394 research outputs found
Functional Studies of Novel Bioactives From Complex Host-Microbiomes as Drug Leads for Cancer, Infectious Disease, Depression and Pain
The drug discovery process has become increasingly complex in comparison to early efforts particularly those involving diseases or conditions that affect large numbers of the human population. It is difficult to point directly to one factor leading evolution of the process but the definition of a mechanism of pharmacological action for a drug lead has noticeably become a higher priority. This evolution has helped diminish the stigma of natural products and compound supply issues. The issue of compound supply has also been addressed to some extent with the emergence of recombinant technologies and new synthetic methodology. With approximately 60 years of research performed after the development of SCUBA, the drug discovery opportunities in the sea are still too numerous to count. Since the FDA approval of the direct-from-the-sea calcium channel blocker Prialt (ziconotide), marine natural products has been validated as a source for new medicines. However, the demand for natural products is extremely high due to the development of high-throughput assays and this bottleneck has created the need for an intense focus on increasing the rate of isolating and elucidating new bioactive secondary metabolites. A cystine-rich peptide asteropusin A (ASPA) was isolated from the marine sponge Asteropus sp. and its structure determined by X-ray crystallography and NMR spectroscopy. Administration of ASPA to veratridine-stimulated cerebrocortical neuron cells enhances calcium influx but does not modify the oscillation frequency or amplitude of the neuronal calcium alone. Ion channel modulation is an emerging target for drug therapy and the discovery of an ion channel interacting knottin from Porifera accompanied by such high quality spatial details is an uncomcombination. Improvements made to the isolation of peptide metabolites from marine sponges of the Family Theonellidae enables the isolation of significant amounts of potential angiogenesis inhibitors like theopapuamide with high purity. The improvements are particularly relevant in future cases where nuisance components like the aurantoside dyes can lead to false indications of cytotoxicity or antifungal activity. The elucidation of a new theopapuamide analog by CID-MS from Theonella invaginata indicates the high level of peptide diversity found within this Family. Two functional studies of marine natural products contribute to the understanding of their mechanisms of biological activity which can provide insight into their future development as drugs. In the first study, aaptamine was found to possess anxiolytic effects in vivo using a chick anxiety model. A large number of neurological receptors and enzymes were screenedin vitro. In vivo functional challenges were then performed to validate the anxiolytic targetamong several putative candidates previously identified by the in vitro studies. The results of those challenges eliminated several anxiety linked receptor targets and indicated aaptamine as a modulator of monoamine oxidase inhibition activity in vivo as an alternative explanation. The second functional study evaluates new latrunculin B analogs and their correlation of predicted binding with G-actin to the inhibition of polymerization. The latrunculins are well-studied sponge derived inhibitors of actin polymerization and the results validate a method for in silico prediction activity this cancer drug target. Natural products which are isolated in high yields can imply the absence of a utility for humans considering that discovery efforts areprimarily focused on producing drug and agrochemical agents. However, compounds which are abundant in one organism imply an ecological impact that can be studied for the development of an alternative use. A significant quantity of fragrant oil was obtained from a Jamaican Plakortis sp. by cryo-trap. The oil was determined to be exclusively n-decan-2-one. The antifouling character of the oil was evaluated by its effects on surface attachment of a Gram negative bacterial model using confocal fluorescence microscopy as well as its effects on the attachment of Dreissena polymorpha (zebra mussel). The ketone ( n-decan-2-one) inhibited attachment of the bacteria and zebra mussels. Although the aliphatic ketone alone is not a potential commercial alternative for antifouling coatings, incorporating the functionality into coating design is a feasible alternative. The unusual amount of oil extracted from the imported fire ant ( Solenopsis sp.) may be an indication of the presence of oleaginous microorganisms or enzymes supporting the digestion of raw sugars. Heat of combustion of the ant oil was 133,000 BTU/gal, an amount within the range of reported values for vegetable oil and biodiesel. This investigation offers a unique perspective of a potentially new source of microorganisms or enzymes useful for reducing the cost of producing an alternative fuel
Concentration, temperature, and density in a hydrogen-air flame by excimer-induced Raman scattering
Single-pulse, vibrational Raman scattering (VRS) is an attractive laser diagnostic for the study of supersonic hydrogen-air combustion. The VRS technique gives a complete thermodynamic description of the gas mixture at a point in the reacting flow. Single-pulse, vibrational Raman scattering can simultaneously provide independent measurements of density, temperature, and concentration of each major species (H2, H2O, O2 and N2) in a hydrogen/air turbulent combustor. Also the pressure can be calculated using the ideal gas law. However, single-pulse VRS systems in current use for measurement of turbulent combustion have a number of shortcomings when applied to supersonic flows: (1) slow repetition rate (1 to 5 Hz), (2) poor spatial resolution (0.5x0.3x0.3 cu mm), and (3) marginal time resolution. Most of these shortcomings are due to the use of visible wavelength flash-lamp pumped dye lasers. The advent of UV excimer laser allows the possibility of dramatic improvements in the single-pulse, vibrational Raman scattering. The excimer based VRS probe will greatly improve repetition rate (100 to 500 Hz), spatial resolution (0.1x0.1x0.1 cu mm) and time resolution (30ns). These improvements result from the lower divergence of the UV excimer, higher repetition rate, and the increased Raman cross-sections (15 to 20 times higher) at ultra-violet (UV) wavelengths. With this increased capability, single-pulse vibrational Raman scattering promises to be an ideal non-intrusive probe for the study of hypersonic propulsion flows
Punishment in an Early Colonial Society: The Inglorious History of Wellington Gaol, 1844–1931
In 1844, a replica of the famous Pentonville Prison was built in Wellington, New Zealand, shortly after the commencement of British colonisation. It never matched the size and scope of the London original and was demolished in 1931. However, the existence of this incongruous New Zealand institution raises important sociological issues. First, it will be argued that it had symbolic importance in maintaining settler identity with the homeland. Second, it had a functional importance in terms of the way it represented the ability of the colonial government to subdue any recalcitrant who sought to challenge the authority of British imperial power. Third, its closure came about because of longstanding pressure from local citizens, for whom its presence had become an unwanted stain on the otherwise untainted local landscape, reflecting New Zealand’s transition from a frontier society to a modern society with the sensibilities associated with it
Settling the Reward Hypothesis
The reward hypothesis posits that, "all of what we mean by goals and purposes
can be well thought of as maximization of the expected value of the cumulative
sum of a received scalar signal (reward)." We aim to fully settle this
hypothesis. This will not conclude with a simple affirmation or refutation, but
rather specify completely the implicit requirements on goals and purposes under
which the hypothesis holds
Glimmerglass Volume 29 Number 10 (1969)
Official Student Newspaper
Issue is 14 pages long
Glimmerglass Volume 29 Number 10 (1969)
Official Student Newspaper
Issue is 14 pages long
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