No description available.

No description available.

Increasing drug resistance towards the front line influenza neUraminidase inhibitor Oseltamivir (Tamiflu®, Roche) has recently been reported, emphasising the need to perform further studies to gain insight into receptor ligand interactions. Recently, influenza neuraminidase activity has been tackled using a novel class of mechanism-based inactivator, which incorporates fluorine atoms at positions C-2 and C-3 of sialic acid. These inactivators are anticipated to be less susceptible to drug induced resistance as they target essential catalytic amino acids. However, individual hydrogen-bonding interactions formed between these inactivators and the neuraminidase in both the Michaelis complex and at the transition-state remain unclear. The syntheses of the four novel monodeoxygenated 2,3-difluorosialic acid inactivators at position C-4,C-7, C-8 and C-9 deploying a Barton-McCombie protocol were accomplished. The time-dependant inactivation of wild type influenza neuraminidase N9 G70C by these monodeoxygenated 2,3-difluorosialic acid inactivators was tested in a fluorescent kinetic assay. Further biochemical evaluation (performed by our collaborators) in ICso measurements against a panel of influenza viruses including wild types (wt.) and Oseltamivir resistant mutants showed potent inhibition of influenza Band H1 N1 strains. We also wished to develop a further understanding of the effects of the monodeoxygenated 2,3-difluorosialic acid inactivators upon inactivation on a physical basis. Hence, we will discuss X-ray crystallographic structures, (obtained by our collaborators) of influenza neuraminidase N9 in complex with the monodeoxygenated 2,3-difluoro-sialic acid inactivators. 11

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This thesis examines the various aspects of catalytically deoxygenating biomass-derived feedstocks including the relevant catalyst materials, conditions and equipment. Preliminary investigations probed the ability of T316 SS, as a reactor material, to perform as an effective hydrogenation catalyst at temperatures above 100 oC, under reducing aqueous-acidic media. Additionally, an external apparatus was developed in order to facilitate the optimization of catalytic hydrogenations. The accuracy and applicability of this system was confirmed using the reduction of levulinic acid to γ-valerolactone. Accurate information pertaining to the quantity of hydrogen consumed was obtained in addition to in situ differential rates reaction allowing for the derivation of the integrated rate law. Subsequently, the newly designed uptake system was used to monitor, and effectively optimize, the deoxygenation of a series of complex furfural-derived substrates towards the attempted production of high-energy density fuels. Commercially available Pd/C and Ru/C catalysts were employed, unsuccessfully, under a variety of reaction conditions. / NSERC, Los Alamos National Laboratories, Ontario Innovation Trust

Over sixty years of oceanographic observations from Ocean Station Papa (OSP) in the northeast Pacific indicate the region is losing dissolved oxygen faster than the average global rate. The greatest negative trends in oxygen concentration occur on isopycnals in the upper water column (σθ = 26.1–26.8 kg m−3) but have considerable uncertainty due to natural variability near the surface. In this thesis, I use eight Argo profiling floats equipped with oxygen optode sensors to assess the 2008—2016 interannual variability of subsurface dissolved oxygen near OSP. I developed a method to implement a time-lag correction to the optode profiles using high frequency CTD data and used reference profiles from the OSP time series to calibrate the dissolved oxygen observations. The time-lag correction markedly improves subsurface bias caused by slow optode response time. The analysis of isopycnal properties indicates that episodic shoaling of the isopycnals can cause rapid reduction of the dissolved oxygen concentration. Changes in ventilation, horizontal mixing, and water mass age were assessed and deemed unlikely drivers for the rapid O2 loss events examined. The dissolved oxygen loss during shoaling events is linked to organic matter export, due to higher concentrations of organic matter and greater respiration rates at shallower depths. Reduced net community production during the “Blob” marine heatwave may have reduced the impact of the second shoaling event examined. Studying the natural variability of dissolved oxygen in these layers can provide context for the uncertainty in the long-term trends, as well as provide insight towards the future potential for extreme oxygen minima from the combined impacts of the long-term trend and natural variability. / Graduate / 2022-09-13

It is well known fact that energy is a big issue for this world and substantial amount of research is going on worldwide for alternative fuels that are environmentally friendly, especially because of the fact that crude petroleum reserves are dwindling. Also, research on alternative fuels is essential for increased energy security. Biodiesel is a renewable, biodegradable, and nontoxic fuel. At present, when homogeneous catalysts are used, biodiesel is primarily produced in batch reactors in which the required energy is provided by heating accompanied by mechanical mixing. Alternatively, ultrasonic processing could be an effective way to attain required mixing while providing the necessary activation energy. We found that, using ultrasonication, a biodiesel yield in excess of 99% can be achieved in a short time duration of five minutes or less in comparison to one hour or more using conventional batch reactor systems. Homogeneous acid or base catalysts dissolve fully in the glycerol layer and partially in the fatty acid methyl esters (biodiesel) layer during the triglyceride transesterification process. Heterogeneous (solid) catalysts, on the other hand, can prevent catalyst contamination making product separation much easier. In the present work, one of the objective was to determine the transesterification kinetics of different pure metal oxide catalysts, mixed metal oxide catalysts, layered double hydroxides with their corresponding yield is presented. It was found that heterogeneous catalysts require much higher temperatures (215oC) and pressures to achieve acceptable conversion levels compared to homogeneous catalysts. For some of the mixed metal oxide solid catalysts a conversion level of 99% was observed. The present study also deals with the catalyst characterization on the basis of their acidity/ basicity and site strength, and surface area. Finally the deoxygenation of fatty acid methyl esters was carried out in order to upgrade the biodiesel. As a result, several aliphatic and aromatic hydrocarbons were detected in the mass spectrometric studies. This dissertation consists of five chapters. Chapter I presents a brief introduction to biodiesel production and the objectives of the study. Chapter II contains a review of literature. Chapter III contains the materials and methods used in this study. In this chapter different principles and theories will be mentioned with regard to the use of ultrasonication towards biodiesel production, reaction kinetics of biodiesel production, catalyst characterizations and thermodynamic analysis of deoxygenation of fatty acid methyl esters. Chapter IV presents the results and its discussions. Finally, Chapter V discusses the summary and conclusions of the study.

The end-Triassic Mass Extinction (ETME) was one of the "Big 5" mass extinctions of the Phanerozoic and is thought to have been caused by a series of environmental changes triggered by the emplacement of the Central Atlantic Magmatic Province (CAMP). While the overall driver of the ETME is well-accepted, the specific roles of subsequent environmental changes in driving the extinction remain unresolved due to both spatial and temporal biases within existing geochemical records. Additionally, recent studies suggest that environmental deterioration may have preceded the emplacement of both CAMP and the ETME. Here, we present nitrogen isotope (δ15N) and iron speciation data from a sedimentary succession located in Grotto Creek, Alaska in order track changes in the marine nitrogen cycle and redox across the upper Norian Stage of the Triassic through lower Hettangain Stage of the Jurassic (~215 to 198 million years ago). The geologic succession at Grotto Creek represents deeper water marine deposition in eastern equatorial Panthalassa, likely capturing regional oceanic redox trends. δ15N records from Grotto Creek show a pronounced positive excursion of +3‰ that initiates in the upper Norian, peaks near the Norian-Rhaetian boundary (NRB; ~208.5), and declines through the ETME and into the Hettangian. Throughout this interval, iron speciation data show persistent anoxic conditions and occasional euxinia occurred in the local bottom waters. We propose that the positive δ15N and iron speciation data from Grotto Creek reflect a progressive deoxygenation of the upper water column with the expansion of the equatorial oxygen minimum zone (OMZ). Specifically, the δ15N excursion reflects a shift in the dominant processing of bioavailable nitrogen from uptake and nitrification under oxic conditions to incomplete denitrification followed by complete denitrification as deoxygenation progressed. Records from existing study sites in other regions of the Panthalassa reflect similar redox fluctuations and support that this deoxygenation was a regional phenomenon. Other recent studies of the Late Norian and Rhaetian also document declines in biodiversity that predate the ETME, as well as, carbon isotope excursions, likely reflecting perturbations to the carbon cycle. Together, this evidence suggests that increasingly low-oxygen conditions initiated at least ~8 Ma before the emplacement of CAMP and likely paved the way for the ETME. / Master of Science / The end-Triassic mass extinction (ETME) occurred ~ 201 million years ago and was associated with a large drop in global diversity. The extinction is thought to be due to a warming climate resulting from greenhouse gasses released during the eruption of the Central Atlantic Magmatic Province (CAMP). Although the ETME is one of the largest extinction events of the last ~500 million years, the environmental changes leading to the extinction, and before the CAMP eruption, are not well understood. We studied the Grotto Creek section in Alaska which is a sequence of sedimentary rocks that record the deep ocean environment from the ancient Panthalassa or Paleo-Pacific Ocean. This section also provides a relatively complete record of the time before, during, and after the ETME. Here, we present the stable isotopes of nitrogen (δ15N) from these rocks that show disturbances to the nitrogen cycling that occurred in the ocean more than ~ 8 million years before the ETME. We show that δ15N and iron data from Grotto Creek document falling ocean oxygen levels before the ETME. We also find that our δ15N agrees with other environmental proxies that also reflect declining oxygen levels in the oceans along with decreases in marine animal diversity well before the ETME. These geochemical records help to show a more complete picture of how environments changed in the Panthalassa before the ETME

No description available.

The cortistatins are a recently identified class of marine natural products that were found to exhibit potent and selective inhibition of human umbilical vein endothelial cells (HUVECs), making them promising leads for the development of anti-angiogenic drugs. In our synthesis, we envisioned that natural cortistatins and unnatural analogs could be prepared by late-stage introduction of isoquinolines to 17-keto precursors, and that these differentially substituted precursors could all be derived from a common key intermediate 112. We developed a robust synthetic route to prepare gram quantities of key intermediate 112 starting from readily available benzylzinc reagent 116 and enol triflate 117. Key intermediate 112 was next converted to cortistatin precursors 108, 109, 110, and 111 in three to eight steps, representing each of the four natural cortistatin ABC-ring substitution patterns. Subsequently, a generally applicable method was developed to introduce the isoquinoline moiety. After complexation to N,N,N',N'-tetramethylethylenediamine (TMEDA), 7-lithio-isoquinoline added to 17-keto precursors to provide the corresponding 1,2-addition products; the resulting tertiary alcohols underwent radical deoxygenation via their trifluoroacetates to afford the desired (17S)-products. This organolithium-addition-deoxygenation sequence provided cortistatins A (1, on a 20-mg scale), J (9), K (10), and L (11) in good overall yields. We also synthesized cortistatin primary amines (176 and 186) and used them to prepare several cortistatin based affinity reagents. By employing these reagents in pull-down experiments, we identified a 55-kD membrane kinase as a putative protein target of cortistatins. We wanted to prepare cortistatin analogs with isoquinoline modifications due to the importance of this ring for the biological activity of cortistatins. This led us to develop a novel and versatile synthesis of substituted isoquinolines. In our method, lithiated o-tolualdehyde tert-butylimines were condensed with different nitriles to generate eneamido anion intermediates, which were trapped in situ with various electrophiles at the C4-position, affording a wide range of substituted isoquinolines. Further diversification was achieved by modification of the work-up conditions and by subsequent transformations. / Chemistry and Chemical Biology