Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signalling

Autophagy is an evolutionarily conserved process that serves to provide nutrients during starvation and to eliminate detrimental cellular components like dysfunctional organelles and damaged proteins. This role of autophagy might be critical in neurons because of their postmitotic nature. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. The study shows that the crucial AuTophaGy protein ATG5 functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of synapse-confined proteome. This function of ATG5 is independent of bulk degradation of synaptic proteins and requires the starvation-induced targeting of PKA regulatory subunit type 1 (R1) to neuronal autophagosomes. Loss of ATG5 in either excitatory or inhibitory neurons causes a drastic accumulation of PKA R1 at synapses, which sequesters the PKA catalytic subunit and causes cAMP-dependent remodelling of the synaptic phosphoproteome. Autophagy-deficient excitatory synapses are characterized by increased thickness of the postsynaptic density and alterations in AMPA receptor GLUR1 trafficking, a phenotype that results in augmented excitatory neurotransmission and appearance of seizures in mice with glutamatergic forebrain-confined ATG5 deletion. My work has identified a previously unknown role of neuronal autophagy in regulating PKA-dependent signalling at glutamatergic synapses and suggest PKA as a target for treating autophagy-associated neurodegenerative diseases

Erben, Marcus: Begriffswandel als Sprachhandlung. Der Beitrag Quentin Skinners zur Methodologie und Funktionsbestimmung der pädagogischen Geschichtsschreibung. Frankfurt am Main: Peter Lang 2013. [Rezension]

Rezension von: Erben, Marcus: Begriffswandel als Sprachhandlung. Der Beitrag Quentin Skinners zur Methodologie und Funktionsbestimmung der pädagogischen Geschichtsschreibung. Frankfurt am Main: Peter Lang 2013, 375 S. ISBN 978-3-631-64355-

Process for the manufacture of carbon or graphite fibers

Carbon or graphite fibers are manufactured by heating polyacrylonitrile fiber materials in various solutions and gases. They are characterized in that the materials are heated to temperatures from 150 to 300 C in a solution containing one or more acids from the group of carbonic acids, sulfonic acids, and/or phenols. The original molecular orientation of the fibers is preserved by the cyclization that occurs before interlacing, which gives very strong and stiff carbon or graphite fibers without additional high temperature stretching treatments

Etablierung einer standardisierten Analyse longitudinaler Aβ-PET Scans zur effektiven Evaluation der BACE-Inhibition im transgenen Alzheimer-Mausmodell

Das erste Ziel der Promotionsarbeit war es eine optimale und standardisierte Analyse der Positron Emissions Tomographie in einem transgenen Kleintiermodell der Amyloid Anreicherung zu etablieren. Hierzu erfolgte die Evaluation einer automatisierten räumlichen Normalisierung und einer Intensitätsskalierung zu verschiedenen Referenzregionen. Insgesamt wurden 114 Aβ PET Scans des Mausmodells PS2APP mit dem Tracer FBB angefertigt. Darunter waren 37 Mäuse mit einem Baseline Scan (BL) im Alter von 8 Monaten und einem kurzfristigen Folgescan (FU) im Alter von 9,5 Monate, sowie 40 Scans im Alter von 13-16 Monaten (TER). Die so akquirierten microPET Dateien wurden durch eine starre, manuelle Fusion auf eine zerebrale MRT Vorlage durch drei Analysten mit unterschiedlichem Erfahrungsniveau untersucht. Im Anschluss wurden die Bilder durch Verwendung einer automatisierten, nicht-linearen Transformation auf altersabhängige Schablonen räumlich normalisiert und die Übereinstimmung der Analysten mittels Fleiss Kappa ermittelt. Zur Berechnung der zerebralen Amyloid Last definierten wir, neben dem reinen SUV (CTX), vier Referenzregionen mit den entsprechenden SUVR. Als Referenzregionen bestimmten wir den Hirnstamm (BST), das Zerebellum (CBL), die weiße Substanz (WM) und das gesamte Gehirn (GLM). Die Ergebnisse wurden anhand der longitudinalen Stabilität und der Übereinstimmung mit dem histologischen Goldstandart verglichen. Die räumliche Normalisierung resultierte in einer nahezu perfekten Übereinstimmung der Analysen. Die Korrelation zur Histologie blieb konstant oder verbesserte sich (alle κ ≥ 0.99). Alle SUVR waren der reinen SUV (CTX) überlegen (d ≥1.21 vs. d = 0.23 und R ≥ 0.66 vs. R ≥ 0.31). Eine Analyse der Skalierung zum GBM auf Voxelebene erbrachte einen physiologisch nicht erklärbaren Abfall der SUVR im Bereich des Rautenhirns. Die optimale Referenzregion definierten wir anhand der Korrelation mit der Histologie, der artifizielle Anhebung der Varianz in der Gruppe, der Effektgröße der longitudinalen kortikalen Amyloid Progression, den Effekt der Pathologie in der Referenzregion und den Einfluss einzelner Tiere. In Zusammenschau der untersuchten Qualitäten war die Intensitätsskalierung zur WM den übrigen SUVR überlegen. Auf Basis dieser Ergebnisse erfolgte im Anschluss, als zweiter Teil, eine multimodale Interventionsstudie zur Untersuchung der Amyloidose unter Therapie mit dem BACE-Inhibitor RO5508887. Hierzu wurden 26 weibliche PS2APP-Swe (TG) und 22 weibliche C57BL/6 (WT) Mäuse im Alter von 9,5 Monaten in einen Placeboarm (TG-VEH) und einen Interventionsarm (TG-BSI) randomisiert. Nach initialer Anfertigung eines Baseline [18F] -FBB PET Scans erfolgte die zweimal tägliche orale Applikation von RO5508887 oder einer entsprechenden Placebolösung über einen Zeitraum von 4 Monaten. Nach 10 und nach 18,5 Wochen wurde jeweils ein FU Scan angefertigt. Im Anschluss an den finalen Scan wurden die Gehirne der Tiere zur histologischen und biochemischen Quantifizierung und Differenzierung entnommen. Der Amyloid Progress war 15.3 ± 4.4% in der Placebo Gruppe und 8.4 ± 2.2% in der Therapiegruppe. Durch die Therapie konnte der Anstieg der Amyloidose signifikant reduziert werden (p<0.001). Diesen Effekt konnte die histologische Analyse in Bezug auf die Plaque-Belastung (-9,7%, p < 0,05) und die Plaque-Dichte (-9,9%, p <0,05) bestätigen. Auch die biochemische Analyse zeiget eine Reduktion des löslichen und unlöslichen Aβ40 ( -47% und -10%), sowie des löslichen und unlöslichen Aβ42 (-61% und -40%). Die akute BACE Inhibition konnte durch eine Reduktion des sAPP-β bei Anstieg des sAPP-α und unveränderten sAPP nachgewiesen werden. Außerdem stellte sich eine negative Korrelation zwischen dem Ausmaß der Amyloidose bei Therapiebeginn und dem Progress unter Therapie dar. Zusätzlich beobachteten wir eine weitere inverse Korrelation zwischen der naiven Amyloid Akkumulation und dem Therapieeffekt. So war die absolute Reduktion der Aβ Deposition unter Behandlung 7,6 ± 1,7% in hoch akkumulierenden Regionen (≥ 10%) und 4,8 ± 2,0% in niedrig akkumulierenden Regionen (<10%). Der relative Behandlungseffekt war 49 ± 11% in hochakkumulierenden Hirnregionen und 69 ± 28% in Regionen mit geringer naiver Akkumulation. In Regionen mit niedrigem, naivem Progresse konnte ein Schwellenwert der regionale Depositionsrate von 3,7%/18,5 Wochen bestimmt werden, unterhalb dem eine vollständige Blockierung der weiteren Signalzunahme angenommen werden kann. Zusammenfassend stellten wir die Überlegenheit einer Analyse von longitudinalen Aβ PET Daten im Mausmodell durch Verwendung einer räumlichen Normalisierung und einer SUVR mit Skalierung zur WM dar. Auf Basis dieser Erkenntnisse konnten wir im Anschluss zeigen, dass der Therapieeffekt einer BACE Inhibition auf den Progress der zerebralen Amyloidose von der Aβ-Last bei Therapiebeginn abhängig ist

Metacognition in decision-making: Exploring age-related changes in confidence

Metacognition is a fundamental human function that supports goal-directed behaviour. By constantly monitoring and evaluating our decisions we are able to detect errors when they occur and adjust the behaviour accordingly. Metacognitive evaluations can be expressed in ratings of decision confidence or error detection reports. Humans are generally capable of forming well-calibrated estimates of their own performance, yet metacognitive abilities have been shown to be specifically affected by healthy ageing. However, the mechanisms underlying this decline remain poorly understood. This thesis aims to investigate the cognitive processes of age-related changes in perceptual metacognitive performance by combining approaches from the fields of error monitoring and decision confidence. For this, we developed a new paradigm for studying the metacognitive evaluation of errors and correct responses that was feasible for adults of all ages. While recording an electroencephalogram (EEG) and response force, a sample of 65 healthy adults from 20 to 76 years made a series of decisions in a modified version of the Flanker task and subsequently indicated how confident they felt about their decision on a four-point scale. Across two studies, conducted in the same large sample, I addressed three specific research questions: first, how is metacognitive performance affected by healthy ageing? Second, what are factors contributing to the observed decline in metacognitive performance? And third, how does an age-related decline in metacognitive performance affect subsequent behaviour? The analysis of behavioural data (Study 1a) showed that metacognitive accuracy declined significantly with older age and that this decline could not be explained by the decline in task performance alone. Independent of age, however, participants adjusted their performance according to their metacognitive evaluation of their previous decision and responded more cautiously after reporting low confidence. The analysis of electrophysiological data (Study 1b) focussed on the modulation of two correlates of error monitoring by confidence and age. The results indicated that the error/correct positivity (Pe/c), a component discussed as a marker of error detection and decision confidence, scaled with reported confidence in errors but did not show the expected modulation by age. The amplitude of the error/correct negativity (Ne/c), a marker of early error monitoring processes, also scaled with reported confidence in errors, but in contrast, was less sensitive to variations in confidence with older age. Finally, Study 2 investigated the effect of age on the relationship between confidence and two response parameters of the initial decision: response time and response force. We replicated a widely reported negative relationship between confidence and response time. Importantly, we showed, for the first time, that confidence was also negatively related to fine-grained changes in peak force, which was intuitively exerted by the participants. Notably, these associations were dependent on the accuracy of the response and changed markedly across age: the relationship between confidence and response time was only found in correct responses and was pronounced with older age, while the relationship between confidence and peak force was only found in errors and only in younger adults. Overall, these findings jointly provide novel insights deepening our understanding of the observed decline in metacognitive performance with older age. A similar modulation of the Pe/c by confidence across the lifespan suggests that the post-decisional process of accumulating evidence about the correctness of a prior decision might generally be intact until old age. Instead, the age-related decline in metacognitive accuracy appears to be related to a multitude of cognitive and neural changes, which might reflect increased noise and hence higher uncertainty in older adults’ computation of confidence. Moreover, I discuss how a metacognitive decline could manifest in real life and how recent findings offer a promising view regarding the effect of training on metacognitive performance

Improved oral bioavailability of poorly water soluble drugs using rapid freezing processes

textA growing number of therapeutic compounds currently being developed by pharmaceutical companies are poorly water soluble leading to limited and/or erratic bioavailability. The rate limiting step for absorption of these compounds is dependent on the dissolution and apparent solubility. Nanoparticle formation has been exploited as a method to improve the bioavailability of these poorly water soluble active pharmaceutical ingredients (API) by increasing the dissolution rates and apparent solubilities. The influence of hydrophilic stabilizers in powder compositions prepared by the spray freezing into liquid (SFL) process using either an emulsion feed dispersion or organic co-solvent feed solutions on enhancing the wetting and dissolution properties of nanostructured aggregates containing itraconazole (ITZ). Subsequently, an in vivo pharmacokinetic study was conducted comparing the SFL processed powder to commercial Sporanox®. An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. Rapid freezing technologies are known to enhance the physico-chemical properties of APIs and thus increase bioavailability. However, the effect of the different freezing geometries and rates in the URF process are unknown. Therefore, this study investigated how solvent properties and thin film geometry of the droplet affect the freezing rate and thus the physico-chemical properties of micronized danazol powders. Amorphous nanoparticles containing tacrolimus (TAC) in a solid dispersion were prepared using the Ultra-rapid Freezing (URF) process. The objective of this study was to assess the effects of combinations of polymeric stabilizers on the maximum degree and extent of supersaturation of TAC. An attempt to establish if an in vitro-in vivo correlation exists between supersaturation and improved pharmacokinetic parameters for orally dosed TAC was performed. Enteric solid dispersions could overcome limitations of premature precipitation of supersaturated solutions by 1.) delaying dissolution until the compound enters the intestines where absorption is favored and 2.) increasing the apparent solubility at higher pH to increase the driving force for absorption. The objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ.Pharmac

Reflecting on hard and soft coups: a comparison of Aquarius by Kleber Mendonça Filho and Land in Anguish by Glauber Rocha

This article aims to study the film Aquarius (2015) by Kleber Mendonça Filho in comparison with Land in Anguish (1967) by Glauber Rocha. The interest in analyzing both films stems from the polemical reception that Aquarius received after its director and cast used the international launch at the Cannes Film Festival in 2016 to protest publically against the impeachment of Brazilian president Dilma Rousseff, denounced by them as a soft coup. Land in Anguish, on the other hand, has long been considered an allegory of Brazil’s political situation after the military coup in 1964. This article will ask if any of the two films can be read as a diagnosis of the country and if how. To do so this study will be guided by the anthropological definition of film developed by German philosopher Martin Seel (2013) who understands the media as the art form that most strongly is capable of moving us, as much emotionally as intellectually, and, in consequence, make us move. I will therefore discuss both Aquarius and Land in Anguish’s potentials to move us and to make us move, asking if they can make us feel and understand Brazil so as to make us act – perchance – within its socio-political structure

Impact of PCA-based preprocessing and different CNN structures on deformable registration of sonograms

Central venous catheters (CVC) are commonly inserted into the large veins of the neck, e.g. the internal jugular vein (IJV). CVC insertion may cause serious complications like misplacement into an artery or perforation of cervical vessels. Placing a CVC under sonographic guidance is an appropriate method to reduce such adverse events, if anatomical landmarks like venous and arterial vessels can be detected reliably. This task shall be solved by registration of patient individual images vs. an anatomically labelled reference image. In this work, a linear, affine transformation is performed on cervical sonograms, followed by a non-linear transformation to achieve a more precise registration. Voxelmorph (VM), a learning-based library for deformable image registration using a convolutional neural network (CNN) with U-Net structure was used for non-linear transformation. The impact of principal component analysis (PCA)-based pre-denoising of patient individual images, as well as the impact of modified net structures with differing complexities on registration results were examined visually and quantitatively, the latter using metrics for deformation and image similarity. Using the PCA-approximated cervical sonograms resulted in decreased mean deformation lengths between 18% and 66% compared to their original image counterparts, depending on net structure. In addition, reducing the number of convolutional layers led to improved image similarity with PCA images, while worsening in original images. Despite a large reduction of network parameters, no overall decrease in registration quality was observed, leading to the conclusion that the original net structure is oversized for the task at hand.Comment: 8 pages, 7 figures Presented at WSCG 202

Heidrun Alzheimer-Haller: Handbuch zur narrativen Volksaufklärung. Moralische Geschichten 1780-1848. Berlin, New York: de Gruyter 2004 (899 S.) [Rezension]

Rezension von: Heidrun Alzheimer-Haller: Handbuch zur narrativen Volksaufklärung. Moralische Geschichten 1780-1848. Berlin, New York: de Gruyter 2004 (899 S.; ISBN 3-11-017601-7; 198,00 EUR)