Design and synthesis of potential antimicrobial agents

Chorismate mutase is one of the essential enzymes in the shikimate pathway and is key to the survival of the organism Mycobacterium tuberculosis. The x-ray crystal structure of this enzyme from Mycobacterium tuberculosis was manipulated to prepare an initial set of in silico protein models of the active site. Known inhibitors of the enzyme were docked into the active site using the flexible ligand / flexible active site side chains approach implemented in CAChe Worksystem (Fujitsu Ltd). The resulting complexes were refined by molecular dynamics studies in explicit water using Amber 9. This yielded a further set of protein models that were used for additional rounds of ligand docking. A binding hypothesis was established for the enzyme and this was used to screen a database of commercially available drug-like compounds. From these results new potential ligands were designed that fitted appropriately into the active site and matched the functional groups and binding motifs founds therein. Some of these compounds and close analogues were then synthesized and submitted for biological evaluation. As a separate part of this thesis, analogues of very active anti-tuberculosis pyridylcarboxamidrazone were also prepared. This was carried out by the addition and the deletion of the substitutions from the lead compound thereby preparing heteroaryl carboxamidrazone derivatives and related compounds. All these compounds were initially evaluated for biological activity against various gram positive organisms and then sent to the TAACF (USA) for screening against Mycobacterium tuberculosis. Some of the new compounds proved to be at least as potent as the original lead compound but less toxic.

The Value of Knowing that You Do Not Know

The value of knowing about data availability and system accessibility is analyzed through theoretical models of Information Economics. When a user places an inquiry for information, it is important for the user to learn whether the system is not accessible or the data is not available, rather than not have any response. In reality, various outcomes can be provided by the system: nothing will be displayed to the user (e.g., a traffic light that does not operate, a browser that keeps browsing, a telephone that does not answer); a random noise will be displayed (e.g., a traffic light that displays random signals, a browser that provides disorderly results, an automatic voice message that does not clarify the situation); a special signal indicating that the system is not operating (e.g., a blinking amber indicating that the traffic light is down, a browser responding that the site is unavailable, a voice message regretting to tell that the service is not available). This article develops a model to assess the value of the information for the user in such situations by employing the information structure model prevailing in Information Economics. Examples related to data accessibility in centralized and in distributed systems are provided for illustration.

Changing Bacterial Growth Efficiencies across a Natural Nutrient Gradient in an Oligotrophic Estuary

Recent studies have characterized coastal estuarine systems as important components of the global carbon cycle. This study investigated carbon cycling through the microbial loop of Florida Bay by use of bacterial growth efficiency calculations. Bacterial production, bacterial respiration, and other environmental parameters were measured at three sites located along a historic phosphorus-limitation gradient in Florida Bay and compared to a relatively nutrient enriched site in Biscayne Bay. A new method for measuring bacterial respiration in oligotrophic waters involving tracing respiration of 13C-glucose was developed. The results of the study indicate that 13C tracer assays may provide a better means of measuring bacterial respiration in low nutrient environments than traditional dissolved oxygen consumption-based methods due to strong correlations between incubation length and δ13C values. Results also suggest that overall bacterial growth efficiency may be lower at the most nutrient limited sites.

Estudo teórico de intermediários tetraédricos acidez / basicidade e estereosseletividade enzimáticos

The present work aimed first, the theoretical study of tetrahedral intermediate stability formed from carbonyl addition reactions using the second (MP2) and third (MP3) order Møller–Plesset perturbation theory. Linear correlations between electronic energy difference of reactions with Wiberg Indexes and C-O bond lengths were obtained, and was observed that the stability of adducts formed depends directly of electronic density involved between these atoms. The knowing of electronic parameters of these structures has an important hole due to the large use on reactions that in his course forms this tetrahedral intermediate. Employing the ONIOM (B3LYP:AMBER) methodology, was evaluated the stereoselectivity of a enzymatic reaction between CAL B enzyme and a long chain ester. In this study, were obtained the electronic energies of ground state and intermediate state of transesterification rate-determing step from two possible proquirals faces Re and Si. The objective was study the enantioselectivity of CAL B and rationalizes it using quantum theory of atoms in molecules (QTAIM). A theoretical study employing inorganic compounds was performed using ab initio CBS-QB3 method aiming to find a link between thermodynamic and equilibrium involving acids and bases. The results observed showed an excellent relationship between difference in Gibbs free energy, ΔG of acid dissociation reaction and ΔG of hydrolysis reaction of the corresponding conjugate base. It was also observed, a relationship between ΔG of hydrolysis reaction of conjugate acids and their corresponding atomic radius showing that stability plays an important role in hydrolysis reactions. The importance of solvation in acid/base behavior when compared to theoretical and experimental ΔG´s also was evaluated.

Novos protocolos teóricos utilizados nos estudos das ligações hidrogênio-hidrogênio, na estabilidade do tetraedrano, seus derivados e das reações de diels-alder e na quantificação da afinidade de fármacos

This thesis was performed in four chapters, at the theoretical level, focused mainly on electronic density. In the first chapter, we have applied an undergraduate minicourse of Diels-Alder reaction in Federal University of Rio Grande do Norte. By using computational chemistry tools students could build the knowledge by themselves and they could associate important aspects of physical-chemistry with Organic Chemistry. In the second chapter, we studied a new type of chemical bond between a pair of identical or similar hydrogen atoms that are close to electrical neutrality, known as hydrogen-hydrogen (H-H) bond. In this study performed with complexed alkanes, provides new and important information about their stability involving this type of interaction. We show that the H-H bond playing a secondary role in the stability of branched alkanes in comparison with linear or less branched isomers. In the third chapter, we study the electronic structure and the stability of tetrahedrane, substituted tetrahedranes and silicon and germanium parents, it was evaluated the substituent effect on the carbon cage in the tetrahedrane derivatives and the results indicate that stronger electron withdrawing groups (EWG) makes the tetrahedrane cage slightly unstable while slight EWG causes a greater instability in the tetrahedrane cage. We showed that the sigma aromaticity EWG and electron donating groups (EDG) results in decrease and increase, respectively, of NICS and D3BIA aromaticity indices. In addition, another factor can be utilized to explain the stability of tetra-tert-butyltetrahedrane as well as HH bond. GVB and ADMP were also used to explain the stability effect of the substituents bonded to the carbon of the tetrahedrane cage. In the fourth chapter, we performed a theoretical investigation of the inhibitory effect of the drug abiraterone (ABE), used in the prostate cancer treatment as CYP17 inhibitor, comparing the interaction energies and electron density of the ABE with the natural substrate, pregnenolone (PREG). Molecular dynamics and docking were used to obtain the CYP1ABE and CYP17-PREG complexes. From molecular dynamics was obtained that the ABE has higher diffusion trend water CYP17 binding site compared to the PREG. With the ONIOM (B3LYP:AMBER) method, we find that the interaction electronic energy of ABE is 21.38 kcal mol-1 more stable than PREG. The results obtained by QTAIM indicate that such stability is due a higher electronic density of interactions between ABE and CYP17

Student Independent Projects Environmental Studies: Energizing the Future: Meeting Future Power Needs of Grenfell College

In this paper I pose the Questions: Is it feasible to install a large wind turbine(S) at Grenfell College as a pilot project, and what will the benefits of the installation be to Grenfell if the project goes ahead? My answers are based on a literature review, data analysis from previous experiments, and a SWOT analysis. I will conclude by recommending a course of action for Grenfell that will move it toward using more renewable energy, and becoming a local resource for alternative energy solutions.

Culture stratégique et libéralisation politique au Myanmar

Le Myanmar traverse un processus de libéralisation politique qui a été entamé par le haut. Le régime militaire a tenu des élections générales en 2010, lesquelles ont placé au pouvoir un nouveau gouvernement composé à la fois de civils et de militaires. Depuis, la majorité des sanctions imposées par plusieurs États occidentaux au Myanmar ont été levées, et on observe une diversification des relations internationales du pays. Imbriqué à la sphère d’influence chinoise depuis quelques années, celui-ci rétablit des contacts diplomatiques et économiques avec l’Occident. Peu de chercheurs ont tenté d’expliquer les causes de cette transition politique, et le lien entre libéralisation politique et diversification des relations internationales n’a pas encore été expliqué. Ce mémoire propose de le faire en utilisant un modèle théorique issu de deux types de littérature, celle sur la culture stratégique et celle sur les transitions politiques. Il suggère que la libéralisation politique du Myanmar s’explique par les luttes d’influences au sein du régime entre deux sous-cultures stratégiques, les hardliners et les softliners. L’application des normes favorisées par les hardliners ayant échoué dans l’atteinte des objectifs stratégiques du régime, les softliners ont pu imposer leurs propres préférences normatives. Il propose également que la libéralisation politique était une étape nécessaire pour que le gouvernement birman puisse diversifier ses relations internationales.

Catalytic enantioselective electrocyclic cascades

A catalytic enantioselective electrocyclic cascade leads to the construction of topologically complex systems comprising multiple rings with up to three stereocentres. This phase-transfer catalysed process offers a new strategy for the rapid and enantioselective generation of complex products bearing all-carbon quaternary stereogenic centres. © 2012 The Royal Society of Chemistry.

Postdoktoral karriär vid Stockholms universitet ur ett jämställdhetsperspektiv

Several previous studies indicate that among newly graduated PhDs, women tend to continue with a postdoctoral academic career to a lesser extent than men do. The Central PhD Student Council (CDR) has investigated to what degree this is also the case for Stockholm University. Using various sources, the relative change of the gender balance of PhD students compared to researchers at a postdoctoral level has been assessed at the four faculties of Stockholm University. For the Faculty of Science, the four different sections have been analysed as well. CDR finds that it is first and foremost at this faculty that a clear change in the gender balance between PhD students and postdoctoral researchers is discerned. Even though the variations between the individual departments and sections at the faculty are large, as a whole the relative decrease of the proportion of women is between 11 % and 21 %, depending on what metric is used. The dropoff of female researchers takes place primarily in already male-dominated areas of research. Unlike at the other faculties, we also find that the proportion of female senior lecturers at the Faculty of Science is lower than what could be expected. The proportion of female professors, even among new recruits, is still lower than the population of hypothetical recruits at all faculties – except at the Faculty of Humanities. We do, however, note that the proportion of female professors at the Faculty of Science is currently increasing and approaching that of the population of hypothetical recruits. At the Faculty of Social Sciences we see that, compared to the rest of the faculty, the proportion of women within the educational sciences is considerably higher and when excluding these subjects the trend towards more female professors disappears. CDR concludes that it is important to increase the directed efforts to encourage support to newly graduated female PhDs within male-dominated areas to stay in academia. Furthermore, it is crucial to study the reasons for a larger female drop-off within certain areas of research in the transition from PhD studies to a postdoctoral level. We further consider it important to ensure that women are given the same possibilities as men to qualify themselves scientifically and not be burdened with teaching and administrative duties to a larger extent than men are.

Pileated Woodpecker Occupancy and the Occurrence and Recruitment of Key Habitat Attributes in a Managed Forest

Thesis (Master's)--University of Washington, 2016-08

GOSPEL SINGING IN THE VALLEY: AN INVESTIGATION INTO THE HYMNODY AND CHORAL SINGING OF THE LISU ON THE CHINA-BURMA/MYANMAR BORDER

This dissertation is an ethnomusicological study of contemporary musical practices of the Christian Lisu in Nujiang Prefecture in northwest Yunnan on the China-Myanmar border. Among all the changes that the Nujiang Lisu have experienced since the twentieth century, the spread of Protestant Christianity throughout Nujiang’s mountainous villages has existed for the longest time and had one of the greatest effects. Combining historical investigation and ethnographic description, this study uses the lens of music to examine the impact of this social change on the Lisu living in this impoverished frontier region. The Lisu characteristics have never been vital in the music written by the Christian Lisu in Nujiang. Compared with the practices described in other ethnomusicological writings on Christian music around the world that I have read, this absence of incorporation of indigenous musical elements is unusual. There are probably many other cases similar to that of the Lisu, but few ethnomusicologists have paid attention to them. I aim to elucidate this particular scenario of Lisu Christian music in relation to three social and cultural forces: the missionary legacy of conventions; the government’s identification of the Lisu as a minority nationality and its national policies toward them since the 1950s; and the transnational religious exchange between the Christian Lisu in China and Myanmar since the late 1980s. My examination focuses on two genres which the Lisu use to express their Christian beliefs today: ddoqmuq mutgguat, derived from American northern urban gospel songs, the basis of the Lisu choral singing; and mutgguat ssat, influenced by the Christian pop of the Burmese Lisu, with instrumental accompaniment and daibbit dance and preferred by the young people. Besides studying these two genres in the religious context, I also juxtapose them with other musical traditions in the overall Nujiang music soundscape and look at their role in local social interactions such as those between sacred and secular, and majority and minority. This dissertation demonstrates that the collective performances of shared repertoires have not only created a sense of affinity for the Nujiang Christian Lisu but also have reinforced the formation of Lisu transnational religious networks.

Culture stratégique et libéralisation politique au Myanmar

Le Myanmar traverse un processus de libéralisation politique qui a été entamé par le haut. Le régime militaire a tenu des élections générales en 2010, lesquelles ont placé au pouvoir un nouveau gouvernement composé à la fois de civils et de militaires. Depuis, la majorité des sanctions imposées par plusieurs États occidentaux au Myanmar ont été levées, et on observe une diversification des relations internationales du pays. Imbriqué à la sphère d’influence chinoise depuis quelques années, celui-ci rétablit des contacts diplomatiques et économiques avec l’Occident. Peu de chercheurs ont tenté d’expliquer les causes de cette transition politique, et le lien entre libéralisation politique et diversification des relations internationales n’a pas encore été expliqué. Ce mémoire propose de le faire en utilisant un modèle théorique issu de deux types de littérature, celle sur la culture stratégique et celle sur les transitions politiques. Il suggère que la libéralisation politique du Myanmar s’explique par les luttes d’influences au sein du régime entre deux sous-cultures stratégiques, les hardliners et les softliners. L’application des normes favorisées par les hardliners ayant échoué dans l’atteinte des objectifs stratégiques du régime, les softliners ont pu imposer leurs propres préférences normatives. Il propose également que la libéralisation politique était une étape nécessaire pour que le gouvernement birman puisse diversifier ses relations internationales.

Behavioral and molecular genetics of reading-related AM and FM detection thresholds

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h2 = 0.20) and FM (h2 = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading.

The preparation of a certified reference material of polar pesticides in freeze-dried water (CRM 606)

The preparation of a certified reference material of polar pesticides in freeze-dried water is described. The pesticides selected were atrazine, simazine, carbaryl, propanil, linuron, fenamiphos and permethrin which were added to 6000 litres of tap water at 50–80 μg · L–1 (200–320 μg · L–1 for permethrin) level in presence of NaCl (2.5 g · L–1) prior lyophilization. After the freeze-drying process the residue was rehomogenized, filled into amber glass bottles and stored at –20 °C, +4 °C and +20 °C. All pesticides were determined by HPLC/diode array detector, except permethrin which was determined by GC/ECD. The results obtained for atrazine, simazine, carbaryl, propanil, linuron and fenamiphos showed no within- or between-bottle inhomogeneity, however the material was non-homogeneous for permethrin and therefore this was withdrawn from further studies. With respect to the stability for over one year, all pesticides were stable at –20 °C. At +4 °C all pesticides were stable for at least 9 months and at +20 °C the stability was demonstrated only during the first month of storage. The content (mass fractions) of atrazine, simazine, carbaryl, propanil and linuron in freeze-dried water (CRM 606) was certified by an interlaboratory testing and a certification campaign.