Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo ...kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output and peripheral naive T cell division to the maintenance of T cells in mice and men. Aging affected naive T cell maintenance fundamentally differently in mice and men. Whereas the naive T cell pool in mice was almost exclusively sustained by thymus output throughout their lifetime, the maintenance of the adult human naive T cell pool occurred almost exclusively through peripheral T cell division. These findings put constraints on the extrapolation of insights into T cell dynamics from mouse to man and vice versa.
► Mice and men are incomparable with respect to their naive T cell maintenance ► Naive T cell maintenance in human adults occurs primarily by cell division ► Throughout life, the naive T cell pool in mice is sustained by thymus output ► In men, naive T cells live 6–10 years, whereas in mice, they live 6–10 weeks
Dolutegravir (DGV) is one of the preferred antiretroviral agents in first-line combination antiretroviral therapy (cART). Though considered to be a well tolerated drug, we aimed to determine the ...actual rate, timing and detailed motivation of stopping DGV in a real-life clinical setting.
A cohort study including all patients who started DGV in two HIV treatment centers in The Netherlands.
All cART-naïve and cART-experienced patients who had started DGV were identified from the institutional HIV databases. Clinical data, including motivation and timing of discontinuation of DGV, were extracted from the patient files. Factors that potentially influenced discontinuation of DGV were compared between patients who stopped or continued DGV by multivariate and Kaplan-Meier analyses.
In total, 556 patients were included, of whom 102 (18.4%) were cART-naïve at initiation of DGV. Median follow-up time was 225 days. Overall, in 85 patients (15.3%), DGV was stopped. In 76 patients (13.7%), this was due to intolerability. Insomnia and sleep disturbance (5.6%), gastrointestinal complaints (4.3%) and neuropsychiatric symptoms such as anxiety, psychosis and depression (4.3%) were the predominant reasons for switching DGV. In regimens that included abacavir, DGV was switched more frequently (adjusted relative risk 1.92, 95% confidence interval 1.09-3.38, P log-rank 0.01). No virologic failures were observed.
A relatively high rate of preliminary discontinuation of DGV due to intolerability was detected in our patient population. In particular, DGV was stopped more frequently if the regimen included abacavir. Multiple factors may explain these unexpected postmarketing observations, which warrant further investigation.
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.
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.
Recent studies have shown that the primary heart tube continues to grow by addition of cells from the coelomic wall. This growth occurs concomitantly with embryonic folding and formation of the ...coelomic cavity, making early heart formation morphologically complex. A scarcity of data on localized growth parameters further hampers the understanding of cardiac growth. Therefore, we investigated local proliferation during early heart formation. Firstly, we determined the cell cycle length of primary myocardium of the early heart tube to be 5.5 days, showing that this myocardium is nonproliferating and implying that initial heart formation occurs solely by addition of cells. In line with this, we show that the heart tube rapidly lengthens at its inflow by differentiation of recently divided precursor cells. To track the origin of these cells, we made quantitative 3D reconstructions of proliferation in the forming heart tube and the mesoderm of its flanking coelomic walls. These reconstructions show a single, albeit bilateral, center of rapid proliferation in the caudomedial pericardial back wall. This center expresses Islet1. Cell tracing showed that cells from this caudal growth center, besides feeding into the venous pole of the heart, also move cranially via the dorsal pericardial mesoderm and differentiate into myocardium at the arterial pole. Inhibition of caudal proliferation impairs the formation of both the atria and the right ventricle. These data show how a proliferating growth center in the caudal coelomic wall elongates the heart tube at both its venous and arterial pole, providing a morphological mechanism for early heart formation.
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.
► Production of substitutes required for initial use of co-substrates was included. ► Land use change emissions from maize, barley, and soybean production were included. ► Mono-digestion had good ...environmental performance, but low bio-energy production. ► Co-digestion with animal feed increased bio-energy, but also environmental impact. ► Co-digestion with roadside grass showed best environmental performance.
The aim of this work was to assess the environmental consequences of anaerobic mono- and co-digestion of pig manure to produce bio-energy, from a life cycle perspective. This included assessing environmental impacts and land use change emissions (LUC) required to replace used co-substrates for anaerobic digestion. Environmental impact categories considered were climate change, terrestrial acidification, marine and freshwater eutrophication, particulate matter formation, land use, and fossil fuel depletion. Six scenarios were evaluated: mono-digestion of manure, co-digestion with: maize silage, maize silage and glycerin, beet tails, wheat yeast concentrate (WYC), and roadside grass. Mono-digestion reduced most impacts, but represented a limited source for bio-energy. Co-digestion with maize silage, beet tails, and WYC (competing with animal feed), and glycerin increased bio-energy production (up to 568%), but at expense of increasing climate change (through LUC), marine eutrophication, and land use. Co-digestion with wastes or residues like roadside grass gave the best environmental performance.
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.
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