Notes and News- Fall 2003

Notes And News Call For Papers 20th National Cowboy Poetry Gathering Visiting Scholars Program Willa Cather Literary A Ward 2004 Map Correctio

p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death

In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducible p25 expression. In this system, no sign of apoptosis was seen before 24 hours of p25 induction. Thus, at that time, cell-cycle-regulatory proteins were analysed by immunoblotting and some of them showed a significant deregulation. Interestingly, after time-course experiments, the earliest feature correlated with p25 expression was the phosphorylation of the retinoblastoma protein (Rb). Indeed, this phosphorylation was observed 6 hours after p25 induction and was abolished in the presence of a Cdk5 inhibitor, roscovitine, which does not inhibit the usual Rb cyclin-D kinases Cdk4 and Cdk6. Furthermore, analyses of levels and subcellular localization of Cdk-related cyclins did not reveal any change following Cdk5 activation, arguing for a direct effect of Cdk5 activity on Rb protein. This latter result was clearly demonstrated by in vitro kinase assays showing that the p25-Cdk5 complex in our cell system phosphorylates Rb directly without the need for any intermediary kinase activity. Hence, Rb might be an appropriate candidate that connects Cdk5 to cell-cycle deregulation during neuronal cell death

MicroRNAs and the Regulation of Tau Metabolism

Abnormal regulation of tau phosphorylation and/or alternative splicing is associated with the development of a large (>20) group of neurodegenerative disorders collectively known as tauopathies, the most common being Alzheimer's disease. Despite intensive research, little is known about the molecular mechanisms that participate in the transcriptional and posttranscriptional regulation of endogenous tau, especially in neurons. Recently, we showed that mice lacking Dicer in the forebrain displayed progressive neurodegeneration accompanied by disease-like changes in tau phosphorylation and splicing. Dicer is a key enzyme in the biogenesis of microRNAs (miRNAs), small noncoding RNAs that function as part of the RNA-induced silencing complex (RISC) to repress gene expression at the posttranscriptional level. We identified miR-16 and miR-132 as putative endogenous modulators of neuronal tau phosphorylation and tau exon 10 splicing, respectively. Interestingly, these miRNAs have been implicated in cell survival and function, whereas changes in miR-16/132 levels correlate with tau pathology in human neurodegenerative disorders. Thus, understanding how miRNA networks influence tau metabolism and possibly other biological systems might provide important clues into the molecular causes of tauopathies, particularly the more common but less understood sporadic forms

Development and validation of an oligonucleotide microarray to characterise ectomycorrhizal fungal communities

Background: In forest ecosystems, communities of ectomycorrhizal fungi (ECM) are influenced by several biotic and abiotic factors. To understand their underlying dynamics, ECM communities have been surveyed with ribosomal DNA-based sequencing methods. However, most identification methods are both time-consuming and limited by the number of samples that can be treated in a realistic time frame. As a result of ongoing implementation, the array technique has gained throughput capacity in terms of the number of samples and the capacity for parallel identification of several species. Thus far, although phylochips (microarrays that are used to detect species) have been mostly developed to trace bacterial communities or groups of specific fungi, no phylochip has been developed to carry oligonucleotides for several ectomycorrhizal species that belong to different genera. Results: We have constructed a custom ribosomal DNA phylochip to identify ECM fungi. Specific oligonucleotide probes were targeted to the nuclear internal transcribed spacer (ITS) regions from 95 fungal species belonging to 21 ECM fungal genera. The phylochip was first validated using PCR amplicons of reference species. Ninety-nine percent of the tested oligonucleotides generated positive hybridisation signals with their corresponding amplicons. Cross-hybridisation was mainly restricted at the genus level, particularly for Cortinarius and Lactarius species. The phylochip was subsequently tested with environmental samples that were composed of ECM fungal DNA from spruce and beech plantation fungal communities. The results were in concordance with the ITS sequencing of morphotypes and the ITS clone library sequencing results that were obtained using the same PCR products. Conclusion: For the first time, we developed a custom phylochip that is specific for several ectomycorrhizal fungi. To overcome cross-hybridisation problems, specific filter and evaluation strategies that used spot signal intensity were applied. Evaluation of the phylochip by hybridising environmental samples confirmed the possible application of this technology for detecting and monitoring ectomycorrhizal fungi at specific sites in a routine and reproducible manner

Vérité et sens chez H.-G. Gadamer

En affirmant que « l’être qui peut être compris est langage », l’herméneutique philosophique de H.-G. Gadamer semble hésiter entre deux directions : celle qui, à la suite de Hegel, pense le langage comme logos, c’est-à-dire comme médiation, communication et circulation d’un sens, et celle qui, à suite de Heidegger le pense comme poïesis, c’est-à-dire comme ouverture de l’étant, venue à l’être de la vérité. On s’interroge sur la façon dont Vérité et Méthode dépasse cette antinomie. Le langage est à la fois ouverture et médiation, logos et poïesis, vérité qui est sens, sens qui est vérité. Mais, en cette unité, la dimension privilégiée n’est-elle pas la poïesis, dans la mesure où le jeu qui se joue dans le langage est toujours celui de la vérité, jamais celui de la liberté ? Son refus du subjectivisme permet-il dès lors à l’herméneutique de maintenir sa prétention à l’universalité ? Lui permet-il de penser l’action, c’est-à-dire l’histoire et la politique ?Indem sie «Sein das verstanden werden kann» als «Sprache» begreift, scheint die philosophische Hermeneutik H.-G. Gadamers zwischen zwei Orientierungsmö: die eine, die der hegelschen Tradition verpflichtet ist, denkt die Sprache als Logos, d.h. als ein Vermittein, Mitteilen und Zirkulieren eines Sinnes. Die zweite denkt im gefolge Heideggers die Sprache als Poïesis, d.h. als ein Erschliessen des Seienden, als das sich Ereignen der Wahrheit. Man kann sich fragen, wie diese Antinomie in Wahrheit und Methode aufgehoben wird. Liegt aber in dieser Einheit der Schwerpunkt nicht auf Poïesis, insofern als das der Sprache inhärentes Spiel immer ein Wahrheits — und nie ein Freiheitsspiel ist? Kann aber eine Hermeneutik, die jeglichen Subjektivismus ablehnt, ihren Universalitätsanspruch aufrechterhalten ? Vermag eine so konzipierte Hermeneutik, das Handeln, d.h. die Geschichte und die Politik überhaupt zu denken

La vraie démocratie et la question de la critique du libéralisme politique dans le Manuscrit de Kreuznach de Marx

Cet article vise à clarifier la position de Marx relativement au libéralisme politique au moment où, en 1843, il se consacre, dans le Manuscrit de Kreuznach, à la critique d’une grande partie de la section « État » des Principes de Hegel. Récusant comme archaïque la critique hégélienne du libéralisme politique, Marx reconnaît à ce dernier le mérite d’avoir séparé la société civile et l’État, mais, ce faisant, Marx entérine aussi la représentation de la société civile que propose le libéralisme. Il se contente d’opposer à l’abstraction libérale de la représentation politique une autre abstraction : celle de la société civile, abstraitement assimilée au « peuple », là où Hegel avait su au contraire en reconnaître l’articulation en groupes sociaux différenciés.This article aims to clarify Marx’s position towards political liberalism when he was writing in 1843 a critical commentary to Hegel’s Principles of the Philosophy of Right. Considering as archaic Hegel’s critic of political liberalism, Marx credits the liberalism for having separated the civil society and the state but it leads Marx to admit the liberal conception of the civil society. Marx contrasts the liberal abstraction of political representation with an other abstraction : the abstraction of civil society reduced to “the people”, where Hegel, on the contrary, was able to recognize the articulation of civil society in different social groups

Analytical performance and clinical utility of the INNOTEST (R) PHOSPHO-TAU(181P) assay for discrimination between Alzheimer's disease and dementia with Lewy bodies

Background: Total tau (T-tau) and beta-amyloid((1-42)) (A beta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. Methods: The analytical performance of the INNOTEST (R) PHOSPHO-TAU((181P)) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and AP1-421 for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. Results: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. Conclusions: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB

Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Acknowledgments This work was supported by The Croatian Science Foundation grant No. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138. We also thank Mate Babić for help in preparation of schematics.Peer reviewedPublisher PD

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin