Bakgrund: Myalgic Encephalomyelitis eller Chronic Fatigue Syndrome (ME/CFS) omfattar ett spektrum av olika symptom som bland annat påverkar de autonoma och neurologiska systemen, kognitiv funktion och ger immunologiska störningar med mera. De karakteristiska symptomen är oförklarlig kronisk trötthet, ansträngningsutlöst fysisk och mental uttröttbarhet Post Exertional Malaise (PEM). Trots forskning inom ett flertal områden är den underliggande molekylära orsaken bakom ME/CFS inte fastställd. Flertalet hypoteser om sjukdomsorsaken finns, varav en är att ME/CFS är en autoimmun sjukdom. Syfte: Syftet med litteraturstudien är att undersöka huruvida det finns autoimmuna aspekter i ME/CFS. Metod: Systematisk litteraturstudie utifrån vetenskapliga artiklar, publicerade 2010—2020 i databasen PubMed. Resultat: Studieresultaten är inte helt entydiga när det kommer till att påvisa autoimmuna aspekter i ME/CFS. Antikroppsstudier riktade mot neuronalt protein hos ME/CFS-patienter och behandlingar riktade mot antikroppar, immunoadsorption och rituximab, gav negativa resultat. Däremot observeras HSP60 (heat shock protein 60) antikroppar för specifika korsreaktiva epitoper i en undergrupp av ME/CFS-patienter, vilket stämmer överens med infektionsutlöst autoimmunitet. Även i de två genstudierna, HLA-association (human leucocyte antigen) och SNP (single nucleotide polymorphism) genotypning i immungener, observeras karakteristiska riskgener för autoimmun sjukdom, tydligast resultat observerades hos de patienter som har en infektionsutlöst ME/CFS. Slutsats: Trots delvis negativa resultat ges visst stöd för hypotesen då dessa indikerar autoimmuna aspekter i en undergrupp av infektionsutlöst ME/CFS. / Background: Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease which is characterized by unexplained and persistent post exertional fatigue (PEM) and a myriad of symptoms related to neurological disturbance, immunological, cognitive and autonomous dysfunction. Despite biomedical research from a disparate field of expertise the pathogenesis and etiology of ME/CFS is not well-understood. Several hypotheses regarding the pathogenesis have been proposed one of which is that ME/CFS is an autoimmune disease. Aim: The purpose of the literature study is to investigate whether there are autoimmune aspects in ME/CFS. Method: A systematic literature study based on scientific articles, published 2010-2020 in the PubMed database. Results: The study results are not entirely consistent when it comes to detecting autoimmune aspects in ME/CFS. Antibody studies targeting neuronal proteins in ME/CFS-patients and antibody treatments, immunoadsorption, and rituximab yielded negative results. In contrast, HSP60 (heat shock protein 60) antibodies for specific cross-reactive epitopes are observed in a subset of ME/CFS patients, which corresponds to infection-triggered autoimmunity. The two gene studies, HLA (human leucocyte antigen) association and genotyping of SNP (single nucleotide polymorphism) in immune genes, observed characteristic risk genes for autoimmune disease. Significant results were observed in ME/CFS- patients with an infection-triggered onset. Conclusion: Despite partially negative results, some support exists for the hypothesis as results indicate autoimmune aspects in ME/CFS with an infection-triggered onset.

Première cause de décès par cancer chez la femme, le cancer du sein développe souvent une résistance à la chimiothérapie pouvant impliquer des transporteurs ABC (ATP Binding Cassette). Ils transportent les médicaments hors de la cellule et diminuent leur efficacité thérapeutique. Nous nous sommes intéressés à la protéine ABCC11 ou MRP8 (Multidrug Resistance Protein 8), exprimée dans le sein et responsable de l'efflux de certains anticancéreux (5FdUMP et méthotrexate). Nous avons démontré que l'expression d'ABCC11 était dépendante des voies de signalisation impliquant ER (Récepteur aux œstrogènes) ou PR (Récepteurs à la Progestérone). De plus, le tamoxifène (antagoniste d'ER) et la dexaméthasone (activateur de PR), utilisés en association avec la chimiothérapie, induisent l'expression d'ABCC11 et influenceraient négativement la réponse aux traitements anticancéreux à base de substrats d'ABCC11. L'expression d'ABCC11 a été positivement corrélée à celles d'ER et PR dans des cancers du sein. En parallèle, nous avons généré 2 modèles in silico en conformation ouverte vers l'intracellulaire ou vers l'extracellulaire et identifier des acides aminés potentiellement critiques dans l'architecture de la protéine ainsi que dans la liaison avec certains substrats (5FdUMP et GMPc). Nous avons également généré les outils moléculaires permettant l'étude de l'impact de 13 SNP (Single Nucleotide Polymorphism) non synonymes d'ABCC11. En raison d'une instabilité des lignées cellulaires, l'étude n'a pu être menée à son terme. Notre travail a ainsi contribué à une meilleure caractérisation d'ABCC11 et souligne sa potentielle valeur pronostic et prédictive dans le traitement du cancer du sein.

Implantation requires complex molecular and cellular events involving coagulation, angiogenesis and immunological processes that need to be well regulated for a pregnancy to establish and progress normally.  The overall aim of this thesis was to study different models associated with atypical angiogenesis, impaired implantation and/or placentation, such as recurrent miscarriage (RM), oocyte donation (OD) and preeclampsia. Histidine-rich glycoprotein (HRG), a serum protein with angiogenic potential has been previously shown to have an impact on implantation and fertility.  In two retrospective case-control studies, women suffering from RM (Study I) and gestational hypertensive disorders (GHD) (Study IV) have been compared to healthy control women, regarding carriership of HRG genotypes (HRG A1042G and C633T SNP, respectively).  According to the findings of this thesis, heterozygous carriers of the HRG A1042G SNP suffer from RM more seldom than homozygous carriers (Study I).  Additionally, the presence of the HRG 633T allele was associated with increased odds of GHD (GHD IV).  Studies II and III comprised a national cohort of relatively young women with optimal health status conceiving singletons with donated oocytes versus autologous oocytes (spontaneously or via IVF).  We explored differences in various obstetric (Study II) and neonatal (Study III) outcomes from the Swedish Medical Birth Register.  Women conceiving with donated oocytes had a higher risk of GHD, induction of labor and cesarean section, as well as postpartum hemorrhage and retained placenta, when compared to autologously conceiving women.  OD infants had higher odds of prematurity and lower birthweight and length when born preterm, compared to neonates from autologous oocytes.  With regard to the indication of OD treatment, higher intervention but neverthelss favourable neonatal outcomes were observed in women with diminished ovarian reserve; the risk of GHD did not differ among OD recipients after adjustment. In conclusion, HRG genetic variation appears to contribute to placental dysfunction disorders.  HRG is potential biomarker that may contribute in the prediction of the individual susceptibility for RM and GHD.  Regarding OD in Sweden, the recipients-despite being of optimal age and health status- need careful preconceptional counselling and closer prenatal monitoring, mainly due to increased prevalence of hypertensive disorders and prematurity.

Notre patrimoine génétique dévoile, de plus en plus, les passerelles démogénétiques d’une susceptibilité plus accrue de certains individus à des maladies infectieuses complexes. En vue d’une caractérisation de la variabilité génétique des populations ouest-africaines, nous avons analysé 659 chromosomes X au locus dys44 qui comprend, 35 SNPs et un microsatellite distribués sur 2853 pb en amont et 5034 pb en aval de l’exon 44 du gène de la dystrophine en Xp21.3. Les génotypes obtenus, par ASO dynamique et électrophorèse sur gel d’acrylamide, ont servi à la détermination des haplotypes. Des paramètres comme la diversité haplotypique (G) et l'indice de fixation (Fst) ont été calculés. Des analyses en composantes principales ainsi que multidimensionnelles ont été réalisées. Sur 68 haplotypes détectés, 26 sont nouveaux, et cette région, avec une diversité haplotypique moyenne (Gmoy) de 0,91 ± 0,03, se révèle beaucoup plus hétérogène que le reste du continent (Gmoy = 0,85 ± 0,04). Toutefois, malgré l’existence de disparités sous régionales dans la distribution des variants du marqueur dys44, l’AMOVA montre d’une manière générale, une faible érosion de l’éloignement génétique entre les populations subsahariennes (Fst = 1,5% ; p<10-5). Certains variants tel que l’haplotype eurasien B006 paraissent indiquer des flux transsahariens de gènes entre les populations nord-africaines et celles subsahariennes, comme l’exemplifie le pool génétique de l’une des populations ubiquitaires de la famille linguistique Nigéro-congolaise : Les Fulani. Nos résultats vont aussi dans le sens d’un héritage phylétique commun entre les Biaka, les Afro-américains et les populations de la sous-famille de langues Volta-Congo. / The unravelling of our genetic heritage has revealed a demogenetic segueway leading to an increased susceptibility of certain individuals to complex infectious diseases. In order to characterize genetic variability among the West African populations, we analyzed 659 X chromosomes at the dys44 locus which comprises 35 SNPs and a microsatellite spanning a region 2853 bp upstream and 5034 bp downstream of exon 44 of the dystrophine gene in Xp21.3. The resulting genotypes, obtained by dynamic allele specific oligonucleotide hybridization and acrylamide gel electrophoresis, were used for haplotype construction. Gene diversity parameters such as the haplotypic diversity (G) and fixation indexes (Fst) were estimated. Multidimensional analysis of the data, including principal component analysis was also performed. Of the 68 distinct haplotypes detected in our data set, 26 were novel. The mean haplotypic diversity (Gmoy) was 0.91 ± 0.03 for this West African region which was shown to be more heterogeneous than the rest of the continent (Gmoy = 0.85 ± 0.04). However, despite certain sub-regional differences in the distribution of dys44 variants, the analysis of molecular variance showed an overall decline in the genetic distance between Sub-Saharan populations (Fst = 1.5% ; p<10-5). Certain variants, such as the Eurasian-specific haplotype B006, appear to suggest a Trans-Saharan gene flux between North African and Sub-Saharan populations as exemplified by the observed genetic pool of one of the ubiquitous populations of the Nigerian-Congolese linguistic family: The Fulani. Our results are also in agreement with a phyletic heritage between the Biaka, the Afro-Americans and the populations of the Volta-Congo language subfamilies.

Le neuroblastome (NB) est la tumeur solide extracranienne la plus fréquente et mortelle chez les jeunes enfants. Il se caractérise par une résistance à la chimiothérapie possiblement en partie dû à la présence de cellules initiatrices de tumeurs (TICs). Des études ont mis en évidence le rôle de CD133 comme un marqueur des TICs dans divers types de cancers. Les buts de notre travail étaient d’abord de démontrer les vertus de TICs des cellules exprimant CD133 et ensuite, en utilisant une analyse globale du génome avec des polymorphismes nucléotidiques simples (SNPs), d’effectuer une analyse différentielle entre les TICs et les autres cellules du NB afin d’en identifier les anomalies génétiques spécifiques. Des lignées cellulaires de NB ont été triées par cytométrie de flux afin d’obtenir deux populations: une enrichie en CD133 (CD133high), l’autre faible en CD133 (CD133low). Afin de déterminer si ces populations cellulaires présentent des propriétés de TICs, des essais sur les neurosphères, les colonies en agar mou et les injections orthotopiques de 500 cellules sélectionnées dans 11 souris ont été réalisées. Après une isolation de l’ADN des populations sélectionnées, nous avons effectué une analyse génotypique par SNP utilisant les puces « Affymetrix Genome-Wide Human SNP Array 6.0 ». Pour vérifier l’expression des gènes identifiés, des Western Blots ont été réalisés. Nos résultats ont démontré que la population CD133 avait des propriétés de TICs in vitro et in vivo. L’analyse génotypique différentielle a permis d’identifier deux régions communes (16p13.3 and 19p13.3) dans la population CD133high ayant des gains et deux autres régions (16q12.1 and 21q21.3) dans la population CD133low possédant des pertes d’hétérozygoties (LOH). Aucune perte n’a été observée. Parmi les gènes étudiés, l’expression protéique d’éphrine-A2 était corrélée à celle de CD133 dans 6 tumeurs et 2 lignées cellulaires de NB. De plus, l’augmentation de la concentration d’anticorps anti-éphrine-A2 dans le milieu diminue la taille des neurosphères. Ainsi, la population CD133high, qui a des vertus de TICs, possède des caractéristiques génotypiques différentes par rapport à celle CD133low. La présence d’éphrine-A2 dans les cellules exprimant CD133 souligne son importance dans le développement des TICs. Ces résultats suggèrent la présence de potentielle cible pour de nouvelles thérapeutiques ciblant les TICs mise en évidence par l’étude génomique. / Neuroblastoma (NB) is the most common and deadly extracranial solid tumor of childhood characterized by a resistance to chemotherapy possibly due to the presence of tumor initiating cells (TICs). Studies showed the role of CD133 as a marker of TICs in various types of cancers. Our goals were first to demonstrate the stemness of TICs expressing CD133 and then, using a global genomic analysis with single nucleotide polymorphism (SNPs), to perform a differential analysis between TICs and other cells of NB to identify the specific genetic abnormalities. NB cell lines were sorted by flow cytometry to obtain two populations: one enriched in CD133 (CD133high), the other low in CD133 (CD133low). To determine whether these cell populations have TICs properties, we test the ability of cells to form either neurosphères or, colonies in soft agar and we also test their carcinogenic properties by orthotopic injections of 500 selected cells in 11 mice. After a DNA extraction on selected populations, a differential genotyping analysis has been made with Affymetrix Genome-Wide Human SNP Array 6.0. To verify the expression of the genes identified, Western blots had been made. Our results have demonstrated that CD133high population presented TICs properties in vitro and in vivo. The differential genotyping analysis allowed identifying two gains common regions (16p13.3 and 19p13.3) in CD133high population and two others loss of heterozygosity (LOH) (16q12.1 and 21q21.3) in CD133low population . No losses were observed. Among the genes studied, ephrin-A2 protein expression was correlated to CD133 expression in 6 NB tumors and 2 NB cell lines. Also, ephrin-A2’s increased concentration influenced the neurospheres by decreasing their size. Thereby, CD133high population, which had TICs properties, possess different genotyping characteristics compared to CD133low population. The presence of ephrine-A2 in cells expressing CD133 emphasizes its importance in the development of TICs. These results suggest the presence of potential target for new therapies targeting the TICs demonstrated by the genomic study.

The primary aim of this study was to determine the effectiveness of array-based technology for detecting and quantifying the presence of mosaicism. This aim was achieved by studying individuals having mosaicism for Down syndrome. SNP arrays were performed on 13 samples from individuals with mosaicism for trisomy 21, 13 samples from individuals with normal chromosome 21complements (negative controls) and 5 samples from individuals with full or partial trisomy 21 (positive controls). In addition, BAC arrays were processed on 6 samples from individuals with mosaicism for trisomy 21, 3 negative controls and 1 positive control. These studies have shown that array-based technology is effective for detecting mosaicism that is present in 20% or more cells with the results being consistent for both platforms. We also demonstrated the strength of array-based technology to identify previously unrecognized chromosomal mosaicism. A second aim of this study was to gain insight regarding the effect that trisomy 21 has on telomere attrition and the frequency of chromosomal instability. This study provides the first reported measure of both chromosome-specific telomere lengths and the frequency of acquired chromosome abnormalities in trisomic cells and isogenic euploid cells obtained from the same individuals. A chromosome-specific telomere length assay was performed on lymphocytes obtained from 24 young individuals with mosaicism for Down syndrome. While differences in overall telomere signal intensities were observed between the euploid and trisomic cells within a person, strikingly similar profiles for chromosome-specific telomere intensities were observed between the cell types within a person. Analyses were also completed on lymphoblast samples obtained from 8 older individuals with mosaicism for Down syndrome, including 5 individuals without dementia and 3 individuals with dementia. In the older study subjects, a significant inverse correlation was observed between telomere length and the frequency of micronuclei, suggesting that telomeric shortening is leading to an increased frequency of chromosomal instability, possibly through dicentric chromosome formation. However, further studies of more individuals, especially additional analyses of older individuals, are needed. These future studies may help to identify genomic regions of interest and serve to inform investigators of potential candidate genes in the etiology of dementia.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Markers on the non-recombining region of chromosome Y is a useful tool for study of diversity between populations. SNPs are the most commom polymorphisms in human genome. Mutation rate of SNPs is very low and so they may be used as genetic markers in evolutionary and population studies. We have analyzed 205 unrelated men from 11 Sub-Saharan Fulani's subpopulations. Fulani are an ethnic group of people spread over many countries, mainly in West Africa. Our samples are from Tindangou area, Banfora area (Burkina Faso), Bongor area, Linia area (Chad), Diafarabé area (Mali), Tcheboua area (Cameroon), Banfora area, Diffa area, Zinder area, Ader area and Abalak area (Niger). Using kit Signet Y-SNP Identification Systems and Luminex instrument with LabMAP Luminex Technology we detected particular Y chromosome's SNPs. LabMAP Luminex Technology is universal array platform, which as a probe using fluorescent polystyrene microspheres. We have observed 12 different haplogroups. Haplogroup E, which is typical African haplogroups, is determined with derivated allele in polymorfism M96. We have detected haplogroup E in maximum of 89,3% in the Fulani's subpopulations. In 7,8% we have detected haplogroup R, which is characteristic of populations in the Euroasia. Gene pool of Fulani's population is influenced with a...

This thesis analyze institutional and political circumstances, which allowed and influenced the Scottich referendum of independence in september 2014. It discribes political development and situation in Scottich Parliament and Government from the creation of devolution to 2014. As a metodological tools this thesis use theories of Institutionalism, Multi - level governance and performance politics. It focuses on the pre-referendum debate as well. Main sources are official reports of departments of Her Majesty Government and White paper of Scottish Goverment for the referenda, both are combined with reports from BBC. It shows limitations and extentions of institutional influence and reach towards independence. Key words: Great Britain, Scottish Parliament, Scottish Government, SNP, Alex Salmond, referendum,BBC

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2017-10-04T22:20:39Z No. of bitstreams: 1 Tese Soniane Costa.pdf: 5470162 bytes, checksum: c446c8cec1a4893eca8260700896103a (MD5) / Made available in DSpace on 2017-10-04T22:20:39Z (GMT). No. of bitstreams: 1 Tese Soniane Costa.pdf: 5470162 bytes, checksum: c446c8cec1a4893eca8260700896103a (MD5) Previous issue date: 2017-03-24 / Funda??o de Amparo ? Pesquisa do Estado da Bahia - FAPEB / The decline of guava is a complex disease, which causes progressive galls in guava roots parasitized by Meloidogyne enterolobii. The objective of the present study is to study the genetic divergence in guava and ara?azeiros accessions by means of SNPs markers developed for Eucalyptus to serve as a subsidy for activities of genetic resources and improvement of guava, such as the broad genomic association and to estimate the number of genes involved in resistance to M. enterolobii, using F2 population of Psidium guajava and P. guineense hybrid.In the evaluation of the genetic diversity of Psidium accessions, presented in chapter I, the transferability of Eucalyptus SNPs to Psidium for application in analyzes of genetic divergence and other applications, including studies of genome association. The segregation results and broad sense heritability estimates in population F2, presented in chapter II, support dominance model controlled by two genes, with epistatic effects, and the presence of only one dominant allele conditions the resistance of the hybrid of P. guajava x P. guineense for M. enterolobii. New hybrids of P. guajava with other accessions of wild Psidium should be developed and evaluated in order to increase the sources of resistance to the pathogen, allowing effective control of the same in commercial areas of guava. Seven markers associated with resistance to Meloidogyne enterolobii in Psidium species presented in Chapter III were identified.The results also suggest the existence of different sources of resistance to the nematode, since several SNPs were identified on chromosome 3 of Eucalyptus. / O decl?nio da goiabeira ? uma doen?a complexa, que causa a podrid?o progressiva das ra?zes das goiabeiras parasitadas por Meloidogyneenterolobii. O objetivo do presente estudo ? estudar a diverg?ncia gen?tica em acessos de goiabeira e ara?azeiros por meio de marcadores SNPs (Polimorfismo de nucleot?deo ?nico) desenvolvidos para Eucalyptus, que servir?o de subs?dio as atividades de recursos gen?ticos e melhoramento da goiabeira, bem como a associa??o gen?mica ampla (GWAS), e estimar o n?mero de genes envolvidos na resist?ncia a M. enterolobii, tendo como refer?ncia a segrega??o em popula??o F2 de h?brido de Psidium guajava x P. guineense. Na avalia??o da diversidade gen?tica dos acessos de Psidium, apresentado no cap?tulo I, relata-se a transferibilidade de SNPs de Eucalyptus para Psidium, estes podem ser utilizados em an?lises de diverg?ncia gen?tica e outras aplica??es, incluindo estudos de associa??o do genoma. Os resultados de segrega??oe as estimativas de herdabilidade no sentido amplo em popula??o F2, apresentado no cap?tulo II, suportam modelo de resist?ncia dominante controlada por dois genes, com efeitos epist?ticos, sendo que, a presen?a de apenas um alelo dominante condiciona a resist?ncia do h?brido de P. guajava x P. guineensepara M.enterolobii. Novos h?bridos de P. guajava com outros acessos de Psidium silvestres devem ser desenvolvidos e avaliados de forma a aumentar as fontes de resist?ncia ao pat?geno, possibilitando efetivo controle do mesmo em ?reas comerciais de goiabeira. Foram identificados sete marcadores associados ? resist?ncia a Meloidogyne enterolobii em esp?cies de Psidium apresentado no cap?tulo III. Os resultados sugerem ainda a exist?ncia de diferentes fontes de resist?ncia ao nematoide, pois foram identificados v?rios SNPs no cromossomo 3 de Eucalyptus.