Safer topical treatment for inflammation using 5α-tetrahydrocorticosterone in mouse models

Use of topical glucocorticoid for inflammatory skin conditions is limited by systemic and local side-effects. This investigation addressed the hypothesis that topical 5α-tetrahydrocorticosterone (5αTHB, a corticosterone metabolite) inhibits dermal inflammation without affecting processes responsible for skin thinning and impaired wound healing. The topical anti-inflammatory properties of 5αTHB were compared with those of corticosterone in C57Bl/6 male mice with irritant dermatitis induced by croton oil, whereas its effects on angiogenesis, inflammation, and collagen deposition were investigated by subcutaneous sponge implantation. 5αTHB decreased dermal swelling and total cell infiltration associated with dermatitis similarly to corticosterone after 24 h, although at a five fold higher dose, but in contrast did not have any effects after 6 h. Pre-treatment with the glucocorticoid receptor antagonist RU486 attenuated the effect of corticosterone on swelling at 24 h, but not that of 5αTHB. After 24 h 5αTHB reduced myeloperoxidase activity (representative of neutrophil infiltration) to a greater extent than corticosterone. At equipotent anti-inflammatory doses 5αTHB suppressed angiogenesis to a limited extent, unlike corticosterone which substantially decreased angiogenesis compared to vehicle. Furthermore, 5αTHB reduced only endothelial cell recruitment in sponges whereas corticosterone also inhibited smooth muscle cell recruitment and decreased transcripts of angiogenic and inflammatory genes. Strikingly, corticosterone, but not 5αTHB, reduced collagen deposition. However, both 5αTHB and corticosterone attenuated macrophage infiltration into sponges. In conclusion, 5αTHB displays the profile of a safer topical anti-inflammatory compound. With limited effects on angiogenesis and extracellular matrix, it is less likely to impair wound healing or cause skin thinning

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Examining Holocene stability of Antarctic Peninsula ice shelves.

Temperatures on the Antarctic Peninsula are increasing at a rate of 3.4°C per century, more than five times the global mean. At the same time, the region's ice shelves have retreated and collapsed, with an area of more than 14,000 square kilometers disappearing within the past two decades. Ice shelf retreat has followed the southward migration of the −9°C mean annual isotherm, referred to as the ‘climatic limit of ice shelf stability’ (Figure 1). Thus, present-day ice shelf retreats on the Antarctic Peninsula have been linked to increased atmospheric temperature [Vaughan et al., 2003]

Mechanisms of Holocene palaeoenvironmental change in the Antarctic Peninsula region

The Antarctic Peninsula is one of the three fastest warming regions on Earth. Here we review Holocene proxy records of marine and terrestrial palaeoclimate in the region, and discuss possible forcing mechanisms underlying past change, with a specific focus on past warm periods. Our aim is to critically evaluate the mechanisms by which palaeoclimate changes might have occurred, in order to provide a longer-term context for assessing the drivers of recent warming. Two warm events are well recorded in the Holocene palaeoclimate record, namely the early Holocene warm period, and the `Mid Holocene Hypsithermal' (MHH), whereas there are fewer proxy data for the `Mediaeval Warm Period' (MWP) and the `Recent Rapid Regional' (RRR) warming. We show that the early Holocene warm period and MHH might be explained by relatively abrupt shifts in position of the Southern Westerlies, superimposed on slower solar insolation changes. A key finding of our synthesis is that the marine and terrestrial records in the AP appear to show markedly different behaviour during the MHH. This might be partly explained by contrasts in the seasonal insolation forcing between these records. Circumpolar Deep Water (CDW) has been implicated in several of the prominent changes through the Holocene but there are still differences in interpretation of the proxy record that make its influence difficult to assess. Further work is required to investigate contrasts between marine and terrestrial proxy records, east—west contrasts in palaeoclimate, the history of CDW, to retrieve a long onshore high resolution record of the Holocene, and determine the role of sea ice in driving or modulating palaeoclimate change, along with further efforts to study the proxy record of the RRR and the MWP