'A habitual disposition to the good': on reason, virtue and realism

Amidst the crisis of instrumental reason, a number of contemporary political philosophers including Jürgen Habermas have sought to rescue the project of a reasonable humanism from the twin threats of religious fundamentalism and secular naturalism. In his recent work, Habermas defends a post-metaphysical politics that aims to protect rationality against encroachment while also accommodating religious faith within the public sphere. This paper contends that Habermas’ post-metaphysical project fails to provide a robust alternative either to the double challenge of secular naturalism and religious fundamentalism or to the ruthless instrumentalism that underpins capitalism. By contrast with Habermas and also with the ‘new realism’ of contemporary political philosophers such as Raymond Geuss or Bernard Williams, realism in the tradition of Plato and Aristotle can defend reason against instrumental rationality and blind belief by integrating it with habit, feeling and even faith. Such metaphysical–political realism can help develop a politics of virtue that goes beyond communitarian thinking by emphasising plural modes of association (not merely ‘community’), substantive ties of sympathy and the importance of pursuing goodness and mutual flourishing

Interactions of Neuroimmune Signaling and Glutamate Plasticity in Addiction

Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe neuroimmune mechanisms that may be linked to aberrant glutamate signaling in addiction. We focus specifically on the nuclear factor-kappa B (NF-κB) pathway, a potentially important neuroimmune mechanism that may be a key player in driving drug-seeking behavior. We highlight the importance of astroglial-microglial crosstalk, and how this interacts with known glutamatergic dysregulations in addiction. Then, we describe the importance of studying non-neuronal cells with unprecedented precision because understanding structure-function relationships in these cells is critical in understanding their role in addiction neurobiology. Here we propose a working model of neuroimmune-glutamate interactions that underlie drug use motivation, which we argue may aid strategies for small molecule drug development to treat substance use disorders. Together, the synthesis of this review shows that interactions between glutamate and neuroimmune signaling may play an important and understudied role in addiction processes and may be critical in developing more efficacious pharmacotherapies to treat SUDs

Взаимосвязь понятий «стиль» и «имидж» как эстетическая проблема

<div><p>The intestinal microbiota influences the development and function of myeloid lineages such as neutrophils, but the underlying molecular mechanisms are unresolved. Using gnotobiotic zebrafish, we identified the immune effector Serum amyloid A (Saa) as one of the most highly induced transcripts in digestive tissues following microbiota colonization. Saa is a conserved secreted protein produced in the intestine and liver with described effects on neutrophils <i>in vitro</i>, however its <i>in vivo</i> functions remain poorly defined. We engineered <i>saa</i> mutant zebrafish to test requirements for Saa on innate immunity <i>in vivo</i>. Zebrafish mutant for <i>saa</i> displayed impaired neutrophil responses to wounding but augmented clearance of pathogenic bacteria. At baseline, <i>saa</i> mutants exhibited moderate neutrophilia and altered neutrophil tissue distribution. Molecular and functional analyses of isolated neutrophils revealed that Saa suppresses expression of pro-inflammatory markers and bactericidal activity. Saa’s effects on neutrophils depended on microbiota colonization, suggesting this protein mediates the microbiota’s effects on host innate immunity. To test tissue-specific roles of Saa on neutrophil function, we over-expressed <i>saa</i> in the intestine or liver and found that sufficient to partially complement neutrophil phenotypes observed in <i>saa</i> mutants. These results indicate Saa produced by the intestine in response to microbiota serves as a systemic signal to neutrophils to restrict aberrant activation, decreasing inflammatory tone and bacterial killing potential while simultaneously enhancing their ability to migrate to wounds.</p></div

Novel Neuroprotective Mechanisms of Memantine: Increase in Neurotrophic Factor Release from Astroglia and Anti-Inflammation by Preventing Microglial Activation

Memantine provides clinically relevant efficacy in patients with Alzheimer's disease and Parkinson’s diseases. In addition to blockade of N-methyl-D-aspartate receptor on neurons, memantine has neurotrophic and neuroprotective effects in in vivo and in vitro studies, however, the mechanism underlying these effects remains unclear. To address this question, primary midbrain neuron-glia cultures and reconstituted cultures were used, and lipopolysaccharide (LPS), an endotoxin from bacteria, was used to produce inflammation-mediated dopaminegic neuronal death. Here, we show that memantine exerted both potent neurotrophic and neuroprotective effects on dopaminergic neurons in rat neuron-glia cultures. The neurotrophic effect of memantine was glia-dependent, since memantine failed to show any positive effect on dopaminergic neurons in neuron-enriched cultures. More specifically, it appears that astroglia, not microglia, are the source of the memantine-elicited neurotrophic effects through the increased production of GDNF. Mechanistic studies revealed that GDNF upregulaton was associated with histone hyperacetylation by inhibiting the cellular histone deacetylase activity. In addition, memantine also displays neuroprotective effects against LPS-induced dopaminergic neuronal damage through its inhibition of microglia over-activation revealed by both OX-42 immunostaining and by the reduction of pro-inflammatory factors production such as extracelluar superoxide anion, intracellular reactive oxygen species, nitric oxide, prostaglandin E2, and tumor necrosis factor-α. These results suggest that memantine therapy for neurodegenerative diseases acts in part through alternative novel mechanisms by reducing microglia-associated inflammation and stimulating the release of neurotrophic factors from astroglia

A High-Throughput Organoid Microinjection Platform to Study Gastrointestinal Microbiota and Luminal Physiology

Background & Aims The human gut microbiota is becoming increasingly recognized as a key factor in homeostasis and disease. The lack of physiologically relevant in vitro models to investigate host–microbe interactions is considered a substantial bottleneck for microbiota research. Organoids represent an attractive model system because they are derived from primary tissues and embody key properties of the native gut lumen; however, access to the organoid lumen for experimental perturbation is challenging. Here, we report the development and validation of a high-throughput organoid microinjection system for cargo delivery to the organoid lumen and high-content sampling. Methods A microinjection platform was engineered using off-the-shelf and 3-dimensional printed components. Microinjection needles were modified for vertical trajectories and reproducible injection volumes. Computer vision (CVis) and microfabricated CellRaft Arrays (Cell Microsystems, Research Triangle Park, NC) were used to increase throughput and enable high-content sampling of mock bacterial communities. Modeling preformed using the COMSOL Multiphysics platform predicted a hypoxic luminal environment that was functionally validated by transplantation of fecal-derived microbial communities and monocultures of a nonsporulating anaerobe. Results CVis identified and logged locations of organoids suitable for injection. Reproducible loads of 0.2 nL could be microinjected into the organoid lumen at approximately 90 organoids/h. CVis analyzed and confirmed retention of injected cargos in approximately 500 organoids over 18 hours and showed the requirement to normalize for organoid growth for accurate assessment of barrier function. CVis analyzed growth dynamics of a mock community of green fluorescent protein– or Discosoma sp. red fluorescent protein-expressing bacteria, which grew within the organoid lumen even in the presence of antibiotics to control media contamination. Complex microbiota communities from fecal samples survived and grew in the colonoid lumen without appreciable changes in complexity. Conclusions High-throughput microinjection into organoids represents a next-generation in vitro approach to investigate gastrointestinal luminal physiology and the gastrointestinal microbiota

Polyamine sensitivity of gap junctions is required for skin pattern formation in zebrafish

Gap junctions allow the direct and bidirectional transfer of small molecules between cells. Polyamine sensitivity, which has been observed for a certain gap junction in vitro, confers rectification property to gap junction. Here we report that the polyamine sensitivity of gap junctions in vivo is crucial for skin pattern formation in zebrafish. Transgenic experiments have revealed that several connexin genes were able to rescue the spot phenotype of mutant zebrafish. Mutational analyses of the N-terminal region of connexins revealed that the ExxxE motif, a hypothetical polyamine-binding site, was important for connexin's role in pattern formation. Ectopic expression of spermidine/spermine N1-acetyltransferase (SSAT), a polyamine metabolic enzyme, also caused stripe pattern changes, which further indicates that the polyamine sensitivity of gap junctions is crucial. This is the first report to show that polyamine sensitivity has a physiologically relevant function and is related to skin pattern formation in animals

(Im)possibilities of Autonomy:? Social Movements In and Beyond Capital, the State and Development

In this paper we interrogate the demand and practice of autonomy in social movements. We begin by identifying three main conceptions of autonomy: (1) autonomous practices vis-à-vis capital; (2) self-determination and independence from the state; and (3) alternatives to hegemonic discourses of development. We then point to limits associated with autonomy and discuss how demands for autonomy are tied up with contemporary re-organizations of: (1) the capitalist workplace, characterized by discourses of autonomy, creativity and self-management; (2) the state, which increasingly outsources public services to independent, autonomous providers, which often have a more radical, social movement history; and (3) regimes of development, which today often emphasize local practices, participation and self-determination. This capturing of autonomy reminds us that autonomy can never be fixed. Instead, social movements' demands for autonomy are embedded in specific social, economic, political and cultural contexts, giving rise to possibilities as well as impossibilities of autonomous practices

Carbon Monoxide and Heme Oxygenase-1 Prevent Intestinal Inflammation in Mice by Promoting Bacterial Clearance

Heme oxygenase-1 (HO-1) and its metabolic by-product, carbon monoxide (CO), protect against intestinal inflammation in experimental models of colitis, but little is known about their intestinal immune mechanisms. We investigated the interactions among CO, HO-1, and the enteric microbiota in mice and zebrafish

Conversationalism, constitutional economics and bicameralism: Strategies for political reform in Hong Kong

Hong Kong has at long last regained the economic momentum lost in the wake of the Asian financial crisis and the collapse of the local property market. However, political friction and uncertainty have escalated rather than subsided, because of deep-rooted divisions over the pace of democratic reform. There are no simple remedies for the constitutional deadlock that has emerged. Nevertheless, it might be possible to improve the overall political climate and both the form and substance of the dialog regarding fundamental institutional reform by borrowing some ideas from constitutional economics