GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson’s disease

EDITED BY : Javier Blesa, Jose L. Lanciego and Jose A. Obeso.The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson’s disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF. In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF. In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD.Xavier d’Anglemont de Tassigny was supported by the Miguel Servet program (grant CP12-03217) from the Health Institute Carlos III. Research by Alberto Pascual and Jose López-Barneo was supported by the Botín Foundation, the Spanish Ministry of Science and Innovation (SAF program) and the Andalusian Government.Peer reviewe

GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson's disease

The glial cell line-derived neurotrophic factor (GDNF) is a well-established trophic agent for dopaminergic (DA) neurons in vitro and in vivo. GDNF is necessary for maintenance of neuronal morphological and neurochemical phenotype and protects DA neurons from toxic damage. Numerous studies on animal models of Parkinson’s disease (PD) have reported beneficial effects of GDNF on nigrostriatal DA neuron survival. However, translation of these observations to the clinical setting has been hampered so far by side effects associated with the chronic continuous intra-striatal infusion of recombinant GDNF. In addition, double blind and placebo-controlled clinical trials have not reported any clinically relevant effect of GDNF on PD patients. In the past few years, experiments with conditional Gdnf knockout mice have suggested that GDNF is necessary for maintenance of DA neurons in adulthood. In parallel, new methodologies for exogenous GDNF delivery have been developed. Recently, it has been shown that a small population of scattered, electrically interconnected, parvalbumin positive (PV+) GABAergic interneurons is responsible for most of the GDNF produced in the rodent striatum. In addition, cholinergic striatal interneurons appear to be also involved in the modulation of striatal GDNF. In this review, we summarize current knowledge on brain GDNF delivery, homeostasis, and its effects on nigrostriatal DA neurons. Special attention is paid to the therapeutic potential of endogenous GDNF stimulation in PD.Xavier d’Anglemont de Tassigny was supported by the Miguel Servet program (grant CP12-03217) from the Health Institute Carlos III. Research by Alberto Pascual and Jose López-Barneo was supported by the Botín Foundation, the Spanish Ministry of Science and Innovation (SAF program) and the Andalusian Government.Peer Reviewe

The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent.

BACKGROUND: Humans and mice with loss of function mutations in GPR54 (KISS1R) or kisspeptin do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods. RESULTS: We show here, using 1 million exon mouse arrays (Exon 1.0 Affymetrix) and quantitative polymerase chain reaction (QPCR) validation to analyse microdissected hypothalamic tissue from Gpr54 and Kiss1 knockout mice, the extent of transcriptional regulation in the hypothalamus. The sensitivity to detect important transcript differences in microdissected RNA was confirmed by the observation of counter-regulation of Kiss1 expression in Gpr54 knockouts and confirmed by immunohistochemistry (IHC). Since Gpr54 and Kiss1 knockout animals are effectively pre-pubertal with low testosterone (T) levels, we also determined which of the validated transcripts were T-responsive and which varied according to genotype alone. We observed four types of transcriptional regulation (i) genotype only dependent regulation, (ii) T only dependent regulation, (iii) genotype and T-dependent regulation with interaction between these variables, (iv) genotype and T-dependent regulation with no interaction between these variables. The results implicate for the first time several transcription factors (e.g. Npas4, Esr2), proteases (Klk1b22), and the orphan 10-transmembrane transporter TMEM144 in the biology of GPR54/kisspeptin function in the hypothalamus. We show for the neuronal activity regulated transcription factor NPAS4, that distinct protein over-expression is seen in the hypothalamus and hippocampus in Gpr54 knockout mice. This links for the first time the hypothalamic-gonadal axis with this important regulator of inhibitory synapse formation. Similarly we confirm TMEM144 up-regulation in the hypothalamus by RNA in situ hybridization and western blot. CONCLUSIONS: Taken together, global transcriptional profiling shows that loss of GPR54 and kisspeptin are not fully equivalent in the mouse hypothalamus.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

University Solidarity Management: Weaving Possibilities on Decolonial Terrain

In the perspective of discussing a university management proposal that places an alternative epistemological conception and understands the multidimensionality of human beings and social systems (as a critique of economic instrumentality) and the multidimensionality of the educational phenomenon, this article presents a theoretical synthesis, an essay of idea, in the sense of proposing a model of solidarity management, in the perspective of its dimensions (Cosmopolitan Rationality; Multidimensional Model of Administration Management; Intercultural Translation). The solidary management of the university centralizes the debate on interculturalityfrom the perspective of emancipation, while activating the reflective process on how to strategically operationalize actions that are guided by an integrative rationality and coordinate the dimensions of the educational phenomenon, in this case: culture, politics, pedagogy and economics. It is in the scope of a democratization of knowledge that this management advances from the “societal” management, as it comprehends a perspective on participation that qualifies the knowledge and practices of social agents in building proposals as credible, and the social organization should focus its efforts and trigger the experiences of the subjects so that the intercultural translation process incorporates comprehensive and purposeful practices within symbolic interactions

A Comparative Study of the Irrigated Zones of Jaguaribe-Apodi and Morada Nova from a (Un) Sustainable Perspective

Large-scale government-sponsored irrigation is a feasible alternative to the development of semiarid regions such as Northeastern Brazil provided perennial rivers and reservoirs are available Brazilian irrigation projects have also generally promoted the participation of farmers as informed agents in the process encouraging training and education towards agribusiness The purpose of this explorative and descriptive study was to analyze and compare the sustainability characteristics of the Jaguaribe-Apodi and Morada Nova irrigation zones in light of the triple bottom line model Elkington 2012 based on information from 18 interviews conducted in September 2015 to November 2015 and submitted to discourse analysis Triple bottom line sustainability envisages a balance between three dimensions social environmental and economic Such a balance was not observed in our study due to insufficient awareness of environmental issues However focusing on a specific context and moment in time the exploratory study design made it difficult to extrapolate our findings Future studies could expand the discussion on the sustainability of irrigation zones by using data triangulation in longitudinal design

Decoloniality and University Management: Unveiling Knowledge in Managerial Narratives

The research analyzes critical this points on talk twenty-one managers of a Federal University, dedicated to the Cooperation International Solidarity, having as theoretical support the South Epistemologies Project, which includes the Interceptor translation ultural and ecology of knowledge, and the Academic Dependency. By means of the speeches Critical Analysis examines four themes and two developments. The themes: “Novelt ” and Symbolic Power , unfolding from the perspective of organizational identity, adhesion and participation of its members; Academic training of students and the training of employees , including the perspective of training; Integration, Mobility, Excellence and Internationalization ; Research and Circulation of Knowledge, unfolding in the configuration of Knowledge, Experiences and Knowledge. Some questions are conclusive: a set of arguments that intend the vision of science, within its Eurocentric aspect, institutionalized and reproduced in academic dependence; the affirmation of interculturality as a power, which manifests itself in the exclusion of difference; the significance that the Institution assumes and that propagates as power struggles; identity fragmentation, in the context of managerial actions; and in the “struggle” “decolonial”, which addresses the confrontation of multiple knowledge in the conformation of “other” possibilities of social life

Striatal GDNF Production Is Independent to Circulating Estradiol Level Despite Pan- Neuronal Activation in the Female Mouse.

Gender difference in Parkinson’s disease (PD) suggests that female sex steroids may promote dopaminergic neuron survival and protect them from degeneration. The glial cell line-derived neurotrophic factor (GDNF) is believed to be dopaminotrophic; thus it is considered as a potential therapeutic target in PD. Additionally, GDNF is endogenously synthetized in the caudate/putamen of humans and striatum in rodents. A neuroprotective role of estrogens on the nigrostriatal pathway via the stimulation of GDNF has been proposed. Since the GDNF-producing parvalbumin (Parv) interneurons express the estrogen receptor alpha in the mouse striatum, we sought to determine whether ectopic estrogenic compound mod- ulates the GDNF synthesis in mice. Using an ovariectomized-estradiol (E 2 ) replacement regimen, which reliably generates a rise of plasma estradiol, we assessed the effects of dif- ferent levels of E 2 on the activation of striatal neuronal populations, and GDNF production. A strong correlation was found between plasma E 2 and the expression of the immediate early gene cFos in the striatum, as well as in other cortical regions. However, moderate and high E 2 treatments failed to induce any striatal GDNF mRNA and protein synthesis. High E 2 only stimulates cFos induction in a low percentage of striatal Parv neurons whereas the majority of cFos-positive cells are medium spiny neurons. Activation of these projecting neurons by E 2 suggests a role of circulating sex steroids in the modulation of striatal neural pathways.Instituto de Salud Carlos III, Miguel Servet Asociación CP12- 03217 (XDADT)Ministerio de Economı́a y Competitividad: Plan Estatal de Investigación Cientı́fica y Técnica y de Innovación 2013-2016 (JLB

Impact of the Secretome of Human Mesenchymal Stem Cells on Brain Structure and Animal behavior in a Rat Model of Parkinson’s Disease

Research in the last decade strongly suggests that mesenchymal stem cell (MSC)-mediated therapeutic benefits are mainly due to their secretome, which has been proposed as a possible therapeutic tool for the treatment of Parkinson's disease (PD). Indeed, it has been shown that the MSC secretome increases neurogenesis and cell survival, and has numerous neuroprotective actions under different conditions. Additionally, using dynamic culturing conditions (through computer-controlled bioreactors) can further modulate the MSC secretome, thereby generating a more potent neurotrophic factor cocktail (i.e., conditioned medium). In this study, we have characterized the MSC secretome by proteomic-based analysis, investigating its therapeutic effects on the physiological recovery of a 6-hydroxidopamine (6-OHDA) PD rat model. For this purpose, we injected MSC secretome into the substantia nigra (SNc) and striatum (STR), characterizing the behavioral performance and determining histological parameters for injected animals versus untreated groups. We observed that the secretome potentiated the increase of dopaminergic neurons (i.e., tyrosine hydroxylase-positive cells) and neuronal terminals in the SNc and STR, respectively, thereby supporting the recovery observed in the Parkinsonian rats' motor performance outcomes (assessed by rotarod and staircase tests). Finally, proteomic characterization of the MSC secretome (through combined mass spectrometry analysis and Bioplex assays) revealed the presence of important neuroregulatory molecules, namely cystatin C, glia-derived nexin, galectin-1, pigment epithelium-derived factor, vascular endothelial growth factor, brain-derived neurotrophic factor, interleukin-6, and glial cell line-derived neurotrophic factor. Overall, we concluded that the use of human MSC secretome alone was able to partially revert the motor phenotype and the neuronal structure of 6-OHDA PD animals. This indicates that the human MSC secretome could represent a novel therapeutic for the treatment of PD.Portuguese Foundation for Science and Technology via a Ciência 2007 program and an FCT (Portuguese Foundation for Science and Technology) Investigator development grant (A.J.S.), predoctoral fellowships to F.G.T. (SFRH/69637/2010), and a fellowship to S.A. (SFRH/BD/81495/2011); a Canada Research Chair in Biomedical Engineering (L.A.B.) and a Schulich School of Engineering postdoctoral fellowship (K.M.P.), cofunded by Programa Operacional Regional do Norte (ON.2 – O Novo Norte), under Quadro de Referência Estratégico Nacional (QREN), through Fundo Europeu de Desenvolvimento Regional (FEDER), PEst-C/SAU/LA0001/2013-2014, cofunded by the Programa Operacional Factores de Competitividade, QREN, the European Union (FEDER), and by The National Mass Spectrometry Network under the contract REDE/1506/REM/2005info:eu-repo/semantics/publishedVersio

DESAFIOS E PERSPECTIVAS DAS NOVAS TECNOLOGIAS NO ENSINO JURÍDICO À LUZ DA RESOLUÇÃO Nº 5/2018 – DCN DO CURSO DE DIREITO

A transformação digital tornou-se imprescindível e não mais eletiva. A Quarta Revolução Industrial é evidente no mundo ao longo do século XXI e é caracterizada pelos recursos digitais. Dessa maneira, o impacto das novas tecnologias na área jurídica é sentido por profissionais do Direito e por suas instituições. O objetivo da pesquisa é analisar em que medida a DCN, Resolução nº 5, de 17 de dezembro de 2018, promove a inclusão das novas tecnologias no Curso de Direito. Como objetivos específicos, intenta apresentar as lawtechs/legaltechs como mecanismos facilitadores de determinadas atividades jurídicas; discorrer sobre as habilidades e competências do século XXI e os métodos participativos; e, por fim, analisar a nova diretriz curricular do Curso de Direito, de acordo com a Resolução nº 5, de 17 de dezembro de 2018, no que tange às novas tecnologias no Curso de Direito. A metodologia utilizada foi uma pesquisa de fonte bibliográfica e documental, mediante análise de artigos nacionais e internacionais nas bases de dados de periódicos e livros doutrinários, com natureza teórico-crítica e exploratória; quanto ao caráter do estudo, é descritivo; com uma abordagem qualitativa. Constatou-se a necessidade da inclusão de disciplinas que abordem as novas tecnologias nos Cursos de Direito, com a utilização de métodos participativos para o desenvolvimento de habilidades e competências do século XXI, a fim de atender às necessidades causadas pelo impacto das novas tecnologias no campo jurídico