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Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of RNF145 as an LXR-regulated target gene. We demonstrate that RNF145 is regulated by LXRs in both human and mouse primary cells and cell lines, and in vivo in mice. Regulation of RNF145 by LXR depends on a functional LXR-element in its proximal promotor. Consistent with LXR-dependent regulation of Rnf145 we show that regulation is lost in macrophages and fibroblasts from Lxrαβ(-/-) mice, and also in vivo in livers of Lxrα(-/-) mice treated with the LXR synthetic ligand T0901317. RNF145 is closely related to RNF139/TRC8, an E3 ligase implicated in control of SREBP processing. However, silencing of RNF145 in HepG2 or HeLa cells does not impair SREBP1/2 processing and sterol-responsive gene expression in these cells. Similar to TRC8, we demonstrate that RNF145 is localized to the ER and that it possesses intrinsic E3 ubiquitin ligase activity. In summary, we report the identification of RNF145 as an ER-resident E3 ubiquitin ligase that is transcriptionally controlled by LXR.

Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear. Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells. These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

“Food is relationships isn’t it,” Yamada san stated in 2017, neatly capturing the importance of food in social life. This article, drawing on the experiences of people with severe food allergies in Japan, illustrates the complexities of safely managing allergies when food—and the importance of sharing the same food—is so important to social life. In particular, I argue that individuals develop and practice skills of vigilance and situational awareness to mitigate physical and social risk which emerge through an affective imagination of what they feel could happen in the future, built on embodied memories of what has been experienced prior (e.g., severe allergic reactions and difficult social experiences with food). The development and enactment of these skills of vigilance happen through an ‘education of attention’ (Gibson in The ecological approach to visual perception, Psychology Press, New York, 1979; Ingold in The perception of the environment: essays on livelihood, dwelling and skill, Routledge, London, 2000) developed over time and in different social settings and constitute a somatic mode of attention (Csordas in Cult Anthropol 8:135–156, 1993) which shapes social interactions and aims to mitigate against any potential perceived social costs for not being able to eat everything.

Placentas can exhibit chromosomal aberrations that are absent from the fetus 1 . The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development. Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.

Proinflammatory macrophages are key in the development of obesity. In addition, reactive oxygen species (ROS), which activate the Fgr tyrosine kinase, also contribute to obesity. Here we show that ablation of Fgr impairs proinflammatory macrophage polarization while preventing high-fat diet (HFD)-induced obesity in mice. Systemic ablation of Fgr increases lipolysis and liver fatty acid oxidation, thereby avoiding steatosis. Knockout of Fgr in bone marrow (BM)-derived cells is sufficient to protect against insulin resistance and liver steatosis following HFD feeding, while the transfer of Fgr-expressing BM-derived cells reverts protection from HFD feeding in Fgr-deficient hosts. Scavenging of mitochondrial peroxides is sufficient to prevent Fgr activation in BM-derived cells and HFD-induced obesity. Moreover, Fgr expression is higher in proinflammatory macrophages and correlates with obesity traits in both mice and humans. Thus, our findings reveal the mitochondrial ROS–Fgr kinase as a key regulatory axis in proinflammatory adipose tissue macrophage activation, diet-induced obesity, insulin resistance and liver steatosis. Electron transport chain (ETC) regulation can have important consequences for cellular bioenergetics. Here, Acín-Pérez et al. show that macrophage ETC regulation by the Fgr kinase can also affect systemic metabolism in the setting of diet-induced obesity.

The placenta is the interface between mother and fetus and inadequate function contributes to short and long-term ill-health. The placenta is absent from most large-scale RNA-Seq datasets. We therefore analyze long and small RNAs (~101 and 20 million reads per sample respectively) from 302 human placentas, including 94 cases of preeclampsia (PE) and 56 cases of fetal growth restriction (FGR). The placental transcriptome has the seventh lowest complexity of 50 human tissues: 271 genes account for 50% of all reads. We identify multiple circular RNAs and validate 6 of these by Sanger sequencing across the back-splice junction. Using large-scale mass spectrometry datasets, we find strong evidence of peptides produced by translation of two circular RNAs. We also identify novel piRNAs which are clustered on Chr1 and Chr14. PE and FGR are associated with multiple and overlapping differences in mRNA, lincRNA and circRNA but fewer consistent differences in small RNAs. Of the three protein coding genes differentially expressed in both PE and FGR, one encodes a secreted protein FSTL3 (follistatin-like 3). Elevated serum levels of FSTL3 in pregnant women are predictive of subsequent PE and FGR. To aid visualization of our placenta transcriptome data, we develop a web application ( https://www.obgyn.cam.ac.uk/placentome/ ). Placental dysfunction can have catastrophic or barely discernible effects ranging from miscarriage to apparently normal birth. Here the authors present a comprehensive analysis of the human placental transcriptome and identify circular RNAs and piRNAs.

SARS-CoV-2 is responsible for a global pandemic, driven in part by the emergence of new viral variants. Where do these new variants come from? One model is that long-term viral persistence in infected individuals allows for viral evolution in response to host pressures, resulting in viruses more likely to replicate efficiently in humans. In this study, we characterize replication in several hospitalized and long-term infected individuals, documenting efficient pathways of viral evolution.

Objectives Given the rapid growth of the field of health policy and systems research (HPSR), it is important to monitor the research environment, especially the evolution of HPSR research outputs in low- and middle-income countries (LMICs). The objective of this study was to generate quantitative metrics to assess the production of HPSR publications and the role of the Alliance for Health Policy and Systems Research (the Alliance) grant-funded projects in 11 LMICs over the past 20 years. Methods We conducted a systematic literature search for HPSR literature from 1999 to 2020 pertaining to 11 target LMIC countries, including grey literature. We analysed the frequency of publications over time, by country and by thematic area. We then used a database of the Alliance’s previous grantees to analyse authorship by Alliance-funded investigators. Results HPSR publications across all 11 target countries increased steadily over the past two decades and the rate of publication increased by an average of 34% per year. The majority of HPSR publications during the study period were in health systems (23%) and health workforce (19%) thematic areas. Nineteen per cent of HPSR publications during this time were authored by Alliance-funded investigators. There was extensive heterogeneity between countries both in number of publications and in proportion of publications authored by Alliance-funded investigators. Conclusions Growth in the HPSR research environment reflects the expanding prominence of the HPSR field and increased HPSR research capacity in the 11 target countries. Alliance-funded investigators made an important contribution to the growth in HPSR output in these countries.

Alzheimer's disease (AD) is linked to comorbidities such as osteoporosis, sarcopenia, and type II diabetes. Currently, there is a lack of mouse models that mimic sporadic AD (sAD) which accounts for ∼95% of AD cases. A new humanized mouse model (hAb) was developed by substituting 3 amino acids in the amyloid beta sequence to the human counterpart. These mice develop an age-dependent sAD like pathology. This study characterized age-related changes in body composition, energy expenditure (EE), movement, bone health, glucose tolerance and insulin sensitivity prior to the development of sAD in the hAb mice. Wild type (WT) and hAb mice (n =10 per group) were characterized from 4 to 16 months of age. At the age of 4 months, and repeated every two months, body mass, whole body lean and fat mass, and the bone mineral density (BMD) of whole body, tibia, femur, and lumbar vertebrae 1-5 were measured using dual-energy X ray absorptiometry (DXA). Glucose and insulin tolerance testing (GTT & ITT) were also performed. EE and movement were measured using metabolic caging, and novel object recognition (NORT) and location (NOLT) testing were performed at age 4 and 16 months. The hAb mice significantly gained more weight and fat compared to WT throughout aging. They also had significantly lower percentage of lean mass and faster rates of lean mass decline throughout aging compared to the WT mice. EE and movement were also lower in the hAb mice. No genotype effects were seen in whole body and regional BMD or the area under the curve for GTT and ITT. The hAb mice spent less time with the novel object in the NORT and NOLT, however this result was not significant. The increased fat, and decreased percentage of lean mass along with reduced movement and energy expenditure in the hAb mice may indicate metabolic dysfunction which may precede sAD development. Future steps include increasing the sample size and investigating sex differences between the hAb female and male mice to determine any sex specific changes.

Preeclampsia (PE) and fetal growth restriction (FGR) complicate 5-10% of pregnancies and are major causes of maternal and fetal morbidity and mortality. Here we demonstrate that measuring circulating cell-free RNAs (cfRNAs) from maternal plasma can accurately predict pregnancies complicated by the combination of PE and FGR. We investigated 751 maternal plasma samples from 195 pregnant women (39 cases; 156 non-cases). We developed machine learning models from our discovery cohort (15 cases; 60 non-cases) and evaluated their predictive performances internally (24 cases; 96 controls) and externally (40 cases; 73 non-cases). We found circulating leptin ( LEP ) and pappalysin2 ( PAPPA2 ) cfRNAs are the strongest cfRNA predictors of complicated pregnancies, each with an area under the receiver operating characteristic curve (AUC) of ~0.82. Using an external validation dataset of women with established PE, the combination of LEP and PAPPA2 had an AUC ~0.951. Our findings show that cfRNAs can predict complications of human pregnancy. Early detection could improve prognosis for preeclampsia and fetal growth restriction, major causes of maternal/fetal morbidity and mortality. Here they show that Leptin and Pappalysin2 cell free RNAs are elevated in maternal plasma in cases of PE + FGR.