9 research outputs found

    Co-evolution of quaternary organization and novel RNA tertiary interactions revealed in the crystal structure of a bacterial protein–RNA toxin–antitoxin system

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    Genes encoding toxin–antitoxin (TA) systems are near ubiquitous in bacterial genomes and they play key roles in important aspects of bacterial physiology, including genomic stability, formation of persister cells under antibiotic stress, and resistance to phage infection. The CptIN locus from Eubacterium rectale is a member of the recently-discovered Type III class of TA systems, defined by a protein toxin suppressed by direct interaction with a structured RNA antitoxin. Here, we present the crystal structure of the CptIN protein–RNA complex to 2.2 Å resolution. The structure reveals a new heterotetrameric quaternary organization for the Type III TA class, and the RNA antitoxin bears a novel structural feature of an extended A-twist motif within the pseudoknot fold. The retention of a conserved ribonuclease active site as well as traits normally associated with TA systems, such as plasmid maintenance, implicates a wider functional role for Type III TA systems. We present evidence for the co-variation of the Type III component pair, highlighting a distinctive evolutionary process in which an enzyme and its substrate co-evolve

    Reactor-produced radioisotopes from ORNL for bone pain palliation

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    The treatment of painful skeletal metastases is a common clinical problem, and the use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical. There are currently several metastatic-targeted agents radiolabeled with various therapeutic radionuclides which are in various stages of clinical investigation. Since neutron rich radionuclides are produced in research reactors and often decay by emission of beta(-) particles, most radionuclides used for bone pain palliation are reactor-produced. Key examples of radionuclides produced by single neutron capture of enriched targets include rhenium-186 and samarium-153. In addition, generator systems are also of interest which provide therapeutic daughter radionuclides from the decay of reactor-produced parent radionuclides. One important example is rhenium-188, available from generators via decay of reactor-produced tungsten-188. Tin-117m is an example of a reactor-produced radionuclide which decays with the emission of low-energy conversion electrons rather than by beta(-) decay. Each of these agents and/or radionuclides has specific advantages and disadvantages, however, the ideal agent for bone pain palliation has not yet been identified. The goal of this paper is to briefly review the production and use of several reactor-produced radionuclides for bone pain palliation, and to discuss the role of the ORNL High Flux Isotope Reactor(HFIR) for the production of many of these radionuclides

    Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs, aspirin, and corticosteroids.

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    Although non-steroidal anti-inflammatory drugs are known to cause peptic ulcer and its complications, controversy exists about the number of deaths from ulcer which are attributable to their use. A case-control study was therefore performed to determine whether prior use of non-steroidal and other anti-inflammatory compounds was associated with an increased case fatality rate from complications of peptic ulcer. Non-steroidal anti-inflammatory drugs were used by 39% of a series of 80 patients who had died from peptic ulcer complications and by 37% of 160 controls who were survivors matched for sex, age, ulcer site, and nature of complication (odds ratio 1.1; 95% confidence interval 0.6 to 2.1). Similarly, the rates of prior use of aspirin by cases and controls were almost identical (odds ratio 1.2; 95% confidence interval 0.5 to 1.9). Thus neither nonsteroidal anti-inflammatory drugs nor aspirin were associated with increased case fatality rates from peptic ulcer complications. In contrast, corticosteroids were associated with an increased mortality (odds ratio 4.2; 95% confidence interval 0.9 to 25.6). Although this increase in the estimated relative risk was not statistically significant, a review of the case records indicated that most deaths in steroid users were due to serious sepsis, indicating that there might be a causal association between use of the drugs and the mode of death
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