Public administration reform for Aboriginal affairs: an institutionalist analysis

Persistent underperformance of public policy and program implementation in Aboriginal affairs is widely recognised. We analysed the results of two case studies of attempted reforms in public administration of Aboriginal primary health care in the Northern Territory, using a framework based on the institutionalist and systemic racism literatures, with the aim of better understanding the sources of implementation failure. Implementation of the agreed reforms was unsuccessful. Contributing factors were as follows: strong recognition of the need for change was not sustained; the seeds of change, present in the form of alternative practices, were not built on; there was a notable absence of sustained political/bureaucratic authorisation; and, interacting with all of these, systemic racism had important consequences and implications. Our framework was useful for making sense of the results. It is clear that reforms in Aboriginal affairs will require government authorities to engage with organisations and communities. We conclude that there are four requirements for improved implementation success: clear recognition of the need for change in 'business as usual'; sustainable commitment and authorisation; the building of alternative structures and methods to enable effective power sharing (consistent with the requirements of parliamentary democracy); and addressing the impact of systemic racism on decision-making, relationships, and risk management

Arteriolar vasoconstrictive response: comparing the effects of arginine vasopressin and norepinephrine

INTRODUCTION: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP). METHODS: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 μg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole). RESULTS: Reduction of arteriolar diameter (NE, -31 ± 12% versus AVP, -49 ± 7%; p = 0.002), cross sectional area (NE, -49 ± 17% versus AVP, -73 ± 7%; p = 0.002), and arteriolar blood flow (NE, -62 ± 13% versus AVP, -80 ± 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals. CONCLUSION: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy

Quantitative Analysis of the DNA Methylation Sensitivity of Transcription Factor Complexes

Although DNA modifications play an important role in gene regulation, the underlying mechanisms remain elusive. We developed EpiSELEX-seq to probe the sensitivity of transcription factor binding to DNA modification in vitro using massively parallel sequencing. Feature-based modeling quantifies the effect of cytosine methylation (5mC) on binding free energy in a position-specific manner. Application to the human bZIP proteins ATF4 and C/EBPβ and three different Pbx-Hox complexes shows that 5mCpG can both increase and decrease affinity, depending on where the modification occurs within the protein-DNA interface. The TF paralogs tested vary in their methylation sensitivity, for which we provide a structural rationale. We show that 5mCpG can also enhance in vitro p53 binding and provide evidence for increased in vivo p53 occupancy at methylated binding sites, correlating with primed enhancer histone marks. Our results establish a powerful strategy for dissecting the epigenomic modulation of protein-DNA interactions and their role in gene regulation

Accurate and sensitive quantification of protein-DNA binding affinity

Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements. It can capture the specificity of the p53 tetramer and distinguish multiple binding modes within a single sample. Additionally, we confirm that newly identified low-affinity enhancer binding sites are functional in vivo, and that their contribution to gene expression matches their predicted affinity. Our results establish a powerful paradigm for identifying protein binding sites and interpreting gene regulatory sequences in eukaryotic genomes

Políticas públicas y estrategias institucionales para el desarrollo e implementación de energías renovables en Argentina (2006-2016)

El objetivo de este trabajo es analizar las principales políticas de promoción para el desarrollo e adopción de las ER implementadas en Argentina en los últimos 10 años. Para ello se propone un abordaje teórico-metodológico socio-técnico que supere las visiones tradicionales estrictamente técnicas o económicas. Para ello se presentan, en primer lugar, la propuesta teóricometodológica analizar las políticas y estrategias institucionales impulsadas en Argentina para el desarrollo e implementación de ER. A continuación se presenta un resumen de las diferentes experiencias, proyectos y políticas en Argentina a escala nacional, provincial y nacional-provincial, y finalmente se concluye con algunas observaciones acerca del proceso de construcción de funcionamiento de las mismas.The aim of this paper is analyze the public policies to promote the development and adoption of renewable energies implemented in Argentina in the last 10 years. This requires a theoretical and methodological approach that overcomes traditional views strictly technical or economical. In this work we show, in first place, the theoretical and methodological proposal to analyze the policies and strategies driven in Argentina for the development and implementation of renewable energies. Secondly, a summary of different experiences, projects and policies in Argentina at the national, provincial and national-provincial level is presented, and finally we concludes with some observations about the working/no working construction processes.Tema 12: Aspectos socioculturales y socio-económicos de la transferencia de tecnología en energías renovables. Experiencias. Metodologías.Facultad de Arquitectura y Urbanism

Políticas públicas y estrategias institucionales para el desarrollo e implementación de energías renovables en Argentina (2006-2016)

El objetivo de este trabajo es analizar las principales políticas de promoción para el desarrollo e adopción de las ER implementadas en Argentina en los últimos 10 años. Para ello se propone un abordaje teórico-metodológico socio-técnico que supere las visiones tradicionales estrictamente técnicas o económicas. Para ello se presentan, en primer lugar, la propuesta teóricometodológica analizar las políticas y estrategias institucionales impulsadas en Argentina para el desarrollo e implementación de ER. A continuación se presenta un resumen de las diferentes experiencias, proyectos y políticas en Argentina a escala nacional, provincial y nacional-provincial, y finalmente se concluye con algunas observaciones acerca del proceso de construcción de funcionamiento de las mismas.The aim of this paper is analyze the public policies to promote the development and adoption of renewable energies implemented in Argentina in the last 10 years. This requires a theoretical and methodological approach that overcomes traditional views strictly technical or economical. In this work we show, in first place, the theoretical and methodological proposal to analyze the policies and strategies driven in Argentina for the development and implementation of renewable energies. Secondly, a summary of different experiences, projects and policies in Argentina at the national, provincial and national-provincial level is presented, and finally we concludes with some observations about the working/no working construction processes.Tema 12: Aspectos socioculturales y socio-económicos de la transferencia de tecnología en energías renovables. Experiencias. Metodologías.Facultad de Arquitectura y Urbanism

Políticas públicas y estrategias institucionales para el desarrollo e implementación de energías renovables en Argentina (2006-2016)

El objetivo de este trabajo es analizar las principales políticas de promoción para el desarrollo e adopción de las ER implementadas en Argentina en los últimos 10 años. Para ello se propone un abordaje teórico-metodológico socio-técnico que supere las visiones tradicionales estrictamente técnicas o económicas. Para ello se presentan, en primer lugar, la propuesta teórico-metodológica analizar las políticas y estrategias institucionales impulsadas en Argentina para el desarrollo e implementación de ER. A continuación se presenta un resumen de las diferentes experiencias, proyectos y políticas en Argentina a escala nacional, provincial y nacional-provincial, y finalmente se concluye con algunas observaciones acerca del proceso de construcción de funcionamiento de las mismas.The aim of this paper is analyze the public policies to promote the development and adoption of renewable energies implemented in Argentina in the last 10 years. This requires a theoretical and methodological approach that overcomes traditional views strictly technical or economical. In this work we show, in first place, the theoretical and methodological proposal to analyze the policies and strategies driven in Argentina for the development and implementation of renewable energies. Secondly, a summary of different experiences, projects and policies in Argentina at the national, provincial and national-provincial level is presented, and finally we concludes with some observations about the working/no working construction processes.Asociación Argentina de Energías Renovables y Medio Ambiente (ASADES

PI3Kγ is a molecular switch that controls immune suppression

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1,2,3,4,5. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors1,2,3,4,5,6,7. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism