Indiana University-Purdue University Indianapolis (IUPUI) / Acute and chronic activation of both ionotropic and metabotropic glutamate (glut) receptors is implicated in many neurodegenerative disorders including AD, dementia, epilepsy, stroke and neurotrauma. TRH and glut receptors (ionotropic & metabotropic) receptors are differentially coexpressed in granule and pyramidal neurons of the hippocampus. The author shows TRH to be protective when added to cultured pituitary adenoma (GH-3) cells and neuron-like pheochromocytoma (PC12) cells either prior to, during, or after glut-induced toxicity (Endo. Soc. Abs. 01), and also shows that the possible neuroprotective mechanism may involve heterologous downregulation of the metabotropic glut receptors, using superfused hippocampal slices and noting a reduction of Gαq/11 (SFN Abs. 02). He has also demonstrated that TRH protected against glut toxicity in fetal cortical cultures (Endo. Soc. Abs. 04). To extend these studies he used 14-day cultured rat fetal hippocampal neurons (Day E17) to determine if TRH is protective against toxicity induced by specific ionotropic and metabotropic glut agonists. Neuronal viability and integrity were assessed by trypan blue exclusion and LDH release after 18 hrs following 30 min exposure to glut agonists. Ten µM dihydroxyphenylglycine (DHPG, a Group 1 receptor agonist) + 30 µM N-methyl-D-aspartate (NMDA)-induced toxicity (42% vs contr. P<0.05); whereas, concurrent and continued treatment with 10 uM but not 1uM 3Me-HTRH resulted in less neuronal death and damage (86% vs contr P<0.05; 53% vs contr. P>0.05) respectively. DHPG treatment alone (10 µM) for 30 min. was non-toxic by both criteria (90% vs contr. P<0.05). The data suggest that TRH may be a selective modulator of glut-induced toxicity.

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Lokale Pyramidenzellen sind die Hauptneurone des Hippocampus und können durch ihre Position und die Morphologie ihrer Dendriten als CA1 und CA3 Pyramidenzellen identifiziert werden. Die Dendriten der exzitatorischen Pyramidenzellen sind mit postsynaptischen Vorwölbungen, den so genannten Spines, bedeckt, welche in einem spezifischen Verteilungsmuster angeordnet sind. Neurotoxine wie das C3 Toxin von Clostridium botulinum sind funktionelle Substanzen, die die neuronale Morphologie verändern und die neuronale Funktion beeinflussen können. In dieser Studie wurden die morphologischen Veränderungen von intrazellulär mit Biocytin gefüllten CA1 Pyramidenzellen qualitativ und quantitativ analysiert. Die hippocampalen Schnittkulturen, in denen sich bekanntermaßen Pyramidenzellen ähnlich entwickeln wie in vivo, wurden dazu herangezogen, die Effekte der C3bot Toxin-Applikation auf die Verzweigung der Dendriten sowie Anzahl und Dichte der dendritischen Spines zu untersuchen. Drei Gruppen von Zellen wurden verglichen: Erstens Neurone, die in serumhaltigem Medium inkubiert worden waren, zweitens Nervenzellen, die in einem Medium ohne Serum inkubiert worden waren und drittens Zellen, die unter Serumentzug dem C3bot Toxin ausgesetzt worden waren. Die Inkubation dauerte 14 Tage, während die Dauer der Toxinexposition zwischen vier und sechs Stunden betrug. Mit Hilfe eines Computers wurden zweidimensionale Nachbildungen der biocytin-markierten CA1 Pyramidenzellen erstellt, und die Gesamtlänge der Dendriten, die Anzahl der dendritischen Verzweigungspunkte und die Gesamtzahl und Dichte der dendritischen Spines gemessen und statistisch ausgewertet. Signifikante Unterschiede wurden zwischen der mit C3 Toxin behandelten Gruppe und der serumhaltig inkubierten Kontrollgruppe beobachtet. Diese signifikanten morphologischen Veränderungen traten selektiv an den Apikaldendriten der toxinbehandelten CA1 Pyramidenzellen auf. Aus der Behandlung resultierte eine Reduktion der Anzahl apikaler Verzweigungspunkte, der Anzahl der apikalen Spines, der Gesamtzahl (basal und apikal addiert) der Spines sowie der Gesamtspinedichte. Im Gegensatz dazu ergaben sich keine signifikanten Unterschiede zwischen der toxinbehandelten Gruppe und der ohne Serum inkubierten Kontrollgruppe, obwohl der Serumentzug im Vergleich zur serumhaltig inkubierten Kontrollgruppe die Entwicklung der Zellen beeinflusste. Auf Grundlage der beobachteten Veränderungen können wir schließen, dass die Behandlung mit C3 bot einen starken Einfluss selektiv auf die Morphologie der Apikaldendriten ausübt. Der Mechanismus, der dieser selektiven Empfindlichkeit der Apikaldendriten gegenüber dem C3 bot Toxin zugrunde liegt, wird Gegenstand weiterer Untersuchungen sein.

Integrating sophisticated statistical methods into database management systems is gaining more and more attention in research and industry. One important statistical method is time series forecasting, which is crucial for decision management in many domains. In this context, previous work addressed the processing of ad-hoc and recurring forecast queries. In contrast, we focus on subscription-based forecast queries that arise when an application (subscriber) continuously requires forecast values for further processing. Forecast queries exhibit the unique characteristic that the underlying forecast model is updated with each new actual value and better forecast values might be available. However, (re-)sending new forecast values to the subscriber for every new value is infeasible because this can cause significant overhead at the subscriber side. The subscriber therefore wishes to be notified only when forecast values have changed relevant to the application. In this paper, we reduce the costs of the subscriber by optimizing the notifications sent to the subscriber, i.e., by balancing the number of notifications and the notification length. We introduce a generic cost model to capture arbitrary subscriber cost functions and discuss different optimization approaches that reduce the subscriber costs while ensuring constrained forecast values deviations. Our experimental evaluation on real datasets shows the validity of our approach with low computational costs.

Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growthpromoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration.

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No description available.

<p>This thesis describes the implementation of a real-time, full search, 16x16 bidirectional motion estimation at 24 frames per second with the record performance of 155 Gop/s (1538 ops/pixel) at a high clock rate of 125 MHz. The core of bidirectional motion estimation uses close to 100% FPGA resources with 7 Gbit/s bandwidth to external memory. The architecture allows extremely controlled, macro level floor-planning with parameterized block size, image size, placement coordinates and data words length. The FPGA chip is part of the board that was developed at the Institute of Computer & Communication Networking Engineering, Technical University Braunschweig Germany, in collaboration with Grass Valley Germany in the FlexFilm research project. The goal of the project was to develop hardware and programming methodologies for real-time digital film image processing. Motion estimation core uses FlexWAFE reconfigurable architecture where FPGAs are configured using macro components that consist of weakly programmable address generation units and data stream processing units. Bidirectional motion estimation uses two cores of motion estimation engine (MeEngine) forming main data processing unit for backward and forward motion vectors. The building block of the core of motion estimation is an RPM-macro which represents one processing element and performs 10-bit difference, a comparison, and 19-bit accumulation on the input pixel streams. In order to maximize the throughput between elements, the processing element is replicated and precisely placed side-by-side by using four hierarchal levels, where each level is a very compact entity with its own local control and placement methodology. The achieved speed was further improved by regularly inserting pipeline stages in the processing chain.</p>

This thesis describes the implementation of a real-time, full search, 16x16 bidirectional motion estimation at 24 frames per second with the record performance of 155 Gop/s (1538 ops/pixel) at a high clock rate of 125 MHz. The core of bidirectional motion estimation uses close to 100% FPGA resources with 7 Gbit/s bandwidth to external memory. The architecture allows extremely controlled, macro level floor-planning with parameterized block size, image size, placement coordinates and data words length. The FPGA chip is part of the board that was developed at the Institute of Computer &amp; Communication Networking Engineering, Technical University Braunschweig Germany, in collaboration with Grass Valley Germany in the FlexFilm research project. The goal of the project was to develop hardware and programming methodologies for real-time digital film image processing. Motion estimation core uses FlexWAFE reconfigurable architecture where FPGAs are configured using macro components that consist of weakly programmable address generation units and data stream processing units. Bidirectional motion estimation uses two cores of motion estimation engine (MeEngine) forming main data processing unit for backward and forward motion vectors. The building block of the core of motion estimation is an RPM-macro which represents one processing element and performs 10-bit difference, a comparison, and 19-bit accumulation on the input pixel streams. In order to maximize the throughput between elements, the processing element is replicated and precisely placed side-by-side by using four hierarchal levels, where each level is a very compact entity with its own local control and placement methodology. The achieved speed was further improved by regularly inserting pipeline stages in the processing chain.

The development of new therapeutical approaches, devised to foster the regeneration of neuronal circuits after injury and/or in neurodegenerative diseases, is of great importance. The impairment of dopaminergic projections is especially severe, because these projections are involved in crucial brain functions such as motor control, reward and cognition. In the work presented here, organotypic brain slice co-cultures of (a) the mesostriatal and (b) the mesocortical dopaminergic projection systems consisting of tissue sections of the ventral tegmental area/substantia nigra (VTA/SN), in combination with the target regions of (a) the striatum (STR) or (b) the prefrontal cortex (PFC), respectively, were used to evaluate different approaches to stimulate neurite outgrowth: (i) inhibition of cAMP/cGMP turnover with 3’,5’ cyclic nucleotide phosphodiesterase inhibitors (PDE-Is), (ii) blockade of calcium currents with nimodipine, and (iii) the co-cultivation with bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs). The neurite growth-promoting properties of the tested substances and cell populations were analyzed by neurite density quantification in the border region between the two brain slices, using biocytin tracing or tyrosine hydroxylase labeling and automated image processing procedures. In addition, toxicological tests and gene expression analyses were conducted. (i) PDE-Is were applied to VTA/SN+STR rat co-cultures. The quantification of neurite density after both biocytin tracing and tyrosine hydroxylase labeling revealed a growth promoting effect of the PDE2A-Is BAY60-7550 and ND7001. The application of the PDE10-I MP-10 did not alter neurite density in comparison to the vehicle control. (ii) The effects of nimodipine were evaluated in VTA/SN+PFC rat co-cultures. A neurite growth-promoting effect of 0.1 µM and 1 µM nimodipine was demonstrated in a projection system of the CNS. In contrast, the application of 10 µM nimodipine did not alter neurite density, compared to the vehicle control, but induced the activation of the apoptosis marker caspase 3. The expression levels of the investigated genes, including Ca2+ binding proteins (Pvalb, S100b), immediate early genes (Arc, Egr1, Egr2, Egr4, Fos and JunB), glial fibrillary acidic protein, and myelin components (Mal, Mog, Plp1) were not significantly changed (with the exception of Egr4) by the treatment with 0.1 µM and 1 µM nimodipine. (iii) Bulk BM-MSCs that were classically isolated by plastic adhesion were compared to the subpopulation Sca-1+Lin-CD45--derived MSCs (SL45-MSCs). The neurite growth-promoting properties of both MSC populations were quantified in VTA/SN+PFC mouse co-cultures. For this purpose, the MSCs were seeded on glass slides that were placed underneath the co-cultures. A significantly enhanced neurite density within the co-cultures was induced by both bulk BM-MSCs and SL45-MSCs. SL45-MSCs increased neurite density to a higher degree. The characterization of both MSC populations revealed that the frequency of fibroblast colony forming units (CFU-f ) is 105-fold higher in SL45-MSCs. SL45-MSCs were morphologically more homogeneous and expressed higher levels of nestin, BDNF and FGF2 compared to bulk BM-MSCs. Thus, this work emphasizes the vast potential for molecular targeting with respect to the development of therapeutic strategies in the enhancement of neurite regrowth.