Skaugevekkelsen

Master's thesis in practical theology. VID Specialized University, Stavanger, May 2019Mot alle forventninger, ble en kort serie med evangeliseringsmøter, som skulle holdes i 1956, i en stor og lite besøkt Høyland kirke i dagens Sandnes, til en stor vekkelse. I løpet av et godt halvår, kom tusenvis av mennesker – noen lokale og noen langveisfra – til Høyland kirke for å høre på den inviterte taleren, Johannes Skauge, og for å gi sitt liv til Jesus Kristus. Dette ble senere kjent som «Skaugevekkelsen». Informasjon fra dokumentkilder, sammen med intervjuer med gjenlevende fra vekkelsen, tegner et detaljert bilde av vekkelsesforløpet og hvordan vekkelsen påvirket enkeltmennesker og det kristne samfunnet i og rundt Sandnes. Et viktig spørsmål er imidlertid hvilke faktorer som er nødvendige, for at slik kristen vekst i det hele tatt skal skje. Alan Hirsch har postulert seks «grunnprinsipper», som han hevder må være på plass der varig kristen vekst finner sted. Det er et slående samsvar mellom vekkelsen i Høyland og disse prinsippene, men også noen ulikheter i fokus og uttrykk, som kaster lys over det norske kirkelandskapet. IIIsubmittedVersio

Resolution limits in electron beam lithography

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Modeling the point-spread function in helium-ion lithography

We present here a hybrid approach to modeling helium-ion lithography that combines the power and ease-of-use of the Stopping and Range of Ions in Matter (SRIM) software with the results of recent work simulating secondary electron (SE) yield in helium-ion microscopy. This approach traces along SRIM-produced helium-ion trajectories, generating and simulating trajectories for SEs using a Monte Carlo method. We found, both through simulation and experiment, that the spatial distribution of energy deposition in a resist as a function of radial distance from beam incidence, i.e. the point spread function, is not simply a sum of Gauss functions.Semiconductor Research Corporation. Nanoscale Research InitiativeNational Science Foundation. Graduate Research Fellowship Progra

A Thematic Analysis Investigating the Impact of Positive Behavioral Support Training on the Lives of Service Providers: “It Makes You Think Differently”

Positive behavioral support (PBS) employs applied behavioral analysis to enhance the quality of life of people who behave in challenging ways. PBS builds on the straightforward and intuitively appealing notion that if people know how to control their environments, they will have less need to behave in challenging ways. Accordingly, PBS focuses on the perspective of those who have behavioral issues, and assesses success via reduction in incidences of challenging behaviors. The qualitative research presented in this report approaches PBS from a different viewpoint and, using thematic analysis, considers the impact of PBS training on the lived experience of staff who deliver services. Thirteen support staff who work for a company supplying social care and supported living services for people with learning disabilities and complex needs in the northwest of England took part. Analysis of interviews identified five major themes. These were: (1) training: enjoyable and useful; (2) widening of perspective: different ways of thinking; (3) increased competence: better outcomes; (4) spill over into private lives: increased tolerance in relationships; and (5) reflecting on practice and moving to a holistic view: “I am aware that people…are not just being naughty.” These themes evidenced personal growth on the part of service providers receiving training. Explicitly, they demonstrated that greater awareness of PBS equipped recipients with an appropriate set of values, and the technical knowledge required to realize them

Inter-rater reliability of paediatric emergency assessment : physiological and clinical features

Objective The Paediatric Admission Guidance in the Emergency Department (PAGE) score is an assessment tool currently in development that helps predict hospital admission using components including patient characteristics, vital signs (heart rate, temperature, respiratory rate, oxygen saturation) and clinical features (e.g. breathing, behaviour, nurse judgement). It aims to assist in safe admission and discharge decision making in environments such as emergency departments and urgent care centres. Determining the inter-rater reliability of scoring tools such as PAGE can be difficult. The aim of this study was to determine the inter-rater reliability of seven clinical components of the PAGE Score. Design Inter-rater reliability was measured by each patient having their clinical components recorded by two separate raters in succession. The first rater was the assessing nurse, the second rater was a research nurse. Setting Two emergency departments and one urgent care centre in the North West of England. Measurements were recorded over one week; data was collected for half a day at each of the three sites. Patients A convenience sample of 90 paediatric attendees (aged 0 to 16), 30 from each of the three sites. Main Outcome Measures Two independent measures for each child were compared using kappa or prevalence-adjusted bias-adjusted kappa (PABAK). Bland-Altman plots were also constructed for continuous measurements. Results Inter-rater reliability ranged from moderate (0.62 [95% CI 0.48 to 0.74] weighted kappa) to very good (0.98 [95% CI 95 to 0.99] weighted kappa) for all measurements except ‘nurse judgement’ for which agreement was fair (0.30 95% CI [0.09 to 0.50] PABAK). Complete information from both raters on all the clinical components of the PAGE score were available for 73 children (81%). These total scores showed good’ inter-rater reliability (0.64 [95% CI 0.53 to 0.74] weighted kappa). Conclusions Our findings suggest different nurses would demonstrate good inter-rater reliability when collecting acute assessments needed for the PAGE score, reinforcing the applicability of the tool. The importance of determining reliability in scoring systems is highlighted and a suitable methodology presented

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1–42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer\u27s disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer\u27s disease patients\u27 brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics

Linguistic measures of chemical diversity and the "keywords" of molecular collections

Computerized linguistic analyses have proven of immense value in comparing and searching through large text collections ("corpora"), including those deposited on the Internet-indeed, it would nowadays be hard to imagine browsing the Web without, for instance, search algorithms extracting most appropriate keywords from documents. This paper describes how such corpus-linguistic concepts can be extended to chemistry based on characteristic "chemical words" that span more than traditional functional groups and, instead, look at common structural fragments molecules share. Using these words, it is possible to quantify the diversity of chemical collections/databases in new ways and to define molecular "keywords" by which such collections are best characterized and annotated

Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification

INTRODUCTION: Amyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors is Displaced by Drug Candidates That Improve Cognitive Deficits

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer\u27s disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer\u27s disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer\u27s therapeutics