No description available.

No description available.

The catalytic N-oxidation of alkylpyridines, a reaction which uses hydrogen peroxide as the oxidizing agent and the water soluble phosphotungstic acid as the catalyst, is a reaction employed in the pharmaceutical industry. The safety concerns of this process revolve around the decomposition of hydrogen peroxide and the liquid-liquid phase separation of the reacting mixture. The decomposition of hydrogen peroxide is an undesired reaction parallel to the desired N-oxidation and is responsible for: 1) a high potential for runaway due to the condition sensitivity of the peroxide group, 2) a potential over-pressurization of the reaction vessel during a runaway due to the production of oxygen, and 3) the enrichment with oxygen of the flammable alkylpyridine environment. The presence of an organic phase and an aqueous phase occurs in a wide range of conditions and results in: 1) a dramatic reduction in the reaction selectivity, and consequently in the efficiency, due to the additional mass transfer constrains imposed by the phase separation, and 2) the safety of the process being seriously compromised because most of the catalyst remains in the aqueous phase, excessively promoting the decomposition of hydrogen peroxide over the N-oxidation. With these concerns in mind, this research aimed to determine conditions for an inherently safer and more efficient N-oxidation reaction and focused on three key targets: i) the possibility of reducing the extend of the decomposition of hydrogen peroxide, thus leading to an inherently safer process, ii) the study of phase equilibrium so as to enable the identification of conditions that increase the efficiency of the N-oxidation and reduces the hazards, and iii) the evaluation of safety parameters that will allow for the control of a potential runaway reaction. Two alkylpyridines were considered: 2-methylpyridine which represents the case of a homogeneous reacting mixture and 2,6-dimethylpyridine to study the two-liquid phase separation effects. The methodology employed calorimetric studies to assess the runaway behavior and to determine the conditions that favor the N-oxidation, and for the N-oxidation of 2,6-dimethylpyridine, thermodynamic studies were incorporated to evaluate the conditions for phase separation.

Reactive hazard associated with chemicals is a major safety issue in process industries. This kind of hazard has caused the occurrence of many accidents, leading to fatalities, injuries, property damage and environment pollution. Reactive hazards can be eliminated or minimized by applying Inherently Safer Design (ISD) principles such as "substitute" or "moderate" strategies. However, ISD would not be a feasible option for industry without an efficient methodology for chemical hazard assessment, which provides the technical basis for applying ISD during process design. In this research, a systematic chemical hazard assessment methodology was developed for assisting the implementation of ISD in the design of inherently safer process. This methodology incorporates the selection of safer chemicals and determination of safer process conditions, which correspond to "substitute" and "moderate" strategies in ISD. The application of this methodology in conjunction with ISD technique can effectively save the time and investment spent on the process design. As part of selecting safer chemicals, prediction models were developed for predicting hazardous properties of reactive chemicals. Also, a hazard index was adopted to rate chemicals according to reactive hazards. By combining the prediction models with the hazard index, this research can provide important information on how to select safer chemicals for the processes, which makes the process chemistry inherently safer. As part of determining safer process conditions, the incompatibility of Methyl Ethyl Ketone Peroxide (MEKPO) with iron oxide was investigated. It was found that iron oxide at low levels has no impact on the reactive hazards of MEKPO as well as the operational safety. However, when iron oxide is beyond 0.3 wt%, it starts to change the kinetics of MEKPO runaway reaction and even the reaction mechanism. As a result, with the presence of a certain level of iron oxide (> 0.3 wt%), iron oxide can intensify the reactive hazards of MEKPO and impose higher risk to process operations. The investigation results can help to determine appropriate materials for fabricating process equipment and safer process conditions.

Gas hydrates are known to form plugs in pipelines. Hydrate plug dissociation times can be predicted using the CSMPlug program. At high methane mole fractions of a methane + ethane mixture the predictions agree with experiments for the relative dissociation times of structure I (sI) and structure II (sII) plugs. At intermediate methane mole fractions the predictions disagree with experiment. Enthalpies of dissociation were measured and predicted with the Clapeyron equation. The enthalpies of dissociation for the methane + ethane hydrates were found to vary significantly with pressure, the composition, and the structure of hydrate. The prediction and experimental would likely agree if this variation in the enthalpy of dissociation was taken in to account. In doing the plug dissociation studies at high methane mole fraction a discontinuity was observed in the gas evolution rate and X-ray diffraction indicated the possibility of the presence of both sI and sII hydrate structures. A detailed analysis by step-wise modelling utilising the hydrate prediction package CSMGem showed that preferential enclathration could occur. This conclusion was supported by experiment. Salts such as tetraisopentylammonium fluoride form semi-clathrate hydrates with melting points higher than 30 ℃ and vacant cavities that can store cages such as methane and hydrogen. The stability of this semi-clathrate hydrate with methane was studied and the dissociation phase boundary was found to be at temperatures of about (25 to 30) K higher than that of methane hydrate at the same pressure.

Heat acclimation increases the local heat loss responses of sweating and skin blood flow which is thought to persist for up to 3 weeks post-acclimation. However, the extent to which increases in local heat loss affect whole-body heat loss as a function of increasing levels of heat stress remains unresolved. Using direct calorimetry, we examined changes in whole-body evaporative heat loss (EHL) during progressive increases in metabolic heat production 1) prior to (Day 0), during (Day 7) and following a 14-day heat acclimation protocol (Day 14) – Induction phase, and; 2) at the end of a 1-week (Day 21) and 2-week decay period (Day 28) – Decay phase. Ten males performed intermittent exercise (3 x 30-min (min) bouts of cycling at 300 (Ex1), 350 (Ex2), and 400 watts•meters2 (W•m2) (Ex3) separated by 10 and 20 min rest periods, respectively). During the induction period, EHL at Day 7 was increased at each of the three exercise bouts (Ex1: + 6%; Ex2 +8%; Ex3: +13%, all p≤0.05) relative to Day 0 (EHL at Ex1: 529 W; Ex2: 625 W; Ex3: 666 W). At Day 14, EHL was increased for all three exercise bouts compared to Day 0 (Ex1: 9%; Ex2: 12%; Ex3: 18%, all p≤0.05). As a result, a lower cumulative change in body heat content (ΔHb) was measured at Day 7 (-30%, p≤0.001) and Day 14 (-47%, p≤0.001). During the decay phase, EHL at Day 21 and 28 was only reduced in Ex 3 (p≤0.05) compared to Day 14. In parallel, ΔHb increased by 39% (p=0.003) and 57% (p≤0.001) on Day 21 and Day 28 relative to Day 14, respectively. When Day 28 was compared to Day 0, EHL remained elevated in each of the exercise bouts (p≤0.05). As such, ΔHb remained significantly lower on Day 28 compared to Day 0 (-16%, p=0.042). We show that 14 days of heat acclimation increases whole-body EHL during exercise in the heat which is maintained 14 days post-acclimation.

Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 µM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo. Pey, A. L., Martinez, A., Charubala, R., Maitland, D. J., Teigen, K., Calvo, A., Pfleiderer, W., Wood, J. M., Schallreuter, K. U. Specific interaction of the diastereomers 7(R)- and 7(S)-tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 µM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo. / ¿ ¿

Zugl.: Halle (Saale), Univ., Diss., 2008

Stuttgart, Univ., Diss., 2000.

Growth hormone signaling influences longevity but the mechanism through which decreased GH action extends lifespan in mice is unknown. It is likely that the key to understanding this phenomenon, and the process of aging itself, is to understand the alterations in metabolism caused by decreased GH action. We investigated changes in energy metabolism in long-lived mice, in hope that these findings can suggest means of improving human health and longevity. These studies consisted of three projects. The influence of altered GH signaling on metabolism was tested by monitoring oxygen consumption, respiratory quotient, and heat production. Intriguingly, long-lived mice have increased oxygen consumption, and decreased respiratory quotient; while short lived mice had opposite effects. These data indicate that decreased GH signaling associates with increased metabolism per unit of body weight and may beneficially affect mitochondrial flexibility by increasing the capacity for fat oxidation; while GH excess generally produces opposite metabolic effects. We then hypothesized that the metabolic characteristics observed in young long-lived mice would persist into old age. Further, we investigated whether caloric restriction or every-other-day diet, two life extending feeding regimens, had any interaction with the metabolic phenotype observed in long-lived mice. The results support our hypothesis that the alterations in metabolism observed in young long-lived mice persist into old age. Neither dietary regimen significantly altered oxygen consumption in GHRKO mice, however, every-other-day diet reduced 24-hour oxygen consumption per gram body weight. These experiments showed that GHRKO mice had increased oxygen consumption regardless of age and life extending dietary interventions we placed them on. We hypothesized that increased oxygen consumption in long-lived mice is the result of increased thermogenesis. To test this hypothesis, we measured oxygen consumption in long-lived mice and controls at the standard lab temperature 23°C, and at 30°C, the murine thermoneutral temperature. When the oxygen consumption of long-lived mice was measured at 30°C, the differences between long-lived and normal mice measured at 23°C were abrogated. These data indicate that increased energy utilization for thermogenesis may contribute to extended longevity of these mutants. Collectively, our results provide important insights into the metabolic characteristics of long-lived mice.