Thesis (doctoral)--Université de Reims Champagne-Ardenne, 2000.

The outer membrane (OM) is a formidable barrier that has made antibiotic drug discovery in Gram-negatives exceedingly difficult. Many antibiotics which are effective against Gram-positive bacteria cannot permeate the Gram-negative OM to reach their intracellular targets. Thus, it is important to explore unconventional approaches to overcome the intrinsic resistance conferred by the OM. Herein, we used both genetic and chemical means to compromise OM integrity to potentiate the activity of large-scaffold antibiotics against Escherichia coli. First, we mapped the genetic interaction network of OM biosynthetic genes using synthetic genetic arrays (SGAs) to reveal permeability determinants of the E. coli OM. This led to the creation of a publicly accessible dataset of ~155,400 double deletion strains with growth data in the presence of the large-scaffold antibiotics rifampicin and vancomycin. Investigations of a subset of synthetic sick interactions revealed connectivity in the context of permeability between lipopolysaccharide (LPS) inner core biosynthetic genes and an enigmatic gene involved in enterobacterial common antigen (ECA) regulation. Second, we leveraged a chemical screening platform based on the observation that disruption of the E. coli OM leads to antagonism of vancomycin activity at cold temperatures to uncover molecules that potentiate Gram-positive-targeting antibiotics at 37 ºC. Two of these compounds, liproxstatin-1 and MAC-0568743, were characterized to bind to LPS and disrupt OM integrity specifically without impacting the inner membrane (IM). Third, we performed genetic and chemical screening to unearth targets capable of potentiating the activity of Gram-positive-targeting antibiotics against E. coli. This validated the OM as a valuable target for antibiotic adjuvants and led to the discovery of two membrane active compounds and an inhibitor of lipid A biosynthesis. Overall, this thesis emphasizes the importance of elucidating biological factors contributing to OM permeability and the attractiveness of the OM as a target for antibiotic potentiators. / Thesis / Doctor of Philosophy (PhD)

There is an urgent need to identify novel antibiotics for multidrug-resistant Gram-negative pathogens. These bacteria are intrinsically resistant to many antimicrobials due to a formidable outer membrane barrier. Herein we investigate the potential of perturbing the outer membrane to sensitize Gram-negative bacteria to otherwise inactive antibiotics. In chapter 2, we identify the ability of mcr-1 mediated resistance to confer protection from the lytic but not outer membrane-perturbing activity of colistin. Exploiting this sensitivity, we show that colistin and clarithromycin in combination are efficacious against mcr-1-expressing Klebsiella pneumoniae in murine infection models. This demonstrates the viability of colistin combination therapies against Gram-negative pathogens harbouring mcr-1, and points to a mechanism of mcr-1-mediated resistance extending beyond the predicted reduction in binding affinity of polymyxins to the outer membrane. We continue to investigate the potential of using outer membrane perturbants with otherwise inactive antimicrobials in chapter 3. In this work, we identify the ability of OM disruption to change the rules of Gram-negative entry, render pre-existing resistance ineffective, reduce the development of spontaneous resistance and attenuate biofilm formation. Together, these data suggest that OM disruption overcomes many traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development. / Thesis / Doctor of Philosophy (PhD)

Yes / An interim report on pottery excavated at the Neolithic islet of Loch Bhorgastail, Isle of Lewis, Scotland, in 2021. / Leverhume Trust, British Academy, Honor Frost Foundation

Yes / This interim report covers archaeological work undertaken at two Neolithic islet sites or crannogs, Loch Bhorgastail and Loch Langabhat, on the Isle of Lewis, Outer Hebrides, from 15-29 July 2017 (Figure 1). Fieldwork in 2017 included photogrammetric survey of both stone-built islets (under and above water), palaeoenvironmental coring of both loch beds, excavation at Loch Langabhat and vegetation clearance at Loch Bhorgastail. This work followed on directly from fieldwork carried out in 2016; the present report should therefore be read in conjunction with that report (Garrow, Sturt & Copper 2017). Our main results for fieldwork in 2017 included: • Construction of detailed 3D photogrammetric models of both sites • A better understanding of the construction techniques used in the creation of both islets • Recovery of c. 0.60m of core material from each loch for palaeoenvironmental assessment • The identification and excavation of occupation deposits and a small structure at Loch Langabhat / Leverhume Trust; British Academy; Honor Frost Foundation

Yes / An interim report on pottery recovered from three loch islet sites in the Outer Hebrides, Scotland, during fieldwork in 2016. / British Academy, Leverhume Trust, Honor Frost Foundation

Yes / An interim report on pottery recovered during underwater surveys undertaken around a series of artificial islets on the islands of North and South Uist in 2022. / Leverhume Trust, British Academy, Honor Frost Foundation

Thesis (M.A.)--University of Central Florida, 2009. / Adviser: Roger Handberg. Includes bibliographical references (p. 133-140).

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 112-126).

Since the start of the space race in the 1950‟s the outer space environment has significantly changed due to human expansion and the subsequent by-products known as outer space pollution/debris. As outer space rapidly evolved from a military high-ground into a commercialised asset exploited by private and state owned enterprises, the treaties negotiated in the 1960‟s and 1970‟s quickly became out-dated. As a result outer space, especially the orbits around the Earth are occupied by countless masses of non-functional manmade objects, some expected to remain for millions of years. This dissertation argues that the current national and international legal framework will be inadequate to address the problem of outer space pollution and that legal and political action will be necessary on a global scale. With the planned developments as set out in the National Space Policy, South Africa is set on becoming a leading provider of outer space services on the African continent and will, as a consequence, have a progressively bigger impact on the outer space environment. With a growing dependence on outer space technologies, developed and developing economies around the world cannot ignore the immense negative consequences that outer space debris could pose to their development. This study will thus, by examining the international and national legal framework regarding outer space pollution, provide legal recommendations pertaining to the principles and obligations that the South African legal framework will have to make provision for, in order to minimise the negative effect on the outer space environment. / LLM (Environmental Law and Governance), North-West University, Potchefstroom Campus, 2014