Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact ...function has not been fully described. Here, we show that in contrast to healthy adult and inflammation‐activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c+ microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin‐like growth factor 1, and its selective depletion from CD11c+ microglia leads to impairment of primary myelination. CD11c‐targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c+ microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis.
Synopsis
Transcriptome profiling of murine microglia identified a population expressing CD11c as a potent source of neurodevelopmental signals in neonatal mice. These cells are a major source of IGF1 that is necessary for myelinogenesis in the developing CNS.
The transcriptome of neonatal microglia differs dramatically from that of homeostatic, immune‐activated and repopulating adult microglia.
A unique CD11c+ microglial subpopulation with a neurosupportive gene signature greatly expands during postnatal neurodevelopment.
Selective deletion of Igf1 from CD11c+ microglia leads to reduction of brain weight and significant impairment in primary myelination.
In contrast to the homeostatic and neuroinflammatory roles of adult microglia, a unique neonatal CD11c‐expressing subpopulation acts to deliver IGF1 and other signals needed for myelination and neurogenesis.
We present the first detailed quantitative study of the stellar populations of the Sagittarius (Sgr) streams within the Stripe 82 region, using photometric and spectroscopic observations from the ...Sloan Digital Sky Survey (SDSS). The star formation history (SFH) is determined separately for the bright and faint Sgr streams, to establish whether both components consist of a similar stellar population mix or have a distinct origin. Best-fitting SFH solutions are characterized by a well-defined, tight sequence in age–metallicity space, indicating that star formation occurred within a well-mixed, homogeneously enriched medium. Star formation rates dropped sharply at an age of ≈5–7 Gyr, possibly related to the accretion of Sgr by the MW. Finally, the Sgr sequence displays a change of slope in age–metallicity space at an age between 11 and 13 Gyr consistent with the Sgr α-element knee, indicating that supernovae Type Ia started contributing to the abundance pattern ≈1–3 Gyr after the start of star formation. Results for both streams are consistent with being drawn from the parent Sgr population mix, but at different epochs. The SFH of the bright stream starts from old, metal-poor populations and extends to a metallicity of Fe/H ≈ −0.7, with peaks at ≈7 and 11 Gyr. The faint SFH samples the older, more metal-poor part of the Sgr sequence, with a peak at ancient ages and stars mostly with Fe/H < −1.3 and age > 9 Gyr. Therefore, we argue in favour of a scenario where the faint stream consists of material stripped (i) earlier, and (ii) from the outskirts of the Sgr dwarf.
ABSTRACT
New data from the Gaia satellite, when combined with accurate photometry from the Pan-STARRS survey, allow us to accurately estimate the properties of the GD-1 stream. Here, we analyse the ...stellar density variations in the GD-1 stream and show that they cannot be due to known baryonic structures such as giant molecular clouds, globular clusters, or the Milky Way’s bar or spiral arms. A joint analysis of the GD-1 and Pal 5 streams instead requires a population of dark substructures with masses ≈107–$10^9 \ \rm {M}_{\odot }$. We infer a total abundance of dark subhaloes normalized to standard cold dark matter $n_{\rm sub}/n_{\rm sub, CDM} = 0.4 ^{+0.3}_{-0.2}$ (68 per cent), which corresponds to a mass fraction contained in the subhaloes $f_{\rm {sub}} = 0.14 ^{+0.11}_{-0.07} {{\ \rm per\ cent}}$, compatible with the predictions of hydrodynamical simulation of cold dark matter with baryons.
PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated ...long-term outcomes combined with the results of pathology review and molecular analysis.
427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.
Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.
Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.
ABSTRACT
The GD-1 stream is one of the longest and coldest stellar streams discovered to date, and one of the best objects for constraining the dark matter properties of the Milky Way. Using data ...from Gaia DR2, we study the proper motions (PMs), distance, morphology, and density of the stream to uncover small-scale perturbations. The PM cleaned data show a clear distance gradient across the stream, ranging from 7 to 12 kpc. However, unlike earlier studies that found a continuous gradient, we uncover a distance minimum at φ1 ≈ −40 deg, after which the distance increases again. We can reliably trace the stream between −85 < φ1 <15 deg, showing an even further extent to GD-1 beyond the earlier extension of Price-Whelan and Bonaca. We constrain the stream track and density using a Boolean matched filter approach and find three large under densities and significant residuals in the stream track lining up with these gaps. The gaps are located at φ1 = −36, −20, and −3 deg, with the gap at −3 deg being surrounded by a clear sinusoidal wiggle. We argue that this wiggle is due to a perturbation since it has the wrong orientation to come from a progenitor. We compute a total initial stellar mass of the stream segment of 1.58 ± 0.07 × 104 M⊙. With the extended view of the spur in this work, we argue that the spur may be unrelated to the adjacent gap in the stream. Finally, we show that an interaction with the Sagittarius dwarf can create features similar to the spur.
Objectives
Human age‐dependent telomere attrition and telomere shortening are associated with several age‐associated diseases and poorer overall survival. The aim of this study was to determine ...longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length.
Design and Methods
Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End‐stage Disease (PREVEND) study, an ongoing community‐based prospective cohort study initiated in 1997. Follow‐up data were available at two time‐points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics.
Results
We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39–60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist–hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001).
Conclusions
Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age‐associated diseases.
Abstract
Background and Aims
Ustekinumab is approved for the treatment of Crohn’s disease CD. Systematically registered prospective real-world data are scarce. We therefore aimed to study the ...effectiveness, safety and usage of ustekinumab for CD in everyday practice.
Methods
We prospectively enrolled CD patients initiating ustekinumab in regular care between December 2016 and January 2019. Clinical (Harvey Bradshaw Index HBI), biochemical (C-reactive protein CRP and faecal calprotectin FCP), extra-intestinal manifestations and, peri-anal fistula activity, ustekinumab dosage, concomitant medication use, and adverse events were documented at weeks 0, 12, 24, and 52. The primary outcome was corticosteroid-free clinical remission.
Results
In total, 221 CD patients were included (98.6% anti-tumour necrosis factor TNF and 46.6% vedolizumab exposed) with a median follow-up of 52.0 weeks interquartile range 49.3–58.4. Corticosteroid-free clinical remission rates at weeks 24 and 52 were 38.2% and 37.1%, respectively. An initial dosing schedule of 8 weeks, compared to 12 weeks, correlated with a lower discontinuation rate 20.0% vs 42.6%, p = 0.01, but comparable corticosteroid-free clinical remission at week 52 (46.3% q8w vs 34.6% q12w, p = 0.20). There was no clinical benefit of combination therapy after 52 weeks when compared to ustekinumab monotherapy combi 40.6% vs mono 36.0%, p = 0.64. At baseline, 28 patients had active peri-anal fistula, of whom 35.7% showed complete clinical resolution after 24 weeks. During follow-up we encountered six severe infections 3.5 per 100 patient-years, with all patients being on concomitant immunosuppressant therapies. Ustekinumab treatment discontinuation was observed in 75 33.9% patients mainly due to lack of response.
Conclusion
Ustekinumab is a relatively safe and effective treatment option for CD patients with prior failure of anti-TNF and anti-integrin therapies.
Abstract
We present panchromatic observations and modeling of supernova (SN) 2020tlf, the first normal Type II-P/L SN with confirmed precursor emission, as detected by the Young Supernova Experiment ...transient survey. Pre-SN activity was detected in
riz
-bands at −130 days and persisted at relatively constant flux until first light. Soon after discovery, “flash” spectroscopy of SN 2020tlf revealed narrow, symmetric emission lines that resulted from the photoionization of circumstellar material (CSM) shed in progenitor mass-loss episodes before explosion. Surprisingly, this novel display of pre-SN emission and associated mass loss occurred in a red supergiant (RSG) progenitor with zero-age main-sequence mass of only 10–12
M
⊙
, as inferred from nebular spectra. Modeling of the light curve and multi-epoch spectra with the non-LTE radiative-transfer code CMFGEN and radiation-hydrodynamical code HERACLES suggests a dense CSM limited to
r
≈ 10
15
cm, and mass-loss rate of 10
−2
M
⊙
yr
−1
. The luminous light-curve plateau and persistent blue excess indicates an extended progenitor, compatible with an RSG model with
R
⋆
= 1100
R
⊙
. Limits on the shock-powered X-ray and radio luminosity are consistent with model conclusions and suggest a CSM density of
ρ
< 2 × 10
−16
g cm
−3
for distances from the progenitor star of
r
≈ 5 × 10
15
cm, as well as a mass-loss rate of
M
̇
<
1.3
×
10
−
5
M
☉
yr
−
1
at larger distances. A promising power source for the observed precursor emission is the ejection of stellar material following energy disposition into the stellar envelope as a result of gravity waves emitted during either neon/oxygen burning or a nuclear flash from silicon combustion.
. de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin‐3 and outcome in the ...general population. J Intern Med 2012; 272: 55–64.
Objective. Galectin‐3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin‐3 and cardiovascular (CV) risk factors and mortality in the general population.
Design and subjects. This study included 7968 subjects from the Prevention of REnal and Vascular ENd‐stage Disease (PREVEND) cohort, with a median follow‐up of approximately 10 years. Plasma galectin‐3 was measured in baseline samples.
Main outcome measures. We investigated the relationships between galectin‐3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all‐cause, CV and cancer mortality.
Results. The mean age of the population was 50 ± 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L−1 and median galectin‐3 was 10.9 ng mL−1 interquartile range (IQR) 9.0–13.1. Galectin‐3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N‐terminal pro‐B‐type natriuretic peptide (P < 0.0001). We observed a strong association between galectin‐3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin‐3 levels (11.0 ng mL−1, IQR 9.1–13.4 vs. men (n = 3967) 10.7 ng mL−1, IQR 8.9–12.8; P < 0.0001), and galectin‐3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin‐3 levels independently predicted all‐cause mortality (hazard ratio per SD galectin‐3 1.09, 95% CI 1.01–1.19; P = 0.036), but not CV and cancer mortality separately.
Conclusions. Galectin‐3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin‐3 predicts all‐cause mortality in the general population.
Abstract
We present the first detailed study of the behaviour of the stellar proper motion across the entire Galactic anticentre area visible in the Sloan Digital Sky Survey (SDSS) data. We use ...recalibrated SDSS astrometry in combination with positions from Gaia DR1 to provide tangential motion measurements with a systematic uncertainty <5 km s−1 for the Main Sequence stars at the distance of the Monoceros Ring. We demonstrate that Monoceros members rotate around the Galaxy with azimuthal speeds of ∼230 km s−1, only slightly lower than that of the Sun. Additionally, both vertical and azimuthal components of their motion are shown to vary considerably but gradually as a function of Galactic longitude and latitude. The stellar overdensity in the anti-centre region can be split into two components, the narrow, stream-like ACS and the smooth Ring. According to our analysis, these two structures show very similar but clearly distinct kinematic trends, which can be summarized as follows: the amplitude of the velocity variation in vϕ and vz in the ACS is higher compared to the Ring, whose velocity gradients appear to be flatter. Currently, no model available can explain the entirety of the data in this area of the sky. However, the new accurate kinematic map introduced here should provide strong constraints on the genesis of the Monoceros Ring and the associated substructure.
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