Antisense-induced ribosomal frameshifting

Programmed ribosomal frameshifting provides a mechanism to decode information located in two overlapping reading frames by diverting a proportion of translating ribosomes into a second open reading frame (ORF). The result is the production of two proteins: the product of standard translation from ORF1 and an ORF1–ORF2 fusion protein. Such programmed frameshifting is commonly utilized as a gene expression mechanism in viruses that infect eukaryotic cells and in a subset of cellular genes. RNA secondary structures, consisting of pseudoknots or stem–loops, located downstream of the shift site often act as cis-stimulators of frameshifting. Here, we demonstrate for the first time that antisense oligonucleotides can functionally mimic these RNA structures to induce +1 ribosomal frameshifting when annealed downstream of the frameshift site, UCC UGA. Antisense-induced shifting of the ribosome into the +1 reading frame is highly efficient in both rabbit reticulocyte lysate translation reactions and in cultured mammalian cells. The efficiency of antisense-induced frameshifting at this site is responsive to the sequence context 5′ of the shift site and to polyamine levels

Optimization of Ribosome Structure and Function by rRNA Base Modification

BACKGROUND: Translating mRNA sequences into functional proteins is a fundamental process necessary for the viability of organisms throughout all kingdoms of life. The ribosome carries out this process with a delicate balance between speed and accuracy. This work investigates how ribosome structure and function are affected by rRNA base modification. The prevailing view is that rRNA base modifications serve to fine tune ribosome structure and function. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, yeast strains deficient in rRNA modifications in the ribosomal peptidyltransferase center were monitored for changes in and translational fidelity. These studies revealed allele-specific sensitivity to translational inhibitors, changes in reading frame maintenance, nonsense suppression and aa-tRNA selection. Ribosomes isolated from two mutants with the most pronounced phenotypic changes had increased affinities for aa-tRNA, and surprisingly, increased rates of peptidyltransfer as monitored by the puromycin assay. rRNA chemical analyses of one of these mutants identified structural changes in five specific bases associated with the ribosomal A-site. CONCLUSIONS/SIGNIFICANCE: Together, the data suggest that modification of these bases fine tune the structure of the A-site region of the large subunit so as to assure correct positioning of critical rRNA bases involved in aa-tRNA accommodation into the PTC, of the eEF-1A•aa-tRNA•GTP ternary complex with the GTPase associated center, and of the aa-tRNA in the A-site. These findings represent a direct demonstration in support of the prevailing hypothesis that rRNA modifications serve to optimize rRNA structure for production of accurate and efficient ribosomes

RRx-001, A novel dinitroazetidine radiosensitizer

The ‘holy grail’ in radiation oncology is to improve the outcome of radiation therapy (RT) with a radiosensitizer—a systemic chemical/biochemical agent that additively or synergistically sensitizes tumor cells to radiation in the absence of significant toxicity. Similar to the oxygen effect, in which DNA bases modified by reactive oxygen species prevent repair of the cellular radiation damage, these compounds in general magnify free radical formation, leading to the permanent “fixation” of the resultant chemical change in the DNA structure. The purpose of this review is to present the origin story of the radiosensitizer, RRx-001, which emerged from the aerospace industry. The activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews

The first stage in the formation of the uranium deposit of Arlit, Niger: Role of a new non-continental organic matter

International audienceThe uranium deposits of Arlit are located in fluvial sandstone rich in organic matter of continental origin (type III) deposited in palaeochannels. Previous studies on Arlit deposits documented that organic matter of continental origin (type III) was the main contributor to the reduction of uranium from the oxidation state of uranium(VI) (U(VI)) to uranium(IV) (U(IV)). This study shows that migrated oils of non-continental origin strongly contributed to the genesis of uranium mineralization. The petrographic analyses showed that (i) solid bitumen, resulting from the polymerization of migrated oils, is present in abundance in the porosity of the sandstone and fractures at the level of the channels of the Tarat Formation (Tamou, Takriza, Southern Taza) and Guézouman Formation (mine sector of Akouta), and (ii) uranium mineralization is mainly associated with this migrated organic matter currently expressed in the form of solid bitumen. The association occurs at an infra-micrometric scale in the solid bitumen. The geochemical analysis, Rock-Eval, Py-GC-MS and GC–MS and the analysis of different indicators and biomarkers (n-alkanes, Pr/Ph, steranes…) indicate the presence of a second organic matter with a different signature to Type –III. The oils present in the porosity of the sandstone of the Guézouman and Tarat formations confirm that channels of these two formations are the traps of the oil migration

Building Healthy Tribal Nations in Montana and Wyoming Through Collaborative Research and Development

We describe a collaborative approach to reducing health disparities affecting Montana and Wyoming tribal nations while promoting health-protective practices and interventions among these populations. Under the auspices of the Montana-Wyoming Tribal Leaders Council, a consortium has undertaken activities to (1) establish the research infrastructure necessary for conducting ongoing health disparities research, (2) develop a target research agenda that addresses tribally identified priority health issues and tests the feasibility of interventions, (3) develop increased research skills and cultural competency through mentoring activities, and (4) develop effective collaborative relationships. All research projects are user-defined and -authorized, and participation is voluntary