Mutational Patterns in RNA Secondary Structure Evolution Examined in Three RNA Families

The goal of this work was to study mutational patterns in the evolution of RNA secondary structure. We analyzed bacterial tmRNA, RNaseP and eukaryotic telomerase RNA secondary structures, mapping structural variability onto phylogenetic trees constructed primarily from rRNA sequences. We found that secondary structures evolve both by whole stem insertion/deletion, and by mutations that create or disrupt stem base pairing. We analyzed the evolution of stem lengths and constructed substitution matrices describing the changes responsible for the variation in the RNA stem length. In addition, we used principal component analysis of the stem length data to determine the most variable stems in different families of RNA. This data provides new insights into the evolution of RNA secondary structures and patterns of variation in the lengths of double helical regions of RNA molecules. Our findings will facilitate design of improved mutational models for RNA structure evolution

The Diversification of the LIM Superclass at the Base of the Metazoa Increased Subcellular Complexity and Promoted Multicellular Specialization

Background: Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass. Results: We have identified and characterized all known LIM domain-containing proteins in six metazoans and three nonmetazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineagespecific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study. Conclusion: Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity

KIAA1109 Variants Are Associated with a Severe Disorder of Brain Development and Arthrogryposis.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands' features.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Synthesis of the safety studies carried out on the GFR2400

International audienceThe present paper is dedicated to the synthesis of the safety studies carried out on the 2400 MWthgas-cooled fast reactor (GFR2400) concept developed at CEA. The analysis of the reference design basisaccidents investigated up to now, has shown margins up to the acceptance criteria, equal at least to300 ◦C for the category 3 situations and larger than 100 ◦C for the category 4 situations. The dimensioningof the decay heat removal (DHR) loops and of the power conversion system (PCS) loops has beenshown adequate even for bounding degraded situations including multiple failures. Furthermore, in thefollowing part of the paper, it is shown how the main insights provided by a level 1 probabilistic safetyassessment (PSA) carried out at an early stage of the design, have led to reinforce the reliability of theDHR function in high pressure conditions by using the PCS as the first mean to cool the core; in the sametime, on the basis of a combination of deterministic augments and of PSA results, a design simplificationprocess has led to add a low pressure DHR loop to replace a high pressure DHR loop. The last sectionis dedicated to prevention and preliminary study of severe accidents (SA). Four SA families have beenidentified depending on the dynamics and on the scale of the considered accident. The possibility to preventcore degradation by using an adapted accident management (nitrogen injection, use of PCS loops)has been preliminarily shown in several particularly challenging situations (loss of active means, unprotectedtransients, full depressurization). Finally, preliminary results regarding analytical studies carriedout on phenomena involved in GFR2400 core degradation (physico-chemistry and neutron physics) arepresented. Then, the application of the separate results aforementioned by considering results of analyticalsimplified thermalhydraulic calculations and of system calculations (carried out with the CATHARE2code) have enabled a preliminary assessment of GFR2400 behaviour in case of core degradation. For som