Placeboeffekte in der pharmakologischen Behandlung von Insomnie

Placeboeffekten wird in neueren Studien ein substantieller Anteil an der Symptomverbesserung in der Pharmakotherapie zugesprochen. Im Bereich der pharmakologischen Behandlung von Insomnie gibt es bisher jedoch kaum Studien, die sich mit der Quantifizierung eines möglichen Placeboeffektes und der Untersuchung seiner zugrunde liegenden Wirkmechanismen befasst haben. Die vorliegende Dissertation verfolgte daher zwei Ziele. Erstens wurde im Rahmen einer Metaanalyse die differentielle Wirksamkeit verschiedener Substanzklassen auf objektive und subjektive Zielgrößen in 31 randomisierten kontrollierten klinischen Studien (RCTs) zur pharmakologischen Behandlung von primärer Insomnie (3820 Patienten) erfasst (Studie 1). Hierbei wurden auch die Symptomverbesserungen innerhalb der Placebo-Kontrollgruppen der klinischen Primärstudien (32 RCTs mit 3969 Patienten) quantifiziert, sowie der Anteil des Placeboeffektes an der Symptomverbesserung in der Medikamentengruppe bestimmt (Studie 2). Dabei zeigte sich sowohl in subjektiven als auch in objektiven Zielgrößen bei einer eher moderaten Wirksamkeit über alle Substanzklassen hinweg, dass im Mittel 63.56% der Symptomverbesserung in der pharmakologischen Behandlung von Insomnie bereits in den Placebo-Kontrollgruppen erreicht wurde. Zweitens wurde Konditionierung - als ein potentiell zugrunde liegender Wirkmechanismus des Placeboeffektes - im Rahmen eines Konditionierungsparadigmas an 39 gesunden Probanden untersucht (Studie 3). In der Machbarkeitsstudie konnte nicht, wie erwartet, demonstriert werden, dass sich in einer Akquisitionsphase gelernte pharmakologisch induzierte Veränderungen der Schlafarchitektur (Amitriptylin induzierte REM-Schlaf Suppression) in einer Evokationsphase durch die Einnahme eines Placebos wieder abrufen (imitieren) lassen. Vielmehr zeigte sich unerwartet ein signifikanter Effekt in die entgegengesetzte Richtung, also signifikant mehr REM-Schlaf in der Experimentalgruppe als in der Placebo-Kontrollgruppe. Die vorliegenden Befunde weisen darauf hin, dass einfache Regeln des assoziativen Lernens nicht ausreichen, um den beobachteten Placeboeffekt zu erklären. Es müssen komplexere Einflüsse, wie eine konditionierte Gegenreaktion oder eine homöostatische Gegenreaktion nach Absetzen der Studienmedikation (Rebound), die mit der Konditionierung interferierte, in Betracht gezogen werden

„Digitale Lerngemeinschaften“ im Praxissemester. Wahrnehmung eines Angebots zur Theorie-Praxis-Relationierung in der Lehrkräftebildung für das Fach Deutsch

Der Artikel stellt erste deutschdidaktische Befunde des Projekts DiLe („Digitale Lerngemeinschaften zur kohärenten Lernbegleitung im Jenaer Modell der Lehrerbildung“) vor. DiLe zielt darauf, die Kooperation zwischen Schule und Universität bei der Begleitung von Praxissemesterstudierenden zu verbessern. Schulische Mentor:innen im Praxissemester erhalten die Gelegenheit, mit Hilfe digitaler Fortbildungsbausteine ihr fachdidaktisches Wissen zu erweitern und im Dialog mit Praxissemesterstudieren-den auf Anforderungssituationen im Unterricht zu beziehen. Der Artikel untersucht, mit welchen Erwartungen die Teilnehmenden im Fach Deutsch in die Fortbildung starten, inwieweit sie diese erfüllt sehen und inwieweit sie deutschdidaktische Fortbildungsinhalte im digitalen Austausch aufgreifen. Als Daten dienen Kurzstatements der Teilnehmenden (prä/post), Mitschnitte von Videokonferenzen sowie nachträgliche Interviews, die allesamt inhaltsanalytisch ausgewertet wurden. Die Diskussion der Befunde geht darauf ein, inwieweit digital gesteuerte Vermittlungs- und Verständigungsprozesse zwischen den Beteiligten einen Beitrag zur Überwindung der doppelten Distanz zwischen Universität und Schule leisten können.   Abstract (english): Digital learning communities during the teaching practicum. Perception of an approach to the connection between theory and practice in the training of teachers of the subject German The article presents first results of the project DiLe („Digital Learning Communities for Coherent Learning Support in the Model of Teacher Education in Jena“). The project aims to improve the cooperation between school and university in the supervision of students in the 5-month teaching practicum. School mentors in the teaching practicum are given the opportunity to expand their academic knowledge of teaching German language and literature with the help of digital training modules. So, they can relate academic knowledge to the requirements of the classroom in a dialog with students in the teaching practicum. The article explores the expectations of the par-ticipants in the subject German. It also asks to what extent they see these expectations fulfilled and to what extent they take up the presented academic knowledge in the digital exchange. Our data consists of short statements of the participants (pre/post), recordings of video conferences as well as interviews. The discussion of the results addresses the extent to which digitally controlled teaching and communica-tion processes between the participants can help to overcome the double distance between university and school

Deep Learning based Model Predictive Control for Compression Ignition Engines

Machine learning (ML) and a nonlinear model predictive controller (NMPC) are used in this paper to minimize the emissions and fuel consumption of a compression ignition engine. In this work machine learning is applied in two methods. In the first application, ML is used to identify a model for implementation in model predictive control optimization problems. In the second application, ML is used as a replacement of the NMPC where the ML controller learns the optimal control action by imitating or mimicking the behavior of the model predictive controller. In this study, a deep recurrent neural network including long-short term memory (LSTM) layers are used to model the emissions and performance of an industrial 4.5 liter 4-cylinder Cummins diesel engine. This model is then used for model predictive controller implementation. Then, a deep learning scheme is deployed to clone the behavior of the developed controller. In the LSTM integration, a novel scheme is used by augmenting hidden and cell states of the network in an NMPC optimization problem. The developed LSTM-NMPC and the imitative NMPC are compared with the Cummins calibrated Engine Control Unit (ECU) model in an experimentally validated engine simulation platform. Results show a significant reduction in Nitrogen Oxides (\nox) emissions and a slight decrease in the injected fuel quantity while maintaining the same load. In addition, the imitative NMPC has a similar performance as the NMPC but with a two orders of magnitude reduction of the computation time.Comment: Submitted to Control engineering Practice (Submission date: March 9, 2022) Revised version (Submission date: June 18, 2022) Accepted on July 30, 202

Machine Learning Integrated with Model Predictive Control for Imitative Optimal Control of Compression Ignition Engines

The high thermal efficiency and reliability of the compression-ignition engine makes it the first choice for many applications. For this to continue, a reduction of the pollutant emissions is needed. One solution is the use of machine learning (ML) and model predictive control (MPC) to minimize emissions and fuel consumption, without adding substantial computational cost to the engine controller. ML is developed in this paper for both modeling engine performance and emissions and for imitating the behaviour of an Linear Parameter Varying (LPV) MPC. Using a support vector machine-based linear parameter varying model of the engine performance and emissions, a model predictive controller is implemented for a 4.5 Cummins diesel engine. This online optimized MPC solution offers advantages in minimizing the \nox~emissions and fuel consumption compared to the baseline feedforward production controller. To reduce the computational cost of this MPC, a deep learning scheme is designed to mimic the behavior of the developed controller. The performance in reducing NOx emissions at a constant load by the imitative controller is similar to that of the online optimized MPC compared to the Cummins production controller. In addition, the imitative controller requires 50 times less computation time compared to that of the online MPC optimization.Comment: Submitted to Advances in Automotive Control - 10th AAC 202

Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD

Country-level gender inequality is associated with structural differences in the brains of women and men

Significance Gender inequality is associated with worse mental health and academic achievement in women. Using a dataset of 7,876 MRI scans from healthy adults living in 29 different countries, we here show that gender inequality is associated with differences between the brains of men and women: cortical thickness of the right hemisphere, especially in limbic regions such as the right caudal anterior cingulate and right medial orbitofrontal, as well as the left lateral occipital, present thinner cortices in women compared to men only in gender-unequal countries. These results suggest a potential neural mechanism underlying the worse outcome of women in gender-unequal settings, as well as highlight the role of the environment in the brain differences between women and men. Abstract Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality

Boundary effects on quantum q-breathers in a Bose-Hubbard chain

We investigate the spectrum and eigenstates of a Bose-Hubbard chain containing two bosons with fixed boundary conditions. In the noninteracting case the eigenstates of the system define a two-dimensional normal-mode space. For the interacting case weight functions of the eigenstates are computed by perturbation theory and numerical diagonalization. We identify paths in the two-dimensional normal-mode space which are rims for the weight functions. The decay along and off the rims is algebraic. Intersection of two paths (rims) leads to a local enhancement of the weight functions. We analyze nonperturbative effects due to the degeneracies and the formation of two-boson bound states.Comment: 10 pages, 11 figures. With minor corrections. Accepted in Physica

Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells

Alzheimer’s disease (AD) is characterized by an increased plaque burden and tangle accumulation in the brain accompanied by extensive lipid alterations. Methylxanthines (MTXs) are alkaloids frequently consumed by dietary intake known to interfere with the molecular mechanisms leading to AD. Besides the fact that MTX consumption is associated with changes in triglycerides and cholesterol in serum and liver, little is known about the effect of MTXs on other lipid classes, which raises the question of whether MTX can alter lipids in a way that may be relevant in AD. Here we have analyzed naturally occurring MTXs caffeine, theobromine, theophylline, and the synthetic MTXs pentoxifylline and propentofylline also used as drugs in different neuroblastoma cell lines. Our results show that lipid alterations are not limited to triglycerides and cholesterol in the liver and serum, but also include changes in sphingomyelins, ceramides, phosphatidylcholine, and plasmalogens in neuroblastoma cells. These changes comprise alterations known to be beneficial, but also adverse effects regarding AD were observed. Our results give an additional perspective of the complex link between MTX and AD, and suggest combining MTX with a lipid-altering diet compensating the adverse effects of MTX rather than using MTX alone to prevent or treat AD

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionalit