Then they came for the dogs!

This paper examines the British state’s desire to liquidate the Pit Bull as a breed. It examines the moral panic that brought the Pit Bull Terrier to public attention and traces the government’s knee-jerk response that resulted in the Dangerous Dogs Act (1991), the legal instrument that mandated Britain’s first attempt at canine genocide. Though public protection was the stated justification of this exercise in state violence, there was and is no evidence to support the case for canine killing through the indiscriminate blanket medium of breed specific legislation. Far from conceiving the dog an aggressor and humans its victims, this paper precedes on the assumption that the dogs are the victims and humans the inhuman aggressor. The paper concludes by examining the factors that provoked the UK’s descent into mass dog killing

Understanding violent street worlds

The thesis is composed of two sections. The first provides a critical overview of the published work assembled in the second. This body of work is composed of journal articles, monographs, papers published in educated collections and research reports. Though these papers address a range of different subjects from street robbery, the culture of gun users to the study of urban street gangs, what unifies these papers is that they collectively help make sense of the violent street world occupied by young men, overwhelmingly from deprived backgrounds, who use weapons, collectively and individually, in street confrontations. In the critical analysis the term violent street world is defined and the body of published work which examines it is then contextualised; first, by a consideration of the external political and social forces that led to its production; second, by reference to the internal academic traditions in which and at times against which these papers were produced. Rather than approach the study of the street world by reference to the actors who inhabit it, the crimes they do or the weapons they use, the thesis makes a case for making the street world itself the object and focus of enquiry. The street world is then studied thematically in four chapters. The themes selected are: street crime in a historical context, the aetiology of street violence, the structure and organisation of the street world and the distinction between street representations and street realities. The analysis concludes with reflections on the key contributions the work assembled has made to our understanding of violent street worlds and their social analysis. The work is original in so far as it contests many current myths that have been proposed to explain street violence while producing more compelling explanations for it. These help explicate why the violence occurs, how and why it is changing, who is involved and why people engage in it. Key words: Gang, street culture, guns, knives, weapon

Zones of entrapment and impunity: on the constitution of vague and strange regimes of power

This article challenges a tendency prominent in critical theory—one that holds that being “vague and strange” constitute qualities of life opposed to the grid-like systems of coercive control intrinsic to the operation of modern power regimes which, by their ascriptive nature, are compelled to suppress all life which exhibits these traits. Consequently, vagueness represents not only the antithesis of modern power, but a source of resistance against it. This article contests this assumption by exploring the vague regimes of power (which, following William Burroughs, we call “interzones”), which also exist within the fabric of the administered order. The article examines how these interzones function and explores two incarnations: zones of entrapment and zones of impunity

Vile sovereignty: the carnival of power

In this paper we seek to extend Bakhtin’s reading of the folk carnival and apply it to help understand the carnivalesque, performative aspects of state power. Drawing on the work of Agamben, Foucault, Lacan and Žižek and recent scholarship on the role of laughter in the Stalinist totalitarian culture, we argue that the state can also laugh and that it can have its own carnival tradition as well. To explore what we propose to call the carnival of power, we examine three iterations of this tradition: the festive exercise of state violence, state carnivalisers, and the carnivalesque style in governance

Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease

We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. CombinedMYCfamily amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development ofTrp53inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.Additional co-authors: Louise Howell, Colin Kwok, Abhijit Joshi, Sarah Leigh Nicholson, Stephen Crosier, David W. Ellison, Stephen B. Wharton, Keith Robson, Antony Michalski, Darren Hargrave, Thomas S. Jacques, Barry Pizer, Simon Bailey, Fredrik J. Swartling, William A. Weiss, Louis Chesler, Steven C. Cliffor

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma

Social and professional influences on antimicrobial prescribing for doctors-in-training: a realist review.

Background: Antimicrobial resistance has led to widespread implementation of interventions for appropriate prescribing. However, such interventions are often adopted without an adequate understanding of the challenges facing doctors-in-training as key prescribers. Methods: The review followed a realist, theory-driven approach to synthesizing qualitative, quantitative and mixed-methods literature. Consistent with realist review quality standards, articles retrieved from electronic databases were systematically screened and analysed to elicit explanations of antimicrobial prescribing behaviours. These explanations were consolidated into a programme theory drawing on social science and learning theory, and shaped though input from patients and practitioners. Results: By synthesizing data from 131 articles, the review highlights the complex social and professional dynamics underlying antimicrobial prescribing decisions of doctors-in-training. The analysis shows how doctors-in-training often operate within challenging contexts (hierarchical relationships, powerful prescribing norms, unclear roles and responsibilities, implicit expectations about knowledge levels, uncertainty about application of knowledge in practice) where they prioritize particular responses (fear of criticism and individual responsibility, managing one's reputation and position in the team, appearing competent). These complex dynamics explain how and why doctors-in-training decide to: (i) follow senior clinicians' prescribing habits; (ii) take (or not) into account prescribing aids, advice from other health professionals or patient expectations; and (iii) ask questions or challenge decisions. This increased understanding allows for targeted tailoring, design and implementation of antimicrobial prescribing interventions. Conclusions: This review contributes to a better understanding of how antimicrobial prescribing interventions for doctors-in-training can be embedded more successfully in the hierarchical and inter-professional dynamics of different healthcare settings

Heuristics for practitioners of policy design: Rules-of-thumb for structuring unstructured problems

This article is an attempt to bridge the divide between academics and practitioners. Informed by both design theory and the reality of policy work, its focus is on ‘problems’. From a practitioners’ perspective, policy design is both an intellectual and political process, an inevitable oscillation between ‘puzzling’ and ‘powering’, in which ‘messy’ or unstructured problems are re-structured from problems as webs of ‘undesirable situations’ to problems as specific, time-and-space bound ‘opportunities for improve- ment’. This requires a questioning habitus in practitioners of policy design. Using a socio-cognitive theory of problem processing, this paper shows how policy design is an iterative process of problem sensing, problem categorization, problem decompos- ition and problem definition. For each of these stages, appropriate rules-of-thumb for questioning and answering can be suggested that induce thought habits and styles for responsive and solid policy designs

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform.

Background The use of clinical MRI scanners to conduct pre-clinical research facilitates comparisons with clinical studies. Here the utility and sensitivity of anatomical and functional MRI data/biomarkers acquired from transgenic mouse models of neuroblastoma using a dedicated radiofrequency (RF) coil on a clinical 3T scanner was evaluated.Methods Multiparametric MRI of transgenic mice bearing abdominal neuroblastomas was performed at 3T, and data cross-referenced to that acquired from the same mice on a pre-clinical 7T MRI system. T2-weighted imaging, quantitation of the native longitudinal relaxation time (T1) and the transverse relaxation rate (R2*), and dynamic contrast-enhanced (DCE)-MRI, was used to assess tumour volume, phenotype and response to cyclophosphamide or cabozantinib.Results Excellent T2-weighted image contrast enabled clear tumour delineation at 3T. Significant correlations of tumour volume (R=0.98, P2* (R=0.87, P2* (Ptrans for each tumour (median Ktrans values of 0.202, 0.168 and 0.114 min-1). Cyclophosphamide elicited a significant reduction in both tumour burden (P1 (P<0.01), whereas cabozantinib induced significant (P<0.01) tumour growth delay.Conclusions Simultaneous multiparametric MRI of multiple tumour-bearing animals using this coil arrangement at 3T can provide high efficiency/throughput for both phenotypic characterisation and evaluation of novel therapeutics, and facilitate the introduction of functional MRI biomarkers into aligned imaging-embedded clinical trials