors during 12 days of differentiation. PSC-HSCs can be used for liver modeling and drug screening assays, hence emerging as a promising and reliable source of HSCs.
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