This article explores the prospect that alteration in the profile of resources relied on by African civil society will affect citizen’s relationships with their states. Description and analysis ...advance an ontological narrative of Africa’s pre- to postcolonial gift-giving, or “gifting” rapidly diverging in this century. Gifting processes exhibit both non-agonistic “horizontal” and agonistic “vertical” dimensions, connecting Ekeh’s “two moral publics” that characterize the continent’s neo-patrimonial political systems. The unfolding context exhibits pluralization, localization, and privatization of financing that a historically determined, multilayered African civil society can access and self-provide. The notion of “civic space” guides analysis of intersections between gifting and African civil society, in relation to governance, resourcing, and equity. A conclusion is that gains in scale and diversity of domestication in gifting to and by civil society are unlikely to bring significant change to Africa’s politics: more likely is a governance future resembling the past.
This is an open access title available under the terms of a CC BY-NC-ND 4.0 License. It is free to read, download and share on Elgaronline.com.
Mapping a wide range of civil society research ...perspectives, this pioneering Research Agenda offers a rich and clear insight for academics and practitioners hoping to embark on future civil society research. Kees Biekart and Alan Fowler bring together over 20 expert contributions from researchers across the globe who are actively engaged in testing the old and generating new knowledge about civil society.
Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose ...production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6-phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance.
Background and objectives
Inhibition of Abelson (Abl) tyrosine kinase as a therapeutic target has been gaining attention in neurodegeneration. Post-mortem Alzheimer’s and Parkinson’s disease brains ...show that the levels of several other tyrosine kinases, including Discoidin Domain Receptors (DDR1/2) are elevated. Knockdown of these tyrosine kinases with shRNA reduces neurotoxic proteins, including alpha-synuclein, beta-amyloid and tau.
Methods
Direct profiling of the pharmacokinetics of multi-kinase inhibitors Nilotinib, Bosutinib, Bafetinib, Radotinib and LCB-03-0110 shows differential levels of brain penetration but the ability of these agents to reduce toxic proteins is independent of brain concentration and selectivity to Abl.
Results
Our results indicate that the effective dose of Nilotinib has the lowest plasma:brain ratio (1%) followed by Bosutinib and Radotinib (5%), Bafetinib (12%) and LCB-03-0110 (12%). However, similar doses of multi-kinase Abl/DDR inhibitor Nilotinib, DDR/Src inhibitor LCB-03-0110 and Abl/Src inhibitor Bosutinib were much more effective than the more selective Abl inhibitors Radotinib and Bafetinib. Taken together, these data suggest that a multi-kinase target that includes Abl and other tyrosine kinases (DDRs, and Src) may offer more advantages alleviating neurodegenerative pathologies than the absolute CNS drug concentration and selectivity to Abl.
Conclusion
DDRs and Src are other potential co-targets with Abl in neurodegeneration.
Abstract
The role of Discoidin Domain Receptors (DDRs) is poorly understood in neurodegeneration. DDRs are upregulated in Alzheimer’s and Parkinson’s disease (PD), and DDRs knockdown reduces ...neurotoxic protein levels. Here we show that potent and preferential DDR1 inhibitors reduce neurotoxic protein levels in vitro and in vivo. Partial or complete deletion or inhibition of DDR1 in a mouse model challenged with α-synuclein increases autophagy and reduces inflammation and neurotoxic proteins. Significant changes of cerebrospinal fluid microRNAs that control inflammation, neuronal injury, autophagy and vesicular transport genes are observed in PD with and without dementia and Lewy body dementia, but these changes are attenuated or reversed after treatment with the DDR1 inhibitor, nilotinib. Collectively, these data demonstrate that DDR1 regulates autophagy and reduces neurotoxic proteins and inflammation and is a therapeutic target in neurodegeneration.
The international development community invests billions of dollars to improve organisational capacity. But real-life practice is poorly understood and undervalued as a distinct professional domain. ...Written by practitioners, this innovative publication is designed to make capacity development more professional and increasingly effective in achieving development goals.
Practical illustrations draw on experiences from the civic, government and private sectors. A central theme is to understand capacity as more than something internal to organisations. This book shows how capacity also stems from connections between different types of actor and the levels in society at which they operate.
The content is crafted for a broad audience of practitioners in capacity development: consultants, managers, front-line workers, trainers, facilitators, leaders, advisors, programme staff, activists, and funding agencies.
Published with SNV
Gold nanoparticles covered with a nematic liquid‐crystal ligand laterally attached via a thioalkyl spacer and a thioalkane “diluent” exhibit 3D ordering in strings jacketed by the mesogens with ...controllable interparticle spacing. The particles form rhombohedral, hexagonal, and rectangular columnar superlattices, not the usual packing modes of spheres.
The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world ...over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.
Utilization of live animals for mechanistic study is challenging yet pivotal to elucidate pathogenesis of neurological diseases. Here, we present a protocol that employs cultured brain slices derived ...from adult mice to examine mRNA metabolism. We describe the preparation of acute brain slices and the treatments of RNA synthesis inhibitor and nucleotide analog to examine the effects of ataxin-1 loss-of-function on Bace1 mRNA stability and transcription in cortex. This protocol also includes electrophysiological recording of spontaneous neuronal activity in hippocampus.
For complete details on the use and execution of this protocol, please refer to Suh et al. (2019).
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•Protocol for acute brain slice cultures derived from adult mice for RNA metabolism study•Assessment of gene knockout effects on target mRNA stability in selected brain regions•Analysis of mRNA synthesis in cultured brain slices by utilizing Click-iT reaction•Electrophysiological analysis of spontaneous neuronal activity in hippocampal slices
Publisher's note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Utilization of live animals for mechanistic study is challenging yet pivotal to elucidate pathogenesis of neurological diseases. Here, we present a protocol that employs cultured brain slices derived from adult mice to examine mRNA metabolism. We describe the preparation of acute brain slices and the treatments of RNA synthesis inhibitor and nucleotide analog to examine the effects of ataxin-1 loss-of-function on Bace1 mRNA stability and transcription in cortex. This protocol also includes electrophysiological recording of spontaneous neuronal activity in hippocampus.
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