Molecular dynamics simulations suggest that RNA three-way junctions can act as flexible RNA structural elements in the ribosome

We present extensive explicit solvent molecular dynamics analysis of three RNA three-way junctions (3WJs) from the large ribosomal subunit: the 3WJ formed by Helices 90–92 (H90–H92) of 23S rRNA; the 3WJ formed by H42–H44 organizing the GTPase associated center (GAC) of 23S rRNA; and the 3WJ of 5S rRNA. H92 near the peptidyl transferase center binds the 3′-CCA end of amino-acylated tRNA. The GAC binds protein factors and stimulates GTP hydrolysis driving protein synthesis. The 5S rRNA binds the central protuberance and A-site finger (ASF) involved in bridges with the 30S subunit. The simulations reveal that all three 3WJs possess significant anisotropic hinge-like flexibility between their stacked stems and dynamics within the compact regions of their adjacent stems. The A-site 3WJ dynamics may facilitate accommodation of tRNA, while the 5S 3WJ flexibility appears to be essential for coordinated movements of ASF and 5S rRNA. The GAC 3WJ may support large-scale dynamics of the L7/L12-stalk region. The simulations reveal that H42–H44 rRNA segments are not fully relaxed and in the X-ray structures they are bent towards the large subunit. The bending may be related to L10 binding and is distributed between the 3WJ and the H42–H97 contact

A Forward-Genetic Screen and Dynamic Analysis of Lambda Phage Host-Dependencies Reveals an Extensive Interaction Network and a New Anti-Viral Strategy

Latently infecting viruses are an important class of virus that plays a key role in viral evolution and human health. Here we report a genome-scale forward-genetics screen for host-dependencies of the latently-infecting bacteriophage lambda. This screen identified 57 Escherichia coli (E. coli) genes—over half of which have not been previously associated with infection—that when knocked out inhibited lambda phage's ability to replicate. Our results demonstrate a highly integrated network between lambda and its host, in striking contrast to the results from a similar screen using the lytic-only infecting T7 virus. We then measured the growth of E. coli under normal and infected conditions, using wild-type and knockout strains deficient in one of the identified host genes, and found that genes from the same pathway often exhibited similar growth dynamics. This observation, combined with further computational and experimental analysis, led us to identify a previously unannotated gene, yneJ, as a novel regulator of lamB gene expression. A surprising result of this work was the identification of two highly conserved pathways involved in tRNA thiolation—one pathway is required for efficient lambda replication, while the other has anti-viral properties inhibiting lambda replication. Based on our data, it appears that 2-thiouridine modification of tRNAGlu, tRNAGln, and tRNALys is particularly important for the efficient production of infectious lambda phage particles

Polluants environnementaux et croissance du squelette (effets des arylhydrocarbures sur les chondrocytes de cartilage de croissance in vitro)

La combustion du tabac libère de nombreux hydrocarbures polyaromatiques (benzo(a)pyrène, BaP) ligands du récepteur des Arylhydrocarbures (AhR) qui s ajoutent aux autres ligands AhR produits par la pollution industrielle (Dioxines, dont TCDD). Connaissant les effets développementaux des agonistes AhR (tabagisme de la femme enceinte) sur la croissance fœtale et infantile, nous avons voulu déterminer si le cartilage était une cible de cette pollution environnementale.Nous étudions l expression du récepteur AhR dans les chondrocytes de croissance (CR) et articulaires (AR) en hypoxie et normoxie. Nous étudions la fonctionnalité du récepteur AhR dans ces tissus et les conditions de cette fonctionnalité. Nous recherchons des gènes cibles des agonistes AhR dans le cartilage et les mécanismes de leurs effets.Nous montrons que le récepteur AhR est exprimé dans les chondrocytes, plus dans les CR que AR. Dans les conditions basales, AhR reste cytoplasmique et ne répond pas à ses agonistes. Un préconditionnement par l IL-1 induit AhR qui est alors fonctionnel et répond à ses agonistes, mais exclusivement en normoxie. La synergie entre IL-1 et la TCDD ou le BaP induit l expression de Cyp1A1 et inhibe celle de MMP-13 de manière AhR-dépendante dans les chondrocytes CR. Les agonistes AhR induisent l expression de IL-1 et de IL-1ra, mais ces effets sont indépendants du AhR.Nous discutons nos résultats sur la fonction du AhR et de ses agonistes dans le cartilage, sur le plan physiologique et pathologique. Nous concluons que le cartilage est bien une nouvelle cible de la pollution environnementale et nous proposons des développements futurs pour ce travail.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Resveratrol, Potential Therapeutic Interest in Joint Disorders: A Critical Narrative Review

Trans-resveratrol (t-Res) is a natural compound of a family of hydroxystilbenes found in a variety of spermatophyte plants. Because of its effects on lipids and arachidonic acid metabolisms, and its antioxidant activity, t-Res is considered as the major cardioprotective component of red wine, leading to the “French Paradox” health concept. In the past decade, research on the effects of resveratrol on human health has developed considerably in diverse fields such as cancer, neurodegenerative and cardiovascular diseases, and metabolic disorders. In the field of rheumatic disorders, in vitro evidence suggest anti-inflammatory, anti-catabolic, anti-apoptotic and anti-oxidative properties of t-Res in various articular cell types, including chondrocytes and synoviocytes, along with immunomodulation properties on T and B lymphocytes. In preclinical models of osteoarthritis and rheumatoid arthritis, resveratrol has shown joint protective effects, mainly mediated by decreased production of pro-inflammatory and pro-degradative soluble factors, and modulation of cellular and humoral responses. Herein, we comprehensively reviewed evidence supporting a potential therapeutic interest of t-Res in treating symptoms related to rheumatic disorders