Exclusion de liaison génétique au locus SPAX2 de cas canadiens-français d’ataxie spastique

Les ataxies héréditaires sont des désordres neuro-dégénératifs qui causent une ataxie comme symptôme primaire; soit une perte de coordination des mouvements volontaires, un sens de l’équilibre déficient et un trouble à la motricité. Elles forment un groupe cliniquement et génétiquement hétérogène. De ce fait, de nombreuses classifications existent basées sur différents critères. Cependant, le consensus actuel veut que le mode de transmission soit le critère premier de classement. On estime la prévalence mondiale des ataxies héréditaires à 6/100 000 bien que ce nombre diffère entre régions. C’est le cas du Québec où la structuration historique du bassin génétique canadien-français a menée à des effets fondateurs régionaux, ce qui a eu comme conséquence de hausser la prévalence régionale de certaines maladies. L’Acadie est également une région canadienne-française avec des effets fondateurs où le taux de prévalence de certaines ataxies héréditaires est plus élevé. Nous avons recruté huit familles canadiennes-françaises provenant de diverses régions du Québec, ayant un lien génétique plus ou moins rapproché avec l’Acadie, dans lesquelles nous avons observé dix cas d’une forme d’ataxie spastique autosomique récessive relativement légère qui a résistée à l’analyse des gènes d’ataxies connues. Nous avons émis l’hypothèse d’être en présence d’une nouvelle forme d’ataxie à effet fondateur pour la population canadienne-française. Afin d’identifier le gène muté responsable de cette ataxie, un criblage génomique des marqueurs SNP pour les individus recrutés fut effectué. Puis, par cartographie de l’homozygotie, une région de 2,5 Mb fut identifiée sur le chromosome 17p13 dans une famille. Une revue de la littérature nous a permis de constater, qu’en 2007, quatre familles nord-africaines atteintes d’une ataxie dénommée SPAX2 qui présentaient des manifestations cliniques semblables avaient déjà été liées au même locus sur le chromosome 17. Afin de supporter notre hypothèse que les malades étaient porteurs de deux copies de la même mutation fondatrice et de cartographier plus finement notre région d’intérêt, les haplotypes de tous les atteints de nos huit familles furent étudiés. Nous avons établie qu’un intervalle de 200 kb (70 SNP), soit du marqueur rs9900036 à rs7222052, était partagé par tous nos participants. Les deux gènes les plus prometteurs des 18 se trouvant dans la région furent séquencés. Aucune mutation ne fut trouvée dans les gènes SLC25A11 et KIF1C. Par la suite, une analyse de liaison génétique stricte avec calcul de LOD score nous a permis d’exclure ce locus de 200 kb comme étant celui porteur du gène muté causant l’ataxie dans la majorité de nos familles. Nous avons donc conclus que malgré qu’une famille soit homozygote pour une grande région du chromosome 17, l’absence d’Informativité des marqueurs SNP dans la région de 200 kb fut responsable de l’apparent partage d’haplotype homozygote. Le travail reste donc entier afin d’identifier les mutations géniques responsables de la présentation ataxique chez nos participants de souche acadienne.

Le locus 1q32 : susceptibilité aux maladies inflammatoires de l’intestin et rôles biologiques de C1orf106 et KIF21B

La maladie de Crohn (MC) et la colite ulcéreuse (CU) sont des maladies inflammatoires de l’intestin (MII) caractérisées par une inflammation chronique du tube digestif. Ces maladies à traits complexes sont le résultat d’un dérèglement du système immunitaire. Les études d’association pangénomique ont identifié au total 99 loci de susceptibilité aux MII. La région 1q32 du chromosome 1 a été identifiée comme locus de susceptibilité à la MC, la CU et la sclérose en plaque. La région autour du marqueur génétique (rs11584383) contient quatre gènes : Chromosome 1 open reading frame 106 (C1orf106), Kinesin family member 21B (KIF21B), Calcium channel, voltage-dependant, L type, alpha 1S subunit (CACNA1S) et Chromosome 1 open reading frame 81 (C1orf81). L’objectif de l’étude est de mettre ces quatres gènes dans un contexte biologique et de déterminer leur rôle potentiel dans les MII. Par réaction de polymérisation en chaîne quantitatif (qPCR), nous avons déterminé le profil d’expression de ces gènes dans des tissus murins et des lignées cellulaires humaines. KIF21B et C1orf106 sont exprimés dans les tissus gastrointestinal et immunitaire. Par la suite, nous avons testé l’implication de KIF21B et C1orf106 dans les voies biologiques connues pour leur rôle dans les MII comme l’activité NF-kB et le stress du réticulum endoplasmique (RE). Nos résultats montrent que la surexpression de KIF21B dans les cellules HEK293T diminue l’activité de NF-kB et la surexpression de C1orf106 augmente le stress du RE et l’activité de la voie Wnt. Globalement, ces résultats suggèrent que KIF21B et C1orf106, dans la région 1q32, sont des gènes candidats prometteurs puisqu’ils interviennent dans des voies biologiques connues des maladies inflammatoire de l’intestin.

Quantitative functional MRI of the Cerebrovascular Reactivity to CO2

Le dioxyde de carbone (CO2) est un résidu naturel du métabolisme cellulaire, la troisième substance la plus abondante du sang, et un important agent vasoactif. À la moindre variation de la teneur en CO2 du sang, la résistance du système vasculaire cérébral et la perfusion tissulaire cérébrale subissent des changements globaux. Bien que les mécanismes exacts qui sous-tendent cet effet restent à être élucidés, le phénomène a été largement exploité dans les études de réactivité vasculaire cérébrale (RVC). Une voie prometteuse pour l’évaluation de la fonction vasculaire cérébrale est la cartographie de la RVC de manière non-invasive grâce à l’utilisation de l’Imagerie par Résonance Magnétique fonctionnelle (IRMf). Des mesures quantitatives et non-invasives de de la RVC peuvent être obtenus avec l’utilisation de différentes techniques telles que la manipu- lation du contenu artériel en CO2 (PaCO2) combinée à la technique de marquage de spin artériel (Arterial Spin Labeling, ASL), qui permet de mesurer les changements de la perfusion cérébrale provoqués par les stimuli vasculaires. Toutefois, les préoccupations liées à la sensibilité et la fiabilité des mesures de la RVC limitent de nos jours l’adoption plus large de ces méthodes modernes de IRMf. J’ai considéré qu’une analyse approfondie ainsi que l’amélioration des méthodes disponibles pourraient apporter une contribution précieuse dans le domaine du génie biomédical, de même qu’aider à faire progresser le développement de nouveaux outils d’imagerie de diagnostique. Dans cette thèse je présente une série d’études où j’examine l’impact des méthodes alternatives de stimulation/imagerie vasculaire sur les mesures de la RVC et les moyens d’améliorer la sensibilité et la fiabilité de telles méthodes. J’ai aussi inclus dans cette thèse un manuscrit théorique où j’examine la possible contribution d’un facteur méconnu dans le phénomène de la RVC : les variations de la pression osmotique du sang induites par les produits de la dissolution du CO2. Outre l’introduction générale (Chapitre 1) et les conclusions (Chapitre 6), cette thèse comporte 4 autres chapitres, au long des quels cinq différentes études sont présentées sous forme d’articles scientifiques qui ont été acceptés à des fins de publication dans différentes revues scientifiques. Chaque chapitre débute par sa propre introduction, qui consiste en une description plus détaillée du contexte motivant le(s) manuscrit(s) associé(s) et un bref résumé des résultats transmis. Un compte rendu détaillé des méthodes et des résultats peut être trouvé dans le(s) dit(s) manuscrit(s). Dans l’étude qui compose le Chapitre 2, je compare la sensibilité des deux techniques ASL de pointe et je démontre que la dernière implémentation de l’ASL continue, la pCASL, offre des mesures plus robustes de la RVC en comparaison à d’autres méthodes pulsés plus âgées. Dans le Chapitre 3, je compare les mesures de la RVC obtenues par pCASL avec l’utilisation de quatre méthodes respiratoires différentes pour manipuler le CO2 artérielle (PaCO2) et je démontre que les résultats peuvent varier de manière significative lorsque les manipulations ne sont pas conçues pour fonctionner dans l’intervalle linéaire de la courbe dose-réponse du CO2. Le Chapitre 4 comprend deux études complémentaires visant à déterminer le niveau de reproductibilité qui peut être obtenu en utilisant des méthodes plus récentes pour la mesure de la RVC. La première étude a abouti à la mise au point technique d’un appareil qui permet des manipulations respiratoires du CO2 de manière simple, sécuritaire et robuste. La méthode respiratoire améliorée a été utilisée dans la seconde étude – de neuro-imagerie – où la sensibilité et la reproductibilité de la RVC, mesurée par pCASL, ont été examinées. La technique d’imagerie pCASL a pu détecter des réponses de perfusion induites par la variation du CO2 dans environ 90% du cortex cérébral humain et la reproductibilité de ces mesures était comparable à celle d’autres mesures hémodynamiques déjà adoptées dans la pratique clinique. Enfin, dans le Chapitre 5, je présente un modèle mathématique qui décrit la RVC en termes de changements du PaCO2 liés à l’osmolarité du sang. Les réponses prédites par ce modèle correspondent étroitement aux changements hémodynamiques mesurés avec pCASL ; suggérant une contribution supplémentaire à la réactivité du système vasculaire cérébral en lien avec le CO2.

Estudio de asociación entre genotipo de DAT1 y transtorno por déficit de atención / hiperactividad

Introducción: El TDAH tiene un componente genético importante; el gen de transportador de Dopamina (DAT1) se ha asociado con susceptibilidad al TDAH y con sus endofenotipos. El VNTR de 40pb en la región 3’UTR aumenta la expresión del DAT1. En Colombia no hay ningún estudio previo que indique evidencia de la asociación genética entre TDAH y el gen DAT1. Objetivo: Determinar asociación entre el VNTR del DAT1 y el fenotipo y/o endofenotipos del TDAH. Métodos: Se seleccionaron 73 pacientes con TDAH y 75 controles, se valoró en los casos inteligencia y funciones ejecutivas. Mediante (PCR) se amplificó el VNTR DAT1. Se establecieron estadísticos genético poblacionales, análisis de asociación y de regresión logística entre las pruebas neuropsicológicas y genotipo. Resultado: El polimorfismo del DAT1 no mostró asociación con TDAH, ni con alteraciones en las funciones ejecutivas. El genotipo 10/10 del VNTR DAT1 se encontró asociado con el índice de velocidad de procesamiento (p <0,05). En el subgrupo hiperactividad hubo asociación con algunas subpruebas de flexibilidad cognitiva, número de respuestas correctas, total de errores, número de respuestas perseverativas (p ≤ 0.01). En el subgrupo mixto se asoció con índice de comprensión verbal (p <0,05). Conclusiones: No hubo asociación entre el polimorfismo VNTR (DAT1) y el fenotipo de TDAH. Se encontraron asociaciones entre genotipo y algunos test de flexibilidad cognitiva e índice de comprensión verbal. Se establecieron los estadísticos genético poblacionales de este polimorfismo para la población analizada, el cual corresponde al primer reporte de una muestra de nuestro país.

Polimorfismos del gen Butirilcolinesterasa responsables de reacciones adversas en pacientes consumidores de “cocaína”

La butirilcolinesterasa humana (BChE; EC 3.1.1.8) es una enzima polimórfica sintetizada en el hígado y en el tejido adiposo, ampliamente distribuida en el organismo y encargada de hidrolizar algunos ésteres de colina como la procaína, ésteres alifáticos como el ácido acetilsalicílico, fármacos como la metilprednisolona, el mivacurium y la succinilcolina y drogas de uso y/o abuso como la heroína y la cocaína. Es codificada por el gen BCHE (OMIM 177400), habiéndose identificado más de 100 variantes, algunas no estudiadas plenamente, además de la forma más frecuente, llamada usual o silvestre. Diferentes polimorfismos del gen BCHE se han relacionado con la síntesis de enzimas con niveles variados de actividad catalítica. Las bases moleculares de algunas de esas variantes genéticas han sido reportadas, entre las que se encuentra las variantes Atípica (A), fluoruro-resistente del tipo 1 y 2 (F-1 y F-2), silente (S), Kalow (K), James (J) y Hammersmith (H). En este estudio, en un grupo de pacientes se aplicó el instrumento validado Lifetime Severity Index for Cocaine Use Disorder (LSI-C) para evaluar la gravedad del consumo de “cocaína” a lo largo de la vida. Además, se determinaron Polimorfismos de Nucleótido Simple (SNPs) en el gen BCHE conocidos como responsables de reacciones adversas en pacientes consumidores de “cocaína” mediante secuenciación del gen y se predijo el efecto delos SNPs sobre la función y la estructura de la proteína, mediante el uso de herramientas bio-informáticas. El instrumento LSI-C ofreció resultados en cuatro dimensiones: consumo a lo largo de la vida, consumo reciente, dependencia psicológica e intento de abandono del consumo. Los estudios de análisis molecular permitieron observar dos SNPs codificantes (cSNPs) no sinónimos en el 27.3% de la muestra, c.293A>G (p.Asp98Gly) y c.1699G>A (p.Ala567Thr), localizados en los exones 2 y 4, que corresponden, desde el punto de vista funcional, a la variante Atípica (A) [dbSNP: rs1799807] y a la variante Kalow (K) [dbSNP: rs1803274] de la enzima BChE, respectivamente. Los estudios de predicción In silico establecieron para el SNP p.Asp98Gly un carácter patogénico, mientras que para el SNP p.Ala567Thr, mostraron un comportamiento neutro. El análisis de los resultados permite proponer la existencia de una relación entre polimorfismos o variantes genéticas responsables de una baja actividad catalítica y/o baja concentración plasmática de la enzima BChE y algunas de las reacciones adversas ocurridas en pacientes consumidores de cocaína.

Búsqueda de selección en el polimorfismo 677C>T (c.665C>T) del gen de la metilentetrahidrofolato reductasa (MTHFR) en una población Colombiana

Se realizó un estudio genético – poblacional en dos grupos etarios de población colombiana con la finalidad de evaluar las diferencias genéticas relacionadas con el polimorfismo MTHFR 677CT en busca de eventos genéticos que soporten la persistencia de este polimorfismo en la especie humana debido que este ha sido asociado con múltiples enfermedades. De esta manera se genotipificaron los individuos, se analizaron los genotipos, frecuencias alélicas y se realizaron diferentes pruebas genéticas-poblacionales. Contrario a lo observado en poblaciones Colombianas revisadas se identificó la ausencia del Equilibrio Hardy-Weinberg en el grupo de los niños y estructuras poblacionales entre los adultos lo que sugiere diferentes historias demográficas y culturales entre estos dos grupos poblacionales al tiempo, lo que soporta la hipótesis de un evento de selección sobre el polimorfismo en nuestra población. De igual manera nuestros datos fueron analizados junto con estudios previos a nivel nacional y mundial lo cual sustenta que el posible evento selectivo es debido a que el aporte de ácido fólico se ha incrementado durante las últimas dos décadas como consecuencia de las campañas de fortificación de las harinas y suplementación a las embarazadas con ácido fólico, por lo tanto aquí se propone un modelo de selección que se ajusta a los datos encontrados en este trabajo se establece una relación entre los patrones nutricionales de la especie humana a través de la historia que explica las diferencias en frecuencias de este polimorfismo a nivel espacial y temporal.  

The development of ISSR-derived SCAR markers around the Seasonal Flowering Locus (SFL) in fragaria vesca

Fragaria vesca is a short-lived perennial with a seasonal-flowering habit. Seasonality of flowering is widespread in the Rosaceae and is also found in the majority of temperate polycarpic perennials. Genetic analysis has shown that seasonal flowering is controlled by a single gene in F. vesca, the SEASONAL FLOWERING LOCUS (SFL). Here, we report progress towards the marker-assisted selection and positional cloning of SFL, in which three ISSR markers linked to SFL were converted to locus-specific sequence-characterized amplified region (SCAR1–SCAR3) markers to allow large-scale screening of mapping progenies. We believe this is the first study describing the development of SCAR markers from ISSR profiles. The work also provides useful insight into the nature of polymorphisms generated by the ISSR marker system. Our results indicate that the ISSR polymorphisms originally detected were probably caused by point mutations in the positions targeted by primer anchors (causing differential PCR failure), by indels within the amplicon (leading to variation in amplicon size) and by internal sequence differences (leading to variation in DNA folding and so in band mobility). The cause of the original ISSR polymorphism was important in the selection of appropriate strategies for SCAR-marker development. The SCAR markers produced were mapped using a F. vesca f. vesca × F. vesca f. semperflorens testcross population. Marker SCAR2 was inseparable from the SFL, whereas SCAR1 mapped 3.0 cM to the north of the gene and SCAR3 1.7 cM to its south.

Topographic and thermal mapping of volcanic terrain using AVTIS ground-based 94-GHz dual-mode radar/radiometric imager

The All-Weather Volcano Topography Imaging Sensor remote sensing instrument is a custom-built millimeter-wave (MMW) sensor that has been developed as a practical field tool for remote sensing of volcanic terrain at active lava domes. The portable instrument combines active and passive MMW measurements to record topographic and thermal data in almost all weather conditions from ground-based survey points. We describe how the instrument is deployed in the field, the quality of the primary ranging and radiometric measurements, and the postprocessing techniques used to derive the geophysical products of the target terrain, surface temperature, and reflectivity. By comparison of changing topography, we estimate the volume change and the lava extrusion rate. Validation of the MMW radiometry is also presented by quantitative comparison with coincident infrared thermal imagery.

Mapping the trickle out benefits of social and environmental enterprises: a pilot study of an East African eco business

• Objectives The objective of this paper is to propose a framework for mapping the sustainable development and poverty alleviation impacts of social and environmental enterprises in Africa. This framework is then piloted with reference to an East African Ecobusiness. • Prior Work This paper is based on data collected as part of a wider research project examining social and environmental enterprises across the 19 countries of Southern and Eastern Africa. In total, the sustainable development and poverty alleviation impacts of 20 in-depth case studies in 4 countries are being examined. • Approach Data was collected using in-depth interviews with multiple stakeholders associated with the case study business. Secondary materials were also analysed and a quantitative survey of customers undertaken. • Results In addition to their impacts on the environment, African eco businesses can also have substantial social, economic and wider poverty alleviation impacts. This paper maps the impacts of a case study East African ecobusiness, as part of developing a social and environmental enterprise impact framework for Africa and the wider developing world. In our case study, positive and negative impacts are identified, while questions are raised in relation to tradeoffs between social and environmental objectives and temporal dimensions of impact. The usefulness of existing frameworks for understanding the social, environmental and development impacts of these kinds of organisations are also considered. • Implications This paper outlines the necessity of building an African-centric impact map to capture the multi-level poverty alleviation and sustainable development impacts of social and environmental enterprise activity in developing world environments. The framework proposed also offers guidance to businesses operating in Africa about the factors that might be considered as part of their wider social and environmental responsibilities. • Value Assessing the impact of social and environmental enterprises, especially as a route to development within low income countries, is receiving increasing attention in academia and beyond. This paper presents a useful contribution to the scarce literature on social and environmental enterprises in Africa.

A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study

Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10-5, 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10-6). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 × 10-4). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.

A SNP-based consensus genetic map for synteny-based trait targeting in faba bean (Vicia faba L.)

Faba bean (Vicia faba L.) is a globally important nitrogen-fixing legume, which is widely grown in a diverse range of environments. In this work, we mine and validate a set of 845 SNPs from the aligned transcriptomes of two contrasting inbred lines. Each V. faba SNP is assigned by BLAST analysis to a single Medicago orthologue. This set of syntenically anchored polymorphisms were then validated as individual KASP assays, classified according to their informativeness and performance on a panel of 37 inbred lines, and the best performing 757 markers used to genotype six mapping populations. The six resulting linkage maps were merged into a single consensus map on which 687 SNPs were placed on six linkage groups, each presumed to correspond to one of the six V. faba chromosomes. This sequence-based consensus map was used to explore synteny with the most closely-related crop species, lentil, and the most closely related fully sequenced genome, Medicago. Large tracts of uninterrupted colinearity were found between faba bean and Medicago, making it relatively straightforward to predict gene content and order in mapped genetic interval. As a demonstration of this, we mapped a flower colour gene to a 2 cM interval of Vf chromosome 2 which was highly collinear with Mt3. The obvious candidate gene from 77 gene models in the collinear Medicago chromosome segment was the previously characterized MtWD40-1 gene (Mt3g092830, Mt3g092840) controlling anthocyanin production in Medicago and re-sequencing of the Vf orthologue showed a putative causative deletion of the entire 5’ end of the gene.

Genetic dissection of heterosis using epistatic association mapping in a partial NCII mating design

Heterosis refers to the phenomenon in which an F1 hybrid exhibits enhanced growth or agronomic performance. However, previous theoretical studies on heterosis have been based on bi-parental segregating populations instead of F1 hybrids. To understand the genetic basis of heterosis, here we used a subset of F1 hybrids, named a partial North Carolina II design, to perform association mapping for dependent variables: original trait value, general combining ability (GCA), specific combining ability (SCA) and mid-parental heterosis (MPH). Our models jointly fitted all the additive, dominance and epistatic effects. The analyses resulted in several important findings: 1) Main components are additive and additive-by-additive effects for GCA and dominance-related effects for SCA and MPH, and additive-by-dominant effect for MPH was partly identified as additive effect; 2) the ranking of factors affecting heterosis was dominance > dominance-by-dominance > over-dominance > complete dominance; and 3) increasing the proportion of F1 hybrids in the population could significantly increase the power to detect dominance-related effects, and slightly reduce the power to detect additive and additive-by-additive effects. Analyses of cotton and rapeseed datasets showed that more additive-by-additive QTL were detected from GCA than from trait phenotype, and fewer QTL were from MPH than from other dependent variables.

A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2-q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1-17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.

Two-Phase Mapping for Projecting Massive Data Sets

Most multidimensional projection techniques rely on distance (dissimilarity) information between data instances to embed high-dimensional data into a visual space. When data are endowed with Cartesian coordinates, an extra computational effort is necessary to compute the needed distances, making multidimensional projection prohibitive in applications dealing with interactivity and massive data. The novel multidimensional projection technique proposed in this work, called Part-Linear Multidimensional Projection (PLMP), has been tailored to handle multivariate data represented in Cartesian high-dimensional spaces, requiring only distance information between pairs of representative samples. This characteristic renders PLMP faster than previous methods when processing large data sets while still being competitive in terms of precision. Moreover, knowing the range of variation for data instances in the high-dimensional space, we can make PLMP a truly streaming data projection technique, a trait absent in previous methods.

Crossing Bowen Street : mapping interventions in the classed subject

Synopsis: Crossing Bowen Street Crossing Bowen Street is an extended novel set in Melbourne, Australia. The protagonist, Meg Flanagan, is accepted to teachers' college. Meg is 24 years old and has worked, and lived out of home, since 17. Having completed her year 12 studies part time while working, she has applied to the Melbourne State College for a Bachelor of Education. Melbourne State College is subsequently 'amalgamated'A into Philip University, the original 19th century sandstone institution which borders MSC. Meg has worked as a medical secretary prior to commencing her studies. An only child, she is the first member of her family to go to university, indeed to finish high school. Tertiary study is exciting for Meg and the novel explores the psychic journey as well as the intellectual one, as Meg experiences challenges to the possibilities for her life and the trajectory along which she once assumed it would flow. The narrative is told through episodic and epistolary forms, with particular periods in Meg's cultural and academic life forming the focus, picking up the integral elements of her journey and examining the psychic context and action. Characters in the undergraduate chapters of the novel are somewhat transient, although very important to Meg's rapidly developing, changing sense of herself. The constant 'trying out' of ways of being and even lifestyles sees Meg losing old 'friendships' and making new, even temporary, ones all the time. This allows the opportunity for Meg to explore her feelings about connecting to others and the nature of her relationships. The Meg reflected back to her by others is of constant interest to her, particularly as she is frequently reminded that others see a very different Meg than she does. The novel commences at the outset of Meg's tertiary career, as she initially articulates the extent of her aspiration, of her sense of the possibility of her own life. Each vignette deals, chronologically, with an aspect of Meg's expanding sense of possibility, socially, emotionally, intellectually. Certain vignettes explore her relations with friends and acquaintances in the course, which in turn provide A In 1988, Federal Labor Minister for Education John Dawkins, devised a plan to end the streaming of Australian tertiary institutions and created what is called the Unified National System. This meant that colleges of advanced education and institutes of technology were either created universities in their own right, or more commonly, merged with an appropriate existing university. This process allows a fascinating insight into the class dimensions of hierarchies and stratifications. The need of universities and their members for status has been profoundly underscored. the background and context for her sexual relationships. That aspect of her developing subjectivity provides a marked contrast, which Meg uses as leverage, when set against her sense of herself as a scholar and her growing notion of entitlement, which allows her to 'choose', where previously she believed she had no choice; the choice is a scholarly career. Within all this, Meg discovers and is deeply empowered by certain political left, and feminist, discourses within the university community. She is equally dismayed and alienated by other feminist practices; her growing engagement with her own agency sees her quickly abandoning feminist subject positions previously dear to her, which served a particular purpose and are now superseded. This notion of feeling betrayed by the promise of a value system (or rather, its practitioners) will recur throughout the action of the novel, as Meg moves into an academic role, first as doctoral student and then as academic, seeking to live her values as practice and to remain true to what her trajectory has taught her. This is crystallised in the novel as the role played by the place she came from, and how that informs, and complicates, who she becomes. The novel seeks to explore the fundamental contradictions in doing so, through Meg's increasing awareness that the academy is not the harmonious, class aware institution she has idealised, but a world driven by status and hierarchies. This realisation must be reconciled in the light of Meg's anxieties about her working-class background. Meg's doctoral training at an elite university underscores her developing sense of what constitutes excellence and the role played by highly influential conservative institutions in maintaining social arrangements. As her academic career unfolds, the holding of a Cambridge PhD allows Meg opportunities to make change as certain privileges are afforded her by virtue of her Cambridge status. Yet it is this very notion that she seeks to challenge. Her growing passion for the State University of Victoria, an institution developed for the education of working-class people, informs her activism within the academy. Why are excellence and equity polarised? Why does the institution matter more than the scholarship? Why is so much practice within universities contrary to the values scholars often claim? These questions are explored through the dynamics of academic working life as student and later as a teacher at a university with an explicit equity agenda. The Start of the End (2003): The action commences on a late Friday after at SUV, when the Department of Communication & Cultural Studies has just been advised of Meg's promotion to Associate Professor. This vignette sees the initial soiree and celebrations and allows Meg to reflect on her experience. As her colleagues and friends are congratulating her, a particular student comes looking for Meg. It is clear that Angela Watson needs course advice particularly from Meg. Their discussion seems a straightforward one on the face of it, but it underscores many things; that Meg has come the full circle in her academic life, and what it is that her journey has really been about. The route to professorial appointment is considered, as is the source of Meg's greatest professional joy and fulfillment; is it scholarship, followed by leadership, in her discipline? It is knowing she has continued to speak and act to change the life chances of all students, wherever possible? Or is it the subtle distilling of both of these, along with the knowledge which emerges from the nexus of teaching and research. That scholarship, new knowledge, surely must be taking us somewhere specific in relation to others? The more we know, the more we can do...to what end? From this reflection, we see the action of the novel unfold. We return to this scene at the end of the novel, as Meg considers the trajectory of her life and its themes in her work. The novel ends as she is faced with the next challenge. Arrival (1989): Acceptance sees Meg as she is attempting to transform her life and create a new one. She has just been advised of her admission to an undergraduate Bachelor of Education program, at the major Melbourne teachers' college. Meg shares her rented home with her high school best friend, Anna, and her fiance, Jason, who appears to be superfluous in her life. Meg is aware he is a partner for who she used to be. We see Meg in her job as a medical secretary and this allows the mapping of Meg's sense of her own world, as she travels between home and work. This first stage of seeking her aspiration- to be an English teacher-evolves. As Meg considers the meaning of what she is about to do and how she knows it is right. This involves a consideration of what work means in our lives and how this is different for jobs according to how they are classed. Her relationship with the life she has known, the person she has been, is changing and this change is represented through her relationship with Jason. Meg's first day at teachers' college demonstrates that she is in a constant, often painful, dialogue with herself. The difficulties she encounters in making sense of the relation between her two 'lives' are thrown into sharp relief. The preparation for college sees Meg interrogating herself about how she can be different. Her initial experiences at the College resonate with her highest expectations of the life that awaits her, of the multiple possibilities currently being authored for her. Her first attendance at classes offers the opportunity to try out some of those possibilities, to test them against those she meets and to map the ways she could discover to 'be'. There is much tension and fear, but also endless excitement and these conflicting emotional states parallel and marble each other. It is on this day that she meets Jennifer Wren, her first real friend at university, who offers so many challenges to Meg. Their friendship involves a constant exhausting shift of subject positions, which Meg is able to look back on with affection in years to come. Going Bowling (1989): within a few weeks of commencing at university, Meg is socializing with some of her new friends, having neatly segmented her home and college lives. Meg has already realised that her friendships fall into separate groups; her friendship with Jennifer and the people Jennifer knows does not find its way into this group. They meet in the city to go bowling and have a meal. While Meg really enjoys these new people, already tensions are developing in relations between the group. Their unofficial leader, Rosemary Marshall, has a tendency to seek control and already resistance is showing. Rosemary particularly does not like Jennifer. Meg is enjoying her flirtation with Pete Danville, whom she has assumed to be gay. His very flattering attention has already developed Meg's confidence and stoked her ego, which has eroded in her stagnating relationship with Jason. Rosie has developed a crush on Pete and seems to take the flirtation with Meg personally. Dynamics in the group become slightly uncomfortable but Meg has grown quickly fond of her new friends, especially flamboyant Marina, another whom Rosemary seems to dislike. The discussions which occur during their evening deepen both the relationships and the tensions between them and draw lines which will determine the outcome of their various friendships. The Ball (1990): In the third year of her degree, much has happened to Meg. She is married to Jason, although she omits him from much of her psychic (and practical) life. Meg and her friends attend the Faculty's annual formal dinner dance. Meg has so far managed to balance the competitiveness which occurs between all of them, both academically and personally. The negotiation of her respective friendships with Jennifer and Marina requires a great deal of diplomacy; the subtext in this is very disturbing to Meg. What exactly is the conflict about? She can't be sure why they don't like each other; it could be Marina's smoking, or Jennifer's confidence to spare, but these things also annoy her, yet she does not fight with either girl as they do with each other. Rose has always insisted that the problem is Jennifer's private school background, but Marina went to a catholic girls' school, so what could the difference be? The ball is initially a happy occasion; the girls dress up and they dance and drink champagne together with the boys. But dynamics operating beneath the surface force their way up. Rosie is ready to force Pete to confront her continuing crush on him; Pete confronts Meg about their ongoing flirtation. Meg gives in and admits to herself for the first time that she does want to be with Pete. He is grown up and exciting and strong. He offers her something she has never had with Jason. Married less than a year, she pushes her husband out of her thoughts. The events of the ball force Meg to confront the differences between all her friends and the discomfort this affords everyone. Rosie's continued need for control over the group is acknowledged. Future Present (1991): Meg lives in Carlton with Pete. This is the busiest year thus far in her academic career and the financial, academic and emotional pressure is showing. This vignette gives us the range of Meg's academic activities and the way her life has fallen since the events at the ball eight months earlier. We see Meg grappling with her own evaluation of the changes in her 'way of being'; trying on different ways of living that she has idealised and finding them just as wanting as the last. Meg faces some key existential questions in this vignette and seeks answers which she finally discovers only she can give. Her relationship with Pete, the values and goals they share (and don't share) are thrown into sharp relief and provide a touchstone for the clearer determination of Meg's aspiration and future. Her relationship with various female friends is also revisited and this offers insight into Meg's constant checking of herself against idealised female templates. There is a crisis of identity and strength which constitutes an important fork in Meg's road. Beyond (1992): Beyond sees Meg determinedly seeking ways she can progress towards her goal, while still constantly checking against herself that postgraduate study (let alone a scholarly life) is available to her. We accompany Meg as she seeks and locates the academic path she wants; this is the backdrop for her further psychic exploration of the women who intimidate yet fascinate her, particularly Heloise Waul, who is a significant influence through Meg's postgraduate career. The sites in which Meg's personal struggles manifest are highlighted in this vignette, particularly in terms of dress and cultural pursuit. The conversations between Meg and Heloise also allow an exploration of the feminist politics of that milieu and the class tensions which operate tacitly within those politics. Bound to the Caucus (1992); Meg has now nearly completed her undergraduate degree and has been active for some time in university life and student politics. Her feminist and socialist education is well advanced. Bound to the Caucus shows us Meg in her student politics world for the first time, where the segue of her activism and academic life have taken her. Meg has found female friends who understand that part of her which struggles with inadequacy, although at this point in the novel this common struggle is not well understood or articulated. It is in this vignette that Meg admits her growing attraction for a Liberal student activist, Stuart Noble; this proscribed liaison raises many questions about values and aspiration, as well as the dominant sexual politics of the time and place. Bound to the Caucus also offers insight into the student activism occurring at universities like Philip in the early 1990s. Divergence (1993): Set in 1993, Meg is now in the early weeks of her honours program, although she has been at work on her thesis on the poet William Blake for some months. Living unhappily in a share household near the University, her relationship with Stuart Noble continues to develop, reaching a crisis point in this period. These events occur in the context of Meg's activist career in the Student Left, particularly as she encounters issues of identity around her class, feminism and difference amongst Left women. While Meg fights these battles passionately in an intense milieu, she considers them emotionally in terms of her changing sense of herself. Meg is increasingly aware that the personal impact of her class is changing for her. Additionally, she explores her relation with a 'boyfriend' of right wing political affiliation; Meg comes to recognise that this relationship is undermining her sense of herself in a way that her relationships with women in the left previously did. Honour Roll (1993): Meg is now undertaking honours and this vignette opens with Meg seeing the honours coordinator, Professor Michaela Moore, who approximates all those apparently middle-class traits to which Meg has such a push-pull relation. We see the return of a chapter of the honours thesis, discussion of the content and the constantly shifting subject positions these experiences offer Meg. This vignette also directly introduces Agnes. Mia and Agnes meet Meg after her supervision and this conversation allows very distinct if tacit class themes to develop. Meg has warmed quickly to Agnes, who is unlike anyone she has known; they have much in common in relation to their work and this binds them. Mia continually presents a viewpoint which irritates Meg, in relation to entitlement: to academic life, to funding, even to questioning how these things are enabled. Honour Roll allows us to see Meg's flourishing theoretical and intellectual life and its role in assisting her emotionally as she re-frames the same conundrums that previously constituted obstacles. The Cusp (1993): Meg's developing friendship with Agnes offers her enormous insights into difference and her developing sense of self and aspiration. While the girls come from diametrical backgrounds, they are united by their passion for their research and scholarly work. Meg is increasingly self-conscious through their discussions in terms of how she has seen herself and allowed herself to dream and seek. Cusp is set at the end of the honours year, prior to the release of results. Meg and Agnes explore their feelings about academia and this leads to discussions of purpose and the role of class within that. This vignette also documents Meg's growing social confidence and those aspects of herself which have become so sure to her, that she no longer considers them at all. Whom (1996): [Not included in this abridged edition]. Set at Cambridge, two thirds into Meg's doctorate, Whom shows Meg in the mental space which will take her back to Melbourne and the State University of Victoria. Having risen to the challenge of doctoral study, she is confronted now by deeper demons, and the need to explore and challenge them in the ambivalent context of Cambridge, which so excites her still, but which has proved empty of the profoundly held higher ideals she expected to see reflected. Set in the midst of Meg's doctoral study, this vignette is dramatically abridged in the submission novel. The importance of Whom lies in its concern with Meg's rapidly shifting sense of herself and her own scholarly subjectivity and the changes to these that the culture of Cambridge has wrought. By the second year of her PhD Meg is crystal clear about her goals and decides to spend the long break at home, rather than travelling, because she wishes to 'touch base' with her future. The action described segues into that in Courting the Enemy. Whom describes Meg's ambivalent and contradictory but passionate feelings about Cambridge. Whom demonstrates Meg's increasing anger at the status and privilege to which her education now automatically admits her, and her need to find some sort of stasis and safety in her emotional life. In this vignette, Meg meets her life partner, Jeremy McCallum (I have intentionally reduced the attention in the novel to Meg's romantic life as she matures into her career). Courting the Enemy (late 1990s): By this time, Meg is a senior lecturer in English at the State University of Victoria, which was established in the nineteenth century as the Worker's College. This vignette starts with Meg's attendance at a University Committee which is considering a transformation in relation to equity in admissions policy. Meg was drawn to SUV because of its transparent and determined commitment to educate the children of working-class people. An attack on the equity admission policy of her university galvanizes Meg and some of her colleagues. The action of the vignette considers the role of the scholar, and of such an institution as SUV, in the light of daily academic life. This vignette is primary in its demonstration of the themes of the novel. In the unabridged version, I took the opportunity to illustrate some of the vast range of administrative, intellectual and even physical demands on a senior scholar in the routine of academic life. In placing Meg in this context, I sought to highlight how a scholar of her values and commitment makes sense of the constantly shifting terrain of her working world and how this continually informs her practice. This vignette is also significant for its retrospective description of Meg's employment at SUV some years earlier. Locus: (1995). This piece of writing stands apart from the rest of the novel. I wished to write in a reflective voice, which might be from Meg's journal, were it not in the (omniscient) third person, in order to consider the headspace and meaning-making which occurs as Meg settles into Cambridge, and the lifestyle her situation allows her. Locus is a deeper engagement with Meg's sense of her identity. It considers the impact on her of the physical journeys she must make to match those of her psyche. These are thoughts too personal for a letter, even to Anna. Meg is exploring her ever shifting self and the growth in her self-belief allows her to explore what is rage; that she was bounded by illusions about her worth. Locus seeks to allow some context for Meg's anger at the role Cambridge plays. I seek to create the space in which Meg's dawning self understanding will lead her to her next, driven, purpose. Letters: throughout the novel letters are used to reveal and inform Meg's relationship with her family. This is an intentional device to distance the birth family in an attempt to blur and muddy an assessment of Meg's class through traditional measures. The letters between Meg and Aunty Jean particularly reveal much of the classed emotional antecedents of Meg's life. There are also letters exchanged with Meg's high school best friend, Anna, who has moved to the country and a very different lifestyle. Meg writes to Anna often, using the acceptance she feels in the friendship and her sense that Anna understands her, to touchstone her own emotional growth. Formal letters from institutions ring changes in settings and mark significant points in the geographical and academic trajectory of the character. All the letters serve to introduce time and event changes consistent with the episodic style of the narrative.