Translation termination depends on the sequential ribosomal entry of eRF1 and eRF3.

Translation termination requires eRF1 and eRF3 for polypeptide-and tRNA-release on stop codons. Additionally, Dbp5/DDX19 and Rli1/ABCE1 are required; however, their function in this process is currently unknown. Using a combination of in vivo and in vitro experiments, we show that they regulate a stepwise assembly of the termination complex. Rli1 and eRF3-GDP associate with the ribosome first. Subsequently, Dbp5-ATP delivers eRF1 to the stop codon and in this way prevents a premature access of eRF3. Dbp5 dissociates upon placing eRF1 through ATP-hydrolysis. This in turn enables eRF1 to contact eRF3, as the binding of Dbp5 and eRF3 to eRF1 is mutually exclusive. Defects in the Dbp5-guided eRF1 delivery lead to premature contact and premature dissociation of eRF1 and eRF3 from the ribosome and to subsequent stop codon readthrough. Thus, the stepwise Dbp5-controlled termination complex assembly is essential for regular translation termination events. Our data furthermore suggest a possible role of Dbp5/DDX19 in alternative translation termination events, such as during stress response or in developmental processes, which classifies the helicase as a potential drug target for nonsense suppression therapy to treat cancer and neurodegenerative diseases

New findings of Prototherium ausetanum (Mammalia, Pan-Sirenia) from paving stones in Girona (Catalonia, Spain)?

Taxonomic and morphological approaches on Eocene sirenians from Catalonia (Spain) benefit from a newly discovered specimen found in a quite unusual locality, the pedestrian zone in the city of Girona. Two fossil-bearing limestone slabs from middle Eocene (Bartonian) layers of a quarry in the wider surrounding area north-west of Barcelona, were CT-scanned in the Clínica Girona to enhance more detailed investigations. Post-processing of the scans and, as far as possible, 3D-reconstruction of the preserved elements in the slabs was performed at Museum für Naturkunde Berlin. Thereby, a skull of a Dugong specimen was used as a reference point. Based on the combined analysis of macroscopic and CT-data, the specimen most likely represents Prototherium ausetanum Balaguer & Alba, 2016 and complements the available information of the holotype and hitherto only known specimen of that species. The Girona specimen is an adult, but small individual that corroborates P. ausetanum as a generally small-sized species compared to other known Prototherium taxa

Three-dimensional Magnetic Resonance Imaging of fossils across taxa

The frequency of life forms in the fossil record is largely determined by the extent to which they were mineralised at the time of their death. In addition to mineral structures, many fossils nonetheless contain detectable amounts of residual water or organic molecules, the analysis of which has become an integral part of current palaeontological research. The methods available for this sort of investigations, though, typically require dissolution or ionisation of the fossil sample or parts thereof, which is an issue with rare taxa and outstanding materials like pathological or type specimens. In such cases, non-destructive techniques could provide a valuable methodological alternative. While Computed Tomography has long been used to study palaeontological specimens, a number of complementary approaches have recently gained ground. These include Magnetic Resonance Imaging (MRI) which had previously been employed to obtain three-dimensional images of pathological belemnites non-invasively on the basis of intrinsic contrast. The present study was undertaken to investigate whether <sup>1</sup>H MRI can likewise provide anatomical information about non-pathological belemnites and specimens of other fossil taxa. To this end, three-dimensional MR image series were acquired from intact non-pathological invertebrate, vertebrate and plant fossils. At routine voxel resolutions in the range of several dozens to some hundreds of micrometers, these images reveal a host of anatomical details and thus highlight the potential of MR techniques to effectively complement existing methodological approaches for palaeontological investigations in a wide range of taxa. As for the origin of the MR signal, relaxation and diffusion measurements as well as <sup>1</sup>H and <sup>13</sup>C MR spectra acquired from a belemnite suggest intracrystalline water or hydroxyl groups, rather than organic residues

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well

Greater capacity to exploit warming temperatures in northern populations of European beech is partly driven by delayed leaf senescence

One of the most widespread consequences of climate change is the disruption of trees’ phenological cycles. The extent to which tree phenology varies with local climate is largely genetically determined, and while a combination of temperature and photoperiodic cues are typically found to trigger bud burst (BB) in spring, it has proven harder to identify the main cues driving leaf senescence (LS) in autumn. We used 905 individual field observations of BB and LS from six Fagus sylvatica populations, covering the range of environmental conditions found across the species distribution, to: (i) estimate the dates of BB and LS of these populations; (ii) assess the main drivers of LS; and (iii) predict the likely variation in growing season length (GSL; defined as the period from BB to LS timing) across populations under current and future climate scenarios. To this end, we first calibrated linear mixed-effects models for LS as a function of temperature, insolation and BB date. Secondly, we calculated GSL for each population as the number of days between BB and LS. We found that: i) there were larger differences among populations in the date of BB than in the date of LS; ii) the temperature through September, October and November was the main determinant of LS, although covariation of temperature with daily insolation and precipitation-related variables suggests that all three variables may affect LS timing; and iii) GSL was predicted to increase in northern populations and to shrink in central and southern populations under climate change. Consequently, the large present-day differences in GSL across the range of beech are likely to decrease under future climates where rising temperatures will alter the relationship between BB and LS. Northern populations are likely to increase their productivity as warmer conditions will enable them to extend their growing season.Peer reviewe

GAD65 Autoantibody Responses in Japanese Latent Autoimmune Diabetes in Adult Patients

OBJECTIVE—To determine whether development of insulin requirement in patients with latent autoimmune diabetes in adults (LADA) is accompanied with the emergence of a type 1 diabetes–like autoimmune response

Conformation-dependent GAD65 autoantibodies in diabetes

Aims/hypothesis. Conformation-dependent autoantibodies directed against GAD65 are markers of Type 1 diabetes. In this study we aimed to determine whether the substitution of GAD65 with GAD67 amino acids would affect the binding of conformation-dependent GAD65 autoantibodies. Methods. We used PCR-based site-directed mutagenesis to generate a series of mutated GAD65 cDNA constructs in which specific GAD65 coding sequences for regions of the protein critical for autoantibody binding were replaced with GAD67 coding sequences. Results. The introduction of a point mutation at position 517, substituting glutamic acid with proline, markedly reduced the binding of disease-associated GAD65 antibodies. The binding of GAD65 antibodies to the E517P mutant was reduced in the sera of all newly diagnosed Type 1 diabetes patients (n=85) by a mean of 72% (p<0.0001) compared with binding to wild-type GAD65. Patients with latent autoimmune diabetes in adults (n=24) showed a similar reduction in binding (79% reduction, p<0.0001). First-degree relatives who subsequently progressed to Type 1 diabetes (n=12) showed a reduction in binding of 80% compared with a reduction of only 65% among relatives who had not progressed to disease (n=38; p=0.025). In healthy GAD65Ab-positive individuals who did not progress to diabetes during a 9-year follow-up period (n=51), binding to GAD65-E517P was reduced by only 28% compared with binding to wild-type GAD65. Conclusions/interpretation. Differences in autoantibody binding to wild-type GAD65 versus GAD65-E517P may provide predictive information about Type 1 diabetes risk beyond that provided by the presence or absence of GAD65 autoantibodies. Lack of binding to mutant GAD65-E517P defines GAD65-positive individuals who are at higher risk of developing diabetes

Structural and chemical embrittlement of grain boundaries by impurities: a general theory and first principles calculations for copper

First principles calculations of the Sigma 5 (310)[001] symmetric tilt grain boundary in Cu with Bi, Na, and Ag substitutional impurities provide evidence that in the phenomenon of Bi embrittlement of Cu grain boundaries electronic effects do not play a major role; on the contrary, the embrittlement is mostly a structural or "size" effect. Na is predicted to be nearly as good an embrittler as Bi, whereas Ag does not embrittle the boundary in agreement with experiment. While we reject the prevailing view that "electronic" effects (i.e., charge transfer) are responsible for embrittlement, we do not exclude the role of chemistry. However numerical results show a striking equivalence between the alkali metal Na and the semi metal Bi, small differences being accounted for by their contrasting "size" and "softness" (defined here). In order to separate structural and chemical effects unambiguously if not uniquely, we model the embrittlement process by taking the system of grain boundary and free surfaces through a sequence of precisely defined gedanken processes; each of these representing a putative mechanism. We thereby identify three mechanisms of embrittlement by substitutional impurities, two of which survive in the case of embrittlement or cohesion enhancement by interstitials. Two of the three are purely structural and the third contains both structural and chemical elements that by their very nature cannot be further unravelled. We are able to take the systems we study through each of these stages by explicit computer simulations and assess the contribution of each to the nett reduction in intergranular cohesion. The conclusion we reach is that embrittlement by both Bi and Na is almost exclusively structural in origin; that is, the embrittlement is a size effect.Comment: 13 pages, 5 figures; Accepted in Phys. Rev.

2018 Ottawa consensus statement : Selection and recruitment to the healthcare professions

Acknowledgments: The authors thank Tom Kinirons and Sarah Stott of Work Psychology Group for supporting the consensus group discussions and workshops, and in preparing the final manuscript. We also gratefully acknowledge Professor Lambert Schuwirth for his helpful comments on an earlier draft of this paperPeer reviewedPostprin