Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases

Dimethyl fumarate (DMF) has been applied for decades in the treatment of psoriasis and now also multiple sclerosis. However, the mechanism of action has remained obscure and involves high dose over long time of this small, reactive compound implicating many potential targets. Based on a 1.9 Å resolution crystal structure of the C-terminal kinase domain of the mouse p90 Ribosomal S6 Kinase 2 (RSK2) inhibited by DMF we describe a central binding site in RSKs and the closely related Mitogen and Stress-activated Kinases (MSKs). DMF reacts covalently as a Michael acceptor to a conserved cysteine residue in the αF-helix of RSK/MSKs. Binding of DMF prevents the activation loop of the kinase from engaging substrate, and stabilizes an auto-inhibitory αL-helix, thus pointing to an effective, allosteric mechanism of kinase inhibition. The biochemical and cell biological characteristics of DMF inhibition of RSK/MSKs are consistent with the clinical protocols of DMF treatment.</p

The Dynamics of CO 2 ‐Driven Granular Flows in Gullies on Mars

Martian gullies are landforms consisting of an erosional alcove, a channel, and a depositional apron. A significant proportion of Martian gullies at the mid‐latitudes is active today. The seasonal sublimation of CO2 ice has been suggested as a driver behind present‐day gully activity. However, due to a lack of in situ observations, the actual processes causing the observed changes remain unresolved. Here, we present results from flume experiments in environmental chambers in which we created CO2‐driven granular flows under Martian atmospheric conditions. Our experiments show that under Martian atmospheric pressure, large amounts of granular material can be fluidized by the sublimation of small quantities of CO2 ice in the granular mixture (only 0.5% of the volume fraction of the flow) under slope angles as low as 10°. Dimensionless scaling of the CO2‐driven granular flows shows that they are dynamically similar to terrestrial two‐phase granular flows, that is, debris flows and pyroclastic flows. The similarity in flow dynamics explains the similarity in deposit morphology with levees and lobes, supporting the hypothesis that CO2‐driven granular flows on Mars are not merely modifying older landforms, but they are actively forming them. This has far‐reaching implications for the processes thought to have formed these gullies over time. For other planetary bodies in our solar system, our experimental results suggest that the existence of gully like landforms is not necessarily evidence for flowing liquids but that they could also be formed or modified by sublimation‐driven flow processes

Experimental Wind Characterization with the SuperCam Microphone under a Simulated martian Atmosphere

Located on top of the mast of the Mars 2020 Perseverance rover, the SuperCam instrument suite includes a microphone to record audible sounds from 100 Hz to 10 kHz on the surface of Mars. It will support SuperCam’s Laser-Induced Breakdown Spectroscopy investigation by recording laser-induced shock-waves but it will also record aeroacoustic noise generated by wind flowing past the microphone. This experimental study was conducted in the Aarhus planetary wind-tunnel under low CO2 pressure with wind generated at several velocities. It focused on understanding the wind-induced acoustic signal measured by microphones instrumented in a real scale model of the rover mast as a function of the wind speed and wind orientation. Acoustic spectra recorded under a wind flow show that the low-frequency range of the microphone signal is mainly influenced by the wind velocity. In contrast, the higher frequency range is seen to depend on the wind direction relative to the microphone. On the one hand, for the wind conditions tested inside the tunnel, it is shown that the Root Mean Square of the pressure, computed over the 100 Hz to 500 Hz frequency range, is proportional to the dynamic pressure. Therefore, the SuperCam microphone will be able to estimate the wind speed, considering an in situ cross-calibration with the Mars Environmental Dynamic Analyzer. On the other hand, for a given wind speed, it is observed that the root mean square of the pressure, computed over the 500 Hz to 2000 Hz frequency range, is at its minimum when the microphone is facing the wind whereas it is at its maximum when the microphone is pointing downwind. Hence, a full 360° rotation of the mast in azimuth in parallel with sound recording can be used to retrieve the wind direction. We demonstrate that the SuperCam Microphone has a priori the potential to determine both the speed and the direction of the wind on Mars, thus contributing to atmospheric science investigations

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

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

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