Bayesian algorithms with applications

Advances in algorithms for approximate sampling from a multivariable target function have led to solutions to challenging statistical inference problems that would otherwise not be considered by the applied scientist. Such sampling algorithms are particularly relevant to Bayesian statistics, since the target function is the posterior distribution of the unobservables given the observables. In this thesis we develop, adapt and apply Bayesian algorithms, whilst addressing substantive applied problems in biology and medicine as well as other applications. For an increasing number of high-impact research problems, the primary models of interest are often sufficiently complex that the likelihood function is computationally intractable. Rather than discard these models in favour of inferior alternatives, a class of Bayesian "likelihoodfree" techniques (often termed approximate Bayesian computation (ABC)) has emerged in the last few years, which avoids direct likelihood computation through repeated sampling of data from the model and comparing observed and simulated summary statistics. In Part I of this thesis we utilise sequential Monte Carlo (SMC) methodology to develop new algorithms for ABC that are more efficient in terms of the number of model simulations required and are almost black-box since very little algorithmic tuning is required. In addition, we address the issue of deriving appropriate summary statistics to use within ABC via a goodness-of-fit statistic and indirect inference. Another important problem in statistics is the design of experiments. That is, how one should select the values of the controllable variables in order to achieve some design goal. The presences of parameter and/or model uncertainty are computational obstacles when designing experiments but can lead to inefficient designs if not accounted for correctly. The Bayesian framework accommodates such uncertainties in a coherent way. If the amount of uncertainty is substantial, it can be of interest to perform adaptive designs in order to accrue information to make better decisions about future design points. This is of particular interest if the data can be collected sequentially. In a sense, the current posterior distribution becomes the new prior distribution for the next design decision. Part II of this thesis creates new algorithms for Bayesian sequential design to accommodate parameter and model uncertainty using SMC. The algorithms are substantially faster than previous approaches allowing the simulation properties of various design utilities to be investigated in a more timely manner. Furthermore the approach offers convenient estimation of Bayesian utilities and other quantities that are particularly relevant in the presence of model uncertainty. Finally, Part III of this thesis tackles a substantive medical problem. A neurological disorder known as motor neuron disease (MND) progressively causes motor neurons to no longer have the ability to innervate the muscle fibres, causing the muscles to eventually waste away. When this occurs the motor unit effectively ‘dies’. There is no cure for MND, and fatality often results from a lack of muscle strength to breathe. The prognosis for many forms of MND (particularly amyotrophic lateral sclerosis (ALS)) is particularly poor, with patients usually only surviving a small number of years after the initial onset of disease. Measuring the progress of diseases of the motor units, such as ALS, is a challenge for clinical neurologists. Motor unit number estimation (MUNE) is an attempt to directly assess underlying motor unit loss rather than indirect techniques such as muscle strength assessment, which generally is unable to detect progressions due to the body’s natural attempts at compensation. Part III of this thesis builds upon a previous Bayesian technique, which develops a sophisticated statistical model that takes into account physiological information about motor unit activation and various sources of uncertainties. More specifically, we develop a more reliable MUNE method by applying marginalisation over latent variables in order to improve the performance of a previously developed reversible jump Markov chain Monte Carlo sampler. We make other subtle changes to the model and algorithm to improve the robustness of the approach.

GDNF Receptors: Veterans and Novices

Neurotrophic factors play essential role in the development and functioning of the nervous system and other organs. Glial cell line-Derived Neurotrophic Factor (GDNF) family ligands (GFLs) are of particular interest because they promote the survival of dopaminergic neurons in vitro, in Parkinson s disease animal models and in patients. GDNF is also a potent survival factor for the central motoneurons and thus is considered as a potential lead for the treatment of amyotrophic lateral sclerosis. The survival promoting receptor complex for GFLs consists of a ligand-specific co-receptor, GFRα and a signal transducing module, receptor tyrosine kinase RET. At least GDNF and persephin, a GFL, have established functions outside central nervous system. GDNF is crucial for enteric nervous system and kidney development as well as for spermatogenesis. Persephin controls calcitonin secretion. Communication between cells often occurs in the extracellular matrix (ECM), a meshwork, which is secreted and deposited by the cells and is mainly composed of fibrillar proteins and polymerized sugars. We evaluated the relationship between GFLs and extracellular matrix components and demonstrated that three GFLs - GDNF, neurturin and artemin bind heparan sulfates with nanomolar affinities. The fourth member of the family - persephin binds these polysaccharides thousand times less tightly. GDNF, neurturin and artemin also bind with high affinity to heparan sulfate proteoglycan (HSPG) isolated from the nervous system, syndecan-3. GDNF signals through HSPGs, evoking Src family kinase activation. This signaling induces cell spreading, hippocampal neurite outgrowth in vitro and cellular migration. Specifically, GDNF signaling through syndecan-3 is important for embryonic cortical neuron migration. Syndecan-3-deficient mice, similarly to mice lacking GDNF, have less GABAergic neurons in their cortex, as compared to the wild-type mice. This fact provides indirect evidence that GDNF interaction with syndecan-3 is important for cortical brain development. Noteworthy, in non-neuronal tissues GFLs may signal via other syndecans. We also present the structural model for a GDNF co-receptor, GFRα1. The X-ray structure of the GFRα1 domain 3 was solved with 1.8 Å resolution, revealing a new protein fold. Later we also solved the structure of the truncated GFRα1 in the complex with GDNF and this model was confirmed by site-directed mutagenesis. In summary, our work contributed to the structural characterization of GFRα-based receptor complex and revealed a new receptor for GDNF, neurturin and artemin the HSPG syndecan-3. This information is critically important for the development of GFRα/RET agonists for the treatment of neurodegenerative diseases.

Role of γ1 Laminin and Its KDI Peptide in the Central Nervous System

Since the 1980 s, laminin-1 has been linked to regeneration of the central nervous system (CNS) and promotion of neuronal migration and axon guidance during CNS development. In this thesis, we clarify the role of γ1 laminin and its KDI tripeptide in development of human embryonic spinal cord, in regeneration of adult rat spinal cord injury (SCI), in kainic acid-induced neuronal death, and in the spinal cord tissue of amyotrophic lateral sclerosis (ALS). We demonstrated that γ1 laminin together with α1, β1, and β3 laminins localize at the floor plate region in human embryonic spinal cord. This localization of γ1 laminin is in spatial and temporal correlation with development of the spinal cord and indicates that γ1 laminin may participate in commissural axon guidance during the embryonic development of the human CNS. With in vitro studies using the Matrigel culture system, we demonstrated that the KDI tripeptide of γ1 laminin provides a chemotrophic guidance cue for neurites of the human embryonic dorsal spinal cord, verifying the functional ability of γ1 laminin to guide commissural axons. Results from our experimental SCI model demonstrate that the KDI tripeptide enhanced functional recovery and promoted neurite outgrowth across the mechanically injured area in the adult rat spinal cord. Furthermore, our findings indicate that the KDI tripeptide as a non-competitive inhibitor of the ionotropic glutamate receptors can provide when administered in adequate concentrations an effective method to protect neurons against glutamate-induced excitotoxic cell death. Human postmortem samples were used to study motor neuron disease, ALS (IV), and the study revealed that in human ALS spinal cord, γ1 laminin was selectively over-expressed by reactive astrocytes, and that this over-expression may correlate with disease severity. The multiple ways by which γ1 laminin and its KDI tripeptide provide neurotrophic protection and enhance neuronal viability suggest that the over-expression of γ1 laminin may be a glial attempt to provide protection for neurons against ALS pathology. The KDI tripeptide is effective therapeutically thus far in animal models only. However, because KDI containing γ1 laminin exists naturally in the human CNS, KDI therapies are unlikely to be toxic or allergenic. Results from our animal models are encouraging, with no toxic side-effects detected even at high concentrations, but the ultimate confirmation can be achieved only after clinical trials. More research is still needed until the KDI tripeptide is refined into a clinically applicable method to treat various neurological disorders.

Molecular background of three lethal fetal syndromes

This study identified the molecular defects underlying three lethal fetal syndromes. Lethal Congenital Contracture Syndrome 1 (LCCS1, MIM 253310) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD, MIM 611890) are fetal motor neuron diseases. They affect the nerve cells that control voluntary muscle movement, and eventually result in severe atrophy of spinal cord motor neurons and fetal immobility. Both LCCS1 and LAAHD are caused by mutations in the GLE1 gene, which encodes for a multifunctional protein involved in posttranscriptional mRNA processing. LCCS2 and LCCS3, two syndromes that are clinically similar to LCCS1, are caused by defective proteins involved in the synthesis of inositol hexakisphosphate (IP6), an essential cofactor of GLE1. This suggests a common mechanism behind these fetal motor neuron diseases, and along with accumulating evidence from genetic studies of more late-onset motor neuron diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), implicates mRNA processing as a common mechanism in motor neuron disease pathogenesis. We also studied gle1-/- zebrafish in order to investigate whether they would be a good model for studying the pathogenesis of LCCS1 and LAAHD. Mutant zebrafish exhibit cell death in their central nervous system at two days post fertilization, and the distribution of mRNA within the cells of mutant zebrafish differs from controls, encouraging further studies. The third lethal fetal syndrome is described in this study for the first time. Cocoon syndrome (MIM 613630) was discovered in a Finnish family with two affected individuals. Its hallmarks are the encasement of the limbs under the skin, and severe craniofacial abnormalities, including the lack of skull bones. We showed that Cocoon syndrome is caused by a mutation in the gene encoding the conserved helix-loop-helix ubiquitous kinase CHUK, also known as IκB kinase α (IKKα). The mutation results in the complete lack of CHUK protein expression. CHUK is a subunit of the IκB kinase enzyme that inhibits NF-κB transcription factors, but in addition, it has an essential, independent role in controlling keratinocyte differentiation, as well as informing morphogenetic events such as limb and skeletal patterning. CHUK also acts as a tumor suppressor, and is frequently inactivated in cancer. This study has brought significant new information about the molecular background of these three lethal fetal syndromes, as well as provided knowledge about the prerequisites of normal human development.

Reach task-associated excitatory overdrive of motor cortical neurons following infusion with ALS-CSF

Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and human studies suggest alterations in excitability of the motor neurons in ALS. Specifically, in studies on human subjects with ALS the motor cortex was reported to be hyperexcitable. The present study was designed to test the hypothesis that infusion of cerebrospinal fluid from patients with sporadic ALS (ALS-CSF) into the rat brain ventricle can induce hyperexcitability and structural changes in the motor cortex leading to motor dysfunction. A robust model of sporadic ALS was developed experimentally by infusing ALS-CSF into the rat ventricle. The effects of ALS-CSF at the single neuron level were examined by recording extracellular single unit activity from the motor cortex while rats were performing a reach to grasp task. We observed an increase in the firing rate of the neurons of the motor cortex in rats infused with ALS-CSF compared to control groups. This was associated with impairment in a specific component of reach with alterations in the morphological characteristics of the motor cortex. It is likely that the increased cortical excitability observed in the present study could be the result of changes in the intrinsic properties of motor cortical neurons, a dysfunctional inhibitory mechanism and/or an underlying structural change culminating in a behavioral deficit.

Unlike Physical Exercise, Modified Environment Increases the Lifespan of SOD1(G93A) Mice However Both Conditions Induce Cellular Changes

8 p.

Brca1 is expressed in human microglia and is dysregulated in human and animal model of ALS

Background: There is growing evidence that microglia are key players in the pathological process of amyotrophic lateral sclerosis (ALS). It is suggested that microglia have a dual role in motoneurone degeneration through the release of both neuroprotective and neurotoxic factors. Results: To identify candidate genes that may be involved in ALS pathology we have analysed at early symptomatic age (P90), the molecular signature of microglia from the lumbar region of the spinal cord of hSOD1(G93A) mice, the most widely used animal model of ALS. We first identified unique hSOD1(G93A) microglia transcriptomic profile that, in addition to more classical processes such as chemotaxis and immune response, pointed toward the potential involvement of the tumour suppressor gene breast cancer susceptibility gene 1 (Brca1). Secondly, comparison with our previous data on hSOD1(G93A) motoneurone gene profile substantiated the putative contribution of Brca1 in ALS. Finally, we established that Brca1 protein is specifically expressed in human spinal microglia and is up-regulated in ALS patients. Conclusions: Overall, our data provide new insights into the pathogenic concept of a non-cell-autonomous disease and the involvement of microglia in ALS. Importantly, the identification of Brca1 as a novel microglial marker and as possible contributor in both human and animal model of ALS may represent a valid therapeutic target. Moreover, our data points toward novel research strategies such as investigating the role of oncogenic proteins in neurodegenerative diseases.

Consumption of fa cai Nostoc soup: A Potential for BMAA exposure from Nostoc cyanobacteria in China?

Grown in arid regions of western China the cyanobacterium Nostoc flagelliforme - called fa cai in Mandarin and fat choy in Cantonese - is wild-harvested and used to make soup consumed during New Year's celebrations. High prices, up to $125 USD/kg, led to overharvesting in Inner Mongolia, Ningxia, Gansu, Qinghai, and Xinjiang. Degradation of arid ecosystems, desertification, and conflicts between Nostoc harvesters and Mongol herdsman concerned the Chinese environmental authorities, leading to a government ban of Nostoc commerce. This ban stimulated increased marketing of a substitute made from starch. We analysed samples purchased throughout China as well as in Chinese markets in the United States and the United Kingdom. Some were counterfeits consisting of dyed starch noodles. A few samples from California contained Nostoc flagelliforme but were adulterated with starch noodles. Other samples, including those from the United Kingdom, consisted of pure Nostoc flagelliforme. A recent survey of markets in Cheng Du showed no real Nostoc flagelliforme to be marketed. Real and artificial fa cai differ in the presence of beta-N-methylamino-L-alanine (BMAA). Given its status as a high-priced luxury food, the government ban on collection and marketing, and the replacement of real fa cai with starch substitutes consumed only on special occasions, it is anticipated that dietary exposure to BMAA from fa cai will be reduced in the future in China.

Apoio a doentes e cuidadores em comunidades virtuais de saúde: o caso da comunidade online ELA Portugal

Dissertação apresentada à Escola Superior de Comunicação Social como parte dos requisitos para obtenção de grau de mestre em Audiovisual e Multimédia.

ALSMon: sistema para monitorizar ALS

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Informática e de Computadores

ALS-Sence: sistema de aquisição e processamento de electromiogramas para pacientes com ALS

Dissertação para obtenção do grau de Mestre em Engenharia de Eletrónica e Computadores

Oligodendroglia metabolically support axons and contribute to neurodegeneration.

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.

Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: a ten-year update.

The objective of this analysis was to evaluate mortality among a cohort of 24,865 capacitor-manufacturing workers exposed to polychlorinated biphenyls (PCBs) at plants in Indiana, Massachusetts, and New York and followed for mortality through 2008. Cumulative PCB exposure was estimated using plant-specific job-exposure matrices. External comparisons to US and state-specific populations used standardized mortality ratios, adjusted for gender, race, age and calendar year. Among long-term workers employed 3 months or longer, within-cohort comparisons used standardized rate ratios and multivariable Poisson regression modeling. Through 2008, more than one million person-years at risk and 8749 deaths were accrued. Among long-term employees, all-cause and all-cancer mortality were not elevated; of the a priori outcomes assessed only melanoma mortality was elevated. Mortality was elevated for some outcomes of a priori interest among subgroups of long-term workers: all cancer, intestinal cancer and amyotrophic lateral sclerosis (women); melanoma (men); melanoma and brain and nervous system cancer (Indiana plant); and melanoma and multiple myeloma (New York plant). Standardized rates of stomach and uterine cancer and multiple myeloma mortality increased with estimated cumulative PCB exposure. Poisson regression modeling showed significant associations with estimated cumulative PCB exposure for prostate and stomach cancer mortality. For other outcomes of a priori interest--rectal, liver, ovarian, breast, and thyroid cancer, non-Hodgkin lymphoma, Alzheimer disease, and Parkinson disease--neither elevated mortality nor positive associations with PCB exposure were observed. Associations between estimated cumulative PCB exposure and stomach, uterine, and prostate cancer and myeloma mortality confirmed our previous positive findings.

Anatomo-functional magnetic resonance imaging of the spinal cord and its application to the characterization of spinal lesions in cats

Les lésions de la moelle épinière ont un impact significatif sur la qualité de la vie car elles peuvent induire des déficits moteurs (paralysie) et sensoriels. Ces déficits évoluent dans le temps à mesure que le système nerveux central se réorganise, en impliquant des mécanismes physiologiques et neurochimiques encore mal connus. L'ampleur de ces déficits ainsi que le processus de réhabilitation dépendent fortement des voies anatomiques qui ont été altérées dans la moelle épinière. Il est donc crucial de pouvoir attester l'intégrité de la matière blanche après une lésion spinale et évaluer quantitativement l'état fonctionnel des neurones spinaux. Un grand intérêt de l'imagerie par résonance magnétique (IRM) est qu'elle permet d'imager de façon non invasive les propriétés fonctionnelles et anatomiques du système nerveux central. Le premier objectif de ce projet de thèse a été de développer l'IRM de diffusion afin d'évaluer l'intégrité des axones de la matière blanche après une lésion médullaire. Le deuxième objectif a été d'évaluer dans quelle mesure l'IRM fonctionnelle permet de mesurer l'activité des neurones de la moelle épinière. Bien que largement appliquées au cerveau, l'IRM de diffusion et l'IRM fonctionnelle de la moelle épinière sont plus problématiques. Les difficultés associées à l'IRM de la moelle épinière relèvent de sa fine géométrie (environ 1 cm de diamètre chez l'humain), de la présence de mouvements d'origine physiologique (cardiaques et respiratoires) et de la présence d'artefacts de susceptibilité magnétique induits par les inhomogénéités de champ, notamment au niveau des disques intervertébraux et des poumons. L'objectif principal de cette thèse a donc été de développer des méthodes permettant de contourner ces difficultés. Ce développement a notamment reposé sur l'optimisation des paramètres d'acquisition d'images anatomiques, d'images pondérées en diffusion et de données fonctionnelles chez le chat et chez l'humain sur un IRM à 3 Tesla. En outre, diverses stratégies ont été étudiées afin de corriger les distorsions d'images induites par les artefacts de susceptibilité magnétique, et une étude a été menée sur la sensibilité et la spécificité de l'IRM fonctionnelle de la moelle épinière. Les résultats de ces études démontrent la faisabilité d'acquérir des images pondérées en diffusion de haute qualité, et d'évaluer l'intégrité de voies spinales spécifiques après lésion complète et partielle. De plus, l'activité des neurones spinaux a pu être détectée par IRM fonctionnelle chez des chats anesthésiés. Bien qu'encourageants, ces résultats mettent en lumière la nécessité de développer davantage ces nouvelles techniques. L'existence d'un outil de neuroimagerie fiable et robuste, capable de confirmer les paramètres cliniques, permettrait d'améliorer le diagnostic et le pronostic chez les patients atteints de lésions médullaires. Un des enjeux majeurs serait de suivre et de valider l'effet de diverses stratégies thérapeutiques. De telles outils représentent un espoir immense pour nombre de personnes souffrant de traumatismes et de maladies neurodégénératives telles que les lésions de la moelle épinière, les tumeurs spinales, la sclérose en plaques et la sclérose latérale amyotrophique.