The contribution of warlordism to the disintegration of the western Roman army (c. AD 395-480)

My thesis investigates the dynamics behind the changing nature of the leadership of the western Roman army in the fifth century through the concept of ‘warlordism’. I carried this out by analyzing those cases of insubordination and military unrest in the officer class of the western Roman army, which can be shown to be linked to the slow decline of central authority and the imperial office in the period 395-480. My thesis demonstrates that theories of ‘Warlordism’, as developed in social sciences, can be useful for both the late Imperial west as for other eras of ancient history, such as the late Roman republic. Warlordism was a way of continuing politics, if necessary by military means, when commanders found themselves outside the legitimate framework. Unlike the case of usurpation of the imperial office, when there was little hope of achieving permanent recognition and acceptance, it offered insubordinate officers a chance of returning to the ruling imperial regime depending on circumstances and the success of their resistance. I propose that warlordism functioned as an alternative to usurpation, a tool for military dissidence, fuelled by an economy of violence. Contrary to modern warlordism, the warlordism of the fifth century AD represented a transient phase which no imperial commander was willing to prolong indefinitely. At some stage, given the means, warlords in the western Roman army wanted to become part of the imperial echelon again. Yet these alternative methods of violent opposition, and the acquisition of force through private means, ensured the breakdown of the state’s monopoly on violence and the disintegration of centralized armies. What started as an accidental revolution became a new form of military rule.

Ubiquitylation of p53 by the APC/C inhibitor Trim39.

Tripartite motif 39 (Trim39) is a RING domain-containing E3 ubiquitin ligase able to inhibit the anaphase-promoting complex (APC/C) directly. Through analysis of Trim39 function in p53-positive and p53-negative cells, we have found, surprisingly, that p53-positive cells lacking Trim39 could not traverse the G1/S transition. This effect did not result from disinhibition of the APC/C. Moreover, although Trim39 loss inhibited etoposide-induced apoptosis in p53-negative cells, apoptosis was enhanced by Trim39 knockdown in p53-positive cells. Furthermore, we show here that the Trim39 can directly bind and ubiquitylate p53 in vitro and in vivo, leading to p53 degradation. Depletion of Trim39 significantly increased p53 protein levels and cell growth retardation in multiple cell lines. We found that the relative importance of Trim39 and the well-characterized p53-directed E3 ligase, murine double minute 2 (MDM2), varied between cell types. In cells that were relatively insensitive to the MDM2 inhibitor, nutlin-3a, apoptosis could be markedly enhanced by siRNA directed against Trim39. As such, Trim39 may serve as a potential therapeutic target in tumors with WT p53 when MDM2 inhibition is insufficient to elevate p53 levels and apoptosis.

Patterns of de novo allo B cells and antibody formation in chronic cardiac allograft rejection after alemtuzumab treatment.

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection.

Primary Production In An Estuarine Environment - Comparison Of Insitu And Simulated Insitu C-14 Techniques

A simulated in situ incubation box has been compared with in situ exposure for 14C production measurements in an estuarine environment. Measurements were made over the course of 14 months, mainly in the Tamar estuary; production rates ranged from less than 1 mg C m−2h−1 to 350 mg C m−2h−1 and there was no significant difference between results from the two methods. In the estuarine waters investigated, the simulated in situ incubator with neutral density filters, used with a Secchi disc to determine sampling depths, gives a satisfactory estimate of in situ primary production.

Identification of Genes Involved in the C. elegans VAB-1 Eph Receptor Tyrosine Kinase Signaling Pathway

The generation of a functional nervous system requires that neuronal cells and axons navigate precisely to their appropriate targets. The Eph Receptor Tyrosine Kinases (RTKs) and their ephrin ligands have emerged as one of the important guidance cues for neuronal and axon navigation. However, the molecular mechanisms of how Eph RTKs regulate these processes are still incomplete. The purpose of this work was to contribute to the understanding of how Eph receptors regulate axon guidance by identifying and characterizing components of the Caenorhabditis elegans Eph RTK (VAB-1) signaling pathway. To achieve this objective I utilized a hyper active form of the VAB-1 Eph RTK (MYR-VAB-1) that caused penetrant axon guidance defects in the PLM mechanosensory neurons, and screened for suppressors of the MYR-VAB-1 phenotype. Through a candidate gene approach, I identified the adaptor NCK-1 as a downstream effector of VAB-1. Molecular and genetic analysis revealed that the nck-1 gene encodes for two isoforms (NCK-1A and NCK-1B) that share similar expression patterns in parts of the nervous system, but also have independent expression patterns in other tissues. Genetic rescue experiments showed that both NCK-1 isoforms can function in axon guidance, but each isoform also has specific functions. In vitro binding assays showed that NCK-1 binds to VAB-1 in a kinase dependent manner. In addition to NCK-1, WSP-1/N-WASP was also identified as an effector of VAB-1 signaling. Phenotypic analysis showed that nck-1 and wsp-1 mutants had PLM axon over extension defects similar to vab-1 animals. Furthermore, VAB-1, NCK-1 and WSP-1 formed a complex in vitro. Intriguingly, protein binding assays showed that NCK-1 can also bind to the actin regulator UNC-34/Ena, but genetic experiments suggest that unc-34 is an inhibitor of nck-1 function. Through various genetic and biochemical experiments, I provide evidence that VAB-1 can disrupt the NCK-1/UNC-34 complex, and negatively regulate UNC-34. Taken together, my work provides a model of how VAB-1 RTK signaling can inhibit axon extension. I propose that activated VAB-1 can prevent axon extension by inhibiting growth cone filopodia formation. This is accomplished by inhibiting UNC-34/Ena activity, and simultaneously activating Arp2/3 through a VAB-1/NCK-1/WSP-1 complex.

Livelihood Strategies of Dock Workers in Durban, c. 1900-1959

This dissertation examines the livelihood strategies of African dock workers in Durban, South Africa, between the Anglo-Boer War and the 1959 strikes. These labourers did not conform to common conceptions of radical dock workers or conservative African migrant workers. While Marxist scholars have been correct to stress the working class consciousness of Durban’s dock workers, this consciousness was also more ambiguous. These workers and their leaders displayed a peculiar mix of concern for workers’ issues and defences of the rights and interests of African traders. Many of Durban’s dock workers were not only wage labourers. In fact, only a minority had wages as their only source of income. The Reserve economy played a role in sustaining the consumption levels of their households and, more importantly, more than half of the former dock workers interviewed for this research engaged in some form of commercial enterprise, often based on the pilferage and sale of cargoes. Some also teamed up with township women who sold pilfered goods while the men were at work. This combination of commercial strategies and wage labour has often been overlooked in the literature. By looking at these livelihood strategies, this dissertation considers how rural and urban economies interacted in households’ strategies and reinterprets the reproduction of labour and the household in order to move beyond dichotomies of proletarian versus rural consciousness. The dock workers’ households were neither proletarian households that were forced to reside in the countryside because of apartheid, nor traditional rural homesteads with a missing migrant member. The households were reproduced in three geographically separate spheres of production and consumption, none of which could reproduce the household on its own. These spheres were dependent on each other, but also separate, as physical distance gave the different household members some autonomy. Such multi-nodal households not only bridged the rural and the urban, but equally straddled the formal/informal divide. For many, their employment on the docks made their commercial enterprises possible, which allowed them to retire early from urban wage labour. Consequently, the interests of wage labourers could not be divorced from those of African small-scale entrepreneurs.

Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis. Although chemotherapy treatment did not modulate mRNA or cell surface expression of the TRAIL receptors death receptor 4, death receptor 5, decoy receptor 1, or decoy receptor 2, it was found to down-regulate expression of the caspase-8 inhibitor, c-FLIP. Stable overexpression of the long c-FLIP splice form but not the short form was found to inhibit chemotherapy/rTRAIL-induced apoptosis. Furthermore, siRNA-mediated down-regulation of c-FLIP, particularly the long form, was found to sensitize colon cancer cells to rTRAIL-induced apoptosis. In addition, treatment of a 5-FU-resistant cell line with 5-FU down-regulated c-FLIP expression and sensitized the chemotherapy-resistant cell line to rTRAIL. We conclude that TRAIL-targeted therapies may be used to enhance conventional chemotherapy regimens in colon cancer regardless of tumor p53 status. Furthermore, inhibition of c-FLIP may be a vital accessory strategy for the optimal use of TRAIL-targeted therapies.

The present-day chemical composition of the SMC from UVES spectra of the sharp-lined, B-type dwarf AV 304

High-resolution spectroscopic VLT/UVES observations are presented for the B-type main-sequence star, AV 304, in the Small Magellanic Cloud (SMC). These spectra have been analysed using LTE model-atmosphere techniques, to derive stellar atmospheric parameters and chemical compositions. As AV 304 is located within the hydrogen burning main-sequence band, its chemical composition should reflect that of the SMC interstellar medium (ISM). A detailed line-by-line differential analysis has been undertaken relative to a Galactic comparison star. A general metal deficiency for the a-process elements O, Si & S of -0.43 +/- 0.05 dex is found for AV 304, with iron having a similar underabundance. Oxygen may be relatively over- abundant by similar to0.1 dex and carbon and aluminium underabundant by similar to0.2 dex. A large nitrogen underabundance (of -1.2 dex relative to hydrogen and -0.7 dex relative to iron) is found. This is interpreted in terms of the CNO bi-cycle having been suppressed in the SMC. Furthermore, the large nitrogen deficiency is in excellent agreement with that found for SMC H II regions. Indeed, this represents a first for stellar astrophysics - confirming the low base-line nitrogen composition of the SMC ISM (viz. 12+log(N/H) similar to 6.66 +/- 0.10 dex).