This work involves the characterization of two genes using mouse models of gene deficiency and thus has two focuses: Focus I: Innate immune responses are vital for pathogen defence but can result in septic shock when excessive. A key mediator of septic shock is TNFα, which is shed into intercellular spaces after cleavage from the plasma membrane by the protease TACE. Here we report that the rhomboid family member iRhom2 interacts with TACE and regulates TNFα shedding in vitro and in vivo. Compared to controls, gene-targeted iRhom2-deficient mice showed reduced serum TNFα after LPS challenge survived a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to adequately control the replication of Listeria monocytogenes and thus succumbed to even mild infections. Our study has identified iRhom2 as a novel regulator of innate immunity that may be an important target for modulating sepsis and pathogen defence. Focus II: Smg1 is a phosphatidylinositol 3-kinase-related kinase (PIKK) associated with multiple cellular functions, including DNA damage responses, telomere maintenance, and nonsense-mediated mRNA decay (NMD). NMD degrades transcripts that harbour premature termination codons (PTCs) due to events such as mutation or alternative splicing (AS). Recognition of PTCs during NMD requires the action of the Upstream frameshift protein Upf1, which must first be phosphorylated by Smg1. However, the physiological function of mammalian Smg1 is not known. Using a gene-trap model of Smg1 deficiency, we show that this kinase is essential for mouse embryogenesis such that Smg1 loss is lethal at embryonic day 8.5 (E8.5). High-throughput RNA sequencing (RNA-Seq) of RNA from cells of Smg1-deficient embryos revealed that Smg1 depletion led to pronounced accumulation of PTC-containing splice variant transcripts from ~9% of genes predicted to contain AS events capable of eliciting NMD. Among these genes are those involved in splicing itself, as well as genes not previously known to be subject to AS-coupled NMD, including several involved in transcription, intracellular signalling, membrane dynamics, cell death and metabolism. Our results demonstrate a critical role for Smg1 in early mouse development and link the loss of this NMD factor to major and widespread changes in the mammalian transcriptome.

This work involves the characterization of two genes using mouse models of gene deficiency and thus has two focuses: Focus I: Innate immune responses are vital for pathogen defence but can result in septic shock when excessive. A key mediator of septic shock is TNFα, which is shed into intercellular spaces after cleavage from the plasma membrane by the protease TACE. Here we report that the rhomboid family member iRhom2 interacts with TACE and regulates TNFα shedding in vitro and in vivo. Compared to controls, gene-targeted iRhom2-deficient mice showed reduced serum TNFα after LPS challenge survived a lethal LPS dose. Furthermore, iRhom2-deficient mice failed to adequately control the replication of Listeria monocytogenes and thus succumbed to even mild infections. Our study has identified iRhom2 as a novel regulator of innate immunity that may be an important target for modulating sepsis and pathogen defence. Focus II: Smg1 is a phosphatidylinositol 3-kinase-related kinase (PIKK) associated with multiple cellular functions, including DNA damage responses, telomere maintenance, and nonsense-mediated mRNA decay (NMD). NMD degrades transcripts that harbour premature termination codons (PTCs) due to events such as mutation or alternative splicing (AS). Recognition of PTCs during NMD requires the action of the Upstream frameshift protein Upf1, which must first be phosphorylated by Smg1. However, the physiological function of mammalian Smg1 is not known. Using a gene-trap model of Smg1 deficiency, we show that this kinase is essential for mouse embryogenesis such that Smg1 loss is lethal at embryonic day 8.5 (E8.5). High-throughput RNA sequencing (RNA-Seq) of RNA from cells of Smg1-deficient embryos revealed that Smg1 depletion led to pronounced accumulation of PTC-containing splice variant transcripts from ~9% of genes predicted to contain AS events capable of eliciting NMD. Among these genes are those involved in splicing itself, as well as genes not previously known to be subject to AS-coupled NMD, including several involved in transcription, intracellular signalling, membrane dynamics, cell death and metabolism. Our results demonstrate a critical role for Smg1 in early mouse development and link the loss of this NMD factor to major and widespread changes in the mammalian transcriptome.

No description available.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1995. / Includes bibliographical references. / Microfiche. / xii, 148 leaves, bound ill. 29 cm

Wood poles are popular and widely used in the Power Supply Industries in all over the world because of their high strength per unit weight, low installation and maintenance costs and excellent durability. Reliability of these components depends on a complex combination of age, usage, component durability, inspection, maintenance actions and environmental factors influencing decay and failure of components. Breakdown or failure of any one or more of these components can lead to outage and cause a huge loss to any organisation. Therefore, it is extremely important to predict the next failure to prevent it or reduce its effect by appropriate maintenance and contingency plans. In Australia, more than 5.3 million wooden poles are in use. This represents an investment of around AU$ 12 billion with a replacement cost varying between AU$1500-2500 per pole. Well-planned inspection and maintenance strategies considering the effect of environmental and human factors can extend the reliability and safety of these components. Maintenance and sophisticated inspection is worthwhile if the additional costs are less than the savings from the reduced cost of failures. Objectives of this research are to: * Investigate decay patterns of timber components based on age and environmental factors (e.g. clay composition) for power supply wood pole in the Queensland region. * Develop models for optimizing inspection schedules and Maintenance plans. Deterioration of wood poles in Queensland is found mostly due to inground soil condition. It is found that the moisture content, pH value (Acidity/ alkalinity), bulk density, salinity and electrical conductivity have influence over the deterioration process. Presence of Kaolin or Quartz has some indirect effect on the degradation process. It allows more water to be trapped inside the soil that cause algae, moss and mould to grow and attack the wood poles. On the other hand, by virtue of permeability, soils with high quartz content allows more water to infiltrate, preventing the growth of micro-organism. This research has increased fundamental understanding of inground wood decay process, developed testing methods for soil factors and proposed integrated models for performance improvement through optimal inspection, repair and replacement strategies considering durability, environmental and human factors in maintenance decisions. A computer program is also developed to analyse "what if" scenario for managerial decisions. This research has enhanced knowledge on the wood decay process in diverse environmental conditions. The outcomes of this research are important, not only to users of timber components with ingrond decay but also to the wood industry in general (the housing sector, railways for wooden sleepers and other structural applications such as timber bridges). Three refereed conference papers have already come out of this research and two more papers for refereed journal publication are in the process. This research can be extended to develop models for: * Qualitative as well as quantitative research database on lab/field wood decay process; * Assessment of the residual life of timber infrastructure; * Optimal condition monitoring and maintenance plans for timber components showing inground decay; And * Cost effective decisions for prevention of timber components and mitigation. Findings of this research can be applied to other equipment or assets showing time dependent failure rate and can be extended further to consider age/usage replacement policies, downtime and liability costs.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniversitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (p. 100-102).

Thesis--University of California, Berkeley, 1960. / "Chemistry General" -t.p. Includes bibliographical references (p. 70-73).

Η μελέτη της διπλής διάσπασης βήτα έχει πρωτεύουσα σπουδαιότητα για τη φυσική των νετρίνων. Θεωρείται ως ο καλύτερος τρόπος για να εξεταστεί ο θεμελιώδης χαρακτήρας των νετρίνων και να καθοριστεί η μάζα τους. Από πειραματικής πλευράς περίπου εννέα διαφορετικού τύπου ισότοπα χρησιμοποιούνται στα πειράματα. Μετά από μια γενική εισαγωγή ακολουθεί μια σύντομη συζήτηση σχετικά με τη φυσική των νετρίνων και της παρουσίας τους στις β διασπάσεις. Η πειραματική προσέγγιση, οι δυσκολίες που αντιμετωπίζουμε καθώς και η τρέχουσα πειραματική κατάσταση στις διπλές βήτα διασπάσεις συζητιούνται, ακολουθούμενες από μια σύντομη συζήτηση των ιδεών και των προτάσεων των μελλοντικών πειραμάτων που σχεδιάζονται. / Double beta decay research has a major role in neutrino physics. It is considered the best way to examine the nature of neutrinos and to determine their mass. From an experimental point of view, nine different isotopes are being used in the experiments. After a general introduction, a brief discussion about neutrino physics and their role in beta decays will follow. The experimental approach, the difficulties that we face and the current double beta decay experiments will be discussed, followed by another summary of the ideas and the proposals of the future experiments.

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