Growing up good?: medical, social hygiene and youth work perspectives on young women, 1918-1939

This thesis explores the discourses and organisations through which girls' development towards adult womanhood was framed and managed during the inter-war period. It examines how contemporary perceptions of social change following the First World War resulted in widespread scrutiny of girls' circumstances and behaviour, particularly their sexual conduct. It argues that representations and responses to girls were increasingly underpinned by the conceptualisation of adolescence as a critical period of change and instability. This understanding of adolescence pervaded both medical and lay discourses. It was interpreted through the prisms of gender and class, and served to legitimise increasing levels of intervention into girls' lives, mainly on the basis of their sexual behaviour or perceived exposure to sexual risk. Adolescence was also represented as the period in which individuals developed moral agency. This study examines the increased importance ascribed to the moral training of the adolescent, in the context of widespread agreement of the need to express traditional moral values in ways that took account of social change. This was seen as particularly important for girls, not only because of their changing circumstances, but because of women's new status as enfranchised citizens. The thesis explores the work of the Girl Guides Association and the Young Women's Christian Association in some detail. These organisations drew upon the discourse of social change, adolescence and citizenship to claim an enhanced role in shaping the development of young women. While histories of girls' youth organisations have tended to portray them as conservative movements intent on socialising girls into their future role as wives and mothers, this study highlights these organisations' commitment to preparing girls to understand and exercise their future responsibilities as citizens, and argues that such organisations were more complex in their purposes, and more varied in their approaches, than has previously been recognised

Growing up good? Medical, social hygiene and youth work perspectives on young women 1918-1939

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Antiinfectives targeting enzymes and the proton motive force.

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance

Antiinfectives targeting enzymes and the proton motive force

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5–2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance

Oxa, Thia, Heterocycle, and Carborane Analogues of SQ109: Bacterial and Protozoal Cell Growth Inhibitors

We synthesized a library of 48 analogues of the Mycobacterium tuberculosis cell growth inhibitor SQ109 in which the ethylenediamine linker was replaced by oxa, thia, or heterocyclic species, and in some cases, the adamantyl group was replaced by a 1,2-carborane or the <i>N</i>-geranyl group by another hydrophobic species. Compounds were tested against <i>M. tuberculosis</i> (H37Rv and/or Erdman), Mycobacterium smegmatis, Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae, Trypanosoma brucei, and two human cell lines (human embryonic kidney, HEK293T, and the hepatocellular carcinoma, HepG2). The most potent activity was found against <i>T. brucei</i>, the causative agent of human African trypanosomiasis, and involved targeting of the mitochondrial membrane potential with 15 SQ109 analogues being more active than was SQ109 in cell growth inhibition, having IC₅₀ values as low as 12 nM (5.5 ng/mL) and a selectivity index of ∼300