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Translation of proteins is a fundamental part of gene expression that is mediated by ribosomes. As ribosomes significantly contribute to both cellular mass and energy consumption, achieving efficient management of the ribosome population is also crucial to metabolism and growth. Inspired by biological evidence for nutrient-dependent mechanisms that control both ribosome-active degradation and genesis, we introduce a dynamical model of protein production, that includes the dynamics of resources and control over the ribosome population. Under the hypothesis that active degradation and biogenesis are optimal for maximizing and maintaining protein production, we aim to qualitatively reproduce empirical observations of the ribosome population dynamics. Upon formulating the associated optimization problem, we first analytically study the stability and global behaviour of solutions under constant resource input, and characterize the extent of oscillations and convergence rate to a global equilibrium. We further use these results to simplify and solve the problem under a quasi-static approximation. Using biophysical parameter values, we find that optimal control solutions lead to both control mechanisms and the ribosome population switching between periods of feeding and fasting, suggesting that the intense regulation of ribosome population observed in experiments allows to maximize and maintain protein production. Finally, we find some range for the control values over which such a regime can be observed, depending on the intensity of fasting.

Antibody microarray data provides a powerful and high-throughput tool to monitor global changes in cellular response to perturbation or genetic manipulation. However, while collecting such data has become increasingly accessible, a lack of specific computational tools has made their analysis limited. Here we present CAT PETR, a user friendly web application for the differential analysis of expression and phosphorylation data collected via antibody microarrays. Our application addresses the limitations of other GUI based tools by providing various data input options and visualizations. To illustrate its capabilities on real data, we show that CAT PETR both replicates previous findings, and reveals additional insights, using its advanced visualization and statistical options., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Conventional dimensionality reduction methods like Multidimensional Scaling (MDS) are sensitive to the presence of orthogonal outliers, leading to significant defects in the embedding. We introduce a robust MDS method, called DeCOr-MDS (Detection and Correction of Orthogonal outliers using MDS), based on the geometry and statistics of simplices formed by data points, that allows to detect orthogonal outliers and subsequently reduce dimensionality. We validate our methods using synthetic datasets, and further show how it can be applied to a variety of large real biological datasets, including cancer image cell data, human microbiome project data and single cell RNA sequencing data, to address the task of data cleaning and visualization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Mirone, Prasad, Miolane, Legrand and Dao Duc.)

Recent advances in Cryo-EM led to a surge of ribosome structures deposited over the past years, including structures from different species, conformational states, or bound with different ligands. Yet, multiple conflicts of nomenclature make the identification and comparison of structures and ortholog components challenging. We present RiboXYZ (available at https://ribosome.xyz), a database that provides organized access to ribosome structures, with several tools for visualisation and study. The database is up-to-date with the Protein Data Bank (PDB) but provides a standardized nomenclature that allows for searching and comparing ribosomal components (proteins, RNA, ligands) across all the available structures. In addition to structured and simplified access to the data, the application has several specialized visualization tools, including the identification and prediction of ligand binding sites, and 3D superimposition of ribosomal components. Overall, RiboXYZ provides a useful toolkit that complements the PDB database, by implementing the current conventions and providing a set of auxiliary tools that have been developed explicitly for analyzing ribosome structures. This toolkit can be easily accessed by both experts and non-experts in structural biology so that they can search, visualize and compare structures, with various potential applications in molecular biology, evolution, and biochemistry., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The exit tunnel is the subcompartment of the ribosome that contains the nascent polypeptide chain and, as such, is involved in various vital functions, including regulation of translation and protein folding. As the geometry of the tunnel shows important differences across species, we focus on key geometrical features of eukaryote and prokaryote tunnels. We used a simple coarse-grained molecular dynamics model to study the role of the tunnel geometry in the post-translational escape of short proteins (short open reading frames [sORFs]) with lengths ranging from 6 to 56 amino acids. We found that the probability of escape for prokaryotes is one for all but the 12-mer chains. Moreover, proteins of this length have an extremely low escape probability in eukaryotes. A detailed examination of the associated single trajectories and energy profiles showed that these variations can be explained by the interplay between the protein configurational space and the confinement effects introduced by the constriction sites of the ribosome exit tunnel. For certain lengths, either one or both of the constriction sites can lead to the trapping of the protein in the "pocket" regions preceding these sites. As the distribution of existing sORFs indicates some bias in length that is consistent with our findings, we finally suggest that the constraints imposed by the tunnel geometry have impacted the evolution of sORFs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Ribosome profiling is a powerful technique which maps the distribution of ribosomes along mRNAs to analyze translation genome-wide. Ribosome density can be affected by multiple factors, such as changes to translation initiation or elongation rates. We describe the application of a metric for identifying genes rate-limited by these rates by analyzing the relative distribution of ribosome footprints along transcripts. This protocol also details two sample analyses comparing gene translation efficiencies and the distribution of ribosome densities on downloadable datasets. For complete details on the use and execution of this protocol, please refer to Flanagan et al. (2022)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Mutations in FMR1 are the most common heritable cause of autism spectrum disorder. FMR1 encodes an RNA-binding protein, FMRP, which binds to long, autism-relevant transcripts and is essential for normal neuronal and ovarian development. In contrast to the prevailing model that FMRP acts to block translation elongation, we previously found that FMRP activates the translation initiation of large proteins in Drosophila oocytes. We now provide evidence that FMRP-dependent translation is conserved and occurs in the mammalian brain. Our comparisons of the mammalian cortex and Drosophila oocyte ribosome profiling data show that translation of FMRP-bound mRNAs decreases to a similar magnitude in FMRP-deficient tissues from both species. The steady-state levels of several FMRP targets were reduced in the Fmr1 KO mouse cortex, including a ∼50% reduction of Auts2, a gene implicated in an autosomal dominant autism spectrum disorder. To distinguish between effects on elongation and initiation, we used a novel metric to detect the rate-limiting ribosome stalling. We found no evidence that FMRP target protein production is governed by translation elongation rates. FMRP translational activation of large proteins may be critical for normal human development, as more than 20 FMRP targets including Auts2 are dosage sensitive and are associated with neurodevelopmental disorders caused by haploinsufficiency., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America.)