NsrR: a key regulator circumventing Salmonella enterica serovar Typhimurium oxidative and nitrosative stress in vitro and in IFN-γ-stimulated J774.2 macrophages

Over the past decade, the flavohaemoglobin Hmp has emerged as the most significant nitric oxide (NO)-detoxifying protein in many diverse micro-organisms, particularly pathogenic bacteria. Its expression in enterobacteria is dramatically increased on exposure to NO and other agents of nitrosative stress as a result of transcriptional regulation of hmp gene expression, mediated by (at least) four regulators. One such regulator, NsrR, has recently been shown to be responsible for repression of hmp transcription in the absence of NO in Escherichia coli and Salmonella, but the roles of other members of this regulon in Salmonella, particularly in surviving nitrosative stresses in vitro and in vivo, have not been elucidated. This paper demonstrates that an nsrR mutant of Salmonella enterica Serovar Typhimurium expresses high levels of Hmp both aerobically and anaerobically, exceeding those that can be elicited in vitro by supplementing media with S-nitrosoglutathione (GSNO). Elevated transcription of ytfE, ygbA, hcp and hcp is also observed, but no evidence was obtained for tehAB upregulation. The hyper-resistance to GSNO of an nsrR mutant is attributable solely to Hmp, since an nsrR hmp double mutant has a wild-type phenotype. However, overexpression of NsrR-regulated genes other than hmp confers some resistance of respiratory oxygen consumption to NO. The ability to enhance, by mutating NsrR, Hmp levels without recourse to exposure to nitrosative stress was used to test the hypothesis that control of Hmp levels is required to avoid oxidative stress, Hmp being a potent generator of superoxide. Within IFN-γ-stimulated J774.2 macrophages, in which high levels of nitrite accumulated (indicative of NO production) an hmp mutant was severely compromised in survival. Surprisingly, under these conditions, an nsrR mutant (as well as an nsrR hmp double mutant) was also disadvantaged relative to the wild-type bacteria, attributable to the combined oxidative effect of the macrophage oxidative burst and Hmp-generated superoxide. This explanation is supported by the sensitivity in vitro of an nsrR mutant to superoxide and peroxide. Fur has recently been confirmed as a weak repressor of hmp transcription, and a fur mutant was also compromised for survival within macrophages even in the absence of elevated NO levels in non-stimulated macrophages. The results indicate the critical role of Hmp in protection of Salmonella from nitrosative stress within and outside macrophages, but also the key role of transcriptional regulation in tuning Hmp levels to prevent exacerbation of the oxidative stress encountered in macrophages

The spectrum of psychosis in multiple sclerosis: a clinical case series

Psychosis in the context of multiple sclerosis (MS) has previously been reported as a rare occurrence. However, recent epidemiological studies have found prevalence rates of psychosis in MS that are two to three times higher than those in the general population. Untreated psychosis in patients with MS can adversely impact on adherence to MS medication, levels of disability, and quality of life. This retrospective case series describes the spectrum of psychotic disorders occurring in association with MS using demographic, clinical, and neuroimaging data. In the discussion, we highlight the particular diagnostic and treatment challenges that such disorders can pose for clinicians and through our case vignettes provide examples of potential interventions for this complex patient population

Corruption and the extractive industries transparency initiative

The Extractive Industries Transparency Initiative (EITI) has received much attention as a scheme that can help reduce corruption in mineral-rich developing economies. To our knowledge, this paper provides the first empirical attempt (using panel data) to explore how EITI membership links to changes in corruption levels. We also examine whether the different stages in EITI implementation (initial commitment, candidature, full compliance) influence the pace of changes in corruption. We find that EITI membership offers, on the whole, a shielding mechanism against the general tendency of mineral-rich countries to experience increases in corruption over time

The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster

The regulatory protein NsrR, a member of the Rrf2 family of transcription repressors, is specifically dedicated to sensing nitric oxide (NO) in a variety of pathogenic and non-pathogenic bacteria. It has been proposed that NO directly modulates NsrR activity by interacting with a predicted [Fe-S] cluster in the NsrR protein, but no experimental evidence has been published to support this hypothesis. Here we report the purification of NsrR from the obligate aerobe Streptomyces coelicolor. We demonstrate using UV-visible, near UV CD and EPR spectroscopy that the protein contains an NO-sensitive [2Fe-2S] cluster when purified from E. coli. Upon exposure of NsrR to NO, the cluster is nitrosylated, which results in the loss of DNA binding activity as detected by bandshift assays. Removal of the [2Fe-2S] cluster to generate apo-NsrR also resulted in loss of DNA binding activity. This is the first demonstration that NsrR contains an NO-sensitive [2Fe-2S] cluster that is required for DNA binding activity

The anthropology of extraction: critical perspectives on the resource curse

Attempts to address the resource curse remain focussed on revenue management, seeking technical solutions to political problems over examinations of relations of power. In this paper, we provide a review of the contribution anthropological research has made over the past decade to understanding the dynamic interplay of social relations, economic interests and struggles over power at stake in the political economy of extraction. In doing so, we show how the constellation of subaltern and elite agency at work within processes of resource extraction is vital in order to confront the complexities, incompatibilities, and inequities in the exploitation of mineral resources

Drama and discounting in the relational dynamics of corporate social responsibility

Employing theoretical resources from Transactional Analysis (TA) and drawing from interviews with managers dealing with social or environmental issues in their role, we explain how CSR activity provides a context for dramas in which actors may ignore, or discount aspects of self, others, and the contexts of their work as they maintain and reproduce the roles of Rescuers, Persecutors and Victims. In doing so, we add to knowledge about CSR by providing an explanation for how the contradictions of CSR are avoided in practice even when actors may be aware of them. Specifically, we theorise how CSR work can produce dramatic stories where adversity is apparently overcome, whilst little is actually achieved at the social level. We also add to the range of psychoanalytic tools used to account for organisational behaviours, emphasising how TA can explain the relational dynamics of CSR

In the shadow of industry:A study of culturization in Papua New Guinea

The activities of extractive industry have recently been framed by a language of corporate social responsibility that relies on a system of legibility and objectification. This process reifies 'cultural units', abstracting them from the rules of kinship, migration, and exchange that ensure social and economic security. I refer to this process and the ideology of 'development' that accompanies it as culturization and examine it in the context of oil extraction in Papua New Guinea's Kutubu region. Drawing on debates on the indigenization and politicization of 'culture', I present culturization as a process that relies on rules of inheritance and property to impose a structure of difference in contexts of extractive industry that ignores the intricacies of sociality that ultimately give life meaning. The aim of the paper is to both illustrate the consequences of this process and consider cognate ideas of 'culture' vis-à-vis 'sociality' to emphasize their mutual theoretical importance to contemporary anthropological inquiry