Interchanging Functionality Among Homologous Elongation Factors Using Signatures of Heterotachy

Numerous models of molecular evolution have been formulated to describe the forces that shape sequence divergence among homologous proteins. These models have greatly enhanced our understanding of evolutionary processes. Rarely are such models empirically tested in the laboratory, and even more rare, are such models exploited to generate novel molecules useful for synthetic biology. Here, we experimentally demonstrate that the heterotachy model of evolution captures signatures of functional divergence among homologous elongation factors (EFs) between bacterial EF-Tu and eukaryotic eEF1A. These EFs are GTPases that participate in protein translation by presenting aminoacylated-tRNAs to the ribosome. Upon release from the ribosome, the EFs are recharged by nucleotide exchange factors EF-Ts in bacteria or eEF1B in eukaryotes. The two nucleotide exchange factors perform analogous functions despite not being homologous proteins. The heterotachy model was used to identify a set of sites in eEF1A/EF-Tu associated with eEF1B binding in eukaryotes and another reciprocal set associated with EF-Ts binding in bacteria. Introduction of bacterial EF-Tu residues at these sites into eEF1A protein efficiently disrupted binding of cognate eEF1B as well as endowed eEF1A with the novel ability to bind bacterial EF-Ts. We further demonstrate that eEF1A variants, unlike yeast wild-type, can function in a reconstituted in vitro bacterial translation system. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-013-9540-9) contains supplementary material, which is available to authorized users

Comparison of the Efficacy of Brolucizumab with Natural Disease Progression in Wet AMD Using Clinical Data from the Phase III HAWK and HARRIER Trials and Modelled Placebo Data

Aim: To compare the treatment effect of brolucizumab, a novel anti-vascular endothelial growth factor therapeutic, with a putative placebo in patients with wet age-related macular degeneration. Materials and Methods: Clinical treatment-effect data from patients receiving brolucizumab 6 mg in the HAWK and HARRIER studies were compared with modelled placebo data using a previously developed and validated indirect response, non-linear, mixed effects model describing the natural visual acuity decline in wet age-related macular degeneration. The placebo model incorporated patient-level data from the sham injection arms of the MARINA and PIER studies, corrected for baseline best corrected visual acuity and age difference between these studies and the HAWK and HARRIER studies. Results: Compared with a modelled placebo, brolucizumab treatment was associated with an overall best corrected visual acuity gain of approximately 22 Early Treatment Diabetic Retinopathy Study letters at Week 48 and 28 letters at Week 96. Conclusions: As anti-vascular endothelial growth factor therapy is now a standard of care for wet age-related macular degeneration, it is not feasible to conduct placebo-controlled trials for new wet age-related macular degeneration treatments. By allowing comparison with the natural decline in visual acuity without treatment, this analysis conveys the clinical importance of brolucizumab for the treatment of wet age-related macular degeneration

Un cas de longévité exceptionnelle chez le chiroptère Rhinolophus ferrumequinum

Two more longevity records of wild male Rhinolophus ferruméquinum are reported : 25.5 and 29.5 year

A convenient category of locally preordered spaces

As a practical foundation for a homotopy theory of abstract spacetime, we extend a category of certain compact partially ordered spaces to a convenient category of locally preordered spaces. In particular, we show that our new category is Cartesian closed and that the forgetful functor to the category of compactly generated spaces creates all limits and colimits.Comment: 26 pages, 0 figures, partially presented at GETCO 2005; changes: claim of Prop. 5.11 weakened to finite case and proof changed due to problems with proof of Lemma 3.26, now removed; Eg. 2.7, statement before Lem. 2.11, typos, and other minor problems corrected throughout; extensive rewording; proof of Lem. 3.31, now 3.30, adde

Radiative Stellar Feedback in Galaxy Formation: Methods and Physics

Radiative feedback (RFB) from stars plays a key role in galaxies, but remains poorly-understood. We explore this using high-resolution, multi-frequency radiation-hydrodynamics (RHD) simulations from the Feedback In Realistic Environments (FIRE) project. We study dwarf through Milky Way masses, and explore RHD effects including H/He photoionization; photoelectric, Lyman Werner, Compton, thermal dust heating; single and multiple-scattering radiation pressure (RP). We also compare fundamentally distinct RHD algorithms: the ray-based LEBRON (exact when optically-thin) and moments-based M1 (exact when optically-thick). In all cases, the dominant RFB channels on galaxy scales are photoionization heating and single-scattering RP. At all masses, most of the ionizing/FUV luminosity from young stars (~half bolometric) is absorbed. In dwarfs, the strongest effect is photoionization heating from the meta-galactic background, suppressing accretion onto galaxies. At MW-mass the meta-galactic background has negligible effects; but local photoionization and single-scattering RP both contribute significantly to regulating the galactic star formation efficiency and lowering central densities. Without some RFB (or other 'rapid' FB), resolved GMCs turn most of their mass into stars, making galaxies dominated by hyper-dense, bound clusters. This makes star formation more violent and 'bursty' when SNe explode in hyper-clustered objects: thus, including RFB tends to 'smooth out' star formation. IR multiple-scattering is rare: the majority of photon absorption occurs in 'normal' GMCs with $A_{V}\sim1$. These conclusions are robust to the RHD method, but M1 produces somewhat stronger RFB effects.Comment: 25 pages, 13 figures, submitted to MNRA

Radiative Stellar Feedback in Galaxy Formation: Methods and Physics

Radiative feedback (RFB) from stars plays a key role in galaxies, but remains poorly-understood. We explore this using high-resolution, multi-frequency radiation-hydrodynamics (RHD) simulations from the Feedback In Realistic Environments (FIRE) project. We study ultra-faint dwarf through Milky Way mass scales, including H+He photo-ionization; photo-electric, Lyman Werner, Compton, and dust heating; and single+multiple scattering radiation pressure (RP). We compare distinct numerical algorithms: ray-based LEBRON (exact when optically-thin) and moments-based M1 (exact when optically-thick). The most important RFB channels on galaxy scales are photo-ionization heating and single-scattering RP: in all galaxies, most ionizing/far-UV luminosity (~1/2 of lifetime-integrated bolometric) is absorbed. In dwarfs, the most important effect is photo-ionization heating from the UV background suppressing accretion. In MW-mass galaxies, meta-galactic backgrounds have negligible effects; but local photo-ionization and single-scattering RP contribute to regulating the galactic star formation efficiency and lowering central densities. Without some RFB (or other 'rapid' FB), resolved GMCs convert too-efficiently into stars, making galaxies dominated by hyper-dense, bound star clusters. This makes star formation more violent and 'bursty' when SNe explode in these hyper-clustered objects: thus, including RFB 'smoothes' SFHs. These conclusions are robust to RHD methods, but M1 produces somewhat stronger effects. Like in previous FIRE simulations, IR multiple-scattering is rare (negligible in dwarfs, ~10% of RP in massive galaxies): absorption occurs primarily in 'normal' GMCs with A_v~1.Comment: 28 pages, 14 figures. Updated to match published MNRAS versio

Simulation of the degradation of a concrete/clay interface:influence of temperature, unsaturated conditions and porosityvariations

For long-lived intermediate-level radioactive waste, the useof concrete as engineering barrier and Callovian-Oxfordian clay asgeological barrier at a depth of 500 m is considered in the Frenchdisposal concept (ANDRA, 2005). Upon emplacement, initially unsaturatedconcrete is expected to experience coupled processes involving heating,re-saturation with groundwater from the clay formation, gas exchanges andgeochemical reactions. After an early period of re-saturation, solutetransport is supposed to be diffusion-controlled because of the extremelylow permeability of the two media. These coupled processes may lead tochanges in the porosity of the concrete or clay barriers. In the presentpaper, a fully coupled Thermo-Hydro-Chemical (THC) response of atwo-phase (gas and solution) mass-transfer model was evaluated and testedby a sensitivity analysis. This study is an extension of a previous modelapplied to an isothermal and fully saturated concrete/clay interface(Burnol et al., 2005); it investigated the coupled effect of temperatureand unsaturated conditions assuming no production of H2(g). The systemwas simulated for a 2000-year period, which covers the most predominantthermal perturbation

Effects of habitat and land use on breeding season density of male Asian Houbara Chlamydotis macqueenii

Landscape-scale habitat and land-use influences on Asian Houbara Chlamydotis macqueenii (IUCN Vulnerable) remain unstudied, while estimating numbers of this cryptic, low-density, over-hunted species is challenging. In spring 2013, male houbara were recorded at 231 point counts, conducted twice, across a gradient of sheep density and shrub assemblages within 14,300 km² of the Kyzylkum Desert, Uzbekistan. Four sets of models related male abundance to: (1) vegetation structure (shrub height and substrate); (2) shrub assemblage; (3) shrub species composition (multidimensional scaling); (4) remote-sensed derived land-cover (GLOBCOVER, 4 variables). Each set also incorporated measures of landscape rugosity and sheep density. For each set, multi-model inference was applied to generalised linear mixed models of visit-specific counts that included important detectability covariates and point ID as a random effect. Vegetation structure received strongest support, followed by shrub species composition and shrub assemblage, with weakest support for the GLOBCOVER model set. Male houbara numbers were greater with lower mean shrub height, more gravel and flatter surfaces, but were unaffected by sheep density. Male density (mean 0.14 km-2, 95% CI, 0.12‒0.15) estimated by distance analysis differed substantially among shrub assemblages, being highest in vegetation dominated by Salsola rigida (0.22 [CI, 0.20‒0.25]), high in areas of S. arbuscula and Astragalus (0.14 [CI, 0.13‒0.16] and 0.15 [CI, 0.14‒0.17] respectively), lower (0.09 [CI, 0.08‒0.10]) in Artemisia and lowest (0.04 [CI, 0.04‒0.05]) in Calligonum. The study area was estimated to hold 1,824 males (CI: 1,645‒2,030). The spatial distribution of relative male houbara abundance, predicted from vegetation structure models, had the strongest correspondence with observed numbers in both model-calibration and the subsequent year’s data. We found no effect of pastoralism on male distribution but potential effects on nesting females are unknown. Density differences among shrub communities suggest extrapolation to estimate country- or range-wide population size must take account of vegetation composition

First results from stimulation assessment and monitoring of the 426°C geothermal well RN-15/IDDP-2 (H2020-DEEPEGS project)

The RN-15/IDDP-2 deep geothermal well of the DEEPEGS EU project on the Mid-Atlantic ridge at Reykjanes, Iceland, is a unique site for geothermal research. With a bottom hole temperature of approximately 426°C, it is one of the hottest geothermal wells ever drilled aiming for fluids at supercritical condition. Consequently, down-hole measurements are reliable to a depth of about 3.5 km, only. Pressure and temperature condition in the reservoir can be inferred using the newly developed wellbore simulator WellboreKit. Due to complete fluid loss, the well has been drilled at flow rates that reach hydraulic stimulation condition. After the drilling, the well was stimulated further by applying different concepts ranging from high flow rate hydraulic stimulation to long-term but low flow rate hydraulic stimulation to increase the reservoir performance at around 4.6 km depth. Thermo-hydro-mechanically coupled numerical modelling was performed to predict the performance response and thus, develop a well stimulation schedule. Processes related to drilling and stimulation are monitored using seismic and magnetotelluric methods to characterize and understand the processes ongoing during injection