Mechanism of completion of peptidyltransferase centre assembly in eukaryotes.

During their final maturation in the cytoplasm, pre-60S ribosomal particles are converted to translation-competent large ribosomal subunits. Here, we present the mechanism of peptidyltransferase centre (PTC) completion that explains how integration of the last ribosomal proteins is coupled to release of the nuclear export adaptor Nmd3. Single-particle cryo-EM reveals that eL40 recruitment stabilises helix 89 to form the uL16 binding site. The loading of uL16 unhooks helix 38 from Nmd3 to adopt its mature conformation. In turn, partial retraction of the L1 stalk is coupled to a conformational switch in Nmd3 that allows the uL16 P-site loop to fully accommodate into the PTC where it competes with Nmd3 for an overlapping binding site (base A2971). Our data reveal how the central functional site of the ribosome is sculpted and suggest how the formation of translation-competent 60S subunits is disrupted in leukaemia-associated ribosomopathies.Bloodwise, MRC, Wellcome Trus

Early immune factors associated with the development of post-acute sequelae of SARS-CoV-2 infection in hospitalized and non-hospitalized individuals

BackgroundInfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown.MethodsWe enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC.ResultsDuring the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular.ConclusionsWe found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC

Hydraulic conductivity estimation from induced polarisation data at the field scale - the Krauthausen case history

Recently, encouraging results have been obtained to estimate hydraulic conductivity in unconsolidated sediments from induced polarisation (IP) measurements. The work focussed on laboratory experiments in order to establish semi-empirical relationships between complex electrical conductivity and hydraulic parameters. Although field studies are certainly important to evaluate the feasibility of the method in practice, only a limited number of case histories have been reported. We carried out an IP survey at the Krauthausen hydrogeological test site in Germany. Multifrequency data were recorded along two profiles with a dipole-dipole configuration and 2 in electrode spacing. The data were inverted with a 2-D inversion code to obtain images of conductivity magnitude and phase for each frequency. We used a novel focussing regularisation scheme that does not suppress sharp boundaries and yields realistic images of the subsurface. The gross structural features compare well with the known lithology, which consists of an approx. 9 in thick sand/gravel aquifer over fine sands and a thin clay layer which constitutes the base at approx. I I in depth. From the complex electrical conductivity distribution we calculate hydraulic conductivity estimates using the empirical equations suggested by Bbmer et al. [Borner, F. D., Schopper J. R., Weller, A., 1996. Evaluation of transport and storage properties in the soil and groundwater zone from induced polarisation measurements. Geophys. Prosp. 44, 583-601] and by Slater and Lesmes [Slater, L. D., Lesmes, D. P., 2002a. Electric hydraulic relationships observed for unconsolidated sediments. Water Res. Research, 3 8 (10), doi:10.1029/2001WR001075] and compare the results with values obtained from grain size data at two boreholes. The Bbmer model yields hydraulic conductivities in the same order of magnitude as the grain size data, whereas the Slater and Lesmes model substantially underestimates hydraulic conductivities. We also compare the specific inner surface estimated from our IP data with values obtained from BET measurements at the two borehole locations. In this case, we observe a reasonable agreement with both the Borner and the Slater and Lesmes equations. Our results constitute an encouraging example where reasonable estimates of hydraulic parameters are obtained at the field scale. (C) 2006 Elsevier B.V. All rights reserved