Bayesian matching of unlabeled marked point sets using random fields, with an application to molecular alignment

Statistical methodology is proposed for comparing unlabeled marked point sets, with an application to aligning steroid molecules in chemoinformatics. Methods from statistical shape analysis are combined with techniques for predicting random fields in spatial statistics in order to define a suitable measure of similarity between two marked point sets. Bayesian modeling of the predicted field overlap between pairs of point sets is proposed, and posterior inference of the alignment is carried out using Markov chain Monte Carlo simulation. By representing the fields in reproducing kernel Hilbert spaces, the degree of overlap can be computed without expensive numerical integration. Superimposing entire fields rather than the configuration matrices of point coordinates thereby avoids the problem that there is usually no clear one-to-one correspondence between the points. In addition, mask parameters are introduced in the model, so that partial matching of the marked point sets can be carried out. We also propose an adaptation of the generalized Procrustes analysis algorithm for the simultaneous alignment of multiple point sets. The methodology is illustrated with a simulation study and then applied to a data set of 31 steroid molecules, where the relationship between shape and binding activity to the corticosteroid binding globulin receptor is explored.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS486 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

A psychopharmacological aspects of human emotional memory for emotional material.

It is often assumed that emotional events are remembered in great clarity and detail. This thesis begins with a review of the literature on memory enhancement by emotional material. This enhancement may involve mechanisms that are psychologically and neurobiologically distinct from the mechanisms usually employed in memory for neutral material, such as modulation of consolidation by emotional arousal via noradrenaline action in the amygdala. Theoretically, pharmacological manipulation of noradrenaline by methylphenidate and benzodiazepines should affect the function of specialised 'emotional memory' mechanisms, altering the balance of emotional and neutral material remembered. A set of four double blind, placebo controlled experiments were designed to investigate this theory. Each was carried out with three groups of 16 healthy human volunteers. Experiment 1 produced some evidence that both 1.5mg lorazepam and 40mg methylphenidate reduced the mnemonic advantage of emotional sections of a story. Experiment 2 compared diazepam (15mg) with placebo and propranolol (80mg) (a ?-blocker which has been reported to impair emotional memory) on two new tasks. Diazepam left implicit memory intact, but impaired explicit memory, particularly for emotional material. In Experiment 3 both diazepam (15mg) and methylphenidate (40mg) altered relative levels of recall for emotional and neutral pictures. In Experiment 4 diazepam (10mg) clearly impaired fear conditioning. However there was no evidence that diazepam (10mg) or methylphenidate (40mg) affected emotional memory during consolidation. Taken together these studies provide evidence for a pharmacological dissociation of fear conditioning and perceptual priming. There was some evidence that benzodiazepines disproportionately impaired explicit emotional memory. However these effects were subtle. Methylphenidate increased the relative amount of emotional material retained on some measures, and decreased or left it unchanged in others. This may be due to differing levels of arousal. A central issue throughout the thesis was the difficulty of separating the 'emotional memory' mechanism from other co-occurring mnemonic properties of emotional stimuli. These may mask effects of the pharmacological manipulations that would be informative to any theory of 'emotional memory'

Bayesian alignment of continuous molecular shapes using random fields

Statistical methodology is proposed for comparing molecular shapes. In order to account for the continuous nature of molecules, classical shape analysis methods are combined with techniques used for predicting random fields in spatial statistics. Applying a modification of Procrustes analysis, Bayesian inference is carried out using Markov chain Monte Carlo methods for the pairwise alignment of the resulting molecular fields. Superimposing entire fields rather than the configuration matrices of nuclear positions thereby solves the problem that there is usually no clear one--to--one correspondence between the atoms of the two molecules under consideration. Using a similar concept, we also propose an adaptation of the generalised Procrustes analysis algorithm for the simultaneous alignment of multiple molecular fields. The methodology is applied to a dataset of 31 steroid molecules

‘There is something in this land that will sustain us’: Osage oil and extraction in indigenous literatures

This thesis focuses on the Osage Nation, whose lands are located in what is currently referred to as Oklahoma in the United States. The Osage Nation has a longstanding and multi-layered relationship with oil and extraction, having secured and retained rights in common to all subsurface minerals beneath their lands since 1906. Since no individual or group of individuals owns the Mineral Estate, the Osage Nation collectively owns what has been referred to the first ‘underground reservation’ of oil, gas, and other subsurface minerals across the 1.47-million-acre Osage County. Specifically, this thesis explores the deeply entangled relationship between Osages and oil extraction through the lens of three novels by Indigenous authors over the span of several decades: John Joseph Mathews’ (Osage) Sundown (1934), Linda Hogan’s (Chickasaw) Mean Spirit (1990), Charles H. Red Corn’s (Osage) A Pipe For February (2002). This project argues that these novels provide fresh perspectives on the matter of oil extraction and its effects on land, environment, politics, and culture; effects felt by both the Osage and settlers within and beyond the scope of the novels themselves. These works highlight the need to look beyond a narrative of Indigenous exploitation to further explore the vexed and occasionally ambivalent relationships between Indigenous peoples and oil extraction, characterised in the case of the Osage by the wealth, opportunity, dispossession, and violence that oil simultaneously brought. Read together and in conversation with other critical theorists, this thesis contends that these novels also open up new avenues of inquiry between the disciplines of Indigenous studies and the environmental humanities in relation to time, power, and economics, providing opportunities for greater collaboration and critique across these areas of study

Memantine for autism spectrum disorder

Background Autism spectrum disorder (ASD; also known as autism) is a developmental disability that begins in childhood and is typically seen in around 1% to 2% of children. It is characterised by social communication difficulties and repetitive and restricted behaviours and routines that can have a negative impact on a child's quality of life, achievement at school, and social interactions with others. It has been hypothesised that memantine, which is traditionally used to treat dementia, may be effective in reducing the core symptoms of autism as well as some co‐occurring symptoms such as hyperactivity and language difficulties. If memantine is being used to treat the core symptoms of autism, it is important to review the evidence of its effectiveness. Objectives To assess the effects of memantine on the core symptoms of autism, including, but not limited to, social communication and stereotypical behaviours. Search methods We searched CENTRAL, MEDLINE, Embase, nine other databases and three trials registers up to February 2022. We also checked reference lists of key studies and checked with experts in the field for any additional papers. We searched for retractions of the included studies in MEDLINE, Embase, and the Retraction Watch Database. No retractions or corrections were found. Selection criteria We included randomised controlled trials (RCTs) of any dose of memantine compared with placebo in autistic people. We also included RCTs in which only one group received memantine, but both groups received the same additional therapy (e.g. a behaviour intervention). Data collection and analysis We used standard Cochrane methods. Our primary outcomes were core autism symptoms and adverse effects. Secondary outcomes were language, intelligence, memory, adaptive behaviour, hyperactivity, and irritability. We used GRADE to assess certainty of evidence. Main results We included three RCTs (two double‐blind and one single‐blind) with 204 participants that examined the short‐term effect (immediately postintervention) of memantine in autistic people. Two studies took place in the USA and the other in Iran. All three studies focused on children and adolescents, with a mean age of 9.40 (standard deviation (SD) 2.26) years. Most participants were male (range across studies 73% to 87%). The diagnosis of ASD was based on the Diagnostic and Statistical Manual of Mental Disorders (4th edition; 4th edition, text revision; or 5th edition). To confirm the diagnosis, one study used the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview‐Revised (ADI‐R); one used ADOS, ADI‐R or the Autism Diagnostic Interview Screener; and one used the Gilliam Autism Rating Scale. Dosage of memantine was based on the child's weight and ranged from 3 mg to 15 mg per day. Comparisons Two studies examined memantine compared with placebo; in the other study, both groups had a behavioural intervention while only one group was given memantine. Risk of bias All studies were rated at high risk of bias overall, as they were at high or unclear risk of bias across all but four domains in one study, and all but two domains in the other two studies. One study was funded by Forest Laboratories, LLC, (Jersey City, New Jersey), Allergan. The study sponsor was involved in the study design, data collection (via contracted clinical investigator sites), analysis and interpretation of data, and the decision to present these results. The other two studies reported no financial support or sponsorship; though in one of the two, the study medication was an in‐kind contribution from Forest Pharmaceuticals. Primary outcomes There was no clear evidence of a difference between memantine and placebo with respect to severity of core symptoms of autism, although we are very uncertain about the evidence. The standardised mean difference in autism symptoms score in the intervention group versus the control group was –0.74 standard deviations (95% confidence interval (CI) −2.07 to 0.58; 2 studies, 181 participants; very low‐certainty evidence; medium effect size); lower scores indicate less severe autistic symptoms. Two studies (144 participants) recorded adverse effects that the authors deemed related to the study and found there may be no difference between memantine and placebo (odds ratio (OR) 0.64, 95% CI 0.17 to 2.39; low‐certainty evidence). Secondary outcomes There may be no difference between memantine and placebo on language (2 studies, 144 participants; low‐certainty evidence); memory or adaptive behaviour (1 study, 23 participants; both low‐certainty evidence); or hyperactivity or irritability (1 study, 121 participants; both low‐certainty evidence). Authors' conclusions It is unclear whether memantine is an effective treatment for autistic children. None of the three included trials reported on the effectiveness of memantine in adults. Further studies using rigorous designs, larger samples, longer follow‐up and clinically meaningful outcome measures that are important to autistic people and their families will strengthen our knowledge of the effects of memantine in autism

Magnetic Resonance Spectroscopy discriminates the response to microglial stimulation of wild type and Alzheimer's disease models.

Microglia activation has emerged as a potential key factor in the pathogenesis of Alzheimers disease. Metabolite levels assessed by magnetic resonance spectroscopy (MRS) are used as markers of neuroinflammation in neurodegenerative diseases, but how they relate to microglial activation in health and chronic disease is incompletely understood. Using MRS, we monitored the brain metabolic response to lipopolysaccharides (LPS)-induced microglia activation in vivo in a transgenic mouse model of Alzheimers disease (APP/PS1) and healthy controls (wild-type (WT) littermates) over 4 hours. We assessed reactive gliosis by immunohistochemistry and correlated metabolic and histological measures. In WT mice, LPS induced a microglial phenotype consistent with activation, associated with a sustained increase in macromolecule and lipid levels (ML9). This effect was not seen in APP/PS1 mice, where LPS did not lead to a microglial response measured by histology, but induced a late increase in the putative inflammation marker myoinositol (mI) and metabolic changes in total creatine and taurine previously reported to be associated with amyloid load. We argue that ML9 and mI distinguish the response of WT and APP/PS1 mice to immune mediators. Lipid and macromolecule levels may represent a biomarker of activation of healthy microglia, while mI may not be a glial marker

Memantine for autism spectrum disorder

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of memantine on the core features of ASD, including, but not limited to, social functioning, communication skills and stereotypical behaviours

Shape analysis and statistical modelling in brain imaging

This thesis considers the registration of shapes, estimation of shape variability and the statistical modelling of human brain magnetic resonance images (MRI). Current shape registration techniques, such as Procrustes analysis, superimpose shapes in order to make inferences regarding the mean shape and shape variability. We apply Procrustes analysis to a subset of the landmarks and give distributional results for the Euclidean distance of a shape from a template. Procrustes analysis is then generalised to minimise a Mahalanobis norm, with respect to a symmetric, positive denite matrix, and the weighted Procrustes estimators for scaling, rotation and translation obtained. This weighted registration criterion is shown, through a simulation study, to reduce the bias and error in maximum likelihood estimates of the mean shape and covariance matrix compared to isotropic Procrustes. A Bayesian Markov chain Monte Carlo algorithm is also presented and shown to be less sensitive to prior information. We consider two MRI data sets in detail. We examine the first data set for large-scale shape dierences between two volunteer groups, healthy controls and schizophrenia patients. The images are registered to a template through modelling the voxel values and we maximise the likelihood over the transformation parameters. Using a suitable labelling and principal components analysis we show schizophrenia patients have less brain asymmetry than healthy controls. The second data set is a sequence of functional MRI scans of an individual's motor cortex taken while they repeatedly press a button. We construct a model with temporal correlations to estimate the trial-to-trial variability in the haemodynamic response using the Expectation-Maximisation algorithm. The response is shown to change with task and through time. For both data sets we compare our techniques with existing software packages and improvements to data pre-processing are suggested. We conclude by discussing potential areas for future research