Avian influenza A(H5N8) virus has caused major epizootics in Europe since 2016. We conducted virologic analysis of aerosol and dust collected on poultry farms in France during 2020-2021. Our results ...suggest dust contributes to viral dispersal, even early in an outbreak, and could be a valuable surveillance tool.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As faults grow over time and become more “mature,” some of their geometrical and mechanical properties evolve, and these changes modify earthquake behavior. It is thus of prime importance to know the ...degree of structural maturity of a fault that is likely to produce large earthquakes. Although this concept is extensively used, there is no common definition or metric to measure the structural maturity of a fault. We analyzed the heterogeneity of the surface traces of 13 large seismogenic faults whose maturity is known qualitatively. We measured the corrugations and step‐over segmentation of the traces from ∼100 m to the fault length scale. Corrugations and some properties of the segmentation are found to vary with fault structural maturity. We provide scaling relationships that quantify the structural maturity of a fault based on its surface trace. These results should help in parameterizing source faults in earthquake models.
Plain Language Summary
Long‐term faults produce earthquakes. Measuring fault properties could thus help us understand earthquake behavior. However, measuring properties of large‐scale faults in particular is difficult. Here, we tackle one of the major long‐term properties of faults, their structural maturity. This property relates to the overall slip longevity of the fault (generally several million years), and it has been shown to impact earthquake behavior; mature and immature faults do not behave similarly. For 13 large seismogenic continental faults whose structural maturity was estimated qualitatively in earlier works, we examined the heterogeneity of the traces these faults form at the ground surface. Using simple tools, we measured the undulations and the discrete “stepping” segmentation of the fault traces over a broad range of scales from ∼100 m to the full fault length (up to ∼1,600 km in this study). We found that the “intensity” of undulations and the density, relative width, and size diversity of the steps separating discrete fault segments all vary with the structural maturity of the faults. These variations are described with simple mathematical functions that characterize fault structural maturity and can be used to better represent source faults in earthquake models.
Key Points
We measure the corrugation and step‐over segmentation of 13 large seismogenic fault traces, at scales greater than ∼100 m
The corrugation level and the step‐over density, relative width, and size diversity vary with the structural maturity of the faults
We provide scaling relations measuring fault structural maturity, which should help to describe source faults better in earthquake models
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Eneolithic Botai culture of the Central Asian steppes provides the earliest archaeological evidence for horse husbandry, ~5500 years ago, but the exact nature of early horse domestication remains ...controversial. We generated 42 ancient-horse genomes, including 20 from Botai. Compared to 46 published ancient- and modern-horse genomes, our data indicate that Przewalski's horses are the feral descendants of horses herded at Botai and not truly wild horses. All domestic horses dated from ~4000 years ago to present only show ~2.7% of Botai-related ancestry. This indicates that a massive genomic turnover underpins the expansion of the horse stock that gave rise to modern domesticates, which coincides with large-scale human population expansions during the Early Bronze Age.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Low-grade inflammation is constitutive of atherosclerosis, and anti-inflammatory therapy inhibiting interleukin-1β (IL-1β) reduces the rate of cardiovascular events. While cholesterol accumulation in ...atheroma plaque and macrophages is a major driver of the inflammatory process, the role of the LXR cholesterol sensors remains to be clarified. Murine and human macrophages were treated with LXR agonists for 48 h before Toll-like receptor (TLR) stimulation. Unexpectedly, we observe that, among other cytokines, LXR agonists selectively increase IL1B mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by activation of HIF-1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis. Treatment of human macrophages with carotid plaque homogenates also leads to induction of IL1B in an LXR-dependent manner. Thus, our work discloses a mechanism by which cholesterol and oxysterols trigger inflammation in atherosclerosis. This suggests perspectives to target IL-1β production in atherosclerotic patients.
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•LXR agonists selectively increase IL1B mRNA levels in human macrophages in vitro•The impact of LXR on IL-1β is dependent on HIF-1α•LXR agonists activate other HIF-1α-dependent pathways, including glycolysis•IL1B induction by atheroma plaque homogenates is blunted by LXR antagonists
Ménégaut et al. show that liver X receptor (LXR) agonists selectively increase IL1β mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by an activation of hypoxia inducible factor (HIF) 1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally ...related to plasma LDL cholesterol levels have been identified so far, and only 1 gene,
, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family.
Using next-generation sequencing, we identified a novel dominant rare variant in the
gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this
-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance-based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after
-E97G overexpression.
Family members carrying the
-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of
-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the
-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human
-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver.
We identified and characterized a novel rare variant in the
gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes
the second identified gene, after
, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.
Chronic inflammation in end-stage renal disease (ESRD) is partly attributed to gut bacterial translocation (GBT) due to loss of intestinal epithelium integrity. Increased levels of circulating ...lipopolysaccharide (LPS) -a surrogate marker of GBT- contribute to maintain a chronic inflammatory state. However, circulating LPS can be neutralized by lipoproteins and transported to the liver for elimination. While ESRD-associated GBT has been widely described, less is known about its changes and impact on clinical outcome after kidney transplantation (KT). One hundred and forty-six renal transplant recipients with serum samples obtained immediately before and 1 year after transplantation (1-Year post KT) were included. Intestinal epithelium integrity (iFABP), total LPS (by measuring 3-hydroxymyristate), LPS activity (biologically active LPS measured by the LAL assay), inflammatory biomarkers (sCD14 and cytokines), lipoproteins and LPS-binding proteins (LBP and phospholipid transfer protein PLTP activity) were simultaneously measured. At 1-Year post KT, iFABP decreased but remained higher than in normal volunteers. Total LPS concentration remained stable while LPS activity decreased. Inflammation biomarkers decreased 1-Year post KT. We concomitantly observed an increase in lipoproteins. Higher sCD14 levels before transplantation was associated with lower incidence of acute rejection. Although GBT remained stable after KT, the contemporary increase in lipoproteins could bind circulating LPS and contribute concomitantly to neutralization of LPS activity, as well as improvement in ESRD-associated chronic inflammation. Chronic exposure to LPS in ESRD could promote endotoxin tolerance and explain why patients with higher pre-transplant sCD14 are less prompt to develop acute rejection after transplantation.
LPCAT3 plays a major role in phospholipid metabolism in the liver and intestine. However, the impact of LPCAT3 on hematopoietic cell and macrophage functions has yet to be described. Our aim was to ...understand the functions of LPCAT3 in macrophages and to investigate whether LPCAT3 deficiency in hematopoietic cells may affect atherosclerosis development.
Mice with constitutive Lpcat3 deficiency (Lpcat3−/−) were generated. We used fetal hematopoietic liver cells to generate WT and Lpcat3−/− macrophages in vitro and to perform hematopoietic cell transplantation in recipient Ldlr−/− mice.
Lpcat3-deficient macrophages displayed major reductions in the arachidonate content of phosphatidylcholines, phosphatidylethanolamines and, unexpectedly, plasmalogens. These changes were associated with altered cholesterol homeostasis, including an increase in the ratio of free to esterified cholesterol and a reduction in cholesterol efflux in Lpcat3−/− macrophages. This correlated with the inhibition of some LXR-regulated pathways, related to altered cellular availability of the arachidonic acid. Indeed, LPCAT3 deficiency was associated with decreased Abca1, Abcg1 and ApoE mRNA levels in fetal liver cells derived macrophages. In vivo, these changes translated into a significant increase in atherosclerotic lesions in Ldlr−/− mice with hematopoietic LPCAT3 deficiency.
This study identifies LPCAT3 as a key factor in the control of phospholipid homeostasis and arachidonate availability in myeloid cells and underlines a new role for LPCAT3 in plasmalogen metabolism. Moreover, our work strengthens the link between phospholipid and sterol metabolism in hematopoietic cells, with significant consequences on nuclear receptor-regulated pathways and atherosclerosis development.
•LPCAT3 controls arachidonic acid incorporation into glycerophospholipids in macrophages.•Alteration of arachidonic acid availability inhibits LXR pathways such as cholesterol efflux in Lpcat3−/− macrophages.•LPCAT3 deficiency in hematopoieic cells promotes atherosclerosis development in recipient Ldlr−/− mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Recent studies have highlighted an important role for lysophosphatidylcholine acyltransferase 3 (LPCAT3) in controlling the PUFA composition of cell membranes in the liver and intestine. In these ...organs, LPCAT3 critically supports cell-membrane-associated processes such as lipid absorption or lipoprotein secretion. However, the role of LPCAT3 in macrophages remains controversial. Here, we investigated LPCAT3's role in macrophages both in vitro and in vivo in mice with atherosclerosis and obesity. To accomplish this, we used the LysMCre strategy to develop a mouse model with conditional Lpcat3 deficiency in myeloid cells (Lpcat3KOMac). We observed that partial Lpcat3 deficiency (approximately 75% reduction) in macrophages alters the PUFA composition of all phospholipid (PL) subclasses, including phosphatidylinositols and phosphatidylserines. A reduced incorporation of C20 PUFAs (mainly arachidonic acid AA) into PLs was associated with a redistribution of these FAs toward other cellular lipids such as cholesteryl esters. Lpcat3 deficiency had no obvious impact on macrophage inflammatory response or endoplasmic reticulum (ER) stress; however, Lpcat3KOMac macrophages exhibited a reduction in cholesterol efflux in vitro. In vivo, myeloid Lpcat3 deficiency did not affect atherosclerosis development in LDL receptor deficient mouse (Ldlr−/−) mice. Lpcat3KOMac mice on a high-fat diet displayed a mild increase in hepatic steatosis associated with alterations in several liver metabolic pathways and in liver eicosanoid composition. We conclude that alterations in AA metabolism along with myeloid Lpcat3 deficiency may secondarily affect AA homeostasis in the whole liver, leading to metabolic disorders and triglyceride accumulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
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