Ventilatory Phenotypes among Four Strains of Adult Rats.

Our purpose in this study was to identify different ventilatory phenotypes among four different strains of rats. We examined 114 rats from three in-house, inbred strains and one outbred strain: Brown Norway (BN;n = 26), Dahl salt-sensitive (n = 24), Fawn-hooded Hypertensive (FHH: n = 27), and outbred Sprague-Dawley rats (SD; n = 37). We measured eupneic (room air) breathing and the ventilatory responses to hypoxia (12% O2-88% N2), hypercapnia (7% CO2), and two levels of submaximal exercise. Primary strain differences were between BN and the other strains. BN rats had a relatively attenuated ventilatory response to CO2 (P \u3c 0.001), an accentuated ventilatory response to exercise (P \u3c 0.05), and an accentuated ventilatory roll-off during hypoxia (P \u3c 0.05). Ventilation during hypoxia was lower than other strains, but hyperventilation during hypoxia was equal to the other strains (P \u3e 0.05), indicating that the metabolic rate during hypoxia decreased more in BN rats than in other strains. Another strain difference was in the frequency and timing components of augmented breaths, where FHH rats frequently differed from the other strains, and the BN rats had the longest expiratory time of the augmented breaths (probably secondary to the blunted CO2 sensitivity). These strain differences not only provide insight into physiological mechanisms but also indicate traits (such as CO2 sensitivity) that are genetically regulated. Finally, the data establish a foundation for physiological genomic studies aimed at elucidating the genetics of these ventilatory control mechanisms

Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting

Sudden infant death syndrome and the central nervous system: a review of the triple-risk theory

Sudden infant death syndrome (SIDS) is the devastating condition in which an infant suddenly and unexplainably passes away over the course of sleeping. This is an unfortunate situation that many new parents dread every night as they lay their newborns to rest. SIDS is the leading cause of death in infants aged from one month to one year, and the medical world still does not fully understand what causes it. However, the triple-risk theory is a new model that sets out to explain the pathology of this syndrome through the combination of genetic vulnerabilities, a critical time period, and external stressors. This thesis summarizes the current research in the realm of the central nervous system (specifically the cerebellum and brainstem) as a means of evaluating the validity of this new model. The analyzed literature concentrated on a few important topics, such as proven risk factors, evidence of homeostatic abnormalities, and significant associations with the occurrence of SIDS. It was found that there was central nervous system dysfunction on most levels, including: damaged Purkinje cells in the cerebellum, malformations of the human choroid plexus, decreased neuropeptide signaling (both orexin and brain-derived neurotrophic factors), malformations of the amino acid neurotransmitters (both excitatory glutamate and inhibitory GABA), and finally significant reductions in the receptor density and activity of the serotonin system. These irregularities were associated, in most studies, with either the prone sleeping position or known maternal nicotine use during pregnancy. In conclusion, the triple-risk model is currently the most accurate description of SIDS, given its reasonable three criteria and present-day research. This is because the studies, and real-life victims, were all concentrated within the critical time period of transition from intra-uterine to extra-uterine life, satisfying the first element of timing. The list of central nervous system dysfunctions found in SIDS cases was compelling enough to fulfill the second factor of inherent vulnerability. Finally, the associations between low oxygen rebreathing and the prone sleep position, or over-heating and tight swaddling displayed a strong relationship with the occurrence of SIDS and satisfied the third and final event, which was the induction of an exogenous stressor. These three factors of the triple-risk model allow for the variations in victim pathology, but still offers a compelling and coherent understanding of the sudden infant death syndrome

The Spectacular Radio-Near-IR-X-ray Jet of 3C 111: X-ray Emission Mechanism and Jet Kinematics

Relativistic jets are the most energetic manifestation of the active galactic nucleus (AGN) phenomenon. AGN jets are observed from the radio through gamma-rays and carry copious amounts of matter and energy from the sub-parsec central regions out to the kiloparsec and often megaparsec scale galaxy and cluster environs. While most spatially resolved jets are seen in the radio, an increasing number have been discovered to emit in the optical/near-IR and/or X-ray bands. Here we discuss a spectacular example of this class, the 3C 111 jet, housed in one of the nearest, double-lobed FR II radio galaxies known. We discuss new, deep Chandra and HST observations that reveal both near-IR and X-ray emission from several components of the 3C 111 jet, as well as both the northern and southern hotspots. Important differences are seen between the morphologies in the radio, X-ray and near-IR bands. The long (over 100 kpc on each side), straight nature of this jet makes it an excellent prototype for future, deep observations, as it is one of the longest such features seen in the radio, near-IR/optical and X-ray bands. Several independent lines of evidence, including the X-ray and broadband spectral shape as well as the implied velocity of the approaching hotspot, lead us to strongly disfavor the EC/CMB model and instead favor a two-component synchrotron model to explain the observed X-ray emission for several jet components. Future observations with NuSTAR, HST, and Chandra will allow us to further constrain the emission mechanisms.Comment: 12 pages, 9 figures, ApJ, in pres

Preparation and humidity sensitive impedance of spinel ceramic nickel germanate

This thesis concerns the formation, sintering and humidity dependent electrical behaviour of the spinel ceramic material nickel germanate, Ni(_2)Ge0(_4).Ni(_2)Ge0(_4) has been prepared via the solid state reaction between NiO and GeO(_2) over a range of temperatures, and characterised using a number of techniques. The sintering behaviour of pressed pellets of Ni(_2)Ge0(_4) has also been investigated, together with a characterisation of the microstructure of the sintered bodies. Substitutional doping of Ni(_2)GeO(_4) with Li as a replacement for Ni is found to promote a high degree of shrinkage in the sintering process, probably due to the formation of a liquid phase. XRD revealed that even when 10 % of the Ni atoms were replaced with Li, no change in the crystal structure could be detected. A C. impedance spectroscopy of Ni(_2)Ge0(_4) samples was used to investigate the humidity sensitivity of this material. Equivalent circuit analysis, based on a network of resistors and constant phase elements, shows that the humidity sensitivity is due to conduction in a surface layer of water, in agreement with the models currently popular in the Uterature. Measurement of the water adsorption isotherm of Ni(_2)Ge0(_4) in pellet form indicates that a single monolayer of water is formed at around 20 %R(_H), with an approximately linear increase in water layer thickness up to around 80 %R(_H), after which capillary condensation causes a large increase in the volume of adsorbed water. The information gained on the thickness of this layer of water has been correlated with the resistance of the layer measured by impedance spectroscopy, and subsequently used to provide evidence for a model of the humidity sensitive conduction. The conduction in the surface layer is thought to be due to dissociation of the water, where the amount of dissociation is exponentially dependent on the humidity

Process issues in redox biocatalysis: Cyclohexanone monooxygenase catalysed chiral lactone syntheses

This thesis investigates the Baeyer-Villiger oxidation of cyclic ketones to optically enriched lactones by the enzyme cyclohexanone monooxygenase (CHMO), cloned into Escherichia coli JM107 pQR210. Two model substrates were selected (2-hexyl cyclopentanone and 4-methyl cyclohexanone) to conduct investigations with. A major constraint found was that whole cell catalysis produced low reaction rates and poor enzyme stability. Isolated enzyme was stabilised effectively by using elevated levels of the cofactor NADPH. Recycle of the expensive NADPH was investigated by detailed studies of thermostable glucose and alcohol dehydrogenases. These were characterised by marked product inhibition. Alcohol dehydrogenase from Thermoanaerobacter brockii (TBADH) was chosen for the ease of removal of the acetone product from the system and the high affinity for NADPH. The interaction between CHMO and TBADH was modeled by simultaneous numerical integration of their rate equations leading to an understanding of the effect of different enzyme ratios on system performance. This model also predicts the conditions necessary to maximise cofactor stability and re-usability. Quantification of a range of processing strategies was performed, fed-batch operation was found to be 2.5 times more productive than batch. Multi-gram syntheses of lactones were performed at 2L scale with both free and immobilised enzymes. NADPH recycle was effective at producing over 700 reaction cycles. Immobilised CHMO was found to be significantly more stable than free enzyme under process conditions, a catalyst with retained activity of 12% and specific activity of 1.2Ug-1 was produced. TBADH produced 42% retained and 13.6Ug-1 specific activity. Co-immobilisation of both enzymes on the same support produced a catalyst with an activity of 0.6Ug-1

A test facility for assessing the performance of IEC61850 substation automation designs

Substation Automation Systems have undergone dramatic changes since the introduction of powerful micro-processing and digital communications devices over Ethernet based networks within the substation. Smart, multifunctional relays, known as Intelligent Electronic Devices, or IEDs, have replaced the traditional panels which contained multiple protection relays, control equipment, metering and status indicators. ActewAGL Distribution, a power utility company servicing Canberra, Australia, has recently decided to undertake a review of its substation automation systems throughout its electrical network. As a result, ActewAGL Distribution has decided to investigate the IEC 61850 – Communication Networks and Systems in Substations standard, by constructing a test facility to assess its performance and capability with the view of implementing the standard into its 132/11kV zone substations network in the near future. This report details the literature review, design, construction, and performance evaluation that was undertaken on the IEC 61850 substation automation designs developed with the use of the test facility. The major achievement of this research project has been the successful development and evaluation of a substation automation system that utilised the IEC 61850 standard incorporated with multiple vendor devices