STOP in the Name of Who's Law? Driving and the Regulation of Contested Space in Central Australia

This article emerges from a study of the incidence of Indigenous driving offending conducted by the authors in the Northern Territory (NT) from 2006 to 2010 on two central Australian communities. It demonstrates how new patterns of law enforcement, set in train by an 'Emergency Intervention' in 2007, ostensibly to tackle child sexual abuse and family violence, led to a dramatic increase in the criminalisation of Indigenous people for driving-related offending. We suggest that the criminalisation of driving-related offending was part of a neocolonial turn in the NT through which the state sought to discipline, normalise and incorporate as yet uncolonised, or unevenly colonised, dimensions of Indigenous domain into the Australian mainstream. In terms of methodology, we adopted a mix of quantitative and qualitative approaches, blending criminal justice and policing data with insights from criminological, anthropological and postcolonial theory. We argue that running together the insights from different disciplinary traditions is necessary to tease out the nuances, ambiguities and complexities of crime control strategies, and their impact, in postcolonial contexts. © The Author(s) 2013

"If Those Old Women Catch You, You're Going To Cop It”: Night Patrols, Indigenous Women, and Place Based Sovereignty in Outback Australia

Night Patrols (‘patrols’) are a uniquely Indigenous Australian form of community self-policing. Patrols do not fit neatly into established paradigms of ‘policing’ emanating from the Global North. They are not part of the apparatus of the state police, nor do they offer commodified private security services and, unlike mainstream police, they cannot legitimately call on a reservoir of coercive powers to ensure compliance. In this article we sketch out what we describe as the ‘contested space’ of Indigenous self-policing, as represented by patrols, through a postcolonial lens, paying particular attention to the role of Indigenous women’s agency in creating, nurturing and sustaining night patrol work within an Indigenous ethics of care and notions of wellbeing. Drawing on international critical postcolonial scholarship we tease out the links between patrol work and broader expressions of sovereign power embedded in Indigenous law. Our key contention is that there are learnings from the Australian experience for other postcolonies, where there are kindred debates regarding the balance between Indigenous and colonial systems of justice and policing. We highlight the experience of patrols in the Northern Territory (NT) where the policing of Indigenous space and place have become a key priority for the Australian Government after a major focus on issues of child abuse and family violence

Conclusions

This section summarises the archaeological results and the conclusions to be drawn from them about the site of Ħal Millieri. The concluding section discusses the significance of the excavations for the history of the casale and for Maltese historiography, and their relationship to the development of medieval church architecture in Malta. The excavations have added a certain amount to what was known about the site of Ħal Millieri prior to the building of its churches and to the first written documentation in 1419/20. The earliest archaeological features are admittedly not very informative. Beneath the church of the Visitation some shallow channels cut into the rock were clearly man-made, but they produced no dating evidence nor were they uncovered over a sufficient area for their purpose to be demonstrable.peer-reviewe

Heat shock response and insulin-associated neurodegeneration

Dysfunctional insulin and insulin-like growth factor-I (IGF-I) signaling contributes to the pathological progression of diabetes, diabetic peripheral neuropathy (DPN), Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD). Despite their prevalence, there are limited therapeutic options available for the treatment of these neurodegenerative disorders. Therefore, establishing a link between insulin/IGF-I and the pathoetiology of these diseases may provide alternative approaches toward their management. Many of the heat shock proteins (Hsps) are well-known molecular chaperones that solubilize and clear damaged proteins and protein aggregates. Recent studies suggest that modulating Hsps may represent a promising therapeutic avenue for improving insulin and IGF-I signaling. Pharmacological induction of the heat shock response (HSR) may intersect with insulin/IGF-I signaling to improve aspects of neurodegenerative phenotypes. Herein, we review the intersection between Hsps and the insulin/IGF systems under normal and pathological conditions. The discussion will emphasize the potential of non-toxic HSR inducers as viable therapeutic agents

Hyperincarceration and Indigeneity

In this article we explore the notion of hyperincarceration in Australia. We argue that hyperincarceration is not only constituted in the prison but also through the state constricting, through a multiplicity of strategies, Indigenous livelihoods on homelands, the practice of language and culture, and the freedoms of civil society

Combining Mutational Signatures, Clonal Fitness, and Drug Affinity to Define Drug-Specific Resistance Mutations in Cancer.

The emergence of mutations that confer resistance to molecularly targeted therapeutics is dependent upon the effect of each mutation on drug affinity for the target protein, the clonal fitness of cells harboring the mutation, and the probability that each variant can be generated by DNA codon base mutation. We present a computational workflow that combines these three factors to identify mutations likely to arise upon drug treatment in a particular tumor type. The Osprey-based workflow is validated using a comprehensive dataset of ERK2 mutations and is applied to small-molecule drugs and/or therapeutic antibodies targeting KIT, EGFR, Abl, and ALK. We identify major clinically observed drug-resistant mutations for drug-target pairs and highlight the potential to prospectively identify probable drug resistance mutations

A C-Terminal Heat Shock Protein 90 Inhibitor Decreases Hyperglycemia-induced Oxidative Stress and Improves Mitochondrial Bioenergetics in Sensory Neurons

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in which hyperglycemia-induced mitochondrial dysfunction and enhanced oxidative stress contribute to sensory neuron pathology. KU-32 is a novobiocin-based, C-terminal inhibitor of the molecular chaperone, heat shock protein 90 (Hsp90). KU-32 ameliorates multiple sensory deficits associated with the progression of DPN and protects unmyelinated sensory neurons from glucose-induced toxicity. Mechanistically, KU-32 increased the expression of Hsp70 and this protein was critical for drug efficacy in reversing DPN. However, it remained unclear if KU-32 had a broader effect on chaperone induction and if its efficacy was linked to improving mitochondrial dysfunction. Using cultures of hyperglycemically stressed primary sensory neurons, the present study investigated whether KU-32 had an effect on the translational induction of other chaperones and improved mitochondrial oxidative stress and bioenergetics. A variation of stable isotope labeling with amino acids in cell culture called pulse SILAC (pSILAC) was used to unbiasedly assess changes in protein translation. Hyperglycemia decreased the translation of numerous mitochondrial proteins that affect superoxide levels and respiratory activity. Importantly, this correlated with a decrease in mitochondrial oxygen consumption and an increase in superoxide levels. KU-32 increased the translation of Mn superoxide dismutase and several cytosolic and mitochondrial chaperones. Consistent with these changes, KU-32 decreased mitochondrial superoxide levels and significantly enhanced respiratory activity. These data indicate that efficacy of modulating molecular chaperones in DPN may be due in part to improved neuronal mitochondrial bioenergetics and decreased oxidative stress

Modulating Molecular Chaperones Improves Mitochondrial Bioenergetics and Decreases the Inflammatory Transcriptome in Diabetic Sensory Neurons

We have previously demonstrated that modulating molecular chaperones with KU-32, a novobiocin derivative, ameliorates physiologic and bioenergetic deficits of diabetic peripheral neuropathy (DPN). Replacing the coumarin core of KU-32 with a meta-fluorinated biphenyl ring system created KU-596, a novobiocin analogue (novologue) that showed neuroprotective activity in a cell-based assay. The current study sought to determine whether KU-596 offers similar therapeutic potential for treating DPN. Administration of 2–20 mg/kg of KU-596 improved diabetes induced hypoalgesia and sensory neuron bioenergetic deficits in a dose-dependent manner. However, the drug could not improve these neuropathic deficits in diabetic heat shock protein 70 knockout (Hsp70 KO) mice. To gain further insight into the mechanisms by which KU-596 improved DPN, we performed transcriptomic analysis of sensory neuron RNA obtained from diabetic wild-type and Hsp70 KO mice using RNA sequencing. Bioinformatic analysis of the differentially expressed genes indicated that diabetes strongly increased inflammatory pathways and that KU-596 therapy effectively reversed these increases independent of Hsp70. In contrast, the effects of KU-596 on decreasing the expression of genes regulating the production of reactive oxygen species were more Hsp70-dependent. These data indicate that modulation of molecular chaperones by novologue therapy offers an effective approach toward correcting nerve dysfunction in DPN but that normalization of inflammatory pathways alone by novologue therapy seems to be insufficient to reverse sensory deficits associated with insensate DPN

Excavation report : introduction

The only buildings of the casale of Ħal Millieri which survive in whole or in part are its four churches. The church of St. John, rebuilt in the seventeenth century, and the contiguous church of St. Michael, now in ruins, do not concern us here. The church of the Annunciation and the remains of that of the Visitation, which formed a similarly contiguous pair, are the subject of this report.peer-reviewe

Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun

Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.This work was supported the Juvenile Diabetes Research Foundation and The National Institutes of Health [grant numbers NS054847 (to R.T.D.), CA120458 and CA109265 (to B.S.J.B.) and NS075311 (to B.S.J.B. and R.T.D.)]