Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage
. The etiology of OA is complex and involves a variety of factors, including ...genetic predisposition, acute injury and chronic inflammation
. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis
. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.
ABSTRACT
We present a study of the metal-enriched cool halo gas traced by Mg ii absorption around 228 galaxies at z ∼ 0.8–1.5 within 28 quasar fields from the MUSE Analysis of Gas around Galaxies ...survey. We observe no significant evolution in the Mg ii equivalent width versus impact parameter relation and in the Mg ii covering fraction compared to surveys at z ≲ 0.5. The stellar mass, along with distance from galaxy centre, appears to be the dominant factor influencing the Mg ii absorption around galaxies. With a sample that is 90 per cent complete down to a star formation rate of ≈0.1 $\rm M_\odot yr^{-1}$ and up to impact parameters ≈250–350 kpc from quasars, we find that the majority ($67^{+12}_{-15}$ per cent or 14/21) of the Mg ii absorption systems are associated with more than one galaxy. The complex distribution of metals in these richer environments adds substantial scatter to previously reported correlations. Multiple galaxy associations show on average five times stronger absorption and three times higher covering fraction within twice the virial radius than isolated galaxies. The dependence of Mg ii absorption on galaxy properties disfavours the scenario in which a widespread intragroup medium dominates the observed absorption. This leaves instead gravitational interactions among group members or hydrodynamic interactions of the galaxy haloes with the intragroup medium as favoured mechanisms to explain the observed enhancement in the Mg ii absorption strength and cross-section in rich environments.
We present a new ‘supercalibration’ technique for measuring systematic distortions in the wavelength scales of high-resolution spectrographs. By comparing spectra of ‘solar twin’ stars or asteroids ...with a reference laboratory solar spectrum, distortions in the standard thorium–argon calibration can be tracked with ∼10 m s−1 precision over the entire optical wavelength range on scales of both echelle orders (∼50–100 Å) and entire spectrographs arms (∼1000–3000 Å). Using archival spectra from the past 20 yr, we have probed the supercalibration history of the Very Large Telescope-Ultraviolet and Visible Echelle Spectrograph (VLT-UVES) and Keck-High Resolution Echelle Spectrograph (HIRES) spectrographs. We find that systematic errors in their wavelength scales are ubiquitous and substantial, with long-range distortions varying between typically ±200 m s−1 per 1000 Å. We apply a simple model of these distortions to simulated spectra that characterize the large UVES and HIRES quasar samples which previously indicated possible evidence for cosmological variations in the fine-structure constant, α. The spurious deviations in α produced by the model closely match important aspects of the VLT-UVES quasar results at all redshifts and partially explain the HIRES results, though not self-consistently at all redshifts. That is, the apparent ubiquity, size and general characteristics of the distortions are capable of significantly weakening the evidence for variations in α from quasar absorption lines.
Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell ...(hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis.
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•PDPN+CD146−CD73+CD164+ marks a self-renewing, multipotent human skeletal stem cell•hSSCs can be isolated from fetal, adult, BMP2-treated human adipose stroma, and iPSCs•hSSCs undergo local expansion in response to acute skeletal injury•Comparison of mouse and human SSCs reveals evolutionary differences in skeletogenesis
Identification of a human skeletal stem cell reveals conserved and species-specific pathways in skeletal development, and response to injury and will guide future regenerative approaches.
Quasar absorption lines provide a precise test of whether the fine-structure constant, α, is the same in different places and through cosmological time. We present a new analysis of a large sample of ...quasar absorption-line spectra obtained using the Ultraviolet and Visual Echelle Spectrograph (UVES) on the Very Large Telescope (VLT) in Chile. We apply the many-multiplet method to derive values of Δα/α≡ (α
z
−α0)/α0 from 154 absorbers, and combine these values with 141 values from previous observations at the Keck Observatory in Hawaii. In the VLT sample, we find evidence that α increases with increasing cosmological distance from Earth. However, as previously shown, the Keck sample provided evidence for a smaller α in the distant absorption clouds. Upon combining the samples, an apparent variation of α across the sky emerges which is well represented by an angular dipole model pointing in the direction RA = 17.3 ± 1.0 h and Dec. =−61°± 10°, with amplitude
. The dipole model is required at the 4.1σ statistical significance level over a simple monopole model where α is the same across the sky (but possibly different from the current laboratory value). The data sets reveal remarkable consistencies: (i) the directions of dipoles fitted to the VLT and Keck samples separately agree; (ii) the directions of dipoles fitted to z < 1.6 and z > 1.6 cuts of the combined VLT+Keck samples agree; and (iii) in the equatorial region of the dipole, where both the Keck and VLT samples contribute a significant number of absorbers, there is no evidence for inconsistency between Keck and VLT. The amplitude of the dipole is clearly larger at higher redshift. Assuming a dipole-only (i.e. no-monopole) model whose amplitude grows proportionally with 'lookback-time distance' (r=ct, where t is the lookback time), the amplitude is (1.1 ± 0.2) × 10−6 GLyr−1 and the model is significant at the 4.2σ confidence level over the null model (Δα/α≡ 0). We apply robustness checks and demonstrate that the dipole effect does not originate from a small subset of the absorbers or spectra. We present an analysis of systematic effects, and are unable to identify any single systematic effect which can emulate the observed variation in α. To the best of our knowledge, this result is not in conflict with any other observational or experimental result.
Abstract
We present two measurements of the temperature–density relationship (TDR) of the intergalactic medium (IGM) in the redshift range 2.55 < z < 2.95 using a sample of 13 high-quality quasar ...spectra and high resolution numerical simulations of the IGM. Our approach is based on fitting the neutral hydrogen column density $N_{\rm H\, \small {I}}$ and the Doppler parameter b of the absorption lines in the Lyα forest. The first measurement is obtained using a novel Bayesian scheme that takes into account the statistical correlations between the parameters characterizing the lower cut-off of the $b\hbox{--}N_{\rm H\, \small {I}}$ distribution and the power-law parameters T0 and γ describing the TDR. This approach yields T0/103 K = 15.6 ± 4.4 and γ = 1.45 ± 0.17 independent of the assumed pressure smoothing of the small-scale density field. In order to explore the information contained in the overall $b\hbox{--}N_{\rm H\, \small {I}}$ distribution rather than only the lower cut-off, we obtain a second measurement based on a similar Bayesian analysis of the median Doppler parameter for separate column-density ranges of the absorbers. In this case, we obtain T0/103 K = 14.6 ± 3.7 and γ = 1.37 ± 0.17 in good agreement with the first measurement. Our Bayesian analysis reveals strong anticorrelations between the inferred T0 and γ for both methods as well as an anticorrelation of the inferred T0 and the pressure smoothing length for the second method, suggesting that the measurement accuracy can in the latter case be substantially increased if independent constraints on the smoothing are obtained. Our results are in good agreement with other recent measurements of the thermal state of the IGM probing similar (over-)density ranges.
ABSTRACT
Sun-like stars are a new probe of variations in the fine-structure constant, α, via the solar twins approach: velocity separations of close pairs of absorption lines are compared between ...stars with very similar stellar parameters, i.e. effective temperature, metallicity, and surface gravity within 100 K, 0.1 dex, and 0.2 dex of the Sun’s values. Here, we assess possible systematic errors in this approach by analysing ≳10 000 archival exposures from the High-Accuracy Radial Velocity Planetary Searcher (HARPS) of 130 stars covering a much broader range of stellar parameters. We find that each transition pair’s separation shows broad, low-order variations with stellar parameters that can be accurately modelled, leaving only a small residual, intrinsic star-to-star scatter of 0–33 m s−1 (average ≈7 m s−1, ≈1 × 10−4 Å at 5000 Å). This limits the precision available from a single pair in a single star. We consider potential systematic errors from a range of instrumental and astrophysical sources (e.g. wavelength calibration, charge transfer inefficiency, stellar magnetic activity, line blending) and conclude that variations in elemental abundances, isotope ratios, and stellar rotational velocities may explain this star-to-star scatter. Finally, we find that the solar twins approach can be extended to solar analogues – within 300 K, 0.3 dex, and 0.4 dex of the Sun’s parameters – without significant additional systematic errors, allowing a much larger number of stars to be used as probes of variation in α, including at much larger distances.
ABSTRACT
The rich absorption spectra of Sun-like stars are enticing probes for variations in the fine-structure constant, α, which gauges the strength of electromagnetism. While individual line ...wavelengths are sensitive to α, they are also sensitive to physical processes in the stellar atmospheres, which has precluded their use so far. Here we demonstrate a new differential approach using solar twins: velocity separations between close pairs of transitions are compared across stars with very similar physical properties, strongly suppressing astrophysical and instrumental systematic errors. We utilize 423 archival exposures of 18 solar twins from the High-Accuracy Radial velocity Planetary Searcher (HARPS), in which calibration errors can be reduced to ≲3 m s−1. For stars with ≈10 high-signal-to-noise ratio spectra (≥200 per pixel), velocity separations between pairs are measured with ≈10 m s−1 statistical precision. A companion paper assesses a range of systematic error sources using 130 stars, with a greater range of stellar parameters, providing accurate corrections for astrophysical effects and a residual, intrinsic star-to-star scatter of 0–13 m s−1. Within these uncertainties, we find no evidence for velocity separation differences in 17 transition pairs between solar twins. In a second companion paper, this is found to limit local (≲50 pc) variations in α to ≈50 parts per billion, ∼2 orders of magnitude less than other Galactic constraints.
Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts
. Here we show that intrinsic ageing of skeletal stem cells ...(SSCs)
in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.
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