Plutonium storage phenomenology

Plutonium has been produced, handled, and stored at Department of Energy (DOE) facilities since the 1940s. Many changes have occurred during the last 40 years in the sources, production demands, and end uses of plutonium. These have resulted in corresponding changes in the isotopic composition as well as the chemical and physical forms of the processed and stored plutonium. Thousands of ordinary food pack tin cans have been used successfully for many years to handle and store plutonium. Other containers have been used with equal success. This paper addressees the exceptions to this satisfactory experience. To aid in understanding the challenges of handling plutonium for storage or immobilization the lessons learned from past storage experience and the necessary countermeasures to improve storage performance are discussed

The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist

The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other’s TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes

The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist

The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other’s TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes

Host-parasite co-metabolic activation of antitrypanosomal aminomethyl-benzoxaboroles

<div><p>Recent development of benzoxaborole-based chemistry gave rise to a collection of compounds with great potential in targeting diverse infectious diseases, including human African Trypanosomiasis (HAT), a devastating neglected tropical disease. However, further medicinal development is largely restricted by a lack of insight into mechanism of action (MoA) in pathogenic kinetoplastids. We adopted a multidisciplinary approach, combining a high-throughput forward genetic screen with functional group focused chemical biological, structural biology and biochemical analyses, to tackle the complex MoAs of benzoxaboroles in <i>Trypanosoma brucei</i>. We describe an oxidative enzymatic pathway composed of host semicarbazide-sensitive amine oxidase and a trypanosomal aldehyde dehydrogenase TbALDH3. Two sequential reactions through this pathway serve as the key underlying mechanism for activating a series of 4-aminomethylphenoxy-benzoxaboroles as potent trypanocides; the methylamine parental compounds as pro-drugs are transformed first into intermediate aldehyde metabolites, and further into the carboxylate metabolites as effective forms. Moreover, comparative biochemical and crystallographic analyses elucidated the catalytic specificity of TbALDH3 towards the benzaldehyde benzoxaborole metabolites as xenogeneic substrates. Overall, this work proposes a novel drug activation mechanism dependent on both host and parasite metabolism of primary amine containing molecules, which contributes a new perspective to our understanding of the benzoxaborole MoA, and could be further exploited to improve the therapeutic index of antimicrobial compounds.</p></div

The role of extracellular vesicles in malaria biology and pathogenesis

In the past decade, research on the functions of extracellular vesicles in malaria has expanded dramatically. Investigations into the various vesicle types, from both host and parasite origin, has revealed important roles for extracellular vesicles in disease pathogenesis and susceptibility, as well as cell-cell communication and immune responses. Here, work relating to extracellular vesicles in malaria is reviewed, and the areas that remain unknown and require further investigations are highlighted

White paper on possible inclusion of mixed plutonium-uranium oxides in DOE-STD-3013-96

This report assesses stabilization issues concerning mixed plutonium-uranium oxides containing 50 mass % Pu. Possible consequences of uranium substitution on thermal stabilization, specific surface areas, moisture readsorption behavior, loss-on-ignition analysis, and criticality safety of the oxide are examined and discussed

Remote-Reading Safety and Safeguards Surveillance System for 3013 Containers

At Hanford's Plutonium Finishing Plant (PFP), plutonium oxide is being loaded into stainless steel containers for long-term storage on the Hanford Site. These containers consist of two weld-sealed stainless steel cylinders nested one within the other. A third container holds the plutonium within the inner cylinder. This design meets the U.S. Department of Energy (DOE) storage standard, DOE-STD- 3013-2000, which anticipates a 50-year storage lifetime. The 3013 standard also requires a container surveillance program to continuously monitor pressure and to assure safeguards are adequate. However, the configuration of the container system makes using conventional measurement and monitoring methods difficult. To better meet the 3013 monitoring requirements, a team from Fluor Hanford (who manages the PFP), Pacific Northwest National Laboratory (PNNL), and Vista Engineering Technologies, LLC, developed a safer, cost-efficient, remote PFP 3013 container surveillance system. This new surveillance system is a combination of two successfully deployed technologies: (1) a magnetically coupled pressure gauge developed by Vista Engineering and (2) a radio frequency (RF) tagging device developed by PNNL. This system provides continuous, 100% monitoring of critical parameters with the containers in place, as well as inventory controls. The 3013 container surveillance system consists of three main elements: (1) an internal magnetic pressure sensor package, (2) an instrument pod (external electronics package), and (3) a data acquisition storage and display computer. The surveillance system described in this paper has many benefits for PFP and DOE in terms of cost savings and reduced personnel exposure. In addition, continuous safety monitoring (i.e., internal container pressure and temperature) of every container is responsible nuclear material stewardship and fully meets and exceeds DOE's Integrated Surveillance Program requirements