Sex differences in metabolic and adipose tissue responses to juvenile-onset obesity in sheep

Sex is a major factor determining adipose tissue distribution and the subsequent adverse effects of obesity-related disease including type 2 diabetes. The role of gender on juvenile obesity and the accompanying metabolic and inflammatory responses is not well established. Using an ovine model of juvenile onset obesity induced by reduced physical activity, we examined the effect of gender on metabolic, circulatory, and related inflammatory and energy-sensing profiles of the major adipose tissue depots. Despite a similar increase in fat mass with obesity between genders, males demonstrated a higher storage capacity of lipids within perirenal-abdominal adipocytes and exhibited raised insulin. In contrast, obese females became hypercortisolemic, a response that was positively correlated with central fat mass. Analysis of gene expression in perirenal-abdominal adipose tissue demonstrated the stimulation of inflammatory markers in males, but not females, with obesity. Obese females displayed increased expression of genes involved in the glucocorticoid axis and energy sensing in perirenal-abdominal, but not omental, adipose tissue, indicating a depot-specific mechanism that may be protective from the adverse effects of metabolic dysfunction and inflammation. In conclusion, young males are at a greater risk than females to the onset of comorbidities associated with juvenile-onset obesity. These sex-specific differences in cortisol and adipose tissue could explain the earlier onset of the metabolic-related diseases in males compared with females after obesity

Enhanced light extraction from InGaN/GaN quantum wells with silver gratings

We demonstrate that an extraction enhancement by a factor of 2.8 can be obtained for a GaN quantum well structure using metallic nanostructures, compared to a flat semiconductor. The InGaN/GaN quantum well is inserted into a dielectric waveguide, naturally formed in the structure, and a silver grating is deposited on the surface and covered with a polymer film. The polymer layer greatly improves the extraction compared to a single metallic grating. The comparison of the experiments with simulations gives strong indications on the key role of weakly guided modes in the polymer layer diffracted by the grating.Peer reviewe

Early growth response gene-2 (Egr-2) regulates the development of B and T cells

The study was supported by Arthritis Research UK. Copyright @ 2011 Li et al.BACKGROUND: Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been shown that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development. METHODS AND FINDINGS: The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2+ lymphocytes resulted in a severe reduction of CD4+CD8+ (DP) cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP) T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow. CONCLUSIONS: Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells.This article is provided by the Brunel Open Access publishing fund

Gene variant effects across sodium channelopathies predict function and guide precision therapy

Pathogenic variants in the voltage-gated sodium channel gene family (SCNs) lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function, but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterised in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. 35 out of 38 of those pairs resulted in similar functional consequences indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% CI = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non conserved domains (odds ratio = 18.6; 95% CI = 10.9 to 34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function (LoF) variants, whereas inactivation sites were associated with gain-of-function (GoF; odds ratio = 42.1, 95% CI = 14.5 to 122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first GoF versus LoF topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org)

Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring

Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity

Maternal body weight and gestational diabetes differentially influence placental and pregnancy outcomes

Context: Maternal obesity and gestational diabetes mellitus (GDM) can both contribute to adverse neonatal outcomes. The extent to which this may be mediated by differences in placental metabolism and nutrient transport remains to be determined. Objective: Our objective was to examine whether raised maternal body mass index (BMI) and/or GDM contributed to a resetting of the expression of genes within the placenta that are involved in energy sensing, oxidative stress, inflammation, and metabolic pathways. Methods: Pregnant women from Spain were recruited as part of the “Study of Maternal Nutrition and Genetics on the Foetal Adiposity Programming” survey at the first antenatal visit (12–20 weeks of gestation) and stratified according to prepregnancy BMI and the incidence of GDM. At delivery, placenta and cord blood were sampled and newborn anthropometry measured. Results: Obese women with GDM had higher estimated fetal weight at 34 gestational weeks and a greater risk of preterm deliveries and cesarean section. Birth weight was unaffected by BMI or GDM; however, women who were obese with normal glucose tolerance had increased placental weight and higher plasma glucose and leptin at term. Gene expression for markers of placental energy sensing and oxidative stress, were primarily affected by maternal obesity as mTOR was reduced, whereas SIRT-1 and UCP2 were both upregulated. In placenta from obese women with GDM, gene expression for AMPK was also reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. Conclusions: Placental gene expression is sensitive to both maternal obesity and GDM which both impact on energy sensing and could modulate the effect of either raised maternal BMI or GDM on birth weight

A tool for assessing the climate change mitigation and health impacts of environmental policies: the Cities Rapid Assessment Framework for Transformation (CRAFT) [version 2; peer review: 3 approved]

Background: A growing number of cities, including Greater London, have set ambitious targets, including detailed policies and implementation plans, to reach global goals on sustainability, health, and climate change. Here we present a tool for a rapid assessment of the magnitude of impact of specific policy initiatives to reach these targets. The decision-support tool simultaneously quantifies the environmental and health impacts of specified selected policies. Methods: The ‘Cities Rapid Assessment Framework for Transformation (CRAFT)’ tool was applied to Greater London. CRAFT quantifies the effects of ten environmental policies on changes in (1) greenhouse gas (GHG) emissions, (2) exposures to environmental hazards, (3) travel-related physical activity, and (4) mortality (the number of attributable deaths avoided in one typical year). Publicly available data and epidemiological evidence were used to make rapid quantitative estimates of these effects based on proportional reductions in GHG emissions and environmental exposures from current baseline levels and to compute the mortality impacts. Results: The CRAFT tool estimates that, of roughly 50,000 annual deaths in Greater London, the modelled hazards (PM2.5 (from indoor and outdoor sources), outdoor NO2, indoor radon, cold, overheating) and low travel-related physical activity are responsible for approximately 10,000 premature environment-related deaths. Implementing the selected polices could reduce the annual mortality number by about 20% (~1,900 deaths) by 2050. The majority of these deaths (1,700) may be avoided through increased uptake in active travel. Thus, out of ten environmental policies, the ‘active travel’ policy provides the greatest health benefit. Also, implementing the ten policies results in a GHG reduction of around 90%. Conclusions: The CRAFT tool quantifies the effects of city policies on reducing GHG emissions, decreasing environmental health hazards, and improving public health. The tool has potential value for policy makers through providing quantitative estimates of health impacts to support and prioritise policy options

Developing and testing accelerated partner therapy for partner notification for people with genital Chlamydia trachomatis diagnosed in primary care: a pilot randomised controlled trial

Background Accelerated partner therapy (APT) is a promising partner notification (PN) intervention in specialist sexual health clinic attenders. To address its applicability in primary care, we undertook a pilot randomised controlled trial (RCT) of two APT models in community settings. Methods Three-arm pilot RCT of two adjunct APT interventions: APTHotline (telephone assessment of partner(s) plus standard PN) and APTPharmacy (community pharmacist assessment of partner(s) plus routine PN), versus standard PN alone (patient referral). Index patients were women diagnosed with genital chlamydia in 12 general practices and three community contraception and sexual health (CASH) services in London and south coast of England, randomised between 1 September 2011 and 31 July 2013. Results 199 women described 339 male partners, of whom 313 were reported by the index as contactable. The proportions of contactable partners considered treated within 6 weeks of index diagnosis were APTHotline 39/111 (35%), APTPharmacy 46/100 (46%), standard patient referral 46/102 (45%). Among treated partners, 8/39 (21%) in APTHotline arm were treated via hotline and 14/46 (30%) in APTPharmacy arm were treated via pharmacy. Conclusions The two novel primary care APT models were acceptable, feasible, compliant with regulations and capable of achieving acceptable outcomes within a pilot RCT but intervention uptake was low. Although addition of these interventions to standard PN did not result in a difference between arms, overall PN uptake was higher than previously reported in similar settings, probably as a result of introducing a formal evaluation. Recruitment to an individually randomised trial proved challenging and full evaluation will likely require service-level randomisation