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Wide-field optical surveys have begun to uncover large samples of fast (trise ≲ 5 d), luminous (Mpeak < -18), blue transients. While commonly attributed to the breakout of a supernova shock into a dense wind, the great distances to the transients of this class found so far have hampered detailed investigation of their properties. We present photometry and spectroscopy from a comprehensive worldwide campaign to observe AT 2018cow (ATLAS 18qqn), the first fast-luminous optical transient to be found in real time at lowredshift. Our first spectra (10 days. The spectrum remains extremely hot throughout its evolution, and the photospheric radius contracts with time (receding below R < 1014 cm after 1 month). This behaviour does not match that of any known supernova, although a relativistic jet within a fallback supernova could explain some of the observed features. Alternatively, the transient could originate from the disruption of a star by an intermediate-mass black hole, although thiswould require long-lasting emission of highly super-Eddington thermal radiation. In either case, AT 2018cow suggests that the population of fast luminous transients represents a new class of astrophysical event. Intensive follow-up of this event in its late phases, and of any future events found at comparable distance, will be essential to better constrain their origins.

We report photometric and spectroscopic observations of the optical transient LSQ13zm. Historical data reveal the presence of an eruptive episode (that we label as '2013a') followed by a much brighter outburst ('2013b') three weeks later, that we argue to be the genuine supernova explosion. This sequence of events closely resemble those observed for SN 2010mc and (in 2012) SN 2009ip. The absolute magnitude reached by LSQ13zm during 2013a (MR = -14.87 ± 0.25mag) is comparable with those of supernova impostors, while that of the 2013b event (MR = -18.46 ± 0.21mag) is consistent with those of interacting supernovae. Our spectra reveal the presence of a dense and structured circumstellar medium, probably produced through numerous pre-supernova mass-loss events. In addition, we find evidence for high-velocity ejecta, with a fraction of gas expelled at more than 20 000km s-1. The spectra of LSQ13zm show remarkable similarity with those of well-studied core-collapse supernovae. From the analysis of the available photometric and spectroscopic data, we conclude that we first observed the last event of an eruptive sequence from a massive star, likely a Luminous Blue Variable, which a short time later exploded as a core-collapse supernova. The detailed analysis of archival images suggest that the host galaxy is a star-forming Blue Dwarf Compact Galaxy.

Neutron stars and stellar-mass black holes are the remnants of massive star explosions 1 . Most massive stars reside in close binary systems 2 , and the interplay between the companion star and the newly formed compact object has been theoretically explored 3 , but signatures for binarity or evidence for the formation of a compact object during a supernova explosion are still lacking. Here we report a stripped-envelope supernova, SN 2022jli, which shows 12.4-day periodic undulations during the declining light curve. Narrow Hα emission is detected in late-time spectra with concordant periodic velocity shifts, probably arising from hydrogen gas stripped from a companion and accreted onto the compact remnant. A new Fermi-LAT γ-ray source is temporally and positionally consistent with SN 2022jli. The observed properties of SN 2022jli, including periodic undulations in the optical light curve, coherent Hα emission shifting and evidence for association with a γ-ray source, point to the explosion of a massive star in a binary system leaving behind a bound compact remnant. Mass accretion from the companion star onto the compact object powers the light curve of the supernova and generates the γ-ray emission., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In recent years, certain luminous extragalactic optical transients have been observed to last only a few days 1 . Their short observed duration implies a different powering mechanism from the most common luminous extragalactic transients (supernovae), whose timescale is weeks 2 . Some short-duration transients, most notably AT2018cow (ref.  3 ), show blue optical colours and bright radio and X-ray emission 4 . Several AT2018cow-like transients have shown hints of a long-lived embedded energy source 5 , such as X-ray variability 6,7 , prolonged ultraviolet emission 8 , a tentative X-ray quasiperiodic oscillation 9,10 and large energies coupled to fast (but subrelativistic) radio-emitting ejecta 11,12 . Here we report observations of minutes-duration optical flares in the aftermath of an AT2018cow-like transient, AT2022tsd (the 'Tasmanian Devil'). The flares occur over a period of months, are highly energetic and are probably nonthermal, implying that they arise from a near-relativistic outflow or jet. Our observations confirm that, in some AT2018cow-like transients, the embedded energy source is a compact object, either a magnetar or an accreting black hole., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: To examine the association between gestational age, telomere length (TL) and rate of shortening in newborns., Study Design: Genomic DNA was isolated from buccal samples of 39 term infants at birth and one year and 32 preterm infants at birth, term-adjusted age (40 weeks post-conception) and age one-year corrected for gestational duration. Telomere length was measured by quantitative real-time PCR. Demographic and clinical data were collected during clinic or research visits and from hospital records. Socioeconomic status was estimated using the deprivation category (DEPCAT) scores derived from the Carstairs score of the subject's postal code., Results: At birth, preterm infants had longer telomeres than infants born at term. However, there was no difference in telomere length between preterm infants and term infants at one year of age, implying that the rate of telomere shortening was greater in pre-term than term infants. Interestingly, TL at age 40 weeks post-conception in preterm infants was significantly longer than term infant TL at birth, suggesting that time since conception is not the only factor that affects rate of shortening. Several factors, including sex, fetal growth restriction, maternal age, maternal booking body mass index (BMI), mother education level and DEPCAT score, also differed between the preterm and term groups., Conclusions: Preterm infants have longer telomeres than term infants at birth. In the studied cohort, the rate of telomere shortening was greater in the premature group compared with the term infants. This finding agrees with previous studies using cord blood, suggesting that the longer TL in premature infants detected at birth do not persist and demonstrating that use of saliva DNA is acceptable for studies of telomere dynamics in infants. However, that the TL at age 40 weeks post-conception in preterm is longer than term infants at birth suggests that biological factors other than time since conception also affect rate of shortening., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Schneper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the U.S. state of Arizona, nearly one-third of households experienced food insecurity during the COVID-19 pandemic, an increase from one-fourth of households before the pandemic. Previous research on food insecurity in the wake of natural and human-instigated disasters demonstrates that groups vulnerable to food insecurity before a disaster are more susceptible to food insecurity during and after that disaster; however, less is known about whether this relationship also holds true during health-related disasters, such as the COVID-19 pandemic. We explore how the COVID-19 pandemic influenced urban food insecurity patterns by analyzing the socio-demographic characteristics of food pantry clients in Maricopa County, Arizona. Using data from Phoenix Rescue Mission (PRM), a local non-profit food service provider, two binomial logistic regression models compare the socio-demographic composition of total and first-time food pantry users before and during the pandemic. In addition to an overall increase in food pantry usage during the pandemic, we find that, while certain socio-demographic groups historically vulnerable to food insecurity experienced the predicted uptick in insecurity during the pandemic, other socio-demographic disparities were attenuated. These somewhat disparate findings illustrate the complex relationship between disasters and food insecurity in an urban context, offering several avenues for future research., Supplementary Information: The online version contains supplementary material available at 10.1007/s12571-022-01336-2., Competing Interests: Ethics approvalThis research was supported by the Virginia G. Piper Charitable Trust. Piper Trust supports organizations that enrich health, well-being, and opportunity for the people of Maricopa County, Arizona. The conclusions, views, and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any supporting funders. The authors have no competing interests to declare that are relevant to the content of this article.Conflict of interestThe authors declared that they have no conflicts of interest., (© The Author(s) 2022.)

Of more than a thousand known cataclysmic variables (CVs), where a white dwarf is accreting from a hydrogen-rich star, only a dozen have orbital periods below 75 minutes 1-9 . One way to achieve these short periods requires the donor star to have undergone substantial nuclear evolution before interacting with the white dwarf 10-14 , and it is expected that these objects will transition to helium accretion. These transitional CVs have been proposed as progenitors of helium CVs 13-18 . However, no known transitional CV is expected to reach an orbital period short enough to account for most of the helium CV population, leaving the role of this evolutionary pathway unclear. Here we report observations of ZTF J1813+4251, a 51-minute-orbital-period, fully eclipsing binary system consisting of a star with a temperature comparable to that of the Sun but a density 100 times greater owing to its helium-rich composition, accreting onto a white dwarf. Phase-resolved spectra, multi-band light curves and the broadband spectral energy distribution allow us to obtain precise and robust constraints on the masses, radii and temperatures of both components. Evolutionary modelling shows that ZTF J1813+4251 is destined to become a helium CV binary, reaching an orbital period under 20 minutes, rendering ZTF J1813+4251 a previously missing link between helium CV binaries and hydrogen-rich CVs., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child's behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.

Over a dozen millisecond pulsars are ablating low-mass companions in close binary systems. In the original 'black widow', the eight-hour orbital period eclipsing pulsar PSR J1959+2048 (PSR B1957+20) 1 , high-energy emission originating from the pulsar 2 is irradiating and may eventually destroy 3 a low-mass companion. These systems are not only physical laboratories that reveal the interesting results of exposing a close companion star to the relativistic energy output of a pulsar, but are also believed to harbour some of the most massive neutron stars 4 , allowing for robust tests of the neutron star equation of state. Here we report observations of ZTF J1406+1222, a wide hierarchical triple hosting a 62-minute orbital period black widow candidate, the optical flux of which varies by a factor of more than ten. ZTF J1406+1222 pushes the boundaries of evolutionary models 5 , falling below the 80-minute minimum orbital period of hydrogen-rich systems. The wide tertiary companion is a rare low-metallicity cool subdwarf star, and the system has a Galactic halo orbit consistent with passing near the Galactic Centre, making it a probe of formation channels, neutron star kick physics 6 and binary evolution., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Food insecurity is an urgent crisis in the United States, with one in nine people lacking a consistent source of the food necessary for an active and healthy lifestyle. This crisis is particularly dire in Maricopa County, Arizona, where 1 in 5 children experience food insecurity, and >1 in 10 residents experience poverty. Mobile food pantries offer an additional resource to address food insecurity; however, there is minimal knowledge about how communities utilize these food distributors. Background: Research on the elderly (people >60 years) and immigrant populations shows that these populations are especially vulnerable to food insecurity. The risk these groups face is compounded in Maricopa County, the 15th largest county in the country with minimal public transit to extant resources. Mobile food pantries offer one solution to this issue, bringing groceries and other important items directly to communities. Methods: This study utilizes data from a food pantry called "Phoenix Rescue Mission" (PRM) on food insecure people's use of PRM's mobile and brick-and-mortar pantries, as well as census data. Using GIS mapping and a multinomial logistic regression model, this research identifies how different demographic groups engage with PRM's brick-and-mortar or mobile pantries. Results: Findings indicate that people aged 60-80 years and immigrant people of color are more likely to use both mobile and brick-and-mortar pantries. Conclusions: This research suggests that mobile pantries can reach the most food insecure populations and local nonprofits and governments can consider implementing mobile pantries to reach food insecure communities., Competing Interests: No competing financial interests exist., (© Lily K. Villa et al., 2022; Published by Mary Ann Liebert, Inc.)

The final fate of massive stars, and the nature of the compact remnants they leave behind (black holes and neutron stars), are open questions in astrophysics. Many massive stars are stripped of their outer hydrogen envelopes as they evolve. Such Wolf-Rayet stars 1 emit strong and rapidly expanding winds with speeds greater than 1,000 kilometres per second. A fraction of this population is also helium-depleted, with spectra dominated by highly ionized emission lines of carbon and oxygen (types WC/WO). Evidence indicates that the most commonly observed supernova explosions that lack hydrogen and helium (types Ib/Ic) cannot result from massive WC/WO stars 2,3 , leading some to suggest that most such stars collapse directly into black holes without a visible supernova explosion 4 . Here we report observations of SN 2019hgp, beginning about a day after the explosion. Its short rise time and rapid decline place it among an emerging population of rapidly evolving transients 5-8 . Spectroscopy reveals a rich set of emission lines indicating that the explosion occurred within a nebula composed of carbon, oxygen and neon. Narrow absorption features show that this material is expanding at high velocities (greater than 1,500 kilometres per second), requiring a compact progenitor. Our observations are consistent with an explosion of a massive WC/WO star, and suggest that massive Wolf-Rayet stars may be the progenitors of some rapidly evolving transients., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Exposure to early life stress (ELS) during childhood or prenatally increases the risk of future psychiatric disorders. The effect of stress exposure during the neonatal period is less well understood. In preterm infants, exposure to invasive procedures is associated with altered brain development and future stress responses suggesting that the neonatal period could be a key time for the programming of mental health. Previous studies suggest that ELS affects the hypothalamic epigenome, making it a good candidate to mediate these effects. In this study, we used a mouse model of early life stress (modified maternal separation; MMS). We hypothesised MMS would affect the hypothalamic transcriptome and DNA methylome, and impact on adult behaviour. MMS involved repeated stimulation of pups for 1.5 h/day, whilst separated from their mother, from postnatal day (P) 4-6. 3'mRNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing were performed on hypothalamic tissue at P6. Behaviour was assessed with the elevated plus, open field mazes and in-cage monitoring at 3-4 months of age. MMS was only associated with subtle changes in gene expression, but there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. ELS has marked effects on DNA methylation in the hypothalamus in early life and results in stress-specific hyperactivity in young adulthood. These results have implications for the understanding of ELS-mediated effects on brain development.

Glucocorticoids (GC) are used in paediatric practice for a broad range of conditions and all paediatricians will prescribe GC, in some form, during their career. A wide variety of GC formulations, doses and administration routes are used for periods of time ranging from days to years. Exposure to exogenous GC can result in hypothalamic-pituitary-adrenal axis suppression-otherwise known as adrenal suppression (AS). Patients with AS may be well most of the time but if GC therapy is reduced or stopped or if additional endogenous GC cannot be generated during illness, then an absolute or relative lack of GC can result in severe illness or death. Here, we highlight the relevance of AS to all paediatricians by providing an overview of the background and discussing the presentation and approaches to the management of this clinical entity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Neonatal encephalopathy due to hypoxia-ischemia is associated with adverse neurodevelopmental effects. The involvement of branched chain amino acids (BCAAs) in this is largely unexplored. Transport of BCAAs at the plasma membrane is facilitated by SLC7A5/SLC3A2, which increase with hypoxia. We hypothesized that hypoxia would alter BCAA transport and metabolism in the neonatal brain. We investigated this using an organotypic forebrain slice culture model with, the SLC7A5/SLC3A2 inhibitor, 2-Amino-2-norbornanecarboxylic acid (BCH) under normoxic or hypoxic conditions. We subsequently analysed the metabolome and candidate gene expression. Hypoxia was associated with increased expression of SLC7A5 and SLC3A2 and an increased tissue abundance of BCAAs. Incubation of slices with 13 C-leucine confirmed that this was due to increased cellular uptake. BCH had little effect on metabolite abundance under normoxic or hypoxic conditions. This suggests hypoxia drives increased cellular uptake of BCAAs in the neonatal mouse forebrain, and membrane mediated transport through SLC7A5 and SLC3A2 is not essential for this process. This indicates mechanisms exist to generate the compounds required to maintain essential metabolism in the absence of external nutrient supply. Moreover, excess BCAAs have been associated with developmental delay, providing an unexplored mechanism of hypoxia mediated pathogenesis in the developing forebrain.

This protocol describes the production of hepatocyte-like cells (HLCs) from human pluripotent stem cells and how to induce hepatic steatosis, a condition characterized by intracellular lipid accumulation. Following differentiation to an HLC phenotype, intracellular lipid accumulation is induced with a steatosis induction cocktail, allowing the user to examine the cellular processes that underpin hepatic steatosis. Furthermore, the renewable nature of our system, on a defined genetic background, permits in-depth mechanistic analysis, which may facilitate therapeutic target identification in the future. For complete details on the use and execution of this protocol, please refer to Sinton et al. (2021)., Competing Interests: Professor David Hay is a founder, director, and shareholder in Stemnovate Limited., (© 2021 The Author(s).)

Introduction: Preterm birth (PTB) is closely associated with atypical cerebral cortical development and cognitive impairment. Early exposure to extrauterine life often results in atypical environmental and biological experiences that co-occur, including early life stress (ELS) and systemic inflammation. Understanding how these experiences interact to shape cortical development is an essential prerequisite to developing therapeutic interventions that will work in the complex postnatal environment of the preterm infant. Here, we studied the effects of a murine model of infection and ELS on the neonatal cortex transcriptome., Methods: We used a mouse model of infection (1 ​mg/kg LPS at postnatal day (P)3) +/- ELS (modified maternal separation; MMS on days P4-P6) at timepoints with neurodevelopmental relevance to PTB. We used 4 groups: control, LPS, MMS and LPS ​+ ​MMS. Cortices were dissected at P6 for 3'RNA sequencing., Results: LPS exposure resulted in reduced weight gain and increased expression of inflammation-associated genes in the brain. More genes were differentially expressed following LPS (15) and MMS (29) than with LPS ​+ ​MMS (8). There was significant overlap between the LPS and MMS datasets, particularly amongst upregulated genes, and when comparing LPS and MMS datasets with LPS ​+ ​MMS. Gene Ontology terms related to the extracellular matrix and cytokine response were enriched following MMS, but not following LPS or LPS ​+ ​MMS. 26 Reactome pathways were enriched in the LPS group, none of which were enriched in the LPS ​+ ​MMS group. Finally, a rank-rank hypergeometric overlap test showed similarities, particularly in upregulated genes, in the LPS and MMS conditions, indicating shared mechanisms., Conclusion: LPS and MMS interact to modify the cortical transcriptome in the neonatal period. This has important implications for understanding the neural basis of atypical cortical development associated with early exposure to extrauterine life., Competing Interests: None., (© 2021 The Authors.)

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis. Following induction of macrovesicular steatosis in hepatocyte-like cells using lactate, pyruvate, and octanoate (LPO), respirometry and transcriptomic analyses revealed compromised electron transport chain activity. 13 C isotopic tracing studies revealed enhanced TCA cycle anaplerosis, with concomitant development of a compensatory purine nucleotide cycle shunt leading to excess generation of fumarate. This model of hepatic steatosis is reproducible, scalable, and overcomes the challenges of studying mitochondrial metabolism in currently available models., Competing Interests: Professor David Hay is a founder, shareholder, and director in Stemnovate Limited. All other authors declare that they have no competing interests., (© 2020 The Author(s).)

An optimal early life environment is crucial for ensuring ideal neurodevelopmental outcomes. Brain development consists of a finely tuned series of spatially and temporally constrained events, which may be affected by exposure to a sub-optimal intra-uterine environment. Evidence suggests brain development may be particularly vulnerable to factors such as maternal nutrition, infection and stress during pregnancy. In this review, we discuss how maternal factors such as these can affect brain development and outcome in offspring, and we also identify evidence which suggests that the outcome can, in many cases, be stratified by socio-economic status (SES), with individuals in lower brackets typically having a worse outcome. We consider the relevant epidemiological evidence and draw parallels to mechanisms suggested by preclinical work where appropriate. We also discuss possible transgenerational effects of these maternal factors and the potential mechanisms involved. We conclude that modifiable factors such as maternal nutrition, infection and stress are important contributors to atypical brain development and that SES also likely has a key role., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites with P <1×10 -5 . In silico replication in the CHARGE consortium of 17 010 individuals validated 16 of these CpG sites. Out of the 16 CpG sites, 13 showed novel association with BP. Conversely, out of the 126 CpG sites identified as being associated ( P <1×10 -7 ) with BP in the CHARGE consortium, 21 were replicated in the current study. Methylation levels of all the 34 CpG sites that were cross-validated by the current study and the CHARGE consortium were heritable and 6 showed association with gene expression. Furthermore, 9 CpG sites also showed association with BP with P <0.05 and consistent direction of the effect in the meta-analysis of the Finnish Twin Cohort (199 twin pairs and 4 singletons; 61% monozygous) and the Netherlands Twin Register (266 twin pairs and 62 singletons; 84% monozygous). Bivariate quantitative genetic modeling of the twin data showed that a majority of the phenotypic correlations between methylation levels of these CpG sites and BP could be explained by shared unique environmental rather than genetic factors, with 100% of the correlations of systolic BP with cg19693031 ( TXNIP ) and cg00716257 ( JDP2 ) determined by environmental effects acting on both systolic BP and methylation levels.

We report the first plausible optical electromagnetic counterpart to a (candidate) binary black hole merger. Detected by the Zwicky Transient Facility, the electromagnetic flare is consistent with expectations for a kicked binary black hole merger in the accretion disk of an active galactic nucleus [B. McKernan, K. E. S. Ford, I. Bartos et al., Astrophys. J. Lett. 884, L50 (2019)AJLEEY2041-821310.3847/2041-8213/ab4886] and is unlikely [

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass, yet unlike white or brown adipose tissues (WAT or BAT) its metabolic functions remain unclear. Herein, we address this critical gap in knowledge. Our transcriptomic analyses revealed that BMAT is distinct from WAT and BAT, with altered glucose metabolism and decreased insulin responsiveness. We therefore tested these functions in mice and humans using positron emission tomography-computed tomography (PET/CT) with 18 F-fluorodeoxyglucose. This revealed that BMAT resists insulin- and cold-stimulated glucose uptake, while further in vivo studies showed that, compared to WAT, BMAT resists insulin-stimulated Akt phosphorylation. Thus, BMAT is functionally distinct from WAT and BAT. However, in humans basal glucose uptake in BMAT is greater than in axial bones or subcutaneous WAT and can be greater than that in skeletal muscle, underscoring the potential of BMAT to influence systemic glucose homeostasis. These PET/CT studies characterise BMAT function in vivo, establish new methods for BMAT analysis, and identify BMAT as a distinct, major adipose tissue subtype.

MRI has enhanced our capacity to understand variations in brain structure and function conferred by the genome. We identified 60 studies that report associations between DNA methylation (DNAm) and human brain structure/function. Forty-three studies measured candidate loci DNAm; seventeen measured epigenome-wide DNAm. MRI features included region-of-interest and whole-brain structural, diffusion and functional imaging features. The studies report DNAm-MRI associations for: neurodevelopment and neurodevelopmental disorders; major depression and suicidality; alcohol use disorder; schizophrenia and psychosis; ageing, stroke, ataxia and neurodegeneration; post-traumatic stress disorder; and socio-emotional processing. Consistency between MRI features and differential DNAm is modest. Sources of bias: variable inclusion of comparator groups; different surrogate tissues used; variation in DNAm measurement methods; lack of control for genotype and cell-type composition; and variations in image processing. Knowledge of MRI features associated with differential DNAm may improve understanding of the role of DNAm in brain health and disease, but caution is required because conventions for linking DNAm and MRI data are not established, and clinical and methodological heterogeneity in existing literature is substantial., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Preterm birth is closely associated with altered brain development and is a leading cause of neurodevelopmental, cognitive and behavioural impairments across the life course. We aimed to investigate neuroanatomic variation and adverse outcomes associated with preterm birth by studying a cohort of preterm infants and controls born at term using brain MRI linked to biosamples and clinical, environmental and neuropsychological data., Methods and Analysis: Theirworld Edinburgh Birth Cohort is a prospective longitudinal cohort study at the University of Edinburgh. We plan to recruit 300 infants born at <33 weeks of gestational age (GA) and 100 healthy control infants born after 37 weeks of GA. Multiple domains are assessed: maternal and infant clinical and demographic information; placental histology; immunoregulatory and trophic proteins in umbilical cord and neonatal blood; brain macrostructure and microstructure from structural and diffusion MRI (dMRI); DNA methylation; hypothalamic-pituitary-adrenal axis activity; social cognition, attention and processing speed from eye tracking during infancy and childhood; neurodevelopment; gut and respiratory microbiota; susceptibility to viral infections; and participant experience. Main analyses include creation of novel methods for extracting information from neonatal structural and dMRI, regression analyses of predictors of brain maldevelopment and neurocognitive outcome associated with preterm birth, and determination of the quantitative predictive performance of MRI and other early life factors for childhood outcome., Ethics and Dissemination: Ethical approval has been obtained from the National Research Ethics Service (NRES), South East Scotland Research Ethics Committee (NRES numbers 11/55/0061 and 13/SS/0143 (phase I) and 16/SS/0154 (phase II)), and NHS Lothian Research and Development (2016/0255). Results are disseminated through open access journals, scientific meetings, social media, newsletters anda study website (www.tebc.ed.ac.uk), and we engage with the University of Edinburgh public relations and media office to ensure maximum publicity and benefit., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Non-alcoholic fatty liver disease (NAFLD) is now the commonest cause of liver disease in developed countries affecting 25-33% of the general population and up to 75% of those with obesity. Recent data suggest that alterations in DNA methylation may be related to NAFLD pathogenesis and progression and we have previously shown that dynamic changes in the cell lineage identifier 5-hydroxymethylcytosine (5hmC) may be important in the pathogenesis of liver disease. We used a model of diet-induced obesity, maintaining male mice on a high-fat diet (HFD) to generate hepatic steatosis. We profiled hepatic gene expression, global and locus-specific 5hmC and additionally investigated the effects of weight loss on the phenotype. HFD led to increased weight gain, fasting hyperglycaemia, glucose intolerance, insulin resistance and hepatic periportal macrovesicular steatosis. Diet-induced hepatic steatosis associated with reversible 5hmC changes at a discrete number of functionally important genes. We propose that 5hmC profiles are a useful signature of gene transcription and a marker of cell state in NAFLD and suggest that 5hmC profiles hold potential as a biomarker of abnormal liver physiology.

Impaired social function is a core feature of many psychiatric illnesses. Adverse experiences during childhood increase risk for mental illness, however it is currently unclear whether stress early in life plays a direct role in the development of social difficulties. Using a rat model of pre-pubertal stress (PPS), we investigated effects on social behaviour, oxytocin and arginine vasopressin (AVP) in the periphery (plasma) and centrally in the paraventricular and supraoptic hypothalamic nuclei. We also explored social performance and AVP expression (plasma) in participants with borderline personality disorder (BPD) who experienced a high incidence of childhood stress. Social behaviour was impaired and AVP expression increased in animals experiencing PPS and participants with BPD. Behavioural deficits in animals were rescued through administration of the AVPR1a antagonist Relcovaptan (SR49059). AVP levels and recognition of negative emotions were significantly correlated in BPD participants only. In conclusion, early life stress plays a role in the precipitation of social dysfunction, and AVP mediates at least part of this effect.

Background: The prevalence of sleep problems among pregnant women is over 50%, and daytime sleepiness is among the most common sleep problems. Previous studies have associated antenatal sleep problems with adverse maternal health and neonatal outcomes, but the consequences of antenatal sleep problems and particularly daytime sleepiness on child psychological development have not been assessed prospectively., Methods: In this prospective cohort study including 111 mother-child dyads, we examined the associations of maternal daytime sleepiness during pregnancy, assessed at 17 and 28 weeks of gestation using the Epworth Sleepiness Scale, with child neuropsychiatric problems and neuropsychological development, assessed with mother-rated questionnaires and individually administered neuropsychological tests, at child age 2.6-5.7 years (mean = 4.3 years)., Results: Independently of sociodemographic and perinatal covariates and maternal depressive and anxiety symptoms during and/or after pregnancy, maternal antenatal daytime sleepiness was associated with increased total [unstandardized regression coefficient (B) = 0.25 standard deviation (s.d.) units; 95% confidence interval (CI) 0.01-0.48] and internalizing (B = 0.25 s.d.s: 95% CI 0.01-0.49) psychiatric problems and ADHD symptoms (B = 0.27 s.d.s: 95% CI 0.04-0.50) in children, and with poorer executive function, particularly in the areas of attention, working memory and inhibitory control (B = -0.39 s.d.s: 95% CI -0.69 to -0.10)., Conclusions: Maternal antenatal daytime sleepiness carries adverse consequences for offspring psychological development. The assessment of sleep problems may be an important addition to standard antenatal care.

Non-alcoholic fatty liver disease (NAFLD) is estimated to affect 24% of the global adult population. NAFLD is a major risk factor for the development of cirrhosis and hepatocellular carcinoma, as well as being strongly associated with type 2 diabetes and cardiovascular disease. It has been proposed that up to 88% of obese adults have NAFLD, and with global obesity rates increasing, this disease is set to become even more prevalent. Despite intense research in this field, the molecular processes underlying the pathology of NAFLD remain poorly understood. Hepatic intracellular lipid accumulation may lead to dysregulated tricarboxylic acid (TCA) cycle activity and associated alterations in metabolite levels. The TCA cycle metabolites alpha-ketoglutarate, succinate and fumarate are allosteric regulators of the alpha-ketoglutarate-dependent dioxygenase family of enzymes. The enzymes within this family have multiple targets, including DNA and chromatin, and thus may be capable of modulating gene transcription in response to intracellular lipid accumulation through alteration of the epigenome. In this review, we discuss what is currently understood in the field and suggest areas for future research which may lead to the development of novel preventative or therapeutic interventions for NAFLD.

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities., Competing Interests: Conflict of interest statement: E.B.B. receives a research grant from Böhringer-Ingelheim to develop cellular and animal models of enhanced FKBP5 function. She is also coinventor on the following patent application: “FKBP5: a novel target for antidepressant therapy” (European Patent no. EP 1687443 B1)., (Copyright © 2019 the Author(s). Published by PNAS.)

Numerous studies in humans and in animal models have demonstrated that exposure to adverse environmental conditions in early life results in long-term structural and functional changes in an organism, increasing the risk of cardiometabolic, neurobehavioural and reproductive disorders in later life. Such effects are not limited to the first generation offspring but may be transmitted to a second or a number of subsequent generations, through non-genomic mechanisms. While the transmission of 'programmed' effects through the maternal line could occur as a consequence of multiple influences, for example, altered maternal physiology, the inheritance of effects through the male line is more difficult to explain and there is much interest in a potential role for transgenerational epigenetic inheritance. In this review, we will discuss the mechanisms by which induced effects may be transmitted through the paternal lineage, with a particular focus on the role of epigenetic inheritance. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

Preterm birth is a significant public health problem worldwide, leading to substantial mortality in the newborn period, and a considerable burden of complications longer term, for affected infants and their carers. The fact that it is so common, and rates vary between different populations, raising the question of whether in some circumstances it might be an adaptive trait. In this review, we outline some of the evolutionary explanations put forward for preterm birth. We specifically address the hypothesis of the predictive adaptive response, setting it in the context of the Developmental Origins of Health and Disease, and explore the predictions that this hypothesis makes for the potential causes and consequences of preterm birth. We describe how preterm birth can be triggered by a range of adverse environmental factors, including nutrition, stress and relative socioeconomic status. Examining the literature for any associated longer-term phenotypic changes, we find no strong evidence for a marked temporal shift in the reproductive life-history trajectory, but more persuasive evidence for a re-programming of the cardiovascular and endocrine system, and a range of effects on neurodevelopment. Distinguishing between preterm birth as a predictive, rather than immediate adaptive response will depend on the demonstration of a positive effect of these alterations in developmental trajectories on reproductive fitness. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.

Epigenetic regulation of gene expression is critical for normal development. Dysregulation of the epigenome can lead to the development and progression of a number of diseases relevant to paediatricians, including disorders of genomic imprinting and malignancies. It has long been recognised that early life events have implications for future disease risk, and epigenetic modifications may play a role in this, although further high-quality research is needed to better understand the underlying mechanisms. Research in the field of epigenetics will contribute to a greater understanding of growth, development and disease; however, paediatricians need to be able to interpret such research critically, in order to use the potential advances brought about through epigenetic studies while appreciating their limitations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Graves' disease (Graves' hyperthyroidism) is a challenging condition for the young person and their family. The excess thyroid hormone generated by autoimmune stimulation of the thyroid stimulating hormone receptor on the thyroid gland can have a profound impact on well-being. Managing the young person with Graves' hyperthyroidism is more difficult than in older people because the side effects of conventional treatment are more significant in this age group and because the disease tends not to resolve spontaneously in the short to medium term. New immunomodulatory agents are available and the anti-B cell monoclonal antibody rituximab is of particular interest because it targets cells that manufacture the antibodies that stimulate the thyroid gland in Graves'., Methods and Analysis: The trial aims to establish whether the combination of a single dose of rituximab (500 mg) and a 12-month course of antithyroid drug (usually carbimazole) can result in a meaningful increase in the proportion of patients in remission at 2 years, the primary endpoint. A single-stage, phase II A'Hern design is used. 27 patients aged 12-20 years with newly presenting Graves' hyperthyroidism will be recruited. Markers of immune function, including lymphocyte numbers and antibody levels (total and specific), will be collected regularly throughout the trial., Discussion: The trial will determine whether the immunomodulatory medication, rituximab, will facilitate remission above and beyond that observed with antithyroid drug alone. A meaningful increase in the expected proportion of young patients entering remission when managed according to the trial protocol will justify consideration of a phase III trial.Ethics and dissemination The trial has received a favourable ethical opinion (North East - Tyne and Wear South Research Ethics Committee, reference 16/NE/0253, EudraCT number 2016-000209-35). The results of this trial will be distributed at international endocrine meetings, in the peer-reviewed literature and via patient support groups., Trial Registration Number: ISRCTN20381716., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Preterm Birth (PTB) accounts for approximately 11% of all births worldwide each year and is a profound physiological stressor in early life. The burden of neuropsychiatric and developmental impairment is high, with severity and prevalence correlated with gestational age at delivery. PTB is a major risk factor for the development of cerebral palsy, lower educational attainment and deficits in cognitive functioning, and individuals born preterm have higher rates of schizophrenia, autistic spectrum disorder and attention deficit/hyperactivity disorder. Factors such as gestational age at birth, systemic inflammation, respiratory morbidity, sub-optimal nutrition, and genetic vulnerability are associated with poor outcome after preterm birth, but the mechanisms linking these factors to adverse long term outcome are poorly understood. One potential mechanism linking PTB with neurodevelopmental effects is changes in the epigenome. Epigenetic processes can be defined as those leading to altered gene expression in the absence of a change in the underlying DNA sequence and include DNA methylation/hydroxymethylation and histone modifications. Such epigenetic modifications may be susceptible to environmental stimuli, and changes may persist long after the stimulus has ceased, providing a mechanism to explain the long-term consequences of acute exposures in early life. Many factors such as inflammation, fluctuating oxygenation and excitotoxicity which are known factors in PTB related brain injury, have also been implicated in epigenetic dysfunction. In this review, we will discuss the potential role of epigenetic dysregulation in mediating the effects of PTB on neurodevelopmental outcome, with specific emphasis on DNA methylation and the α-ketoglutarate dependent dioxygenase family of enzymes.

Purpose: Measures of white matter (WM) microstructure inferred from diffusion magnetic resonance imaging (dMRI) are useful for studying brain development. There is uncertainty about agreement between FA and MD values obtained from region-of-interest (ROI) versus whole tract approaches. We investigated agreement between dMRI measures using ROI and Probabilistic Neighbourhood Tractography (PNT) in genu of corpus callosum (gCC) and corticospinal tracts (CST)., Materials and Methods: 81 neonates underwent 64 direction DTI at term equivalent age. FA and MD values were extracted from a 8 mm 3 ROI placed within the gCC, right and left posterior limbs of internal capsule. PNT was used to segment gCC and CSTs to calculate whole tract-averaged FA and MD. Agreement between values obtained by each method was compared using Bland-Altman statistics and Pearson's correlation., Results: Across the 3 tracts the mean difference in FA measured by PNT and ROI ranged between 0.13 and 0.17, and the 95% limits of agreement did not include the possibility of no difference. For MD, the mean difference in values obtained from PNT and ROI ranged between 0.101 and 0.184 mm 2 /s × 10 -3  mm 2 /s: the mean difference in gCC was 0.101 × 10 -3  mm 2 /s with 95% limits of agreement that included the possibility of no difference, but there was significant disagreement in MD values measured in the CSTs., Conclusion: Agreement between dMRI measures of neonatal WM microstructure calculated from ROI and whole tract averaged methods is weak. ROI approaches may not provide sufficient representation of tract microstructure at the level of neural systems in newborns., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers., Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood., Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts., Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire., Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression., Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An in vitro NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear. Additionally, the epigenetic mark 5-hydroxymethylcytosine (5hmC), a cell lineage identifier, is rapidly lost during cell culture, alongside expression of the Ten-eleven-translocation ( TET ) methylcytosine dioxygenase enzymes, restricting meaningful epigenetic analysis. Hepatocyte-like cells (HLCs) derived from human embryonic stem cells can provide a non-neoplastic, renewable model for liver research. Here, we have developed a model of NAFLD using HLCs exposed to lactate, pyruvate and octanoic acid (LPO) that bear all the hallmarks, including 5hmC profiles, of liver functionality. We exposed HLCs to LPO for 48 h to induce lipid accumulation. We characterized the transcriptome using RNA-seq, the metabolome using ultra-performance liquid chromatography-mass spectrometry and the epigenome using 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) sequencing. LPO exposure induced an NAFLD phenotype in HLCs with transcriptional and metabolomic dysregulation consistent with those present in human NAFLD. HLCs maintain expression of the TET enzymes and have a liver-like epigenome. LPO exposure-induced 5hmC enrichment at lipid synthesis and transport genes. HLCs treated with LPO recapitulate the transcriptional and metabolic dysregulation seen in NAFLD and additionally retain TET expression and 5hmC. This in vitro model of NAFLD will be useful for future mechanistic and therapeutic studies.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'., (© 2018 The Authors.)

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18 fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133 xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)