The avascular nature of cartilage makes it a unique tissue
, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular ...invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.
We search for an isotropic stochastic gravitational-wave background (GWB) in the newly released 11 year data set from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav). ...While we find no evidence for a GWB, we place constraints on a population of inspiraling supermassive black hole (SMBH) binaries, a network of decaying cosmic strings, and a primordial GWB. For the first time, we find that the GWB constraints are sensitive to the solar system ephemeris (SSE) model used and that SSE errors can mimic a GWB signal. We developed an approach that bridges systematic SSE differences, producing the first pulsar-timing array (PTA) constraints that are robust against SSE errors. We thus place a 95% upper limit on the GW-strain amplitude of AGWB < 1.45 × 10−15 at a frequency of f = 1 yr−1 for a fiducial f−2/3 power-law spectrum and with interpulsar correlations modeled. This is a factor of ∼2 improvement over the NANOGrav nine-year limit calculated using the same procedure. Previous PTA upper limits on the GWB (as well as their astrophysical and cosmological interpretations) will need revision in light of SSE systematic errors. We use our constraints to characterize the combined influence on the GWB of the stellar mass density in galactic cores, the eccentricity of SMBH binaries, and SMBH-galactic-bulge scaling relationships. We constrain the cosmic-string tension using recent simulations, yielding an SSE-marginalized 95% upper limit of G < 5.3 × 10−11-a factor of ∼2 better than the published NANOGrav nine-year constraints. Our SSE-marginalized 95% upper limit on the energy density of a primordial GWB (for a radiation-dominated post-inflation universe) is GWB(f) h2 < 3.4 × 10−10.
The subgenual anterior cingulate cortex (subgenual ACC) plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this ...understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions. Using Pavlovian conditioning procedures in macaque monkeys, we examined the contribution of the subgenual ACC to autonomic arousal associated with positive emotional events. After such conditioning, autonomic arousal increases in response to cues that predict rewards, and monkeys maintain this heightened state of arousal during an interval before reward delivery. Here we show that although monkeys with lesions of the subgenual ACC show the initial, cue-evoked arousal, they fail to sustain a high level of arousal until the anticipated reward is delivered. Control procedures showed that this impairment did not result from differences in autonomic responses to reward delivery alone, an inability to learn the association between cues and rewards, or to alterations in the light reflex. Our data indicate that the subgenual ACC may contribute to positive affect by sustaining arousal in anticipation of positive emotional events. A failure to maintain positive affect for expected pleasurable events could provide insight into the pathophysiology of psychological disorders in which negative emotions dominate a patient’s affective experience.
The frequency dependence of radio pulse arrival times provides a probe of structures in the intervening media. Demorest et al. was the first to show a short-term (∼100-200 days) reduction in the ...electron content along the line of sight to PSR J1713+0747 in data from 2008 (approximately MJD 54750) based on an apparent dip in the dispersion measure of the pulsar. We report on a similar event in 2016 (approximately MJD 57510), with average residual pulse-arrival times −3.0, −1.3, and −0.7 s at 820, 1400, and 2300 MHz, respectively. Timing analyses indicate possible departures from the standard −2 dispersive-delay dependence. We discuss and rule out a wide variety of potential interpretations. We find the likeliest scenario to be lensing of the radio emission by some structure in the interstellar medium, which causes multiple frequency-dependent pulse arrival-time delays.
The built and social neighborhood environment where a child lives has been increasingly studied as an exposure that may affect child weight long term. We conducted a systematic review of primary ...research articles published in 2011 through 2019 that reported results from longitudinal analyses of associations between neighborhood environment characteristics and child obesity or weight. Neighborhood environment measures included proximity to food stores, parks, and recreational facilities, walkability, crime, perceived safety, and social cohesion. Information on study population, exposure and outcome measures, and main results were extracted from 39 studies and results were presented for full cohorts and stratified by sex. Most studies were prospective cohorts (90%) with a median follow-up time of six years. Studies analyzing changes in the neighborhood versus changes in weight were less common than approaches analyzing baseline measures of the neighborhood environment in relation to obesity incidence or weight trajectories. Associations varied by sex, race/ethnicity, and age group. Within the food environment domain, the strongest evidence of adverse impact was for fast food restaurants but the effect was only apparent among girls. Results suggested green space, parks, and recreational facilities may have a beneficial effect on weight. Increased crime and low perceived safety may be risk factors for increased weight although not all studies were consistent. Standardization of measures across studies, investigation of multiple social and physical environment measures simultaneously, effect modification by demographic characteristics, and change in the environment vs change in weight analyses are needed to strengthen conclusions.
•Greenspace and recreational facilities appear to have a protective association with weight trajectories in children.•Increases in crime appear to be a risk factor for weight gain.•Exposure measures and neighborhood definitions should be standardized and include sensitivity analyses of these measures.•Future studies should be conducted in other contexts such as low- and middle- income countries and rural areas.
Dense arrays of single-crystal silicon nanowires (SiNWs) have been used as a platform for laser desorption/ionization mass spectrometry of small molecules, peptides, protein digests, and endogenous ...and xenobiotic metabolites in biofluids. Sensitivity down to the attomole level has been achieved on the nanowire surfaces by optimizing laser energy, surface chemistry, nanowire diameter, length, and growth orientation. An interesting feature of the nanowire surface is that it requires lower laser energy as compared to porous silicon and MALDI to desorb/ionize small molecules, therefore reducing background ion interference. Taking advantage of their high surface area and fluid wicking capabilities, SiNWs were used to perform chromatographic separation followed by mass analysis of the separated molecules providing a unique platform that can integrate separation and mass spectrometric detection on a single surface.
•Real world datasets are needed to assess biomarker performances in daily routine practice.•The stromal CD8+TILs were found to be the strongest predictor for PFS and OS in advanced NSCLC on anti-PD-1 ...monotherapy.•The combination of stromal CD8+TILs, albumin and LDH best predicted OS.
Immune checkpoint inhibitors (ICI), such as anti-PD-1 agents, have become part of the standard of care treatment of advanced non-small cell lung cancer (NSCLC). Predictive biomarkers are needed to identify patients that benefit from anti-PD-1 treatments. Tumor infiltrating lymphocytes (TILs) and PD-L1 are major players in the ICI mechanism of action. In this study, we assess the impact of real-world clinicopathological variables, including TILs and PD-L1, on anti-PD-1 efficacy.
We performed a monocenter retrospective study in advanced NSCLC treated with nivolumab or pembrolizumab between January 2015 and February 2019. The impact of baseline clinical and pathological variables was assessed by univariate and multivariate models. TILs, defined as CD8+T-cells, and PD-L1 were scored in tumor and stroma, and correlated with progression free survival (PFS) and overall survival (OS).
We included 366 patients of whom 141 were assessed for tumor and stromal TILs. The median follow-up time was 487 days. In the whole cohort, PFS was associated with high tumor PD-L1, high albumin and good performance. OS was associated with low LDH, high albumin, good performance and ‘first-line treatment’. In the TILs subcohort, stromal TILs had the strongest impact on PFS and OS. Stromal TILs were a stronger marker for PFS and OS than tumoral TILs, tumoral PD-L1 or stromal PD-L1. Remaining factors for PFS and OS were albumin and albumin with LDH, respectively.
This real-world study on clinicopathological features shows that stromal CD8 + TILs were the strongest predictor for PFS and OS in patients with advanced NSCLC on anti-PD-1 therapy. Other predictors for PFS and OS included albumin and albumin together with LDH, respectively. This study highlights the pivotal role of the stromal compartment in the mechanisms of action of ICI, and the need for further studies aiming to overcome this stromal firewall.
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