Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice.

Glucocorticoids are potent and widely used medicines but often cause metabolic side effects. A murine model of corticosterone treatment resulted in increased hypothalamic expression of the melanocortin antagonist AgRP in parallel with obesity and hyperglycemia. We investigated how these adverse effects develop over time, with particular emphasis on hypothalamic involvement. Wild-type and Agrp-/- male mice were treated with corticosterone for 3 weeks. Phenotypic, biochemical, protein, and mRNA analyses were undertaken on central and peripheral tissues, including white and brown adipose tissue, liver, and muscle, to determine the metabolic consequences. Corticosterone treatment induced hyperphagia within 1 day in wild-type mice, which persisted for 3 weeks. Despite this early increase in food intake, the body weight only started to increase after 10 days. Hyperinsulinemia occurred at day 1. Also, although after 2 days, alterations were present in the genes often associated with insulin resistance in several peripheral tissues, hyperglycemia only developed at 3 weeks. Throughout, sustained elevation in hypothalamic Agrp expression was present. Mice with Agrp deleted [using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, Agrp-/-] were partially protected against corticosterone-induced hyperphagia. However, Agrp-/- mice still had corticosterone-induced increases in body weight and adiposity similar to those of the Agrp+/+ mice. Loss of Agrp did not diminish corticosterone-induced hyperinsulinemia or correct changes in hepatic gluconeogenic genes. Chronic glucocorticoid treatment in mice mimics many of the metabolic side effects seen in patients and leads to a robust increase in Agrp. However, AgRP does not appear to be responsible for most of the glucocorticoid-induced adverse metabolic effects.MR

Menopause induces changes to the stratum corneum ceramide profile, which are prevented by hormone replacement therapy

Abstract The menopause can lead to epidermal changes that are alleviated by hormone replacement therapy (HRT). We hypothesise that these changes could relate to altered ceramide production, and that oestrogen may have a role in keratinocyte ceramide metabolism. White Caucasian women were recruited into three groups: pre-menopausal (n = 7), post-menopausal (n = 11) and post-menopausal taking HRT (n = 10). Blood samples were assessed for hormone levels, transepidermal water loss was measured to assess skin barrier function, and stratum corneum lipids were sampled from photoprotected buttock skin. Ceramides and sphingomyelins were analysed by ultraperformance liquid chromatography with electrospray ionisation and tandem mass spectrometry. Post-menopausal stratum corneum contained lower levels of ceramides, with shorter average length; changes that were not evident in the HRT group. Serum oestradiol correlated with ceramide abundance and length. Ceramides had shorter sphingoid bases, indicating altered de novo ceramide biosynthesis. Additionally, post-menopausal women had higher sphingomyelin levels, suggesting a possible effect on the hydrolysis pathway. Treatment of primary human keratinocytes with oestradiol (10 nM) increased production of CER[NS] and CER[NDS] ceramides, confirming an effect of oestrogen on cutaneous ceramide metabolism. Taken together, these data show perturbed stratum corneum lipids post-menopause, and a role for oestrogen in ceramide production

Rescaling Egocentric Vision:Collection Pipeline and Challenges for EPIC-KITCHENS-100

This paper introduces the pipeline to extend the largest dataset in egocentric vision, EPIC-KITCHENS. The effort culminates in EPIC-KITCHENS-100, a collection of 100 hours, 20M frames, 90K actions in 700 variable-length videos, capturing long-term unscripted activities in 45 environments, using head-mounted cameras. Compared to its previous version (Damen in Scaling egocentric vision: ECCV, 2018), EPIC-KITCHENS-100 has been annotated using a novel pipeline that allows denser (54% more actions per minute) and more complete annotations of fine-grained actions (+128% more action segments). This collection enables new challenges such as action detection and evaluating the “test of time”—i.e. whether models trained on data collected in 2018 can generalise to new footage collected two years later. The dataset is aligned with 6 challenges: action recognition (full and weak supervision), action detection, action anticipation, cross-modal retrieval (from captions), as well as unsupervised domain adaptation for action recognition. For each challenge, we define the task, provide baselines and evaluation metrics.Published versionResearch at Bristol is supported by Engineering and Physical Sciences Research Council (EPSRC) Doctoral Training Program (DTP), EPSRC Fellowship UMPIRE (EP/T004991/1). Research at Catania is sponsored by Piano della Ricerca 2016-2018 linea di Intervento 2 of DMI, by MISE - PON I&C 2014-2020, ENIGMA project (CUP: B61B19000520008) and by MIUR AIM - Attrazione e Mobilita Internazionale Linea 1 - AIM1893589 - CUP E64118002540007

Observation of a topological insulator Dirac cone reshaped by non-magnetic impurity resonance

The massless Dirac electrons found at topological insulator surfaces are thought to be influenced very little by weak, non-magnetic disorder. However, a resonance effect of strongly perturbing non-magnetic impurities has been theoretically predicted to change the dispersion and physical nature of low-energy quasiparticles, resulting in unique particle-like states that lack microscopic translational symmetry. Here we report the direct observation of impurities reshaping the surface Dirac cone of the model three-dimensional topological insulator bismuth selenide. A pronounced kink-like dispersion feature is observed in disorder-enriched samples, and found to be closely associated with the anomaly caused by impurity resonance in the surface state density of states, as observed by dichroic angle-resolved photoemission spectroscopy. The experimental observation of these features, which closely resemble theoretical predictions, has significant implications for the properties of topological Dirac cones in applied scenarios that commonly feature point-defect disorder at surfaces or interfaces. Topological insulators - influence of surface impurities: The electronic properties of topological insulators are robust against perturbations, including the presence of non-magnetic impurities. However, surface impurities can give rise to resonant states near the Dirac point, and if their density becomes sufficiently high it is predicted that they can substantially modify the dispersion of the Dirac cone and develop a collective behaviour that results in the formation of particle-like states that lack microscopic translational symmetry. L. Andrew Wray at Purdue University and at the New York University Shanghai, and colleagues, used angle-resolved photoemission spectroscopy to experimentally observe the reshaping of the surface Dirac cone in a defect-rich sample of the topological insulator Bi2Se3. These results indicate that surface impurities can provide a useful handle to control the properties of topological insulators

Chronic glucocorticoid treatment induces hepatic lipid accumulation and hyperinsulinaemia in part through actions on AgRP neurons

Funder: Mawer-Fitzgerald Endowment FundAbstract: Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects. These may occur through direct actions of GCs on peripheral organs, but could also be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Therefore, the aim of this study was to examine the metabolic effects of chronic treatment with the GC corticosterone (Cort, 75 μg/ml in drinking water) in mice lacking the glucocorticoid receptor (GR) on AgRP neurons. Female AgRP-GR KO mice had delayed onset of Cort-induced hyperphagia. However, AgRP-GR KO had little impact on the increased body weight or adiposity seen with 3 weeks Cort treatment. Cort caused hepatic steatosis in control mice, but in Cort treated female AgRP-GR KO mice there was a 25% reduction in liver lipid content and lower plasma triglycerides. Additionally, Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test. In conclusion, these data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment

Chronic glucocorticoid treatment induces hepatic lipid accumulation and hyperinsulinaemia in part through actions on AgRP neurons

From Springer Nature via Jisc Publications RouterHistory: received 2021-01-11, accepted 2021-06-04, registration 2021-06-24, pub-electronic 2021-07-02, online 2021-07-02, collection 2021-12Publication status: PublishedFunder: Mawer-Fitzgerald Endowment FundFunder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265; Grant(s): MRC_MC_UU_12012.1Abstract: Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects. These may occur through direct actions of GCs on peripheral organs, but could also be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Therefore, the aim of this study was to examine the metabolic effects of chronic treatment with the GC corticosterone (Cort, 75 μg/ml in drinking water) in mice lacking the glucocorticoid receptor (GR) on AgRP neurons. Female AgRP-GR KO mice had delayed onset of Cort-induced hyperphagia. However, AgRP-GR KO had little impact on the increased body weight or adiposity seen with 3 weeks Cort treatment. Cort caused hepatic steatosis in control mice, but in Cort treated female AgRP-GR KO mice there was a 25% reduction in liver lipid content and lower plasma triglycerides. Additionally, Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test. In conclusion, these data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form

Genotype effects contribute to variation in longitudinal methylome patterns in older people

Background: DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals. Methods: We performed a longitudinal analysis to quantify the variation in the rate of change of DNA methylation between individuals using whole blood DNA methylation array profiles collected at 2-4 time points (N = 2894) in 954 individuals (67-90 years). Results: After stringent quality control, we identified 1507 DNA methylation CpG sites (rsCpGs) with statistically significant variation in the rate of change (random slope) of DNA methylation among individuals in a mixed linear model analysis. Genes in the vicinity of these rsCpGs were found to be enriched in Homeobox transcription factors and the Wnt signalling pathway, both of which are related to ageing processes. Furthermore, we investigated the SNP effect on the random slope. We found that 4 out of 1507 rsCpGs had one significant (P < 5 × 10/1507) SNP effect and 343 rsCpGs had at least one SNP effect (436 SNP-probe pairs) reaching genome-wide significance (P < 5 × 10). Ninety-five percent of the significant (P < 5 × 10) SNPs are on different chromosomes from their corresponding probes. Conclusions: We identified CpG sites that have variability in the rate of change of DNA methylation between individuals, and our results suggest a genetic basis of this variation. Genes around these CpG sites have been reported to be involved in the ageing process

Genetic stratification of depression in UK Biobank

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup

Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice.

Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However, the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake, and adiposity. As expected, Cort increased plasma Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-induced leucine zipper (Tsc22d3) mRNA increased, which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy, or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances