The structural developments of regional television in Britain and Germany

This paper compares the structural developments of regional television in Britain and Germany from the early days of broadcasting to the present from an institutional and organisational perspective. Drawing on a series of interviews with policy-makers and other key personalities, it is argued that the combination of political administrative borders and regional television boundaries, as exists in the German Länder, provides a fruitful basis for a strong regional television service. During the post-war period divergences between Länder borders and Consortium of Public-Law Broadcasting Institutions of the Federal Republic of Germany (ARD) broadcasting boundaries, palpably manifest in south-west Germany, have been harmonised, leading to thorough conformity. However, in centralised England questions of regionalism have strangely played such an important role in the evolution of television, and there are evident disjunctures between regional boundaries and television regions. This applies to the regional structure of Independent Television (ITV) as well as to the regional initiatives of the BBC, which, since the mid-1980s, increasingly takes over ITV's regional duties, fulfilling primarily political demands

A Preconditioned Inexact Active-Set Method for Large-Scale Nonlinear Optimal Control Problems

We provide a global convergence proof of the recently proposed sequential homotopy method with an inexact Krylov--semismooth-Newton method employed as a local solver. The resulting method constitutes an active-set method in function space. After discretization, it allows for efficient application of Krylov-subspace methods. For a certain class of optimal control problems with PDE constraints, in which the control enters the Lagrangian only linearly, we propose and analyze an efficient, parallelizable, symmetric positive definite preconditioner based on a double Schur complement approach. We conclude with numerical results for a badly conditioned and highly nonlinear benchmark optimization problem with elliptic partial differential equations and control bounds. The resulting method is faster than using direct linear algebra for the 2D benchmark and allows for the parallel solution of large 3D problems.Comment: 26 page

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs (“precision medicine”) for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal

A direct method for the numerical solution of optimization problems with time-periodic PDE constraints

In der vorliegenden Dissertation entwickeln wir auf der Basis der Direkten Mehrzielmethode eine neue numerische Methode für Optimalsteuerungsprobleme (OCPs) mit zeitperiodischen partiellen Differentialgleichungen (PDEs). Die vorgeschlagene Methode zeichnet sich durch asymptotisch optimale Skalierung des numerischen Aufwandes in der Zahl der örtlichen Diskretisierungspunkte aus. Sie besteht aus einem Linearen Iterativen Splitting Ansatz (LISA) innerhalb einer Newton-Typ Iteration zusammen mit einer Globalisierungsstrategie, die auf natürlichen Niveaufunktionen basiert. Wir untersuchen die LISA-Newton Methode im Rahmen von Bocks kappa-Theorie und entwickeln zuverlässige a-posteriori kappa-Schätzer. Im Folgenden erweitern wir die LISA-Newton Methode auf den Fall von inexakter Sequentieller Quadratischer Programmierung (SQP) für ungleichungsbeschränke Probleme und untersuchen das lokale Konvergenzverhalten. Zusätzlich entwickeln wir klassische und Zweigitter Newton-Picard Vorkonditionierer für LISA und beweisen gitterunabhängige Konvergenz der klassischen Variante auf einem Modellproblem. Anhand numerischer Ergebnisse können wir belegen, dass im Vergleich zur klassichen Variante die Zweigittervariante sogar noch effizienter ist für typische Anwendungsprobleme. Des Weiteren entwickeln wir eine Zweigitterapproximation der Lagrange-Hessematrix, welche gut in den Rahmen des Zweigitter Newton-Picard Ansatzes passt und die im Vergleich zur exakten Hessematrix zu einer Laufzeitreduktion von 68% auf einem nichtlinearen Benchmarkproblem führt. Wir zeigen weiterhin, dass die Qualität des Feingitters die Genauigkeit der Lösung bestimmt, während die Qualität des Grobgitters die asymptotische lineare Konvergenzrate, d.h., das Bocksche kappa, festlegt. Zuverlässige kappa-Schätzer ermöglichen die automatische Steuerung der Grobgitterverfeinerung für schnelle Konvergenz. Für die Lösung der auftretenden, großen Probleme der Quadratischen Programmierung (QPs) wählen wir einen strukturausnutzenden zweistufigen Ansatz. In der ersten Stufe nutzen wir die durch den Mehrzielansatz und die Newton-Picard Vorkonditionierer bedingten Strukturen aus, um die großen QPs auf äquivalente QPs zu reduzieren, deren Größe von der Zahl der örtlichen Diskretisierungspunkte unabhängig ist. Für die zweite Stufe entwickeln wir Erweiterungen für eine Parametrische Aktive Mengen Methode (PASM), die zu einem zuverlässigen und effizienten Löser für die resultierenden, möglicherweise nichtkonvexen QPs führen. Weiterhin konstruieren wir drei anschauliche, contra-intuitive Probleme, die aufzeigen, dass die Konvergenz einer one-shot one-step Optimierungsmethode weder notwendig noch hinreichend für die Konvergenz der entsprechenden Methode für das Vorwärtsproblem ist. Unsere Analyse von drei Regularisierungsansätzen zeigt, dass de-facto Verlust von Konvergenz selbst mit diesen Ansätzen nicht verhindert werden kann. Des Weiteren haben wir die vorgestellten Methoden in einem Computercode mit Namen MUSCOP implementiert, der automatische Ableitungserzeugung erster und zweiter Ordnung von Modellfunktionen und Lösungen der dynamischen Systeme, Parallelisierung auf der Mehrzielstruktur und ein Hybrid Language Programming Paradigma zur Verfügung stellt, um die benötigte Zeit für das Aufstellen und Lösen neuer Anwendungsprobleme zu minimieren. Wir demonstrieren die Anwendbarkeit, Zuverlässigkeit und Effektivität von MUSCOP und damit der vorgeschlagenen numerischen Methoden anhand einer Reihe von PDE OCPs von steigender Schwierigkeit, angefangen bei linearen akademischen Problemen über hochgradig nichtlineare akademische Probleme der mathematischen Biologie bis hin zu einem hochgradig nichtlinearen Anwendungsproblem der chemischen Verfahrenstechnik im Bereich der präparativen Chromatographie auf Basis realer Daten: Dem Simulated Moving Bed (SMB) Prozess

Phenotyping Young GluA1 Deficient Mice – A Behavioral Characterization in a Genetic Loss-of-Function Model

Alterations of glutamatergic neurotransmission have been implicated in neurodevelopmental and neuropsychiatric disorders. Mice lacking the GluA1 AMPA receptor subunit, encoded by the Gria1 gene, display multiple phenotypical features associated with glutamatergic dysfunction. While the phenotype of adult GluA1 deficient (Gria1-/- ) mice has been studied comprehensively, there are relevant gaps in knowledge about the course and the onset of behavioral alterations in the Gria1 knockout mouse model during post-weaning development. Based on former investigations in young wild-type mice, we exposed female and male adolescent Gria1-/- mice to a behavioral home-cage based testing battery designed for the purpose of severity assessment. Data obtained from mice with a constitutive loss of GluA1 were compared with those from wild-type littermates. We identified several genotype-dependent behavioral alterations in young Gria1-/- mice. While the preference for sweetness was not affected by genotype during adolescence, Gria1-/- mice displayed limited burrowing performance, and reached lower nest complexity scores. Analysis of home-cage based voluntary wheel running performance failed to confirm genotype-dependent differences. In contrast, when exposed to the open field test, Gria1-/- mice showed pronounced hyperlocomotion in early and late adolescence, and female Gria1 -/- mice exhibited thigmotaxis when prepubescent. We found increased corticosterone metabolite levels in fecal samples of adolescent Gria1-/- mice with females exhibiting increased adrenocortical activity already in prepubescence. Considering the course of behavioral modifications in early and late adolescence, the results do not support a persistent level of distress associated with GluA1 deficiency in the line. In contrast, the laboratory-specific readouts indicate transient, mild impairments of behavioral patterns relevant to animal welfare, and suggest a mild overall burden of the line

Development of behavioral patterns in young C57BL/6J mice: a home cage-based study

Evidence exists that behavioral patterns only stabilize once mice reach adulthood. Detailed information about the course of behavioral patterns is of particular relevance for neuroscientific research and for the assessment of cumulative severity in genetically modified mice. The analysis considered five age groups focusing on behavioral assessments in the animals’ familiar home cage environment during the adolescence phase. We confirmed age- and sex-specific differences for several of the behavioral parameters and fecal corticosterone metabolites. Interestingly, an age-dependent decline in saccharin preference was detected in female mice. Regardless of sex, relevant levels of burrowing activity were only observed during later developmental phases. The development of nest complexity following the offer of new material was affected by age in female mice. In female and male mice, an age-dependency was evident for wheel running reaching a peak at P 50. A progressive increase with age was also observed for Open field activity. The data sets provide guidance for behavioral studies and for development of composite measure schemes for evidence-based severity assessment in young mice. Except for the burrowing test, the different behavioral tests can be applied in different age groups during post-weaning development. However, age- and sex-specific characteristics need to be considered