In this thesis, we will give our discovery of original symmetric presentations of several important groups. We have investigated permutation and monomial progenitors 2*8: (23: 22), 2*9: (32: 24), 2*10: (24: (2 × 5)), 5*4:m (23: 22), 7*8:m (32: 24), and 3*5:m (24: (2 × 5)). The finite images of the above progenitors include the Mathieu sporadic group M12, the linear groups L2(8) and L2(13), and the extensions S6 × 2, 28 : .L2(8) , and 27 : .A5. We will show our construction of the four groups S3 , L2(8), L2(13), and S6 × 2 over S3, 22, S3 : 2, and S5, by using the technique of double coset enumeration. We will also provide isomorphism types all of the groups that have appeared as finite homomorphic images. We will show that the group L2(8) does not satisfy the conditions of Iwasawas Lemma and that the group L2(13) is simple by Iwasawas Lemma. We give constructions of M22 × 2 and M22 as homomorphic images of the progenitor S6.

This thesis presents results based on data collected with the 930 MHz EISCAT UHF radar system and three SKiYMet specular meteor radars. It describes in detail a method for meteoroid orbit calculation. The EISCAT UHF system comprises three identical 32 m parabolic antennae: one high-power transmitter/receiver and two remote receivers. Precise meteoroid deceleration and radar cross section are determined from 410 meteor head echoes simultaneously observed with all three receivers between 2002 and 2005, during four 24h runs at the summer/winter solstice and the vernal/autumnal equinox. The observations are used to calculate meteoroid orbits and estimate meteor visual magnitudes. None of the observed meteors appear to be of extrasolar or asteroidal origin; comets, particularly short period (<200 years) ones, may be the dominant source for the particles observed. About 40% of the radiants are associated with the north apex sporadic meteor source and 58% of the orbits are retrograde. The geocentric velocity distribution is bimodal with a prograde population centred around 38 km/s and a retrograde population peaking at 59 km/s. The absolute visual magnitudes of meteors are estimated to be in the range of +9 to +5 using a single-object numerical ablation model. They are thus observable using intensified CCD cameras with telephoto lenses. The thesis also investigates diurnal meteor rate differences and sporadic meteor radiant distributions at different latitudes using specular meteor trail radar measurements from 68°N, from 55°N and from 8°S. The largest difference in amplitude of the diurnal flux variation is at equatorial latitudes, the lowest variation is found at high latitudes. The largest seasonal variation of the diurnal flux is observed with the high-latitude meteor radar. The investigations show a variation in the sources with both latitude and time of day. The EISCAT UHF system and the high-latitude meteor radar are located close to the Arctic Circle. Such a geographical position means that zenith points towards the North Ecliptic Pole (NEP) once every day all year round. This particular geometry allows the meteoroid influx from the north ecliptic hemisphere to be compared throughout the year as the ecliptic plane coincides with the local horizon. Considering only the hour when NEP is closest to zenith, the EISCAT UHF head echo rate is about a factor of three higher at summer solstice than during the other seasons, a finding which is consistent with the high-latitude meteor radar measurements. / Avhandlingens resultat är baserade på mätningar med den trestatiska EISCAT UHF-radarn och tre SKiYMet meteorradarsystem. En metod för meteoroidbanberäkning presenteras i detalj. EISCAT UHF-systemet består av tre identiska, 32 m stora parabolantenner: en högeffektssändare/mottagare och två fjärrstyrda mottagare. Under fyra 24-timmarsmätningar vid vår-/höstdagjämning och sommar-/vintersolstånd mellan 2002 och 2005 detekterades 410 meteoriska huvudekon simultant med alla tre mottagare. Dessa trestatiska meteorers atmosfärsinbromsning och radartvärsnitt har fastställts mycket noggrant och använts till att beräkna meteoroidernas banor samt uppskatta meteorernas luminositeter. Ingen av de observerade meteoroiderna verkar vara av interstellärt eller asteroidursprung. Deras troligaste ursprung är kometer, framför allt kortperiodskometer (<200 år). Ungefär 40% av meteorradianterna kan associeras till norra apex, ett källområde för sporadiska meteorer, och totalt är 58% av partiklarnas banor retrograda. Meteoroidernas geocentriska hastighetsfördelning har två lokala maxima: ett för den prograda populationen vid 38 km/s och ett för den retrograda vid 59 km/s. Genom att anpassa datat till en numerisk ablationsmodell som simulerar meteoroidernas färd genom atmosfären har de detekterade meteorernas absoluta visuella magnituder uppskattats till mellan +9 och +5. Detta innebär att de är observerbara med bildförstärkta, teleskopiska CCD-kameror. Avhandlingen diskuterar även hur sporadiska meteorers dygns- och säsongsinflöde beror på geografisk latitud och meteorradianternas distribution på himmelssfären. Detta utreds med hjälp av spårekon detekterade under perioden 1999-2004 med tre meteorradarsystem på latituderna 68°N, 55°N och 8°S. Dygnsinflödet varierar mest på låga latituder och minst på höga. Ju högre latitud, desto mer förändras däremot dygnsinflödet över året. Avhandlingen visar att de dominerande källområdena varierar med säsong, över dygnet och med latitud. Både EISCAT UHF-systemet och meteorradarn på 68°N är belägna nära polcirkeln. Detta innebär att norra ekliptiska polen (NEP) är i zenit en gång per dygn, året om. Vid just denna tidpunkt sammanfaller ekliptikan med den lokala horisonten, vilket möjliggör att det observerade meteorinflödet från norra ekliptiska hemisfären kan jämföras över året. Under timmen då NEP är närmast zenit har EISCAT UHF uppmätt ett ungefär tre gånger högre meteorinflöde vid sommarsolståndet än under de andra säsongerna, vilket överensstämmer med resultaten från meteorradarn på 68°N.

Hintergrund: Die sporadische Creutzfeldt-Jakob-Krankheit (sCJK) ist eine seltene neurodegenerative Erkrankung. Bisher existieren nur wenige Studien im Hinblick auf das Initialstadium der Erkrankung. Ziel dieser Studie war es unter Berücksichtigung des M129V-Genotyps und des Prionproteintyps maximal zwei Erstsymptome begrenzt auf einen Zeitraum von 2 Wochen, den ärztlichen Erstkontakt und die erste fachärztliche Diagnose zu erfassen. Material und Methoden: In der vorliegenden Dissertation wurden retrospektiv Akten von 492 Patienten mit einer neuropathologisch gesicherten oder klinisch wahrscheinlichen sCJK ausgewertet, die im Zeitraum von 1993 bis 2003 an das Göttinger Surveillance-Zentrum für CJK gemeldet worden waren. Bei 204 Patienten des Gesamtkollektivs war zusätzlich der Prionproteintyp bekannt. Mithilfe eines Dokumentationsbogens wurden die relevanten Parameter erfasst und statistisch ausgewertet. Ergebnisse: Zehn Prozent aller Patienten klagten über Prodromalsymptome wie Kopfschmerz, Müdigkeit, gestörte Schlaf-Wach-Rhythmik, Summen bzw. "komisches Gefühl im Kopf", Hörstörungen, Gewichtsverlust oder Photophobie. Patienten mit dem Subtyp MV-2 oder VV-1 gaben keine Prodromalsymptome an. Das häufigste Erstsymptom stellte die Demenz (37%) dar, gefolgt von zerebellären (34%), visuellen (15%) oder psychiatrischen (14%) Symptomen. Fünfzehn Prozent berichteten innerhalb von 2 Wochen bereits über 2 Erstsymptome. Als erster ärztlicher Kontakt wurde der Hausarzt (41%) aufgesucht, gefolgt vom niedergelassenen Neurologen (17%) oder einem Krankenhaus (13%), unabhängig von der Spezialisierung der Abteilung. Die fachärztliche Erstdiagnose lautete nur in 35% der Fälle CJK (in 42% bei MM-Patienten, 28% bei MV-Patienten, 25% bei VV-Patienten). Die Meldung eines CJK-Verdachtsfalles an das Göttinger CJK-Surveillance-Zentrum erfolgte überwiegend durch Neurologen, gefolgt von Psychiatern oder von anderen Berufsgruppen. Diskussion: Diese erste detaillierte Analyse von Erstsymptomen und ärztlichen Erstkontakten unterstreicht, wie relevant das Wissen von CJK und den atypischen CJK-Subtypen für Ärzte verschiedener Fachrichtungen ist. Hieraus entsteht die Hoffnung, dass in Zukunft insbesondere auch atypische CJK-Formen frühzeitig erkannt werden können.

A typical automobile system consists of many Electronic Control Units (ECUs) for the purposes of safety, comfort, and entertainment applications. FlexRay is a high bandwidth protocol for such automotive requirements, which facilitates communication between distributed ECUs. This thesis addresses some of the issues associated with the design and implementation of the FlexRay protocol. The number of ECUs that are used in automobiles has an increasing trend to implement more functionality, which demands more bandwidth. By minimizing bandwidth requirements for servicing a given workload of periodic and sporadic real-time tasks, one can connect more ECUs to the same FlexRay bus. With this motivation, the first part of this thesis proposes new algorithms for minimizing bandwidth usage of ECUs in both the static and the dynamic segments of FlexRay. FlexRay provides a time-triggered static segment for the transmission of time critical periodic messages. The static segment consists of a fixed number of static slots each with a fixed duration. The duration of the static slot and the number of slots are design parameters which need to be fixed so as to meet all the deadline requirements of the workload in the application. The static slot duration can be minimized by packing the signals into message frames, while respecting scheduling constraints. Since message frames also contain overhead information, the duration of message frames can be optimized by proper signal packing, based on the network utilization constraints of individual ECUs. The thesis proposes a novel algorithm for packing of signals into message frames and fixing the static slot duration so that the total duration of the static segment is minimized. The dynamic segment of FlexRay caters to the transmission of event-triggered signals. A novel algorithm has been proposed to obtain the minimum duration of the dynamic segment while meeting the deadline constraints of all sporadic messages in their worst-case arrival instances. We also extend all these algorithms to the case of slot multiplexing scheme provided by FlexRay 3.0. Modern automobiles provide infotainment and in-car telemetry functions, which produce a high volume of soft deadline messages. This makes the problem of analyzing scheduling algorithms for such traffic important. The dynamic segment of the FlexRay cycle is used for transmission of such soft deadline messages. The second part of this thesis addresses the issue of analyzing the quality of performance in servicing of the soft deadline tasks in the FlexRay protocol. Two quality measures, namely, the average delay in servicing of the soft deadline tasks and the fraction of tasks that miss their deadlines, are considered. The generation of different soft deadline messages is modeled as independent Poisson processes. The generated messages are queued in different queues and are serviced according to pre-assigned priorities for different queues as per the FlexRay protocol. By analyzing this multiple queue model under some mild assumptions, upper bounds on the arrival rates for different messages are derived so that all the queues are stable. Analytical expressions are also derived for average delay and for deadline miss ratio. The correctness of these approximate analytical expressions are demonstrated through simulation studies.

Abstract Meniere’s disease (MD) is an inner ear disorder characterized by vertigo, tinnitus and sensorineural hearing impairment. An inherited form of the disease is called familial Meniere’s disease (FMD). The aim of this thesis was to describe the clinical and genetic features of Finnish FMD and to study its prevalence in Finland. In addition genetic factors previously associated with MD were studied in Finnish MD patients. A total of 38 Meniere-families were analysed in this study. In most of the families the mode of inheritance was found to be autosomal dominant. Meniere-like symptoms such as tinnitus or vertigo were common in these families even in individuals without a full triad of MD. Familial patients were affected earlier, suffered from longer spells of vertigo and had more autoimmune diseases compared to sporadic MD patients. The prevalence of FMD was studied among the patients treated in the Oulu University Hospital and Kainuu Central Hospital during the years 2005-2010. A family history of MD was probable in 23.4% of the cases, but only 9.3% could be confirmed, as it was not possible to gain information from deceased generations. Six candidate genes previously associated with MD were screened for mutations in Finnish MD patients. Two possibly adverse variations were observed in the KCNE1 gene in two patients but in none of the controls. The role of these variations in MD is still unclear and needs further study. The association of MD to the five other genes could not be confirmed, nor was Finnish FMD linked to a previously suggested locus on chromosome 12. / Tiivistelmä Menieren tauti on sisäkorvan sairaus, jolle on tyypillistä huimaus, korvien soiminen ja kuulon heikkeneminen. Tauti voi esiintyä myös perinnöllisenä. Tutkimustyön tavoitteena oli selvittää perinnöllisyyden osuutta Menieren taudissa, kuvata suomalaisen perinnöllisen Menieren taudin tyypilliset piirteet ja tutkia suomalaisessa aineistossa aikaisemmin tautiin yhdistettyjä perinnöllisiä tekijöitä. Tutkimuksessa analysoitiin 38 sukua, joissa Menieren tautia esiintyi perinnöllisenä. Suurimmassa osassa tapauksista periytyminen tapahtui vallitsevasti. Suvuissa esiintyi paljon Meniere-tyypistä oirehdintaa, kuten tinnitusta ja huimausta, ilman Menieren taudin koko taudinkuvaa. Meniere-suvuissa potilaat sairastuivat keskimääräistä aikaisemmin, kärsivät pidemmistä huimauskohtauksista ja sairastivat enemmän autoimmuunitauteja. Perinnöllisen Menieren taudin yleisyyttä tutkittiin Kainuun keskussairaalassa ja Oulun yliopistollisessa sairaalassa vuosina 2005−2010 hoidettujen potilaiden keskuudessa. Potilaista 23,4 %:lla Menieren taudin sukuhistoria oli positiivinen; kuitenkin vain 9,3 % pystyttiin vahvistamaan, sillä tietojen kerääminen edesmenneiltä sukupolvilta ei ollut mahdollista. Kuuden Menieren tautiin aikaisemmin yhdistetyn geenin merkitystä tutkittiin suomalaisessa aineistossa mutaatio- ja ehdokasgeenianalyysillä. KCNE1-geenistä löydettiin kaksi mahdollisesti proteiinia vaurioittavaa sekvenssinvaihtelua, joita ei havaittu kontrollihenkilöillä. Muutosten merkitys Menieren taudin synnyssä jäi kuitenkin epävarmaksi ja vaatii jatkotutkimuksia. Muiden geenien yhteyttä sairauteen ei pystytty vahvistamaan. Suomalainen Menieren tauti ei myöskään kytkeytynyt aikaisemmin ehdotettuun lokukseen kromosomissa 12.

The aim of the study was to evaluate the importance of brain MRI's findings, and modify the criteria for brain MR imaging in NF1 patients according to this data, to improve the quality of life with early detection of important NF1 complications. Description of the whole cohort, with emphasise to possible cause of high range of sporadic NF1 cases. Evaluation the possibility diagnosis or follow up of brain gliomas by plasmatic values of neuron specific enolase (NSE) and S100B protein. Subjects and methods: I analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery. I evaluated the incidence of brain MRI findings, clinical development, age at gliomas manifestation and necessity of treatment. I also described the whole cohort and made statistic analysis of plasmatic values of NSE and S100B protein in NF1 patients, with and without brain gliomas. Results: OPGs were found in 77/285 (27 %) children and GOOPs in 29/285 (10.2 %) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30.5 %). Totally, 43/87 (49.4 %), respectively 43/285 (15.1 %) children with brain glioma were treated, and 4/285 (1.4 %) of this children died. Obstructive hydrocephalus was found in 22/285 (7.7 %) patients and was caused...

<p>Modern microbialites and microbial mats are the focus of ongoing research as they provide an opportunity to understand microbial-mineral interactions during carbonate precipitation and the generation of biosignatures that can inform our interpretation of the geological record. This study determined the natural abundance isotopic compositions ([13]C, [14]C) of the primary carbon pools and microbial communities associated with modern freshwater microbialites located in Pavilion Lake and in carbonate rich microbial mats on the nearby Cariboo Plateau in British Columbia, Canada. </p> <p> Natural abundance [14]C analysis of carbon pools associated with the Pavilion Lake microbialites demonstrated that structures were actively growing and that groundwater carbon inputs to the lake and microbialites were minimal. Rather, ambient dissolved inorganic carbon (DIC) was the primary carbon source for both microbial communities and recent carbonate. </p> <p> Isotopic enrichment of calcium carbonate within microbial communities associated with the microbialites was identified as a biosignature of microbial photosynthetic influence driving precipitation. Elevated oxygen concentrations and pH within the microenvironment of small, sporadic nodular microbial surface communities was concurrent with in situ precipitation of carbonate with δ[13]C values higher than predicted abiotic values and δ[13]C of bulk organic matter and phospholipid fatty acids (PLFA) that were consistent with a photosynthetically dominated community. Elevated carbonate δ[13]C values were also noted in the thin surface microbial mat recovered from shallow (11m) microbialites. These samples showed increased biomass during summer sampling periods as compared to deeper samples, consistent with expected high rates of photosynthetic activity due to higher light levels and temperature at these depths. These results contrast other recent studies of modern microbialite systems that identified biosignatures of heterotrophic influences on precipitation of carbonates. PLFA profiles demonstrated that the surface microbial mat community consisting of both photosynthetic and heterotrophic microbes was stable over seasonal and spatial changes in light and temperature. However, changes in microbial biomass with depth and season indicated that microbial activity and growth plays an important role in the development of isotopic biosignatures. </p> <p> Biosignatures of high levels of photosynthetic activity were also observed in carbonate, rich microbial mats that exhibited undersaturated p CO2 concentrations during the summer and DIC δ[13]C values enriched above values predicted for isotopic equilibrium with atmospheric CO2. Seasonal and annual shifts in the balance of heterotrophy and autotrophy in the lakes and microenvironment of the mat accounted for observed variations in DIC and associated carbonate δ[13]C values. In contrast to other organic rich microbial mats, bulk organic δ[13]C values were not enriched and the systems did not show evidence of CO2 limitation. Rather, these results indicated that low bulk organic δ[13]C values and large isotopic discriminations can exist under conditions of high DIC concentrations and carbonate content that provide a non limiting carbon source to replenish photosynthetic drawdown. </p> / Thesis / Doctor of Philosophy (PhD)

Sporadic-E layers (Es) are layers of metallic ions that appear in the lower E-region of the ionosphere and can last from under one hour to several hours. Es are found at all latitudes, but polar cap Es, and specifically over Svalbard at a latitude of around 78◦ , are the focus of this study. Data is provided from several instruments: the EISCAT Svalbard Dynasonde, the EISCAT Svalbard Incoherent Scatter Radar (ESR), SuperDARN, and modelled data from the latest Horizontal Wind Model (HWM14). Data on the Interplanetary Magnetic Field (IMF) is acquired from the NASA OMNIWeb data base. It is found that polar cap Es are a summer phenomenon, confined to the later afternoon to a couple of hours after midnight in universal time (UT), with a peak occurrence between 18-21 UT. The layer heights are mostly confined to ∼92-120 km, although there is a discrepancy between Es found in ESR data and Dynasonde data, with ESR events being confined to 92-110 km, and Dynasonde events to 95-120 km. It is also found that Es occurrence is dependent on Interplanetary Magnetic Field (IMF) direction, with a higher occurrence during a southward and eastward IMF. The Dynasonde automatic signal processing of echoes is found to be unreliable at times with intense E-region density enhancements, such as Es. From a Superposed Epoch Analysis (SEA) on Es found in ESR data, it is found that there is a density buildup from the start of the events, peaking by 30 % of the Es lifetime, that is followed by fading at a slower rate until the end of the layer lifetime. Layer thickness is found to be largely confined to &lt;9 km. From SuperDARN E-field data it is found that layers can form and migrate downwards to low altitudes for a strictly northward E-field. ’Flat’, low altitude layers are found during E-field directions in both the southwest and northwest quadrants. Some cases of Es formation and migration fit current theories and whilst some does not. Indications of particle precipitation that induce layer formation is found. / Sporadiska E-skikt (Es) är lager av metalliska joner som uppträder i den nedre delen av jonosfärens E-region, och kan pågå från under en timme till flera timmar. Es återfinns på alla breddgrader, men Es i polarområdet, och specifikt över Svalbard på en latitud av cirka 78◦ , är fokuset för denna studie. Data tillhandahålls från flera instrument: EISCAT Svalbard Dynasonde, EISCAT Svalbard Incoherent Scatter Radar (ESR), SuperDARN och modellerade data från en updaterad modell för horisontella neutrala vindar (HWM14). Data om det interplanetära magnetfältet (IMF) hämtas från NASAs OMNIWeb databas. Det visas att Es i polarområdet är ett sommarfenomen, begränsat till mellan eftermiddagen och ett par timmar efter midnatt i universell tid (UT), med en toppförekomst mellan 18-21 UT. Höjd för skikten är mestadels begränsade till ∼92-120 km, men det finns en diskrepans mellan Es funna ur ESR-data och Dynasonde-data, med fallen från ESR data begränsade till 92-110 km och fall från Dynasonde-datan till 95-120 km. Det visas också att Es-förekomsten är beroende av det interplanetära magnetfältets (IMF) riktning, med en högre förekomst under IMF riktat söderut och österut. Dynasondens automatiska signalbehandling av ekon visas vara opålitlig under intensiva förhöjningar i E-regionens densitet, såsom är fallet vid sporadiska E-skikt. Genom en ’Superposed Epoch Analysis’ (SEA) som genoförs för de Es som lokaliseras i ESR-datan, visar det sig att det finns en densitetsuppbyggnad från början av Es fallen, med en densitetstopp vid 30 % av Es-livslängden, som sedan följs av en långsammare avtrappning tills skiktet helt dött ut. Skikttjockleken visar sig vara i stort sett begränsad till &lt;9 km. Ur E-fältdata från SuperDARN visar det sig att lager kan bildas och migrera nedåt, till låga höjder för ett nordligt riktat E-fält. ’Platta’ skikt på låg höjd återfinns under E-fältsriktningar i både sydvästra och nordvästra kvadranten. Vissa fall med Es formation och migration följer teorin på området medan andra fall inte gör det. Det finns vissa indikationer på att partikelprecipitation kan inducera skiktbildning.

No description available.

La maladie de Parkinson (MP) est une affection neurodégénérative invalidante et incurable. Il est maintenant clairement établi que d’importants déterminants génétiques prédisposent à son apparition. La recherche génétique sur des formes familiales de la MP a mené à la découverte d’un minimum de six gènes causatifs (SNCA, LRRK2, Parkin, PINK1, DJ-1 and GBA) et certains, par exemple LRRK2, contiennent des variations génétiques qui prédisposent également aux formes sporadiques. La caractérisation des protéines codées par ces gènes a mené à une meilleure compréhension des mécanismes moléculaires sousjacents. Toutefois, en dépit de ces efforts, les causes menant à l’apparition de la MP restent inconnues pour la majorité des patients. L’objectif général des présents travaux était d’identifier des mutations prédisposant à la MP dans la population canadienne-française du Québec à partir d’une cohorte composée principalement de patients sporadiques. Le premier volet de ce projet consistait à déterminer la présence de mutations de LRRK2 dans notre cohorte en séquençant directement les exons contenant la majorité des mutations pathogéniques et en effectuant une étude d’association. Nous n’avons identifié aucune mutation et l’étude d’association s’est avérée négative, suggérant ainsi que LRRK2 n’est pas une cause significative de la MP dans la population canadienne-française. La deuxième partie du projet avait pour objectif d’identifier de nouveaux gènes causatifs en séquençant directement des gènes candidats choisis à cause de leurs implications dans différents mécanismes moléculaires sous-tendant la MP. Notre hypothèse de recherche était basée sur l’idée que la MP est principalement due à des mutations individuellement rares dans un grand nombre de gènes différents. Nous avons identifié des mutations rares dans les gènes PICK1 et MFN1. Le premier code pour une protéine impliquée dans la régulation de la transmission du glutamate tandis que le second est un des acteurs-clés du processus de fusion mitochondriale. Nos résultats, qui devront être répliqués, suggèrent que le séquençage à grande échelle pourrait être une méthode prometteuse d’élucidation des facteurs de prédisposition génétiques à la MP ; ils soulignent l’intérêt d’utiliser une population fondatrice comme les canadiens-français pour ce type d’étude et devraient permettre d’approfondir les connaissances sur la pathogénèse moléculaire de la MP. / Parkinson’s disease (PD) is a complex neurological disorder with significant genetic predisposing factors which are extremely heterogeneous. Investigations of familial forms of the disorder revealed causative mutations in six different genes, namely SNCA, LRRK2, Parkin, PINK1, DJ-1 and GBA, and functional analyses of these gene products pinpointed dysfunction of key molecular pathways involved in the neurodegenerative process of the disorder. Further sequencing and genome-wide association studies indicated that some of these genes, including LRRK2, also contain variants predisposing to sporadic forms of PD. Despite these significant breakthroughs, the vast majority of PD genetic predisposing factors remain unknown. Our goal was to identify mutations predisposing to PD in the French Canadian (FC) population from a cohort mostly composed of late-onset sporadic cases. We therefore sequenced the two exons of LRRK2 that contain most of the pathogenic mutations and we performed a case-control association study. Sequencing analysis did not reveal any reported or novel mutations and the case-control association study did not provide any positive signal, thus indicating that common variants in LRRK2 are unlikely to be a significant cause of late-onset PD in the FC population. Because of the allelic and non-allelic genetic heterogeneity observed for PD, we hypothesized that dozens of genes may carry rare pathogenic mutations. The second part of this research project was therefore aimed at identifying new PD causative genes by direct sequencing of genes functionally associated with the known causative gene pathways. Our screening uncovered several rare mutations likely pathogenic in the PICK1 and the MFN1 genes. PICK1 is involved in internalization of AMPA receptors whereas MFN1 is one of the core components of the mitochondrial fusion/fission machinery. Although these observations will need to be replicated, our findings support the previously suspected pathogenic role for glutamate excitotoxicity and imbalanced mitochondrial dynamics in Parkinson’s disease. They further emphasize the value of inbred populations in genetic studies of PD and provide new clues to the molecular pathogenesis of the disorder.