Certified reference materials for radionuclides in Bikini Atoll sediment (IAEA-410) and Pacific Ocean sediment (IAEA-412).

The preparation and characterization of certified reference materials (CRMs) for radionuclide content in sediments collected offshore of Bikini Atoll (IAEA-410) and in the open northwest Pacific Ocean (IAEA-412) are described and the results of the certification process are presented. The certified radionuclides include: (40)K, (210)Pb ((210)Po), (226)Ra, (228)Ra, (228)Th, (232)Th, (234)U, (238)U, (239)Pu, (239+240)Pu and (241)Am for IAEA-410 and (40)K, (137)Cs, (210)Pb ((210)Po), (226)Ra, (228)Ra, (228)Th, (232)Th, (235)U, (238)U, (239)Pu, (240)Pu and (239+240)Pu for IAEA-412. The CRMs can be used for quality assurance and quality control purposes in the analysis of radionuclides in sediments, for development and validation of analytical methods and for staff training.

Risk of hemoptysis in cystic fibrosis clinical trials: A retrospective cohort study.

BACKGROUND: Cystic fibrosis (CF) is characterized by airway infection and inflammation resulting in respiratory complications including hemoptysis. The objectives of this study were to characterize the risk of hemoptysis attributable to underlying disease and in the presence of standard of care therapy. METHODS: This retrospective cohort study estimated hemoptysis rates overall and by relevant risk factors utilizing adverse event data from longitudinal prospective CF clinical trials. RESULTS: Of the 1008 participants, 73% were ≤18 years old; of 929 with available spirometry, 27% had an FEV1<70% predicted. During the average 8.2 months of follow-up, 8% experienced ≥1 hemoptysis events (95% CI: 6%, 10%). Of the 125 events, 76% were mild in severity and only 9% were serious. Hemoptysis rates were greater among adults than children, those with FEV1<70% predicted, and participants infected with P. aeruginosa but not with S. aureus. CONCLUSIONS: Hemoptysis is a common adverse event among CF clinical trial participants, and particularly in adults with more severe lung disease. These results can be used to predict event occurrence in future clinical trials.

Certified Reference Material IAEA-446 for radionuclides in Baltic Sea seaweed.

A Certified Reference Material (CRM) for radionuclides in seaweed (Fucus vesiculosus) from the Baltic Sea (IAEA-446) is described and the results of the certification process are presented. The (40)K, (137)Cs, (234)U and (239+240)Pu radionuclides were certified for this material, and information values for 12 other radionuclides ((90)Sr, (99)Tc, (210)Pb ((210)Po), (226)Ra, (228)Ra, (228)Th, (230)Th, (232)Th, (235)U, (238)U, (239)Pu and (240)Pu) are presented. The CRM can be used for Quality Assurance/Quality Control of analysis of radionuclides in seaweed and other biota samples, as well as for development and validation of analytical methods, and for training purposes.

Degradation of cyclin D3 independent of Thr-283 phosphorylation.

Cyclin D3 has been shown to play a major role in the regulation of cell cycle progression in lymphocytes. It is therefore important to understand the mechanisms involved in the regulation of this protein. We have previously shown that both basal and cAMP-induced degradation of cyclin D3 in Reh cells is dependent on Thr-283 phosphorylation by glycogen synthase kinase-3beta (GSK-3beta). We now provide evidence of an alternative mechanism being involved in the regulation of cyclin D3 degradation. Treatment of lymphoid cells with okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), induces rapid phosphorylation and proteasomal degradation of cyclin D3. This degradation is not inhibited by the GSK-3beta inhibitors lithium or Kenpaullone, or by substitution of Thr-283 with Ala on cyclin D3, indicating that cyclin D3 can be degraded independently of Thr-283 phosphorylation and GSK-3beta activity. Interestingly, in vitro experiments revealed that PP1, but not PP2A, was able to dephosphorylate cyclin D3 efficiently, and PP1 was found to associate with His-tagged cyclin D3. These results support the hypothesis that PP1 constitutively keeps cyclin D3 in a stable, dephosphorylated state, and that treatment of cells with OA leads to phosphorylation and degradation of cyclin D3 through inhibition of PP1.

Finding regulatory modules through large-scale gene-expression data analysis.

MOTIVATION: The use of gene microchips has enabled a rapid accumulation of gene-expression data. One of the major challenges of analyzing this data is the diversity, in both size and signal strength, of the various modules in the gene regulatory networks of organisms. RESULTS: Based on the iterative signature algorithm [Bergmann,S., Ihmels,J. and Barkai,N. (2002) Phys. Rev. E 67, 031902], we present an algorithm-the progressive iterative signature algorithm (PISA)-that, by sequentially eliminating modules, allows unsupervised identification of both large and small regulatory modules. We applied PISA to a large set of yeast gene-expression data, and, using the Gene Ontology database as a reference, found that the algorithm is much better able to identify regulatory modules than methods based on high-throughput transcription-factor binding experiments or on comparative genomics.

Exact solution of a stochastic directed sandpile model.

We introduce and analytically solve a directed sandpile model with stochastic toppling rules. The model clearly belongs to a different universality class from its counterpart with deterministic toppling rules, previously solved by Dhar and Ramaswamy. The critical exponents are D(//)=7/4, tau=10/7 in two dimensions and D(//)=3/2, tau=4/3 in one dimension. The upper critical dimension of the model is three, at which the exponents apart from logarithmic corrections reach their mean-field values D(//)=2, tau=3/2.

Consequences of nucleic acid conformation on the binding of a trinuclear platinum drug.

BBR3464, a charged trinuclear platinum compound, is the first representative of a new class of anticancer drugs to enter phase I clinical trials. The structure of BBR3464 is characterized by two [trans-PtCl(NH(3))(2)] units linked by a tetraamine [trans-Pt(NH(3))(2)¿H(2)N(CH(2))(6)NH(2)¿(2)] unit. The +4 charge of BBR3464 and the separation of the platinating units indicate that the mode of DNA binding will be distinctly different from those of classical mononuclear drugs such as cisplatin, cis-[PtCl(2)(NH(3))(2)]. The reaction of BBR3464 with three different nucleic acid conformations was assessed by gel electrophoresis. Comparison of single-stranded DNA, RNA, and double-stranded DNA indicated that the reaction of BBR3464 with single-stranded DNA and RNA was faster than that with duplex DNA, and produced more drug-DNA and drug-RNA adducts. Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry was used to further characterize the binding modes of BBR3464 with the DNA substrates. BBR3464 binding to different nucleic acid conformations raises the possibility that the adducts of single-stranded DNA and RNA may play a role in the different antitumor efficacies of this novel drug as compared with cisplatin.

Sequence-dependent extrusion of a small DNA hairpin at the N4 virion RNA polymerase promoters.

Bacteriophage N4 virion RNA polymerase promoters contain five to seven-base inverted repeats separated by three bases and centered at position -12 from the site of transcription initiation. We have previously shown that these inverted repeats extrude as hairpins at physiological superhelical densities in a Mg(II)-dependent manner. Mg(II)-dependent hairpin extrusion at promoters P1 and P2 displays quantitative differences in reactivity to structural probes at different DNA superhelical densities, with extrusion at P2 being more favored at low superhelical density. Analyses of mutant promoters using structure-specific probes revealed that specific sequences, at the closing base-pair of the hairpin and at the loop (i.e. 5'-C-GXA-G-3' where X=G, A, T), are required for extrusion of the small promoter hairpins at physiological superhelical density. The sequence-dependent requirements for extrusion of the small N4 promoter hairpins may be generally applicable for other such sequences found both in prokaryotic and eukaryotic genomes.