Ten to 15% of the population is temperamentally shy and have elevated physiological stress responses to novel social situations. Yet, the neural mechanisms underlying this personality trait are not fully understood (Beaton et al., 2009; Schmidt et al., 1997). Efficiently attending to, acting on, and remembering relevant stimuli and filtering out less important information is critical given the sheer volume of sensory and perceptual stimuli the brain is exposed to. Relevant stimuli that garner attention are remembered and consolidated with existing memories. Stimuli that do not warrant extended attention are ignored or habituated to in a process underpinned by cortical and subcortical inhibitory brain networks that reduce processing load on finite attentional resources (Freedman et al., 1991; Adler et al., 1998). Inefficient filtering of irrelevant stimuli could underpin anxiety in those with temperamental shyness and anxiety (Aron, Aron, & Davies, 2005). We measured the P50 auditory event-related potential (ERP) using a paired auditory click paradigm, as well as self-reported social anxiety and shyness, and salivary cortisol in two groups of healthy young adults selected for being very shy or very gregarious. While shy and gregarious groups demonstrated a similar P50 ERP to sound one (S1), the shy group showed elevated P50 amplitudes in response to the second sound (S2) compared to the gregarious group. Participants categorized as being lower or higher on social anxiety displayed a reverse pattern: those higher in social anxiety had a reduced response to S1 compared to those lower in social anxiety, yet a similar response to S2. Further, higher salivary cortisol predicted smaller differences and larger ratios in the P50 ERP from S1 to S2.

Das Ziel der Studie war es, den vorbeschriebenen Befund des P50-Gating-Defizits bei Schizophrenie, insbesondere die Unterschiede zwischen den verschiedenen Subgruppen nach Leonhard zu replizieren und darüber hinaus diejenigen kortikalen Areale zu detektieren, die während Bedingungen gesteigerten sensorischen Gatings mit signifikanter Aktivierung reagieren. Ferner sollten mögliche Differenzen im Muster kortikaler Aktivierung zwischen gesunden Kontrollen und Patienten aufgedeckt werden, um das kortikale Substrat defizitären sensorischen Gatings zu ermitteln. / The aim of the study was to replicate previously described findings of P50-Gating-deficits in patients suffering from schizophrenia, especially concerning the differences between subgroups based on Leonhard's Classification of endogenous psychosis. Futhermore cortical areas should be detected, which show significant activation during conditions of increased sensory gating. Possible differences in patterns of cortical activiation between these subgroups should be detected in order to identify cortical substrates of deficient sensory gating.

INTRODUCTION: Cytochrome P450 2B (CYP2B) is a drug-metabolizing enzyme subfamily found in both the brain and liver, which metabolizes clinical drugs, drugs of abuse (e.g. nicotine), toxicants and endogenous neurochemicals. Brain CYP2B’s role in the local metabolism of centrally acting substrates is important to investigate because of its ability to metabolize a variety of centrally active substrates. Additionally, CYP2B regulation by genetics, and exposure to xenobiotics, results in great inter-individual differences in the brain expression of this enzyme. METHODS: We investigated the time-course of rat brain CYP2B induction after chronic nicotine treatment. Using the rat model of brain CYP2B induction, combined with intracerebroventricular (ICV) inhibition of CYP2B, we assessed the effects of brain CYP2B in the response to the anaesthetic substrate, propofol. We also investigated the role of brain CYP2B-mediated activation of the pesticide chlorpyrifos on its neurotoxicity. RESULTS: Nicotine’s induction of rat brain CYP2B was long lasting, returning to basal levels by day 7, and was unaffected by nicotinic receptor blockade. Induction of CYP2B in rat brain, by chronic nicotine treatment, reduced the anaesthetic efficacy of propofol, through increased brain CYP2B-mediated metabolic inactivation. Inhibition of brain CYP2B, using mechanism based inhibitors of the enzyme, inhibited both basal and induced brain CYP2B activity, and prolonged propofol sleep time by reducing the local brain inactivation of the anaesthetic. Inhibition of rat brain, and not hepatic, CYP2B was able to effectively block local brain production of the toxic chlorpyrifos oxon, significantly attenuating the reductions in brain acetylcholinesterase activity and body temperature. Additionally, inhibition of brain CYP2B also significantly reduced the behavioural toxicity after chlorpyrifos exposure in a chlorpyrifos (CP) dose- and time-dependent manner. CONCLUSION: These studies indicate that rat brain CYP2B enzymes are active in vivo and play a meaningful role in the local metabolism of, and the response to, centrally acting substrates (i.e. propofol, chlorpyrifos). These data provide a first demonstration of the important role that brain CYP-mediated metabolism plays in the response to centrally acting substrates (i.e. clinical drugs, toxicants, endogenous neurochemicals), potentially contributing to the inter-individual variability seen in human responses to centrally active drugs and toxicants.

INTRODUCTION: Cytochrome P450 2B (CYP2B) is a drug-metabolizing enzyme subfamily found in both the brain and liver, which metabolizes clinical drugs, drugs of abuse (e.g. nicotine), toxicants and endogenous neurochemicals. Brain CYP2B’s role in the local metabolism of centrally acting substrates is important to investigate because of its ability to metabolize a variety of centrally active substrates. Additionally, CYP2B regulation by genetics, and exposure to xenobiotics, results in great inter-individual differences in the brain expression of this enzyme. METHODS: We investigated the time-course of rat brain CYP2B induction after chronic nicotine treatment. Using the rat model of brain CYP2B induction, combined with intracerebroventricular (ICV) inhibition of CYP2B, we assessed the effects of brain CYP2B in the response to the anaesthetic substrate, propofol. We also investigated the role of brain CYP2B-mediated activation of the pesticide chlorpyrifos on its neurotoxicity. RESULTS: Nicotine’s induction of rat brain CYP2B was long lasting, returning to basal levels by day 7, and was unaffected by nicotinic receptor blockade. Induction of CYP2B in rat brain, by chronic nicotine treatment, reduced the anaesthetic efficacy of propofol, through increased brain CYP2B-mediated metabolic inactivation. Inhibition of brain CYP2B, using mechanism based inhibitors of the enzyme, inhibited both basal and induced brain CYP2B activity, and prolonged propofol sleep time by reducing the local brain inactivation of the anaesthetic. Inhibition of rat brain, and not hepatic, CYP2B was able to effectively block local brain production of the toxic chlorpyrifos oxon, significantly attenuating the reductions in brain acetylcholinesterase activity and body temperature. Additionally, inhibition of brain CYP2B also significantly reduced the behavioural toxicity after chlorpyrifos exposure in a chlorpyrifos (CP) dose- and time-dependent manner. CONCLUSION: These studies indicate that rat brain CYP2B enzymes are active in vivo and play a meaningful role in the local metabolism of, and the response to, centrally acting substrates (i.e. propofol, chlorpyrifos). These data provide a first demonstration of the important role that brain CYP-mediated metabolism plays in the response to centrally acting substrates (i.e. clinical drugs, toxicants, endogenous neurochemicals), potentially contributing to the inter-individual variability seen in human responses to centrally active drugs and toxicants.

The Fanconi Anemia (FA)/BRCA DNA damage repair pathway plays a critical role in the cellular response to stress induced by DNA alkylating agents and greatly influences drug response in cancer treatment. We recently reported that FA/BRCA DNA damage repair pathway genes are overexpressed and causative for resistance in multiple myeloma (MM) cell lines selected for resistance to melphalan. We hypothesized that the FA/BRCA DNA damage repair pathway mediates response and resistance to chemotherapeutic agents used to treat multiple myeloma and other cancers, and targeting this pathway is vital to overcoming drug resistance. In this dissertation, we show that FA/BRCA pathway genes are collectively overexpressed in MM, prostate, and ovarian cancer cell lines selected for resistance to melphalan and cisplatin, respectively. Interestingly, cells selected for resistance to topoisomerase II inhibitors selectively overexpress only FANCF. We also show that FA/BRCA pathway expression can be inhibited by the proteasome inhibitor bortezomib. FA/BRCA pathway mRNA expression was inhibited by bortezomib in myeloma cell lines and patient samples. FANCD2 gene and protein expression are downregulated by bortezomib, and remain attenuated in the face of melphalan treatment. Melphalan-induced FANCD2 foci formation was also inhibited by bortezomib, and this drug enhanced melphalan-induced DNA damage, likely via inhibition of FA-mediated DNA damage repair. Next, we analyzed regulation of the FA/BRCA pathway. We demonstrate that NF-kappaB, specifically the Re1B/p50 subunits, transcriptionally regulates members of the FA/BRCA pathway, and inhibition of these subunits by siRNA, BMS-345541, and bortezomib reduces FA/BRCA pathway expression. Furthermore, knocking down Re1B and p50 simultaneously attenuates FANCD2 protein expression and results in diminished DNA repair and enhanced sensitivity to melphalan. Importantly, melphalan resistance was restored when FANCD2 was re-expressed in these cells. We also show that bortezomib regulates FANCD2 protein expression directly, by inhibiting FANCD2 synthesis. Finally, we demonstrate that low-dose bortezomib arrests cells in G0/G1 and also overcomes the S-phase arrest induced by melphalan, likely via inhibition of ATR. Overall, our findings provide evidence for targeting the FA/BRCA pathway, either directly or indirectly, via inhibition of NF-kappaB or ATR, to enhance chemotherapeutic response and reverse drug resistance in multiple myeloma and other cancers.

Framtagandet av byggnadsinformationsmodeller (BIM) sker på många olika sätt och blir allt vanligare i dagens samhälle. I dagsläget sker datainsamlingen för att skapa en BIM med hjälp av terrester och flygburen laserskanning vilket gör det till en dyr och tidskrävande process. Denna studie syftar till att undersöka noggrannheten och precisionen i Apples LiDAR-sensor, samt undersöka hur enkelt det är för en mjukvara som automatiskt modellerar BIM att urskilja objekt ur ett punktmoln skannat med LiDAR-sensorn. För att uppnå detta har en friggebod skannats in sju gånger med en iPhone 13 Pro Max samt en gång med en terrester laserskanner P50 från Leica. Längder har beräknats i punktmolnen mellan måltavlor som placerats på friggeboden och avvikelser har beräknats mellan dessa längder där längderna i P50 punktmolnet varit referens. Utifrån dessa avvikelser har medeltal, standardosäkerhet, medeltalets standardosäkerhet, Root Mean Square (RMS) och skevhet beräknats. IPhone punktmolnen passades in på P50 punktmolnet med hjälp av funktionen ”best-fit registration” i mjukvaran Leica Cyclone 3DR för att studera hur stora avvikelser som uppkommer. Båda punktmolnen modellerades i mjukvaran Faramoon där skillnaderna i objektens geometriska egenskaper har jämförts med varandra. Analysen av längdavvikelser resulterade i att längderna mätta i samtliga iPhone punktmoln är positivt förskjutna relativt längderna i P50 punktmolnet. Skevhetsmåttet för samtliga punktmoln var negativt. RMS-värdet och standardosäkerheten för längdavvikelserna varierade med mer än en decimeter mellan punktmolnen. Standardosäkerheten varierade mellan 0,071 meter och 0,173 meter och RMS-värdet varierade mellan 0,082 meter och 0,184 meter. Resultatet av inpassningen med iPhone punktmolnen på P50 punktmolnet var även det varierande, på grund av att fördelningen av avvikelserna varierade mellan punktmolnen. Resultatet av modelleringen av BIM i Faramoon resulterade i att mjukvaran har svårt att modellera en BIM utifrån iPhone punktmolnen och att skillnaden i geometriska egenskaper uppgår till meternivå.  Studien visar att noggrannheten och precisionen i Apple LiDAR-sensor är varierande mellan olika skanningar men uteslutande på decimeternivå. Vilket gör att det inte rekommenderas att använda sensorn för mättekniska ändamål eller för automatiskt skapande av BIM. Sensorn kan istället användas för visuella tillämpningar, exempelvis till att skapa 3D modeller med hög osäkerhet. / The development of building information models (BIM) is becoming increasingly common in today’s society. At present, data collection to create a BIM is performed by using terrestrial and airborne laser scanning with a high resolution and almost mm uncertainty, which makes it an expensive and time-consuming process.  This study aims to investigate the accuracy and precision of Apple's LiDAR- sensor and explore how well a software that automatically models BIM can distinguish objects from a point cloud scanned with the LiDAR-sensor. To achieve this, a garden shed has been scanned seven times with an iPhone 13 Pro Max and once with the terrestrial laser scanner P50 from Leica. Lengths have been calculated in the point clouds between targets placed on the garden shed and deviations have been calculated between these lengths where the lengths in the P50 point cloud have been used as reference. Based on these deviations, the mean, standard uncertainty, standard uncertainty of the mean, the Root Mean Square (RMS) and skewness have been calculated. The iPhone point cloud was fitted to the P50 point cloud using the “best fit registration” function in the software Leica Cyclone 3DR to study how similar the iPhone point cloud is to the P50 point cloud. Both point clouds were modelled using a scan-to-BIM software i.e., Faramoon software, where the differences in the geometric properties of the objects have been compared with each other. The analysis of length deviations resulted in the lengths measured in all iPhone point clouds being shifted in the positive direction around the lengths in the P50 point cloud. The skewness for all point clouds was negative. The RMS value and the standard uncertainty for the length deviations varied by more than one decimetre. The standard uncertainty varies between 0.071 meters to 0.173 meters and the RMS value varies between 0.082 meters and 0.184 meters. The result of the alignment with the iPhone point clouds on the P50 point cloud was variable as the distribution of deviations between the point clouds were different. The result of the modelling of BIM in Faramoon resulted in that the software has it difficult to model a BIM based on the iPhone point clouds and that the difference in geometric properties between iPhone and P50 were up to meter level.  The study shows that the accuracy and precision of the Apple LiDAR-sensor vary between different scans but exclusively at the decimetre level. This means that it is not recommended to use the sensor for geodetic purposes or for the automatic creation of BIM. However, the Apple LiDAR-sensor can be used for visualizations of, for example, 3D models with high uncertainty.

Thesis (Ph. D.)--Indiana University, 2008. / Title from screen (viewed June 24, 2009). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Maureen Harrington. Includes vita. Non-Latin script record. Includes bibliographical references (leaves 126-132).

Based on data from 2083 wind turbines installed in Sweden since 1988, the annual energy production (AEP) predictions considered at the project planning phases of the wind turbines in Sweden have been compared to the wind-index-corrected production data. The production data and the predicted AEP data are taken from Vindstat, a database that collects information directly from wind turbine owners in Sweden. The mean error for all analyzed wind turbines was 11.9%,which means that, overall, the predicted AEP has been overestimated. There has been improved accuracy with time and error in prediction decreasing from 12% to 6.3% for wind turbines installed in the 2000s and 2010s, respectively. However, the overall improvement in accuracy seems to have stagnated around 2005 despite the refinement of forecasting methods and better data availability. From the results analyzed for effects of terrain, the error is smaller for wind turbines in forest areas than in open terrain, indicating that the complexity of forest terrain is not the reason behind the error. Also, there is no apparent increase of error with wind farm size, which could have been expected if the wind farm blockage effect was a primary reason for the overestimations. Comparison between significant wind turbine manufacturers Vestas and Enercon in the Swedish context, the error was more prominent for Enercon.

No description available.

L’objectif de cette thèse a été de développer des outils d’exploration des modifications perceptuelles lors de l’écoute de sons complexes dans la schizophrénie et de confronter les résultats de ces outils à des données neurophysiologiques. Le premier résultat de notre thèse est d’avoir confirmé dans la modalité auditive des modifications de l’organisation perceptuelle lors de l’écoute de sons complexes. En effet, nous avons montré, chez les patients souffrant de schizophrénie comparativement aux témoins, d’une part une difficulté de catégorisation des sons environnementaux de type son d’impact, et d’autre part, une modification de la perception de la familiarité et de la bizarrerie pour des sons environnementaux et abstraits, indiquant une modification d’organisation des données de l’audition dans une forme univoque et consensuelle.Le deuxième résultat de notre thèse est d’avoir confirmé, par une méthode d’induction perceptuelle consistant à présenter des stimuli plus ou moins envahissants, la présence d’un sentiment d’envahissement perceptuel plus important chez les patients souffrants de schizophrénie comparativement aux témoins. Cet envahissement perceptuel était corrélé significativement avec une mesure neurophysiologique du filtrage sensoriel par potentiels évoqués dans le paradigme des doubles clics audio (diminution d’amplitude de la composante P50 au deuxième stimulus comparativement au premier stimulus). Nous avons également traduit et validé en langue française un auto-questionnaire appelé Sensory Gating Inventory (SGI) permettant de compléter l’évaluation psychophysiologique des modifications perceptuelles reliées aux anomalies du filtrage sensoriel. / The aim of this PhD was to develop tools for analyzing perceptual modifications induced by complex sounds in schizophrenia and to relate these changes to neurophysiological data. The first result of our work enabled to confirm that complex sounds modify the auditory perceptual organization. Indeed, we first showed a deficit of categorization of environmental sounds (impact sounds) in patients with schizophrenia compared with controls, and secondly a difference in the perception of familiarity and strangeness for environmental and abstract sounds, indicating a modification of data organization of hearing in a unique and consensual form.The second result of our work revealed, by a perceptual induction method, the presence of a larger perceptual sense of inundation in patients suffering from schizophrenia compared with controls when submitted to more or less invasive stimuli. This perceptual inundation was significantly correlated with a neurophysiological measurement of sensory gating with evoked responses in the paradigm of double audio clicks (decrease in amplitude of the P50 component after the second stimulus as compared to the first stimulus). We have also translated a self-administered questionnaire called “Sensory Gating Inventory” (SGI) to French and validated it in order to complete the psychophysiological assessment of perceptual changes related to abnormal sensory gating.