The emerging role of H3K9me3 as a potential therapeutic target in acute myeloid leukaemia

Growing evidence has demonstrated that epigenetic dysregulation is a common pathological feature in human cancer cells. Global alterations in the epigenetic landscape are prevalent in malignant cells across different solid tumours including, prostate cancer, non-small-cell lung cancer, renal cell carcinoma, and in haemopoietic malignancy. In particular, DNA hypomethylation and histone hypoacetylation have been observed in acute myeloid leukaemia (AML) patient blasts, with histone methylation being an emerging area of study. Histone 3 lysine 9 trimethylation (H3K9me3) is a post-translational modification known to be involved in the regulation of a broad range of biological processes, including the formation of transcriptionally silent heterochromatin. Following the observation of its aberrant methylation status in haematological malignancy and several other cancer phenotypes, recent studies have associated H3K9me3 levels with patient outcome and highlighted key molecular mechanisms linking H3K9me3 profile with AML aetiology in a number of large-scale meta-analysis. Consequently, the development and application of small molecule inhibitors which target the histone methyltransferases or demethylase enzymes known to participate in the oncogenic regulation of H3K9me3 in AML represents an advancing area of ongoing study. Here, we provide a comprehensive review on how this particular epigenetic mark is regulated within cells and its emerging role as a potential therapeutic target in AML, along with an update on the current research into advancing the generation of more potent and selective inhibitors against known H3K9 methyltransferases and demethylases

Role of Subsurface Geo-Energy Pilot and Demonstration Sites in Delivering Net Zero

Recent research suggests that the effects of climate change are already tangible, making the requirement for net zero more pressing than ever. New emissions targets have been announced in April 2021 by various governments, including by the United Kingdom, United States, and China, prior to the Conference of the Parties (COP26) in Glasgow. Part of the solution for net zero will be geo-energy technologies in the subsurface, these include: mine water geothermal, aquifer thermal energy storage (ATES), enhanced geothermal systems and other thermal storage options, compressed air energy storage (CAES), and carbon dioxide capture and storage (CCS) including bioenergy CCS (BECCS). Subsurface net zero technologies have been studied by geologists at laboratory scale and with models, but also require testing at greater-than laboratory scale and in representative conditions not reproducible in laboratories and models. Test, pilot and demonstration facilities aid rock characterisation process understanding and up-scaling, and thereby provide a bridge between laboratory testing and computer modelling and full-scale operation. Examples of test sites that have progressed technology development include the Otway International Test Centre (Australia, CCS) and the Äspö Hard Rock Laboratory (Sweden, geological radioactive waste disposal). These sites have provided scale up for key research questions allowing science issues of relevance to regulation, licencing and permitting to be examined at scale in controlled environments. Successful operations at such sites allow research to be seen at first hand to inform the public, regulators, supply chain companies and investors that such technologies can work safely and economically. A Geological Society conference on the “Role of subsurface research labs in delivering net zero” in February 2021 considered the value of test sites and gaps in their capability. Gaps were identified in two areas: 1) test facilities to aid the design of low cost, high resolution, unobtrusive seismic and other monitoring for a seismically noisy urban environment with a sensitive human population, for example for ATES in urban areas; and 2) a dedicated through-fault zone test site to understand fault transmissivity and reactivation. Conference participants also recommended investment and development in test sites, shared facilities and risk, joint strategies, data interoperability and international collaboration

Small-Scale Vertical Movements of Summer Flounder Relative to Diurnal, Tidal, and Temperature Changes

Observation of animal movements on small spatial scales provides a means to understand how large-scale species distributions are established from individual behavioral decisions. Small-scale vertical movements of 14 Summer Flounder Paralichthys dentatus residing in Chesapeake Bay were observed by using depth data collected with archival tags. A generalized linear mixed model was employed to examine the relationship between these vertical movements and environmental covariates such as tidal state, time of day, lunar phase, and temperature. Vertical movements increased with warming water temperatures, and this pattern was most apparent at night and during rising and falling tides. Fish generally exhibited greater vertical movements at night, but the difference between vertical movements in the day and those at night decreased as fish increased in size. Results from this study fill a void in understanding the small-scale movements of Summer Flounder and could be incorporated into individual-based models to investigate how species distributions develop in response to environmental conditions

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Effects of Potassium in Liquid Feed, Lime Type in the Base Dressing and Cultivar on the Yield, Quality and Composition of Tomatoes Grown in Peat

Three concentrations of K in the liquid feed, two lime sources and three cultivars were compared in a long-season crop of tomatoes grown in a peat substrate with 14 1 per plant. Increasing the K concentration from 180 to 280 mg/l increased the yield but a further rise to 380 mg/l did not give a significant increase. The higher levels of K reduced uneven ripening and increased the levels of soluble solids, titratable acidity and electrical conductivity of the fruit purée. The use of dolomitic limestone only or a blend of dolomitic and ground limestones as lime sources had no effect on fruit yield, visual quality or composition. Two modern cultivars, Sonatine and Virosa, had better early yields than Ailsa Craig, an old cultivar, but similar total yields. Ailsa Craig produced a much higher proportion of fruit with uneven ripening, and early in the season its fruit had a lower soluble-solids content than did the modern cultivars. A seasonal decline in the electrical conductivity of the fruit purée was noted.European ComnmissionDeposited by bulk impor