Biosynthesis and Synthesis of Pyrrolizidine Alkaloids and Analogues

This thesis deals with three aspects of research into pyrrolizidine alkaloids: (a) the synthesis of macrocyclic pyrrolizidine alkaloid analogues incorporating (+)-heliotridine (A); (b) the study of the biosynthesis of pyrrolizidine bases using specifically labelled molecules; and (c) the investigation of the pyrrolizidine alkaloid content of plants not previously studied. (a). Synthesis of macrocyclic pyrrolizidine alkaloid analogues incorporating (+) -heliotridine The synthesis of a series of novel macrocyclic diesters of (+)-heliotridine (A) has been achieved by the use of the Corey-Nicolaou double activation method of lactonisation. The base (A) was obtained by the alkaline hydrolysis of (+)-echinatine, a natural pyrrolizidine monoester isolated by methanolic extraction of Cynoglossum officinale. An alternative method of production of (+)-heliotridine utilised a short, known conversion of the pyrrolizidine base (+)-retronecine into (+)-heliotridine which was carried out with modifications. The treatment of (+)-heliotridine (A) with glutaric anhydride derivatives selectively yielded 9-monoesters of (+)-heliotridine. Lactonisation of these monoesters was effected via the corresponding pyridine-2-thiolesters. The macrocyclic nature of these 11-membered pyrrolizidine alkaloid analogues was confirmed by spectroscopic studies. An X-ray analysis of 7,9-O,O'-(3,3-dimethylglutaryl)heliotridine (B) revealed the conformation of this bislactone in the solid state. The ester carbonyl groups of (B) are anti-parallel. Attempted synthesis of 10-membered bislactones of (+)-heliotridine was unsuccessful. (b). Study of the biosynthesis of pyrrolizidine bases The biosynthetic portion of the project was to attempt to gain insight into the various processes taking place in the biosynthesis of different base portions of pyrrolizidine alkaloids by plants. Previous work had shown that 1,4-diaminobutane (putrescine) is a good precursor of retronecine. A series of putrescines specifically labelled with 2H or 13C were synthesised by known routes. They were isolated as their dihydrochloride salts. These salts were each mixed with a known activity of a radioactive tracer and were fed to Cynoglossum officinale by the xylem pricking method. The plants were later harvested and extracted to yield samples of (+)-echinatine, i.e. esters of (+)-heliotridine (A). Scintillation counting showed the specific incorporations to be below 0.5% per C4-unit of the base portion and the 2H and 13C n.m.r. spectra of the (+)-echinatine samples, also showed evidence of the disappointingly low incorporations. An exception was noted with the use of [1-13C]-putrescine dihydrochloride. A 13C n.m.r. spectrum of (+)-echinatine was obtained in which the expected four (C-3,-5,-8 and -9) of the eight signals of the base portion, (+)-heliotridine (A), were enriched. The conditions of feeding were varied over the two subsequent summers but the same low incorporations always resulted. Only the base portion of (+)-echinatine was radioactive as shown by alkaline hydrolysis of each (+)-echinatine sample. An investigation of Cynoglossum australe revealed the presence of a mixture of (+)-cynaustraline and (+)-cynaustine. Biosynthetic interest arises because of the presence of two rare 8B-bases, (+)-isoretronecanol (C) and (+)-supinidine. (D) respectively. The specifically 2H labelled compounds previously synthesised were fed to batches of young Cynoglossum australe plants. However, again the specific incorporations were low and inconclusive 2H n.m.r. spectra were obtained. The experiments were repeated the following summer, but the same results were obtained. Alkaline hydrolysis of the alkaloid samples proved that the radioactivity present was located exclusively in the base portions, (C) and (D) , of the alkaloids. Putrescine with a radioactive 3H label was fed as the dihydrochloride to several young Cynoglossum australe plants by the wick method. A good incorporation (> 1%) into each alkaloid was obtained, and radioactive samples of the two 1-hydroxymethyl pyrrolizidines (C) and (D) were obtained after separation of the alkaloids and subsequent hydrolysis. Each 8B-necine was then fed in turn to different batches of young Cynoglossum australe plants. Isoretronecanol (C) was a precursor for both alkaloids, but supinidine (D) was only incorporated into cynaustine. This finding is consistent with conversion of isoretronecanol into supinidine in the biosynthetic pathway

Remote oil spill detection and monitoring on ice-covered waters

The spillage of oil in Polar Regions is particularly serious due to the threat to the environment and the difficulties in detecting and tracking the full extent of the oil seepage beneath the sea ice. Development of fast and reliable sensing techniques is highly desirable. In this paper hyperspectral imaging is proposed as a potential tool to detect the presence of oil beneath the sea ice. A feasibility study project was initiated to explore the detectability of the oil under ice layer. Some preliminary results obtained during this project are discussed

Remote oil spill detection and monitoring beneath sea ice

The spillage of oil in Polar Regions is particularly serious due to the threat to the environment and the difficulties in detecting and tracking the full extent of the oil seepage beneath the sea ice. Development of fast and reliable sensing techniques is highly desirable. In this paper hyperspectral imaging combined with signal processing and classification techniques are proposed as a potential tool to detect the presence of oil beneath the sea ice. A small sample, lab based experiment, serving as a proof of concept, resulted in the successful identification of oil presence beneath the thin ice layer as opposed to the other sample with ice only. The paper demonstrates the results of this experiment that granted a financial support to execute full feasibility study of this technology for oil spill detection beneath the sea ice

West Africa Dwarf sheep management systems and exposure to potential stressors in the savannah agroecological zone of Ghana

This study was conducted in the savannah agroecological zone of Ghana to assess the different sheep management systems and identify potential stressors that compromise sheep productivity under these systems. A questionnaire and on-farm observations were used to obtain data from 176 farms on management system types, resources, husbandry practices and productivity. Four management systems were identified in the study area, namely extensive (41.5%), semi-intensive (38.1%), intensive (6.3%) and tethering (14.2%). Feeding systems used were free grazing/scavenging (24.43%), herded grazing (17.05%), zero-grazing/intensive feeding (6.25%), grazing plus supplementation (38.07%) and restricted grazing in the rainy season (14.2%). Most (87%) farmers under the extensive system did not house their sheep at all, but 88.1% of farmers using the semi-intensive system housed their sheep year round. Floor spacing per sheep was 1.06, 2.31, 2.17 and 1.47 sheep/m2 for the intensive, semi-intensive, extensive, and tethering, respectively. Preweaning mortality was significantly higher (40%) than post-weaning to yearling (34.9%) and adult mortality rates (14.3%) (ꭓ2 = 292, P <0.001). The extensive system has the highest (32.8%) mortality rate and the intensive system the least (14.9%) (ꭓ2 = 151, P <0.001). Reproductive indices (lambing percentage, age at first lambing, lambing intervals, and abortion rates) were all significantly influenced by the management system, with sheep managed under the semi-intensive and intensive systems performing better than sheep managed under the extensive system and tethering. Extensive management and tethering of sheep may expose Djallonké sheep to disease stress, chronic undernutrition, heat stress and walking stress compared to sheep under more intensive systems

Seeing Crime and Punishment Through a Sociological Lens: Contributions, Practices, and the Future

There is a rich intellectual history to the sociological study of crime and punishment that encompasses multiple and interrelated traditions. Some of these traditions trace their roots to the European social theorists of the nineteenth century, particularly Emile Durkheim, Max Weber, and Karl Marx. Although only Durkheim and Weber systematically studied law (and only Durkheim actually studied punishment), all three social theorists facilitated the development of sociological research and theory on crime and punishment. Durkheim\u27s Suicide: A Study in Sociology, for example, investigated the relationship between social integration and suicide rates, which, in turn, provided a model of inquiry for multiple generations of sociologists investigating the social causes of crime, delinquency, and social deviance. Similarly, Durkheim\u27s The Division of Labor in Society inspired sociologists to examine the relationship between social structure and the organization of law and punishment. Weber\u27s ideas concerning the rationalization of society and the legitimate bases of legal authority compelled sociologists to think comparatively and brought a historical dimension to sociological inquiry on law and punishment. Marxist sensibilities begat a small, but vibrant, industry of radical criminologists and sociologists of law and punishment who located both the causes and control of crime in the exploitation, injustice, and class conflict inherent in capitalist society

Random population fluctuations bias the Living Planet Index

The Living Planet Index (LPI) is a standardized indicator for tracking population trends through time. Due to its ability to aggregate many time series in a single metric, the LPI has been proposed as an indicator for the Convention on Biological Diversity’s post-2020 Global Biodiversity Strategy. However, here we show that random population fluctuations introduce biases when calculating the LPI. By combining simulated and empirical data, we show how random fluctuations lead to a declining LPI even when overall population trends are stable and imprecise estimates of the LPI when populations increase or decrease nonlinearly. We applied randomization null models that demonstrate how random fluctuations exaggerate declines in the global LPI by 9.6%. Our results confirm substantial declines in the LPI but highlight sources of uncertainty in quantitative estimates. Randomization null models are useful for presenting uncertainty around indicators of progress towards international biodiversity targets.DATA AVAILABILITY: Empirical data of population time series in the Living Planet database are available from the dedicated website maintained by the Zoological Society of London (ZSL) (http://stats.livingplanetindex.org/) and are subject to the Data Use Policy by the Indicators & Assessments Unit at the ZSL and WWF International. Simulated data to replicate the results are available from https://doi.org/10.5281/zenodo.4744533.CODE AVAILABILITY : All simulation outputs and code (R scripts) to reproduce the results in this manuscript are available from https://doi.org/10.5281/zenodo.4744533.EXTENDED DATA FIG. 1: The nine steps to calculating the Living Planet Index (LPI).EXTENDED DATA FIG. 2: The Living Planet Index (LPI) for randomly fluctuating populations that are stable on average.EXTENDED DATA FIG. 3: Starting population sizes of time series added to the Living Planet Index have declined between 1950 and 2015.EXTENDED DATA FIG. 4: Larger population fluctuations cause less precise estimates of the Living Planet Index (LPI) in nonlinear population trajectories.EXTENDED DATA FIG 5: Population fluctuations cause generalised additive models (GAM) to misestimate starting and ending populations when populations decrease from 100 to 40 individuals.EXTENDED DATA FIG 6: Population fluctuations cause generalised additive models (GAM) to misestimate starting and ending populations when populations increase from 100 to 160 individuals.EXTENDED DATA FIG 7: The reshuffling null model used to account for random population fluctuations.EXTENDED DATA FIG. 8: Cumulative population declines can occur in the Living Planet Index even when average population declines are zero.EXTENDED DATA FIG. 9: Cumulative population changes represent empirical trajectories more accurately than average changes as time series lengths increase.The National Research Foundation of South Africa and the Jennifer Ward Oppenheimer Research Grant.https://www.nature.com/natecolevolhj2022Zoology and Entomolog

Reply to: Capturing stochasticity properly is key to understanding the nuances of the Living Planet Index

DATA AVAILABILITY : Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.REPLYING TO E. J. Talis & H. J. Lynch Nature Ecology & Evolution https://doi.org/ 10.1038/s41559-023-0286-w (2023)http://www.nature.com/natecolevolhj2024Zoology and EntomologyNon

The Enduring Significance of Racism: Discrimination and Delinquency Among Black American Youth

Prominent explanations of the overrepresentation of Black Americans in criminal justice statistics focus on the effects of neighborhood concentrated disadvantage, racial isolation, and social disorganization. We suggest that perceived personal discrimination is an important but frequently neglected complement to these factors. We test this hypothesis with longitudinal data on involvement in general and violent juvenile delinquency in a sample of Black youth from a variety of communities in 2 states. We examine the direct effects of concentrated disadvantage and racial isolation and the direct and mediating effects of social organization, support for violence, and personal discrimination. Consistent with our hypothesis, perceived personal discrimination has notable direct effects on both general and violent delinquency and is an important mediator between neighborhood structural conditions and offending; moreover, its effects exceed those associated with neighborhood conditions

Influence of Exposure History on the Immunology and Development of Resistance to Human Schistosomiasis Mansoni

Schistosomiasis is a parasitic blood fluke infection of 200 million people worldwide. We have shown that humans can acquire immunity to reinfection after repeated exposures and cures with the drug praziquantel. The increase in resistance to reinfection was associated with an increase in schistosome-specific IgE. The ability to develop resistance and the rate at which resistance was acquired varied greatly in two cohorts of men within close geographic proximity and with similar occupational exposures to schistosomes. These differences are likely attributable to differences in history of exposure to Schistosoma mansoni infection and immunologic status at baseline, with those acquiring immunity faster having lifelong S. mansoni exposure and immunologic evidence of chronic S. mansoni infection. As many conflicting results have been reported in the literature regarding immunologic parameters associated with the development of resistance to schistosome infection, exposure history and prior immune status should be considered in the design of future immuno-epidemiologic studies