Failure to Downregulate the Epithelial Sodium Channel Causes Salt Sensitivity in Hsd11b2 Heterozygote Mice

In vivo, the enzyme 11β-hydroxysteroid dehydrogenase type 2 influences ligand access to the mineralocorticoid receptor. Ablation of the encoding gene, HSD11B2, causes the hypertensive syndrome of apparent mineralocorticoid excess. Studies in humans and experimental animals have linked reduced 11β-hydroxysteroid dehydrogenase type 2 activity and salt sensitivity of blood pressure. In the present study, renal mechanisms underpinning salt sensitivity were investigated in Hsd11b2(+/-) mice fed low-, standard-, and high-sodium diets. In wild-type mice, there was a strong correlation between dietary sodium content and fractional sodium excretion but not blood pressure. High sodium feeding abolished amiloride-sensitive sodium reabsorption, consistent with downregulation of the epithelial sodium channel. In Hsd11b2(+/-) mice, the natriuretic response to increased dietary sodium content was blunted, and epithelial sodium channel activity persisted. High-sodium diet also reduced renal blood flow and increased blood pressure in Hsd11b2(+/-) mice. Aldosterone was modulated by dietary sodium in both genotypes, and salt sensitivity in Hsd11b2(+/-) mice was associated with increased plasma corticosterone levels. Chronic administration of an epithelial sodium channel blocker or a glucocorticoid receptor antagonist prevented salt sensitivity in Hsd11b2(+/-) mice, whereas mineralocorticoid receptor blockade with spironolactone did not. This study shows that reduced 11β-hydroxysteroid dehydrogenase type 2 causes salt sensitivity of blood pressure because of impaired renal natriuretic capacity. This reflects deregulation of epithelial sodium channels and increased renal vascular resistance. The phenotype is not caused by illicit activation of mineralocorticoid receptors by glucocorticoids but by direct activation of glucocorticoid receptors

Action of earthworms on flint burial – a return to Darwin’s estate

For thirty years, from the early 1840s, Charles Darwin documented the disappearance of flints in the grounds of Down House in Kent, at a location originally known as the “Stony Field”. This site (Great Pucklands Meadow - GPM) was visited in 2007 and an experiment set up in this ungrazed grassland. Locally-sourced flints (either large - 12 cm, or small – 5 cm dia.) were deposited at two densities within sixteen 1 m2 plots in a randomised factorial design. The area selected was distant from public access routes and remained unmown throughout the duration here reported. Fixed point photographs were taken at the outset to enable later photogrammetric analysis. After 6 years, the site was re-examined. The flints had generally been incorporated into the soil. Photographs were re-taken, proportion of buried flints recorded and measurements made of burial depth from a quarter of each plot. Results showed that large flints were more deeply incorporated than smaller (p=0.025), but more of the latter were below the soil surface. A controlled laboratory experiment was also conducted using Aporrectodea longa (the dominant earthworm species in GPM) to assess effects of casting in the absence of other biota. Results suggested that this species has a major influence on flint burial through surface casting. Combined with a long term, but small scale collection of A. longa casts from an area close to GPM, all results were consistent with those provided by Darwin and showed that rate of flint burial was within the range 0.21-0.96 cm y-1

Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort study.

Background The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding UK Research and Innovation and National Institute for Health Research

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Effects of Ascent to High Altitude on Human Antimycobacterial Immunity

Backgroun

Exploring High Aspect Ratio Gold Nanotubes as Cytosolic Agents: Structural Engineering and Uptake into Mesothelioma Cells.

The generation of effective and safe nanoagents for biological applications requires their physicochemical characteristics to be tunable, and their cellular interactions to be well characterized. Here, the controlled synthesis is developed for preparing high-aspect ratio gold nanotubes (AuNTs) with tailorable wall thickness, microstructure, composition, and optical characteristics. The modulation of optical properties generates AuNTs with strong near infrared absorption. Surface modification enhances dispersibility of AuNTs in aqueous media and results in low cytotoxicity. The uptake and trafficking of these AuNTs by primary mesothelioma cells demonstrate their accumulation in a perinuclear distribution where they are confined initially in membrane-bound vesicles from which they ultimately escape to the cytosol. This represents the first study of the cellular interactions of high-aspect ratio 1D metal nanomaterials and will facilitate the rational design of plasmonic nanoconstructs as cytosolic nanoagents for potential diagnosis and therapeutic applications.BLF-Papworth Fellowship from the British Lung Foundation and the Victor Dahdaleh Foundation

Design catalogue for eco-engineering of coastal artificial structures:a multifunctional approach for stakeholders and end-users

Coastal urbanisation, energy extraction, food production, shipping and transportation have led to the global proliferation of artificial structures within the coastal and marine environments (sensu “ocean sprawl”), with subsequent loss of natural habitats and biodiversity. To mitigate and compensate impacts of ocean sprawl, the practice of ecoengineering of artificial structures has been developed over the past decade. Eco-engineering aims to create sustainable ecosystems that integrate human society with the natural environment for the benefit of both. The science of eco-engineering has grown markedly, yet synthesis of research into a user-friendly and practitioner-focused format is lacking. Feedback from stakeholders has repeatedly stated that a “photo user guide” or “manual” covering the range of eco-engineering options available for artificial structures would be beneficial. However, a detailed and structured “user guide” for eco-engineering in coastal and marine environments is not yet possible; therefore we present an accessible review and catalogue of trialled eco-engineering options and a summary of guidance for a range of different structures tailored for stakeholders and end-users as the first step towards a structured manual. This work can thus serve as a potential template for future eco-engineering guides. Here we provide suggestions for potential eco-engineering designs to enhance biodiversity and ecosystem functioning and services of coastal artificial structures with the following structures covered: (1) rock revetment, breakwaters and groynes composed of armour stones or concrete units; (2) vertical and sloping seawalls; (3) over-water structures (i.e., piers) and associated support structures; and (4) tidal river walls