Tetrahydroisoquinoline Neurotoxins in Parkinson Disease

The goal of this dissertation work was to (1) determine the distribution of several tetrahydroisoquinoline (TIQ) derivatives in rodent, normal human and Parkinson disease (PD) brain, (2) quantify the levels of these TIQ derivatives in common food sources in an effort to link specific food intake patterns with the development of PD and (3) examine the neurotoxicity of select TIQ derivatives in human dopaminergic cell culture. The TIQs are a family of monoamine alkaloids that share structural homology with 1-methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP), can be formed from dopamine or its oxidized metabolites and may be involved in the pathogenesis of monoaminergic cell death. In our studies, we utilize enantiomeric-selective high-performance liquid chromatography with electrochemical detection (HPLC-EC) and liquid chromatography with tandem mass spectroscopy (LC-MS/MS) to determine the concentrations of TIQ derivatives in brain, as well as in common dietary plants in the United States. The dopaminergic SH-SY5Y human neuroblastoma cell line was utilized to document the neurotoxicity of N-methylated salsolinol derivatives. Several TIQ derivatives were detected in all regions subjected to analysis. In general, salsolinols were present at higher concentrations than TIQ and its benzyl and methyl derivatives, especially in human brain. Moreover, salsolinols were concentrated in areas with increased dopamine synthesis and turnover such as the ventral midbrain and striatum, respectively. Significantly lower levels of (R)salsolinol, (S)salsolinol, N-methyl-(R)salsolinol andN-methyl-(S)salsolinol were found in the caudate nuclei of PD in comparison with normal human brain. N-methyl-norsalsolinol was detected in all regions of rodent and human brain subjected to analysis. In comparison to normal human controls, N-methyl-norsalsolinol levels were significantly lower in the substantia nigra and caudate nuclei from PD patients. N-methyl-norsalsolinol-immunoreactivity co-localized with a general neuronal marker and a monoaminergic cell marker. N-methyl-norsalsolinol-immunoreactivity was not observed in glia. Our analysis of common foods revealed high concentrations of TIQ derivatives in banana, cherry, peach, grapefruit, avocado, button mushroom, leaf lettuce and celery. Enantiomeric salsolinol derivatives were detected as racemic mixtures, without evidence of stereoselective synthesis. Utilizing a lifetime food-item intake questionnaire, we identified trends for increased intake of several plants products in PD patients. Members of the rue (Rutaceae), banana (Musaceae), gourd (Cucurbitaceae), carrot (Apiaceae) and nightshade (Solanaceae) families were found to be highly consumed in both normal human and PD groups, and to concentrate several potentially neurotoxic TIQ derivatives. We correlated indices of cellular energy production and cell viability in dopaminergic SH-SY5Y cells after exposure to N-methyl-norsalsolinol and N-methyl-(R/S)salsolinol. Both toxins induce dose-dependent decreases in cell survival with LC50 values of 0.305 mM and 0.377 mM after 24 hrs, respectively. These results suggest that cell death induced by these N-methylated salsolinols is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex I. Their concentration in dopaminergic regions of human brain and relatively potent cytotoxicity among TIQs makes these compounds strong candidates for both an endogenous and exogenous link to cell death in PD

Connexins : substrates and regulators of autophagy

Connexins mediate intercellular communication by assembling into hexameric channel complexes that act as hemichannels and gap junction channels. Most connexins are characterized by a very rapid turn-over in a variety of cell systems. The regulation of connexin turn-over by phosphorylation and ubiquitination events has been well documented. Moreover, different pathways have been implicated in connexin degradation, including proteasomal and lysosomal-based pathways. Only recently, autophagy emerged as an important connexin-degradation pathway for different connexin isoforms. As such, conditions well known to induce autophagy have an immediate impact on the connexin-expression levels. This is not only limited to experimental conditions but also several pathophysiological conditions associated with autophagy (dys) function affect connexin levels and their presence at the cell surface as gap junctions. Finally, connexins are not only substrates of autophagy but also emerge as regulators of the autophagy process. In particular, several connexin isoforms appear to recruit pre-autophagosomal autophagy-related proteins, including Atg16 and PI3K-complex components, to the plasma membrane, thereby limiting their availability and capacity for regulating autophagy

Sur le potentiel critique des approches sociomatérielles dans l’éducation

This paper has as central argument that the recently emerging sociomaterial approach to education has an inherently critical potential, but that this capacity is not yet fully deployed and explored in educational studies. In order to make this argument, this paper starts, first, with a concise description of representationalist versus relational thinking, and argues that sociomaterial studies have to be situated in the latter current. Consequently, the role of critique that is largely upheld in representationalist thinking –that is, a role primarily directed at debunking and unveiling– needs to be rethought. In order to reconceive this role, the paper secondly elaborates upon the key characteristics of sociomaterial studies in education in order to show such relational thinking takes shape in and during the conduct of sociomaterial research. These characteristics are crucial in order to fully apprehend the critical prospect of sociomaterial approaches in education. The role of critique, then, amounts to an engaged attitude vis-à-vis the practices under investigation, and more particularly points to critical creativity as offering some horizons of change.Este artículo tiene como argumento central que el recientemente emergente enfoque sociomaterial tiene un inherente potencial crítico para la educación, pero esta capacidad no ha sido completamente puesta en práctica o explorada en estudios educativos. Para argumentar estas ideas, este artículo empieza, en primer lugar, con una concisa descripción de representacionalismo en contraposición al pensamiento relacional, y propone que los estudios sociomateriales deben situarse en esta última corriente. En consecuencia, la función crítica que es ampliamente apoyada en el pensamiento representacional –que es una función principalmente dirigida a desacreditar y develar– requiere ser repensada. Para concebir nuevamente esta función, el artículo en segundo lugar profundiza sobre las principales características de los estudios sociomateriales en educación para demostrar que tal pensamiento relacional toma forma dentro y durante la realización de la investigación sociomaterial. Estas características son decisivas para aprehender completamente la perspectiva crítica de los enfoques sociomateriales en educación. La función de la crítica, entonces, equivale a una actitud comprometida con las prácticas objeto de investigación y dirige la atención hacia la creatividad crítica que ofrece algunos horizontes de cambio.Cet article a comme argument central que l’approche sociomatériel récemment émergent dans la recherche éducative a un potentiel intrinsèquement critique, mais que cette capacité n’est pas encore totalement déployée et explorée dans les études pédagogiques. Afin de rendre cet argument, cet article commence, d’abord, avec une description concise de la pensée représentationaliste et la pensée relationnelle, et argumente que les études sociomatérielles doivent être situées dans le dernier courant. Par conséquence, le rôle de la critique qui est largement adopté dans la pensée représentationaliste –i.e., un rôle adressé principalement aux démystification et dévoilement– doit être repensée. Afin de ressaisir ce rôle, le document explique deuxièmement les caractéristiques clés des études sociomatérielles dans l’éducation, afin de montrer que telle pensée relationnelle prend forme dans, et pendant, la conduite de la recherche sociomatériel. Ces caractéristiques sont essentielles pour appréhender pleinement la perspective critique des approches sociomatérielles dans l’éducation. Le rôle de la critique, puis, s’élève à une attitude engagée vis-à-vis des pratiques sous enquête, et plus particulièrement à la créativité critique qui offre des horizons du changement

\u27Out of time\u27. Constructing teacher professionality as a perpetual project on the eTwinning digital platform

This paper seeks to understand what digital schooling platforms do to teacher professionality; that is, the combination of professional knowledge, discretion and responsibility that enables a teacher to be professional. Specifically, we explore how the European Commission’s (EC) teacher professional learning platform eTwinning promotes a projectified (i.e., project-focused) and platformed (i.e., largely occurring on digital platforms) version of teacher professionality. Informed by recent thinking around ‘projectification’; that is, the ability of the project form to shape work practices, as well as the topological nature of timespace within a project, we argue that projectified teacher learning and professionality are now constituted through platform dynamics as a perpetual project-initself. As such, the projectified teacher is left simultaneously in-time (i.e., within the bounds of the project timespace) and out-of-time (i.e., out of possibilities of progress that can exist outside of the project), and thus faces the insuperable task of never-ending self-improvement through and as the project form (teacher-as-project). (DIPF/Orig.

‘Out of time’ : Constructing teacher professionality as a perpetual project on the eTwinning digital platform

This paper seeks to understand what digital schooling platforms do to teacher professionality; that is, the combination of professional knowledge, discretion and responsibility that enables a teacher to be professional. Specifically, we explore how the European Commission’s (EC) teacher professional learning platform eTwinning promotes a projectified (i.e., project-focused) and platformed (i.e., largely occurring on digital platforms) version of teacher professionality. Informed by recent thinking around ‘projectification’; that is, the ability of the project form to shape work practices, as well as the topological nature of timespace within a project, we argue that projectified teacher learning and professionality are now constituted through platform dynamics as a perpetual project-initself. As such, the projectified teacher is left simultaneously in-time (i.e., within the bounds of the project timespace) and out-of-time (i.e., out of possibilities of progress that can exist outside of the project), and thus faces the insuperable task of never-ending self-improvement through and as the project form (teacher-as-project)

Involvement of the hypothalamic-pituitary-thyroid axis and its interaction with the hypothalamic-pituitary-adrenal axis in the ontogeny of avian thermoregulation: a review

The emergence of thermoregulation in avian species is a complex matter in which neural as well as hormonal processes are involved. In a previous paper, the neural aspects of primary avian thermoregulation were discussed. In this paper the role of the hypothalamus-pituitary-thyroid axis (HPT-axis) and the hypothalamus-pituitary-adrenal axis (HPA-axis) in the ontogeny of avian thermoregulation is evaluated. The regulatory mechanisms and different important hormones of both axes, which have stimulatory or inhibitory effects, are discussed. Because the onset of functionality of the thermoregulatory system is of great interest, the ontogeny and functionality of the hormonal axes are clarified. There is a great difference between precocial and altricial birds in hormonal events as well as in neural processes which are involved in the emergence of thermoregulation. In precocial avian species the HPT-axis becomes functional during the mid- to late embryonic period while the same axis only becomes fully functional during the first week post-hatch in altricial avian species. As early as the sixties, the emergence of homeothermy in chickens was investigated. It was concluded that the thyroid gland plays an important role in the thermoregulatory mechanisms of newly hatched chicks. More recent studies however were not able to show any direct effect of the thyroid hormones on the thermoregulation of day-old chicks, although blocking the conversion of T4 to T3 caused a decrease in body temperature in young chicks. Thyrotropin releasing hormone (TRH) is known to act in thermoregulation in mammals and several authors have found an effect of TRH on the metabolism of young and older chicks. However, the exact mechanism still remains unclear. Because the HPT- and the HPA-axis show close relationships, the role of the HPA-axis in the ontogeny of thermoregulation is also taken into consideration in this review. In mammals as well as in birds, corticotropin releasing hormone (CRH) is involved in the primary thermoregulation. We conclude that the HPT-axis has an important role in the ontogeny of avian thermoregulation. The exact role of the HPA-axis remains largely unclear although at least CRH is definitely of some importance

When mindfulness interacts with neuroticism to enhance transformational leadership : the role of psychological need satisfaction

Transformational leadership is a popular and well-researched leadership style. Although much is understood about its positive consequences, less research has focused on antecedents of transformational leadership. In this research we draw upon self-determination theory and incorporate a self-regulatory approach to investigate if and how leader mindfulness influences transformational leadership. The analyses show that autonomy, competence and relatedness need satisfaction mediate between mindfulness and transformational leadership, indicating that mindfulness is associated with psychological need satisfaction. Furthermore, the data show that neuroticism moderates the relationship between mindfulness and relatedness need satisfaction. Generally speaking, the association between mindfulness and relatedness need satisfaction is positive. When neuroticism is also high, mindfulness has the largest impact. Or conversely, when emotional stability is high, mindfulness has the smallest association with relatedness need satisfaction. This is in line with evidence suggesting that mindfulness may primarily exert its influence through emotional self-regulation. Furthermore, the moderated mediation model for relatedness need satisfaction is significant, indicating that neuroticism is a boundary condition for the indirect effect of mindfulness on transformational leadership through relatedness need satisfaction

Leader psychological need satisfaction trickles down:The role of leader-member exchange

This article addresses the impact of leader psychological need satisfaction on employees. We draw on the self-determination theory (SDT) and leader-member exchange (LMX) theory to investigate if and how leader psychological need satisfaction trickles down to employee psychological need satisfaction. Adopting a multi-actor, multilevel design, results from 1036 leader–employee dyads indicate that employee-rated LMX mediates the trickle-down effect of leader psychological need satisfaction. Additional analyses of leader psychological needs show that leader competence is the main psychological need that underlying this relationship. We also found an unexpected negative association between leader autonomy need satisfaction and employee competence need satisfaction. Overall, this study shows the importance of both (1) leaders’ psychological need satisfaction and (2) employee perceptions of the relationship quality for employee psychological need satisfaction

Genetic markers for SSG-resistance in Leishmania donovani and SSG-treatment failure of visceral leishmaniasis patients in the Indian subcontinent

The current standard to assess pentavalent antimonial (SSG) susceptibility of Leishmania is a laborious in vitro assay of which the result has little clinical value because SSG-resistant parasites are also found in SSG-cured patients. Candidate genetic markers for clinically relevant SSG-resistant parasites identified by full genome sequencing were here validated on a larger set of clinical strains. We show that 3 genomic locations suffice to specifically detect the SSG-resistant parasites found only in patients experiencing SSG treatment failure. This finding allows the development of rapid assays to monitor the emergence and spread of clinically relevant SSGresistant Leishmania parasites