Conceptualizing kirchnerismo

What is the nature of kirchnerismo? The experience of the period encompassed by the presi-dencies of Nestor and Cristina Kirchner have generated greater controversy regarding its characterization. The article critically reviews the analysis that Ernesto Laclau and Guillermo O´Donnell made of kirchneris-mo through their respective conceptual models of populism and delegative democracy.Fil: Peruzzotti, Carlos Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Torcuato di Tella; Argentin

The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis.

Multiple sclerosis is one of the most common causes of chronic neurological disability beginning in early to middle adult life. Multiple sclerosis is idiopathic in nature, yet increasing correlative evidence supports a strong association between one's genetic predisposition, the environment and the immune system. Symptoms of multiple sclerosis have primarily been shown to result from a disruption in the integrity of myelinated tracts within the white matter of the central nervous system. However, recent research has also highlighted the hitherto underappreciated involvement of gray matter in multiple sclerosis disease pathophysiology, which may be especially relevant when considering the accumulation of irreversible damage and progressive disability. This review aims at providing a comprehensive overview of the interplay between inflammation, glial/neuronal damage and regeneration throughout the course of multiple sclerosis via the analysis of both white and gray matter lesional pathology. Further, we describe the common pathological mechanisms underlying both relapsing and progressive forms of multiple sclerosis, and analyze how current (as well as future) treatments may interact and/or interfere with its pathology. Understanding the putative mechanisms that drive disease pathogenesis will be key in helping to develop effective therapeutic strategies to prevent, mitigate, and treat the diverse morbidities associated with multiple sclerosis.The authors thank Dr. Gillian Tannahill and Prof. Alasdair Coles for critically reviewing the article, and Prof. Kenneth J Smith for the illuminating discussions on MS pathophysiology. We acknowledge the contribution of past and present members of Pluchino laboratory, who have contributed to (or inspired) this manuscript. Research in the author’s laboratory is supported by the National Multiple Sclerosis Society (NMSS; RG-4001-A1), the Italian Multiple Sclerosis Foundation (FISM; RG 2010/R/31), the Italian Ministry of Health (GR08/7) the European Research Council (ERC) 2010-StG (RG 260511-SEM_SEM), the European Community (EC) 7th Framework Program (FP7/2007–2013; RG 280772-iONE), The Evelyn Trust (RG 69865), The Bascule Charitable Trust (RG 75149), The Great Britain Sakakawa Foundation and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. GM was supported by an European Neurological Society (ENS) Training fellowship. LPJ was supported by the Wellcome Trust [RRZA/057 RG79423]. JDB was supported by a NIH-OxCam fellowship.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.pneurobio.2015.02.00

Topotecan Decreases the Expression of Programmed Death-Ligand 1 in Glioblastoma Cell Lines; Implications for Immunotherapy

Glioblastoma (GBM) is the most aggressive primary brain tumor and thrives in a microenvironment of relative immunosuppression. The poor clinical outcome of these malignant tumors requires the development of novel treatment options/therapeutic regimens. Accordingly, numerous immunotherapies for GBM are currently being tested in ongoing clinical trials. Herein we have examined the ability of the FDA approved drug topotecan to suppress programmed death-ligand 1 (PD-L1) expression. Our results suggest a role for topotecan as an adjuvant therapy in treatment regimens targeting certain GBM patient subpopulations in whom the expression of PD-L1 has been confirmed.This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke/National Institutes of Health (NINDS/NIH)

Metabolic determinants of the immune modulatory function of neural stem cells.

BACKGROUND: Neural stem cells (NSCs) display tissue trophic and immune modulatory therapeutic activities after transplantation in central nervous system disorders. The intercellular interplay between stem cells and target immune cells is increased in NSCs exposed to inflammatory cues. Here, we hypothesize that inflammatory cytokine signalling leads to metabolic reprogramming of NSCs regulating some of their immune modulatory effects. METHODS: NSC lines were prepared from the subventricular zone (SVZ) of 7-12-week-old mice. Whole secretome-based screening and analysis of intracellular small metabolites was performed in NSCs exposed to cocktails of either Th1-like (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β, 100 U/ml) or Th2-like (IL-4, IL-5 and IL-13; 10 ng/ml) inflammatory cytokines for 16 h in vitro. Isotopologues distribution of arginine and downstream metabolites was assessed by liquid chromatography/mass spectrometry in NSCs incubated with U-(13)C6 L-arginine in the presence or absence of Th1 or Th2 cocktails (Th1 NSCs or Th2 NSCs). The expression of arginase I and II was investigated in vitro in Th1 NSCs and Th2 NSCs and in vivo in the SVZ of mice with experimental autoimmune encephalomyelitis, as prototypical model of Th1 cell-driven brain inflammatory disease. The effects of the inflammatory cytokine signalling were studied in NSC-lymph node cells (LNC) co-cultures by flow cytometry-based analysis of cell proliferation following pan-arginase inhibition with N(ω)-hydroxy-nor-arginine (nor-NOHA). RESULTS: Cytokine-primed NSCs showed significantly higher anti-proliferative effect in co-cultures vs. control NSCs. Metabolomic analysis of intracellular metabolites revealed alteration of arginine metabolism and increased extracellular arginase I activity in cytokine-primed NSCs. Arginase inhibition by nor-NOHA partly rescued the anti-proliferative effects of cytokine-primed NSCs. CONCLUSIONS: Our work underlines the use of metabolic profiling as hypothesis-generating tools that helps unravelling how stem cell-mediated mechanisms of tissue restoration become affected by local inflammatory responses. Among different therapeutic candidates, we identify arginase signalling as novel metabolic determinant of the NSC-to-immune system communication.This work has received support from the National Multiple Sclerosis Society (NMSS, partial grants RG-4001-A1), the Italian Multiple Sclerosis Association (AISM, grant 2010/R/31 and grant 2014/PMS/4), the Italian Ministry of Health (GR08-7), the European Research Council (ERC) under the ERC-2010-StG Grant agreement n° 260511-SEM_SEM and the UK Regenerative Medicine Platform Acellular hub (Partnership award RG69889) and core support grant from the Wellcome Trust and MRC to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute. LPJ was supported by a Wellcome Trust Research Training Fellowship (RG79423).This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12974-016-0667-

Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms

Recent evidence suggests that neural stem/precursor cells (NPCs) promote recovery in animal models with delayed neuronal death via a number of indirect bystander effects. A comprehensive knowledge of how transplanted NPCs exert their therapeutic effects is still lacking. Here, we investigated the effects of a delayed transplantation of adult syngenic NPCs—injected intravenously 72 h after transient middle cerebral artery occlusion—on neurological recovery, histopathology and gene expression. NPC-transplanted mice showed a significantly improved recovery from 18 days post-transplantation (dpt) onwards, which persisted throughout the study. A small percentage of injected NPCs accumulated in the brain, integrating mainly in the infarct boundary zone, where most of the NPCs remained undifferentiated up to 30 dpt. Histopathological analysis revealed a hitherto unreported very delayed neuroprotective effect of NPCs, becoming evident at 10 and 30 dpt. Tissue survival was associated with downregulation of markers of inflammation, glial scar formation and neuronal apoptotic death at both mRNA and protein levels. Our data highlight the relevance of very delayed degenerative processes in the stroke brain that are intimately associated with inflammatory and glial responses. These processes may efficaciously be antagonized by (stem) cell-based strategies at time-points far beyond established therapeutic windows for pharmacological neuroprotectio

RNA Nanotherapeutics for the Amelioration of Astroglial Reactivity.

In response to injuries to the CNS, astrocytes enter a reactive state known as astrogliosis, which is believed to be deleterious in some contexts. Activated astrocytes overexpress intermediate filaments including glial fibrillary acidic protein (GFAP) and vimentin (Vim), resulting in entangled cells that inhibit neurite growth and functional recovery. Reactive astrocytes also secrete inflammatory molecules such as Lipocalin 2 (Lcn2), which perpetuate reactivity and adversely affect other cells of the CNS. Herein, we report proof-of-concept use of the packaging RNA (pRNA)-derived three-way junction (3WJ) motif as a platform for the delivery of siRNAs to downregulate such reactivity-associated genes. In vitro, siRNA-3WJs induced a significant knockdown of Gfap, Vim, and Lcn2 in a model of astroglial activation, with a concomitant reduction in protein expression. Knockdown of Lcn2 also led to reduced protein secretion from reactive astroglial cells, significantly impeding the perpetuation of inflammation in otherwise quiescent astrocytes. Intralesional injection of anti-Lcn2-3WJs in mice with contusion spinal cord injury led to knockdown of Lcn2 at mRNA and protein levels in vivo. Our results provide evidence for siRNA-3WJs as a promising platform for ameliorating astroglial reactivity, with significant potential for further functionalization and adaptation for therapeutic applications in the CNS.The authors wish to acknowledge J. Bernstock and G. Pluchino for their critical insights throughout the execution of the study. This work was funded by the European Research Council (ERC) under the ERC-2010-StG grant agreement n° 260511-SEM_SEM, the Bascule Charitable Trust (RG 75149 to SP), the International Foundation for Research in Paraplegia (RG 69318 to S.P.), Wings for Life (RG 82921 to S.P.) and a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust – MRC Cambridge Stem Cell Institute. LPJ was supported by a research training fellowship from the Wellcome Trust (RRZA/057 RG79423)

Probing the Binding Site of Abl Tyrosine Kinase Using in Situ Click Chemistry

Modern combinatorial chemistry is used to discover compounds with desired function by an alternative strategy, in which the biological target is directly involved in the choice of ligands assembled from a pool of smaller fragments. Herein, we present the first experimental result where the use of in situ click chemistry has been successfully applied to probe the ligand-binding site of Abl and the ability of this enzyme to form its inhibitor. Docking studies show that Abl is able to allow the in situ click chemistry between specific azide and alkyne fragments by binding to Abl-active sites. This report allows medicinal chemists to use protein-directed in situ click chemistry for exploring the conformational space of a ligand-binding pocket and the ability of the protein to guide its inhibitor. This approach can be a novel, valuable tool to guide drug design synthesis in the field of tyrosine kinases

PosterVote:expanding the action repertoire for local political activism

Online and digital technologies support and extend the action repertoires of localized social movements. In this paper we examine the ways by which digital technologies can support ‘on-the-ground ’ activist communities in the development of social movements. After identifying some of the challenges of deploying conventional voting and consultation technologies for activism, we examine situated political action in local communities through the design and deployment of a low-cost community voting prototype, PosterVote. We deploy PosterVote in two case studies with two local community organizations identifying the features that supported or hindered grassroots democratic practices. Through interviews with these communities, we explore the design of situated voting systems to support grassroots democratic practices and participation within an ecology of social action. Author Keywords Democracy; activism; participation; e-votin

Broadening the notion of democratic accountability: Participatory innovation in Latin America

This article focuses on a set of democratic innovations that were introduced in recent years in Latin America that involve the participation of civil society as an active agent of accountability. Participatory innovations are redefining the traditional scenario in which the practice of democratic representation takes place, adding novel arenas and mechanisms to engage actors that traditionally were not actively involved in accountability politics. The proliferation of alternative means for holding governments accountable undermines the traditional view of democratic representation, which continues to view elections as the quintessential mechanism of citizen control. The conventional way of thinking about the role of citizens in the practice of democratic accountability-which was largely modeled around the act of electoral delegation-must be reconceptualized to make room for other mechanisms of citizen control beyond the sporadic act of voting.Fil: Peruzzotti, Carlos Enrique. Universidad Torcuato Di Tella. Departamento de Ciencia Política y Estudios Internacionales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin