Molybdenum-99 is the most important isotope because its daughter isotope, technetium-99 m, has been the most widely used medical radioisotope. The primary method employed to produce Mo-99 derives ...from the fission of U-235 incorporated in so-called irradiation targets. Pushed by the international Mo-99 crisis that occurred in 2009/2010, Brazil has decided to construct a new research reactor, the Brazilian Multipurpose Reactor (RMB), to produce this vital radioisotope to meet the Brazilian domestic demand. As part of this effort, it has been developed the process for manufacturing the target to be used in the production of Mo-99 by nuclear fission. The low enriched uranium (LEU) aluminide with the predominant phase UAl2 was the starting material. The picture-frame technique was used to clad UAl2–Al briquette with aluminum to obtain plate-type targets. It was developed an innovative method that allows increasing the productivity of this type of target based on multi-core rolling. A thermomechanical treatment was designed to get targets composed basically of a mixture of UAl3/UAl4 that are the required phases for a proper radiochemical dissolution after irradiation. The manufacturing process proved to be suitable for domestic production of targets, fulfilling the specification to produce Mo-99 in the Brazilian Multipurpose Reactor.
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•Increasing productivity in manufacturing dispersion plate-type targets.•A novel procedure to fabricate dispersion plate-type targets for Mo-99 production.•Low-cost irradiation targets for cheaper Mo-99 production.•Decreasing dispersion plate-type targets production cost for Mo-99 production.•Decreasing cost of the target manufacture for Mo-99 production.
Amyloid beta (Abeta) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress ...have been implicated in Abeta-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Abeta-induced neuronal cell death. Abeta activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1-/- neurons were defective in Abeta-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease.
Endoplasmic reticulum (ER) stress transducers transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. BBF2 human homolog on chromosome 7 (BBF2H7) and ...old astrocyte specifically induced substance (OASIS), ER-resident transmembrane proteins, have recently been identified as novel ER stress transducers that have roles in chondrogenesis and osteogenesis, respectively. However, the molecular mechanisms that regulate the activation of BBF2H7 and OASIS under ER stress conditions remain unresolved. Here, we showed that BBF2H7 and OASIS are notably unstable proteins that are easily degraded via the ubiquitin-proteasome pathway under normal conditions. ER stress conditions enhanced the stability of BBF2H7 and OASIS, and promoted transcription of their target genes. HMG-CoA reductase degradation 1 (HRD1), an ER-resident E3 ubiquitin ligase, ubiquitinated BBF2H7 and OASIS under normal conditions, whereas ER stress conditions dissociated the interaction between HRD1 and BBF2H7 or OASIS. The stabilization of OASIS in Hrd1(-/-) cells enhanced the expression of collagen fibers during osteoblast differentiation, whereas a knockdown of OASIS in Hrd1(-/-) cells suppressed the production of collagen fibers. These findings suggest that ER stress stabilizes OASIS family members and this is a novel molecular mechanism for the activation of ER stress transducers.
β‐Cell death is an important pathogenic component of both type 1 and type 2 diabetes. Recent findings indicate that cell signalling pathways emanating from the endoplasmic reticulum (ER) play an ...important role in the regulation of β‐cell death during the progression of diabetes. Homeostasis within the ER must be maintained to produce properly folded secretory proteins, such as insulin, in response to the body's need for them. However, the sensitive protein‐folding environment in the ER can be perturbed by genetic and environmental factors leading to ER stress. To counteract ER stress, β‐cells activate cell signalling pathways termed the unfolded protein response (UPR). The UPR functions as a binary switch between life and death, regulating both survival and death effectors. The outcome of this switch depends on the nature of the ER stress condition, the regulation of UPR activation and the expression and activation of survival and death components. This review discusses the mechanisms and the components in this switch and highlights the roles of this UPR's balancing act between life and death in β‐cells.
Endoplasmic reticulum (ER) stress-mediated cell death has an important role in the pathogenesis of chronic diseases, including diabetes and neurodegeneration. Although proapoptotic programs activated ...by ER stress have been extensively studied, identification and characterization of antiapoptotic programs that counteract ER stress are currently incomplete. Through the gene expression profiling of beta-cells lacking Wolfram syndrome 1 gene (WFS1), a causative gene for Wolfram syndrome, we discovered a novel antiapoptotic gene of the unfolded protein response (UPR), apoptosis antagonizing transcription factor (AATF). Here, we study the regulation of AATF, identify its target genes, and determine the basis for its antiapoptotic activities in response to ER stress. We show that AATF is induced by ER stress through the PERK-eIF2alpha pathway and transcriptionally activates the v-akt murine thymoma viral oncogene homolog 1 (AKT1) gene through signal transducer and activator of transcription 3 (Stat3), which sustains Akt1 activation and promotes cell survival. Ectopic expression of AATF or a constitutively active form of AKT1 confers on cells resistance to ER stress-mediated cell death, whereas RNAi-mediated knockdown of AATF or AKT1 renders cells sensitive to ER stress. We also discovered a positive crosstalk between the AATF and WFS1 signaling pathways. Thus, WFS1 deficiency or AATF deficiency mediates a self-perpetuating cycle of cell death. Our results reveal a novel antiapoptotic program relevant to the treatment of diseases caused by ER stress-mediated cell death.
We previously identified a stromal cell-derived inducing activity (SDIA), which induces differentiation of neural cells, including midbrain tyrosine hydroxylase-positive (TH+)dopaminergic neurons, ...from mouse embryonic stem cells. We report here that SDIA induces efficient neural differentiation also in primate embryonic stem cells. Induced neurons contain TH+neurons at a frequency of 35% and produce a significant amount of dopamine. Interestingly, differentiation of TH+neurons from undifferentiated embryonic cells occurs much faster in vitro (10 days) than it does in the embryo (≈5 weeks). In addition, 8% of the colonies contain large patches of Pax6+-pigmented epithelium of the retina. The SDIA method provides an unlimited source of primate cells for the study of pathogenesis, drug development, and transplantation in degenerative diseases such as Parkinson's disease and retinitis pigmentosa.
Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
Genetic analysis of the cellular adaptation to malfolded proteins in the endoplasmic reticulum (the unfolded protein response - UPR) has revealed a novel signaling pathway initiated by activation of ...IRE1, an ER-resident protein kinase and endonuclease. In yeast, Ire1p activates gene expression by promoting a non-conventional splicing event that converts the mRNA encoding the Hac1p transcription factor from an inefficiently translated inactive mRNA to an actively translated one. Hac1p binds to the promoters of genes encoding chaperones and other targets of the UPR and activates them. Recently, mammalian IRE1 homologues have been identified and their response to ER stress is regulated by binding to the ER chaperone BiP. The mechanisms by which mammalian IRE1 activates gene expression have not been completely characterized and mammalian HAC1 homologues have not been identified. Surprisingly, mammalian IRE1s are able to activate both JUN N-terminal kinases and an alternative ER-stress signaling pathway mediated by the transcription factor ATF6. This indicates that the mammalian UPR is more complex than that found in yeast.
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•The larvicidal activity of m-pentadecadienyl-phenol is based on the compound structure.•Proteomic analysis of larvae of Aedes aegypti after exposure to m-pentadecadienyl phenol ...showed 12 spots differentially expressed.•The natural insecticide caused elevated detoxification response.•The insecticide caused overexpression of proteins that could indicate generation of reactive oxygen species and liberation of lysosomal content.•Proteins overexpressed may lead to responses of apoptotic pathways.
Nowadays, dengue fever is considered the most important arbovirosis worldwide and its control is still based upon combating the vector Aedes aegypti. Besides monitoring of mosquito populations resistant to conventional insecticides, the search for new environmentally safe insecticides and conduction of molecular studies focusing on the elucidation of mode of action and possible resistance mechanisms are considered the key for a sustainable management of the mosquito vector. Thus, the present work aimed to assess changes in protein expression of 3rd-instar larvae of Ae. aegypti after exposure to the natural insecticide m-pentadecadienyl-phenol. Bidimensional electrophoresis followed by mass spectrometry resulted in identification of 12 proteins differentially expressed between control and treated groups. Larvae exposed to the toxic compound for 24h showed elevated detoxification response (glutathione-S-transferase), increased levels of stress-related proteins (HSP70) as well as evidence of lysosome stabilization to enable survival. Furthermore, expression of proteins involved in protection of peritrophic membrane and metabolism of lipids indicated systemic effect of toxic effects in treated larvae.
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