In utero undernutrition in male mice programs liver lipid metabolism in the second-generation offspring involving altered lxra DNA methylation

SummaryObesity and type 2 diabetes have a heritable component that is not attributable to genetic factors. Instead, epigenetic mechanisms may play a role. We have developed a mouse model of intrauterine growth restriction (IUGR) by in utero malnutrition. IUGR mice developed obesity and glucose intolerance with aging. Strikingly, offspring of IUGR male mice also developed glucose intolerance. Here, we show that in utero malnutrition of F1 males influenced the expression of lipogenic genes in livers of F2 mice, partly due to altered expression of Lxra. In turn, Lxra expression is attributed to altered DNA methylation of its 5′ UTR region. We found the same epigenetic signature in the sperm of their progenitors, F1 males. Our data indicate that in utero malnutrition results in epigenetic modifications in germ cells (F1) that are subsequently transmitted and maintained in somatic cells of the F2, thereby influencing health and disease risk of the offspring

Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health

Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.info:eu-repo/semantics/acceptedVersio

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Observations of the Crab Nebula and Pulsar with the Large-sized Telescope Prototype of the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) is a next-generation ground-based observatory for gamma-ray astronomy at very high energies. The Large-Sized Telescope prototype (LST-1) is located at the CTA-North site, on the Canary Island of La Palma. LSTs are designed to provide optimal performance in the lowest part of the energy range covered by CTA, down to ≃20 GeV. LST-1 started performing astronomical observations in 2019 November, during its commissioning phase, and it has been taking data ever since. We present the first LST-1 observations of the Crab Nebula, the standard candle of very-high-energy gamma-ray astronomy, and use them, together with simulations, to assess the performance of the telescope. LST-1 has reached the expected performance during its commissioning period—only a minor adjustment of the preexisting simulations was needed to match the telescope’s behavior. The energy threshold at trigger level is around 20 GeV, rising to ≃30 GeV after data analysis. Performance parameters depend strongly on energy, and on the strength of the gamma-ray selection cuts in the analysis: angular resolution ranges from 0.°12-0.°40, and energy resolution from 15%-50%. Flux sensitivity is around 1.1% of the Crab Nebula flux above 250 GeV for a 50 hr observation (12% for 30 minutes). The spectral energy distribution (in the 0.03-30 TeV range) and the light curve obtained for the Crab Nebula agree with previous measurements, considering statistical and systematic uncertainties. A clear periodic signal is also detected from the pulsar at the center of the Nebula

Star tracking for pointing determination of Imaging Atmospheric Cherenkov Telescopes: Application to the Large-Sized Telescope of the Cherenkov Telescope Array

We present a novel approach to the determination of the pointing of Imaging Atmospheric Cherenkov Telescopes (IACTs) using the trajectories of the stars in their camera s field of view. The method starts with the reconstruction of the star positions from the Cherenkov camera data, taking into account the point spread function of the telescope, to achieve a satisfying reconstruction accuracy of the pointing position. A simultaneous fit of all reconstructed star trajectories is then performed with the orthogonal distance regression (ODR) method. ODR allows us to correctly include the star position uncertainties and use the time as an independent variable. Having the time as an independent variable in the fit makes it better suitable for various star trajectories. This method can be applied to any IACT and requires neither specific hardware nor interface or special data-taking mode. In this paper, we use the Large-Sized Telescope (LST) data to validate it as a useful tool to improve the determination of the pointing direction during regular data taking. The simulation studies show that the accuracy and precision of the method are comparable with the design requirements on the pointing accuracy of the LST (=14''). With the typical LST event acquisition rate of 10 kHz, the method can achieve up to 50 Hz pointing monitoring rate, compared to O(1) Hz achievable with standard techniques. The application of the method to the LST prototype (LST-1) commissioning data shows the stable pointing performance of the telescope

Performance of the joint LST-1 and MAGIC observations evaluated with Crab Nebula data

Aims. Large-Sized Telescope 1 (LST-1), the prototype for the Large-Sized Telescope at the upcoming Cherenkov Telescope Array Observatory, is concluding its commissioning phase at the Observatorio del Roque de los Muchachos on the island of La Palma. The proximity of LST-1 to the two MAGIC (Major Atmospheric Gamma Imaging Cherenkov) telescopes makes it possible to carry out observations of the same gamma-ray events with both systems. Methods. We describe the joint LST-1+MAGIC analysis pipeline and used simultaneous Crab Nebula observations and Monte Carlo simulations to assess the performance of the three-telescope system. The addition of the LST-1 telescope allows for the recovery of events in which one of the MAGIC images is too dim to survive analysis quality cuts. Results. Thanks to the resulting increase in the collection area and stronger background rejection, we found a significant improvement in sensitivity, allowing for the detection of 30% weaker fluxes in the energy range between 200 GeV and 3 TeV. The spectrum of the Crab Nebula, reconstructed in the energy range between ∼60 GeV and ∼10 TeV, is in agreement with previous measurements

The role of nutrition on epigenetic modifications and their implications on health

Nutrition plays a key role in many aspects of health and dietary imbalances are major determinants of chronic diseases including cardiovascular disease, obesity, diabetes and cancer. Adequate nutrition is particularly essential during critical periods in early life (both pre- and postnatal). In this regard, there is extensive epidemiologic and experimental data showing that early sub-optimal nutrition can have health consequences several decades later. The hypothesis that epigenetic mechanisms may link such nutritional imbalances with altered disease risk has been gaining acceptance over recent years. Epigenetics can be defined as the study of heritable changes in gene expression that do not involve alterations in the DNA sequence. Epigenetic marks include DNA methylation, histone modifications and a variety of non-coding RNAs. Strikingly, they are plastic and respond to environmental signals, including diet. Here we will review how dietary factors modulate the establishment and maintenance of epigenetic marks, thereby influencing gene expression and, hence, disease risk and health. (C) 2012 Elsevier Masson SAS. All rights reserved

GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis

Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL-1 beta secretion and neutrophil cell death remain unclear. Here, we show that neutrophil-targeted expression of the disease-associated gain-of-function Nlrp3(A350V) mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm the activity of the canonical NLRP3 and NLRC4 inflammasomes in neutrophils, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes also promote maturation and secretion of interleukin (IL)-1 beta in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage in neutrophils, and canonical inflammasome-induced pyroptosis and secretion of mature IL-1 beta are blunted in GSDMD-knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis. We also show that Salmonella Typhimurium-induced pyroptosis is markedly increased in Nox2/Gp91(Phox)-deficient neutrophils that lack NADPH oxidase activity and are defective in PMA-induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome-induced neutrophil pyroptosis and mitogen-induced NETosis, respectively