Dissertations / Theses: 'Studio genetico'

1

Rossi, Marco <1979&gt. "Studio clinico e genetico di nuove malattie ereditarie del bovino." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2008. http://amsdottorato.unibo.it/739/1/Tesi_Rossi_Marco.pdf.

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2

Rossi, Marco <1979&gt. "Studio clinico e genetico di nuove malattie ereditarie del bovino." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2008. http://amsdottorato.unibo.it/739/.

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3

Scarparo, Pamela. "Studio dei fattori di rischio genetico nella Trombocitopenia da Eparina." Doctoral thesis, Università degli studi di Padova, 2010. http://hdl.handle.net/11577/3427560.

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Heparin induced thrombocytopenia (HIT) is a rare and life threatening complication of heparin therapy, characterized by great reduction of platelet’s count, that may be complicated in 30-50% of cases by a paradoxical thrombotic syndrome (HITT), either arterial or venous. As reported by major clinical series in the literature, about 1% of patients receiving unfractionated heparin (UFH) or low molecular weight heparin (LMWH) develop IgG-mediated heparin-induced thrombocytopenia. HIT pathogenesis can be due to antibodies (Abs) formation, which are direct against a complex formed by Heparin (H) and PF4. H/PF4 antibodies bind the platelets receptor FcγRIIA, inducing platelet activation and aggregation, by modulating the affinity of GpIIb-IIIa for fibrinogen and induce release of platelet granules. PECAM-1 has been shown to negatively regulate platelet activation downstream FcγRIIA, but the mechanism of this process is still unclear. Moreover the receptor FcγRIIIA, expressed on macrophages, seems to play an important role on the clearance of IgG-coated platelets. However HIT and HITT does not develop in all patients, different factors may play a role in the onset of clinical syndrome, like: heparin type, antibodies functionality, individual genetic variations (genetic polymorphisms), and in vivo cofactors, such as local trauma. In particular we have studied four different polymorphisms, located in the four receptor previously described: FcγRIIA-H131R, GpIIb/IIIa-HPA1, PECAM1-L125V (in linkage disequilibrium with S563N and R670G) and FcγRIIIA-F158V. The aim of the present study is to understand if polymorphisms of platelets receptors may influence the clinical features of patients who develop H/PF4/Abs, combining immunological, functional and genetic studies. In particular our aim is to discover why some patients with Abs develop HIT syndrome, with or without thrombotic complications, while other not. First we used ELISA commercial test to determine the presence of H/PF4 antibodies in the plasma samples, than we used HIPA as functional test to understand whether the antibodies found were or not able to activate donor’s platelets. Using the 4T score for HIT and the result of immunological and functional test, we define three groups of patients: 51 H/PF4/Ab patients, with antibodies not able to activate platelets and without thrombocytopenia. 50 HIT patients with antibodies able to activate platelets and thrombocytopenia 53 HITT patients with antibodies able to activate platelets, thrombocytopenia and thrombosis. We used molecular biology techniques to determine the genotype for the four polymorphisms previously described, in particular: for FcγRIIA-H131R, PECAM1-L125V and FcγRIIIA-F158V we perform an allele-specific PCR, and for HPA1 polymorphism we set an allelic discrimination real time PCR using taqman probes. Hardy–Weinberg equilibrium was tested for each polymorphism. Allele or genotype frequencies between patients and controls were compared by the χ2 test. Than we use Multiple Regression analysis for multiple confront between different polymorphisms. Comparing the polymorphisms frequencies between the three patients groups (H/PF4/Ab;HIT;HITT) we found some significative differences, in particular between HIT and HITT group. The frequency of the R/R131 genotype (FcγRIIA) is increased in HITT group (p<0,05), the same for the a/b genotype frequency (GpIIIa-HPA1) (p<0,05). The frequency of the polymorphic setting VNG (V/V125-N/N563-G/G670) for the PECAM receptor is also increased in the HITT group compare with the other two groups, but the p value is not statistically significative. We found that R/R131 associated with a/b-HPA1 have a relation with HITT but with a p-value (0,07) near significance. There were no great differences between the genotypes of the four polymorphisms comparing HIT group with H/PF4/Ab group. We suppose that platelets R/R for the receptor FcγRIIA, cleared less efficiently than H/H ones, can circulate longer enhancing the risk for HIT thrombosis. We can suggest that the setting VNG for PECAM1 can have less inhibitory activity on FcγRIIA receptor. Furthermore the b allele for the HPA1 polymorphism is a known risk factor for thrombosis. Together these polymorphisms could create a genetic setting that could enhance thrombotic complications in HIT pathology. We found a p value = 0,07, near significance, for the association of R/R and a/b with HITT (Multiple regression analysis), we think that increasing our cases we could obtain a significant association (p value < 0,05).
La piastrinopenia indotta da eparina (HIT) è una rara e grave complicanza della terapia eparinica, caratterizzata da una marcata riduzione del numero delle piastrine (trombocitopenia) che può esere complicata nel 30-50% dei casi da episodi trombotici sia venosi che arteriosi (HITT). La letteratura al riguardo riporta che circa l’1% dei pazienti che ricevono Eparina standard o a basso peso molecolare sviluppano una trombocitopenia da eparina IgG-mediata. L’eziologia della HIT dipende dalla formazione di anticorpi (Abs) rivolti contro un complesso formato da eparina (H), a dosi terapeutiche, e fattore piastrinico 4 (PF4). Gli immunocomplessi H/PF4/Abs che si legano al recettore piastrinico FcγRIIA, inducono attivazione piastrinica e aggregazione, modulando l’affinità della GpIIb/IIIa per il fibrinogeno. PECAM1 regola negativamente l’attivazione piastrinica mediata da FcγRIIA, anche se i meccanismi di tale inibizione non sono ancora stati del tutto chiariti. Le piastrine ricoperte da IgG sono poi riconosciute e rimosse dai macrofagi splenici per mezzo del recettore FcγRIIIA. La HIT e la HITT non si sviluppano in tutti i pazienti che ricevano eparina, numerosi fattori potrebbero giocare un ruolo nella patogenesi: il tipo di eparina utilizzata, l’eterogeneità degli anticorpi, variazioni genetiche interindividuali (polimorfismi) e altri cofattori come stati infiammatori del paziente. In questo studio si sono presi in considerazione in particolare quattro differenti polimorfismi genetici che si trovano sui recettori precedentemente citati: FcγRIIA-H131R, GpIIb/IIIa-HPA1, PECAM1-L125V (in linkage disequilibrium con S563N e R670G) e FcγRIIIA-F158V. L’obiettivo del presente lavoro, combinando studi immunologici, funzionali e genetici, è determinare se i polimorfismi genetici di alcuni recettori piastrinici e monocitari siano implicati nell’insorgenza della HIT o nelle complicanze trombotiche di questa patologia, a parità di presenza di anticorpi E’ stato utilizzato un test ELISA per determinare la presenza degli anticorpi H/PF4 nel plasma dei pazienti e successivamente un test HIPA per determinare se tali anticorpi fossero funzionalmente in grado di attivare le piastrine di donatori in vitro. Utilizzando lo score clinico delle 4T e i risultati dei test immunologico e funzionale, sono stati definiti tre gruppi di pazienti: 51 pazienti H/PF4/Ab, con anticorpi non in grado di attivare le piastrine, senza trombocitopenia. 50 pazienti HIT, con anticorpi funzionalmente in grado di attivare le piastrine e trombocitopenia. 53 pazienti HITT, con anticorpi funzionalmente in grado di attivare le piastrine, trombocitopenia e trombosi. Per determinare il genotipo di tutti i pazienti per i quattro polimorfismi in analisi, sono state utilizzate diverse tecniche di biologia molecolare: per FcγRIIA-H131R, PECAM1-L125V e FcγRIIIA-F158V è stata messa a punto una PCR allele-specifica, per il polimorfismo HPA1, invece, una discriminazione allelica in real time PCR, utilizzando sonde Taqman. Le differenze tra le frequenze alleliche e genotipiche dei tre gruppi di pazienti sono state analizzate con il test statistico del χ2 . Successivamente è stata utilizzata una Multiple Regression Analysis per il confronto tra polimorfismi multipli. Prima di procedere all’analisi statistica è stato testato l’equilibrio di Hardy-Weinberg per ogni polimorfismo. Sono emerse alcune differenze significative confrontando le frequenze dei polimorfismi tra i tre gruppi di pazienti (H/PF4/Ab;HIT;HITT), in particolare tra il gruppo HIT e HITT. La frequenza del genotipo R/R (FcγRIIA) è aumentata nel gruppo HITT (p<0,05), così come la frequenza del genotipo a/b (GpIIIa-HPA1) (p<0,05). Anche la frequenza del setting polimorfico VNG (V/V125-N/N563-G/G670) per il recettore PECAM1 è aumentata nel gruppo HITT rispetto agli altri gruppi, anche se non in modo statisticamente significativo. L’analisi multivariata ha mostrato che l’associazione tra R/R131 e a/b-HPA1 è in relazione con il gruppo HITT, con una p vicina alla significatività statistica (0,07). Non sono state invece rilevate differenze significative per i quattro polimorfismi analizzati tra il gruppo HIT e il gruppo H/PF4/Ab. Possiamo quindi supporre che le piastrine R/R (per il recettore FcγRIIA), eliminate in modo meno efficace delle H/H, rimangano in circolo più a lungo, portando ad un rischio trombotico maggiore nella HIT; tale rischio è aumentato anche dall’allele b di HPA1 (polimorfismo protrombotico per diverse patologie). Si può inoltre ipotizzare che il setting VNG per PECAM 1 possa avere un minor effetto inibitorio sul recettore FcγRIIA. Insieme questi polimorfismi potrebbero creare un setting genetico che porti una maggior frequenza trombotica nella Trombocitopenia da eparina. Per l’associazione dei genotipi R/R e a/b con la HITT, abbiamo ottenuto un valore p=0,07 vicino alla significatività (Multivariate regression analysis); possiamo quindi supporre che aumentando la nostra casistica potremo riuscire ad ottenere un’associazione statisticamente significativa (p<0,05).

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4

Portillo, Ivan <1979&gt. "Studio genetico ed epidemiologico su Erysiphe necator agente eziologico dell'Oidio della vite." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2789/1/Portillo_Ivan_Tesi.pdf.

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The objective was to analyse population structure and to determine genetic diversity of Erysiphe necator (syn. Uncinula necator) populations obtained from some vineyards located in the South-East Po valley (Italy). Powdery mildew is one of the most important fungal diseases of grapes (Vitis vinifera L.) throughout the world. The causal agent is the haploid, heterothallic ascomycete E. necator. It is an obligate biotrophic fungus and it can be found only on green organs of plants belonging to the family Vitaceae. For this pathogen, two sympatric populations (groups A and B) have been described in Europe and Australia. The two genetic groups differ at multiple genetic loci and previous studies reported a lack of interfertility among isolates of the two groups. There are now several well documented examples of plant pathogen species, such as Leptosphaeria maculans, Gaeumannomyces graminis var. tritici, Botrytis cinerea and Erysiphe syringae, which are indeed composed of genetically differentiated clades, that have led to the description of new groups or even new species. Several studies have suggested that genetic E. necator group A and B correlated with ecological features of the pathogen; some researchers proposed that group A isolates over-winter as resting mycelium within dormant buds, and in spring originate infected shoots, known as Flag shoots, while group B isolates would survive as ascospores in overwintering cleistothecia. However, the association between genetic groups and mode of over-wintering has been challenged by recent studies reporting that flag-shoot may be originated indifferently by group A or group B isolate. Previous studies observed a strong association between the levels of disease severity at the end of the growing season and the initial compositions of E. necator populations in commercial vineyards. The frequencies of E. necator genetic groups vary considerably among vineyards, and the two groups may coexist in the same vineyard. This finding suggests that we need more information on the genetics and epidemiology of E. necator for optimize the crop management In this study we monitored E. necator populations in different vineyards in Emilia – Romagna region (Italy), where the pathogen overwinters both as flagshoots and as cleistothecia. During the grape growing season, symptomatic leaves were sampled early in the growing season and both leaves and berries later during the epidemic growth of the disease. From each sample, single-conidial isolate was obtained. Each isolates was grown on V. vinifera leaf cv. Primitivo and after harvesting the mycelium, the DNA was purified and used as template for PCR amplification with SCAR primers (Sequences Characterised Amplified Region ), -tubulin, IGS sequences and Microsatellite markers (SSR). Amplified DNA from b-tubulin and IGS loci was digested with AciI and XhoI restriction enzymes, respectively, to show single-nucleotide polymorphisms specific for the two genetic groups. The results obtained indicated that SCAR primers are not useful to study the epidemiology. of E. necator conversely the b-tubulin IGS sequences and SSR. Summarize the results obtained with b-tubulin, IGS sequences, in treated vineyards we have found individuals of group B along all grape growing season, whereas in the untreated vineyard individuals of the two genetic groups A and B coexisted throughout the season, with no significant change of their frequency. DNA amplified from ascospores of single cleistothecia showed the presence of markers diagnostic for either groups A and B and were seldom observed also the coexistence of both groups within a claistothecium. These results indicate that individuals of the two groups mated in nature and were able to produced ascospores. With SSR we showed the possibility of recombination between A and B groups in field isolates. During winter, cleistothecia were collected repeatedly in the same vineyards sampling leaves fallen on ground, exfoliating bark from trunks, and from soil. From each substrate, was assess the percentage of cleistothecia containing viable ascospores. Our results confirmed that cleisthotecia contained viable ascospores, therefore they have the potential to be an additional and important source of primary inoculum in Emilia-Romagna vineyards.

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5

Portillo, Ivan <1979&gt. "Studio genetico ed epidemiologico su Erysiphe necator agente eziologico dell'Oidio della vite." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2789/.

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The objective was to analyse population structure and to determine genetic diversity of Erysiphe necator (syn. Uncinula necator) populations obtained from some vineyards located in the South-East Po valley (Italy). Powdery mildew is one of the most important fungal diseases of grapes (Vitis vinifera L.) throughout the world. The causal agent is the haploid, heterothallic ascomycete E. necator. It is an obligate biotrophic fungus and it can be found only on green organs of plants belonging to the family Vitaceae. For this pathogen, two sympatric populations (groups A and B) have been described in Europe and Australia. The two genetic groups differ at multiple genetic loci and previous studies reported a lack of interfertility among isolates of the two groups. There are now several well documented examples of plant pathogen species, such as Leptosphaeria maculans, Gaeumannomyces graminis var. tritici, Botrytis cinerea and Erysiphe syringae, which are indeed composed of genetically differentiated clades, that have led to the description of new groups or even new species. Several studies have suggested that genetic E. necator group A and B correlated with ecological features of the pathogen; some researchers proposed that group A isolates over-winter as resting mycelium within dormant buds, and in spring originate infected shoots, known as Flag shoots, while group B isolates would survive as ascospores in overwintering cleistothecia. However, the association between genetic groups and mode of over-wintering has been challenged by recent studies reporting that flag-shoot may be originated indifferently by group A or group B isolate. Previous studies observed a strong association between the levels of disease severity at the end of the growing season and the initial compositions of E. necator populations in commercial vineyards. The frequencies of E. necator genetic groups vary considerably among vineyards, and the two groups may coexist in the same vineyard. This finding suggests that we need more information on the genetics and epidemiology of E. necator for optimize the crop management In this study we monitored E. necator populations in different vineyards in Emilia – Romagna region (Italy), where the pathogen overwinters both as flagshoots and as cleistothecia. During the grape growing season, symptomatic leaves were sampled early in the growing season and both leaves and berries later during the epidemic growth of the disease. From each sample, single-conidial isolate was obtained. Each isolates was grown on V. vinifera leaf cv. Primitivo and after harvesting the mycelium, the DNA was purified and used as template for PCR amplification with SCAR primers (Sequences Characterised Amplified Region ), -tubulin, IGS sequences and Microsatellite markers (SSR). Amplified DNA from b-tubulin and IGS loci was digested with AciI and XhoI restriction enzymes, respectively, to show single-nucleotide polymorphisms specific for the two genetic groups. The results obtained indicated that SCAR primers are not useful to study the epidemiology. of E. necator conversely the b-tubulin IGS sequences and SSR. Summarize the results obtained with b-tubulin, IGS sequences, in treated vineyards we have found individuals of group B along all grape growing season, whereas in the untreated vineyard individuals of the two genetic groups A and B coexisted throughout the season, with no significant change of their frequency. DNA amplified from ascospores of single cleistothecia showed the presence of markers diagnostic for either groups A and B and were seldom observed also the coexistence of both groups within a claistothecium. These results indicate that individuals of the two groups mated in nature and were able to produced ascospores. With SSR we showed the possibility of recombination between A and B groups in field isolates. During winter, cleistothecia were collected repeatedly in the same vineyards sampling leaves fallen on ground, exfoliating bark from trunks, and from soil. From each substrate, was assess the percentage of cleistothecia containing viable ascospores. Our results confirmed that cleisthotecia contained viable ascospores, therefore they have the potential to be an additional and important source of primary inoculum in Emilia-Romagna vineyards.

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6

MONTIERI, PASQUA. "Studio clinico e genetico-molecolare in paraparesi spastiche ereditarie ad esordio precoce." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2010. http://hdl.handle.net/2108/1178.

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Le paraparesi spastiche ereditarie (HSPs) rappresentano un gruppo eterogeneo di disturbi neurologici con interessamento del motoneurone superiore (UMND) la cui caratteristica clinica prevalente è la spasticità e l’ipostenia piramidale degli arti inferiori. HSP può essere classificata clinicamente in accordo alla modalità di ereditarietà, età di insorgenza o il fenotipo clinico. Questo disturbo è ereditato più spesso secondo la modalità autosomica dominante, meno frequentemente con ereditarietà autosomica recessiva e raramente secondo modalità di trasmissione X-linked. Pochi studi epidemiologici sono stati condotti sulle HSPs, ma la prevalenza è stimata tra 3-10:100 000, di cui le forme di HSP ad ereditarietà autosomica dominante costituiscono circa l’80% dei casi nei paesi Occidentali (con le forme più comuni in SPG4 e SPG3A). A dispetto di una eterogeneità genetica con 46 loci genetici (di cui 5 riservati) e 20 geni identificati, è più difficile separare le diverse entità nosografiche sul piano clinico. Questa uniformità fenotipica forse riflette un pathway finale comune nei processi della malattia da cui esita una degenerazione retrograda assonale dei tratti cortico-spinali e delle colonne posteriori. Studi recenti hanno permesso di identificare i geni di circa la metà di questi loci, suggerendo un’interruzione a più livelli come possibile causa di danno assonale: nel trasporto assonale e nella regolazione citoscheletrica, nelle funzioni mitocondriali, nel mantenimento e assemblaggio della mielina e nella migrazione neuronale. Questo studio ha l’obiettivo di effettuare un’indagine genetico-molecolare di famiglie affette da forme ad esordio precoce di ADHSP, ARHSP e casi apparentemente sporadici, sia con fenotipo clinico “non complicato” che “complicato”. Uno studio di linkage a 2 punti è stato effettuato in una famiglia ADHSP per 8 loci noti autosomico dominanti (SPG3A, SPG4, SPG6, SPG8, SPG10, SPG12, SPG13, SPG31). I risultati indicano che il disturbo in questa famiglia era legato al locus noto SPG3A. Attraverso il sequenziamento diretto degli esoni codificanti e delle regioni fiancheggianti gli introni del gene SPG3A è stata individuata una nuova mutazione missenso nell’esone 12 al nucleotide c.1246 C>T (p.R416C). La Arginina 416 è altamente conservata tra le specie. Ho analizzato i 3 geni HSP ad esordio precoce, SPG3A, SPG5A and SPG42, attraverso l’analisi di sequenziamento diretto nel restante campione composto dai probandi di 9 famiglie non imparentate autosomico dominanti, 3 autosomico recessive e 18 pazienti con paraplegia spastica apparentemente sporadica, con forme pure e complesse di malattia. L’analisi MLPA effettuata nei pazienti candidati per SPG3A (kit P165-HSP-B1, MRC-Holland) non ha individuato nessun cambiamento patogenetico. Attraverso il sequenziamento diretto ho evidenziato cinque mutazioni, di cui tre nuove, una che segrega in due famiglie non imparentate e le altre in casi apparentemente sporadici. Quattro di queste mutazioni sono missenso: c.1246 C>T (p.R416C) e c.1243 C>T (p.R415W) nel gene SPG3A, c.995 T>C (p.F264S) e c.344C>T (p.S115F) nel gene SPG5A. Una è un’inserzione che esita in un frameshift con l’introduzione di uno stop prematuro al codone C-terminale della proteina: c.1362insT (p.A453CfsX470) nel gene SPG5A. Nessun cambio patogenetico è stato individuato nel gene SPG42. È interessante che sia l’esordio precoce sia possibili fenomeni di anticipazione genetica siano stati osservati nelle due famiglie che presentano la mutazione p.R416C in ATL1. Questi risultati confermano i dati osservati in letteratura per cui i geni SPG3A e SPG5A mostrano un’alta frequenza mutazionale nelle forme ad esordio precoce di ADHSP e ARHSP (rispettivamente il 20 e il 7%) e nei casi apparentemente sporadici.
The hereditary spastic paraplegias (HSPs) are an etiologically heterogeneous group of neurological disorders which results from the selective degeneration of upper motor neurons (UMNs), of which key diagnostic clinical ﬁndings are spasticity and pyramidal weakness of lower limbs. HSP can be classified clinically according to mode of inheritance, age of onset or clinical phenotype. The disorder is inherited most often as an autosomal dominant trait, with autosomal recessive and X-linked inheritance occurring rarely and very rarely, respectively. Few epidemiological studies of HSP have been done, but prevalence is estimated at 3–10 cases per 100 000 population in western countries, in which approximately ADHSPs account for 80% of all HSPs (with SPG4 and SPG3A being the most common forms). Although genetically diverse with 46 genetic loci for HSP (of which 5 reserved) and 20 genes identified, it is often difficult to separate the disorders on clinical grounds. This phenotypic uniformity perhaps reflects a final common pathway in the disease process which results in degeneration of the corticospinal tracts and posterior columnes. Advances in recent years identifying the genes at half of these loci have suggested that disruption in any of the following: axonal transport, cytoskeleton regulation, mitochondrial function, myelin maintenance and assembly and neuronal migration may cause axonal damage in HSP. This study aims at genetic-molecular investigation of families affected by early onset forms of ADHSP, ARHSP, and apparently sporadic cases, as with “uncomplicated” or “complicated” clinical phenotype. Two point linkage analyses were performed in a ADHSP family to 8 known autosomal dominant loci (SPG3A, SPG4, SPG6, SPG8, SPG10, SPG12, SPG13, SPG31). The data indicated that the disorder in this kindred was linked to the known HSP locus SPG3A. Sequencing the SPG3A gene coding exons and ﬂanking intronic regions disclosed a novel heterozygous missense mutation in exon 12 at nucleotide c.1246 C>T (p.Arg416Cys). The Arginine 416 is highly conserved among species. I analysed the coding region and exon–intron boundaries of 3 “early onset” HSP genes, SPG3A, SPG5A and SPG42, by direct sequencing in a total serie of 9 unrelated autosomal dominant and 3 autosomal recessive hereditary spastic paraplegia index patients, and in 18 unrelated index patients with apparently sporadic hereditary spastic paraplegia, manifesting either pure or complex forms of the disease. Multiplex ligation-dependent probe ampliﬁcation performed in SPG3A candidate patients (probe mixtures P165-HSP-B1, MRC-Holland, The Netherlands) did not detect any pathogenic changes. By direct sequencing I identiﬁed five, including three novel, mutations, one segregating in two unrelated families, the others in apparently sporadic cases. Four of these mutations were missense: c.1246 C>T (p.R416C) and c.1243 C>T (p.R415W) in SPG3A gene, c. 995 T>C (p.F264S) and c.344C>T (p.S115F) in SPG5A gene. One resulted in a frameshift with the introduction of a premature stop codon at the C-terminal of the protein: c.1362insT (p.A453CfsX470) in SPG5A gene. Any pathogenic changes was detected in SPG42 gene. Interestingly, both early-age onset and possible anticipatory phenomena were observed in the two families showing mutation p.R416C in ATL1. These results confirm data observed in literature according to which the SPG3A and SPG5A genes show an high mutational frequency in early onset forms of ADHSP and ARHSP (respectively 20% and 7%) and apparently sporadic cases.

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KHAN, MOHAMMAD FAISAL JAMAL. "Studio genetico, epigenetico e istologico delle schisi orofacciali: influenza del sesso nella predisposizione alla malattia." Doctoral thesis, Università degli studi di Ferrara, 2017. http://hdl.handle.net/11392/2488255.

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Le Schisi Orofacciali (OFC), comprendenti le labio/Palatoschisi (CL/P) e le Palatoschisi (CPO) sono quarte più frequenti malformazioni congenite. Si presentano prevalentemente in forma non-sindromica (nsCL/P e nsCPO), con eziologia multifattoriale. La loro prevalenza alla nascita varia a seconda del sesso: le CL/P sono più comuni tra i maschi, mentre le CP sono più comuni tra le femmine. Nel presente studio abbiamo esplorato il ruolo delle differenze di sesso nella eziologia delle OFC non sindromiche (nsOFC), con indagini genetiche, epigenetiche ed istologiche. Lo studio genetico ha utilizzato triadi genitori-figlio affetto degli studi EUROCRAN e ITALCLEFT. Abbiamo analizzato due varianti comuni del gene TGFA (Transforming growth factor α) (TGFA/Taq1/4nt del e TGFA/11nt ins/del), osservando che la variante TGFA/Taq1/4nt del associa a rischoi di nsCL/P in modo opposto nei maschi rispetto alle femmine.Lo studio genetico è stato esteso a indagini specifiche per le forme di nsCPO studiando varianti funzionali nei geni LOXL3 (Lysyl oxidase like 3) e GRHL3 (Grainyhead like 3). I risultati hanno evidenziato una significativa segregazione asimmetrica degli alleli minori della variante di GRHL3 ma non di LOXL3. L’associazione è risultata essere influenzata dal genere del figlio affetto, con un rischio di nsCPO aumentato di tre volte negli omozigoti recessivi ed significativamente associata alla mancata supplementazione in gravidanza con acido folico o alla esposizione al fumo di tabacco.L'interazione dei geni fetali con l'ambiente intrauterino materno è un elemento critico che condiziona il corretto sviluppo del feto, ed alterate combinazioni genotipo-ambiente possono portare ad anomalie di sviluppo, quali i difetti di chiusura del tubo neurale, patologie cardiache congenite e nsOFC. Utilizzando una biobanca di campioni di tessuto labiale da casi di nsCL/P, abbiamo eseguito per la prima volta indagini epigenetiche analizzando i livelli di metilazione genomica globale (promotore di LINE-1) nei tessuti adiacenti alla schisi. Abbiamo osservato un significativo aumento di metilazione sul lato mediale del labbro superiore rispetto al lato laterale. La differenza è risultata particolarmente evidente nei maschi nati da madri che durante la gravidanza non hanno praticato la supplementazione con acido folico.I risultati di questo studio, seppur preliminari, evidenziano l'importanza dell’epigenetica nell’eziologia delle nsCL/P ed aprono la strada a nuove e più estese indagini.Utilizzando la biobanca tissutale abbiamo analizzato le dimensioni delle fibre muscolari dell’orbicularis oris (OO) in casi di nsCL/P. Non abbiamo osservato differenze tra i due lati della schisi. Tuttavia, il lato mediale nei maschi è risultato con fibre di diametro significativamente minore rispetto alle femmine. L’indagine non ha rilevato alcuna significativa differenza di diametro tra le fibre muscolari del lato mediale e quelle del lato laterale della schisi. Tuttavia, confrontando il valori rilevati nei due sessi, è risultato che nei maschi la sezione delle fibre muscolari nel lato mediale è significativamente più piccola rispetto a quella osservata nelle femmine.In conclusione, entrambi gli studi genetici in triadi nsOFC hanno prodotto risultati di associazione sesso-specifica, dando enfasi al ruolo del dimorfismo sessuale negli studi di associazione genetica di nsOFC. I risultati dello studio epigenetico evidenziano livelli di metilazione influenzati dal sesso e dipendenti dalla supplementazione con acido folico. Infine, l’analisi del diametro delle fibre muscolari del OO nei due sessi consolida ulteriormente le differenze endogene di sesso osservate nei casi con nsOFC. Nel complesso, i risultati conseguiti suggeriscono l’esistenza differenze nei due sessi nello sviluppo del labbro. Queste differenze sesso-specifiche potrebbero essere estese anche ad altri distretti anatomici, ed avere un ruolo anche in altre anomalie congenite.
The Orofacial clefts (OFC), including Cleft Lip w/o Palate (CL/P) and Cleft Palate only (CPO) are the fourth most common birth defect. They occur as syndromic and nonsyndromic (nsCL/P and nsCPO), and have a multifactorial etiology. Their birth prevalence varies with sex, with CL/P being common in males and CP on the contrary are common in females. In the present thesis we factored sex differences, alongside common phenomenon’s affecting the cleft etiology and help value the sex dependent endogenous differences in nsOFC. Our first approach was the family based association analysis, to explore genes-sex influence on the susceptibility of nsOFC. We genotyped nsCL/P case-parent trios from EUROCRAN and ITALCLEFT studies, for selected transforming growth factor A (TGFA), TGFA/Taq1/4nt and TGFA/11nt insertion deletion. We observed a sex dependent association of TGFA/taq1/4nt variant in developing nsCL/P, with an opposite effects in male and female infants. The work was further extended to nsCPO group, where we checked lysyl oxidase like 3 (LOXL3) and Grainyhead like 3 (GRHL3) in the susceptibility of developing nsCPO and tested for gene-sex and gene-environment interaction. For this, we genotyped nsCPO case-parents trios for selected variants in the two genes. We observed no significant segregation of minor allele for LOXL3. Whereas the GRHL3 showed a significant segregation of minor allele. Moreover, there appeared a female biased risk for both LOXL3 and GRHL3 variant. For both tested genes there was no risk with mothers genotype. The risk of both gene-variant was influenced by infants genotype, with a threefold increased risk for GRHL3 variant for homozygous infants. Furthermore, for LOXL3 variant, the mothers environment factors showed no evidence of nsCPO risk with infant genotype, while GRHL3 variant showed significant risk to infants born to mothers without folic acid supplementation and smoking. The interaction of the fetal genes with the mothers intra-uterine environment is a critical window for proper development of the fetus, where any disruptions or modifications can influence fetal development as well can lead to birth related anomalies such as NTDs, CHDs and nsOFC. We checked changes in global LINE-1 DNA methylation on the closest possible tissue (lip) involved in the etiology of cleft. A significantly increased in methylation on the medial side was observed. We also observed significant scores inclined to males born to non-folic acid supplemented mothers. The outcome of the present study entails the importance of epigenetic modification and opens a new directional window in the etiology of cleft. This study is the first to explore methylation status in human cleft lip and warrants replications with a larger set of samples. An advantage of CL/P lip tissue bank, directed us to different level from genetic to histology, where we explored sex dependent differences in the orbicularis oris (OO) muscle fibre diameter on the lateral and medial sides of the cleft lip. We observed no significant change in the muscle fibre diameter for the two cleft sides. However, the medial side of male against female appeared significant, with males having smaller muscle diameter compared to females. Both family based association study, entails sex based segregation of minor allele, consolidating our emphasis of sexual dimorphism in gene association studies of nsOFC, which is generally ignored. Moreover the epigenetic study throws light on sex based modification of genes, reflecting that the two sexes can respond differently to the mothers in-utero environment. In addition our histological evaluation on OO muscle diameter in the two sexes further validate the endogenous sex based differences observed in the nsOFC. Based on our result it appears reasonable to suggest differential gene regulation mechanism in two sexes that can influences human phenotypes, including reproductive, physiological and disease traits, such as OFC.

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Pertica, G. "STUDIO DI PATOLOGIE GENETICHE E CARATTERI DI INTERESSE A BASE EREDITARIA NEGLI ANIMALI D'AFFEZIONE." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150053.

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Primary hypertrophic cardiomyopathy (HCM) is the most common cardiac disease in cats and humans, characterized by an impressive phenotypic and genotypic heterogeneity. Autosomal dominant inheritance and two causative mutations in cardiac myosin binding protein C 3 gene (MYBPC3), at position A31P and R820W, were respectively identified in Maine Coon and Ragdoll cats with HCM. Beyond the reported Maine Coon and Ragdoll mutations, A74T, another single nucleotide polymorphism (SNP) in MYBPC3, was suspected to cause HCM in Maine Coon. In the present work, HCM-associated mutations have been genotyped by direct sequencing in 741 Italian cats examined through standardized ultrasound. The prevalence of the mutations and their correlation with the disease in Maine Coon and Ragdoll cats have been calculated. In one more focused cohort of 393 samples, the MYBPC3 region including A31P and A74T loci it has been analyzed more in detail. Multiple alignment have been performed clustering samples by different breeds and several “geno-variants” have been recorded. Future research will be directed to apply high density array (75.000 SNPs) to the research on feline hypertrophic cardiomyopathy, aiming at identifying more mutations in the affected animals and at evaluating their association with the developments of the disease. X-linked progressive retinal atrophy 2 (XLPRA2) is a severe, early-onset, and progressive rod and cone disease of dogs, caused by a 2 bp microdeletion in RPGRORF15. This study provides a list of the relevant DE miRNAs associated with retinal degeneration and disease progression in XLPRA2-mutant retinas at the most relevant disease-related ages: before (3 wks), during (7 wks), and after (16 wks) the peak of photoreceptor death, to further examine their role in retinal development and in RPGRORF15 mutant retinas. Expression profiles of age-matched 3, 7, and 16 wks old normal and XLRPA2-mutant retinas (3/age/group) were analyzed using miRNA-specific Affymetrix microarrays (46,228 probes/7,815 probe sets/177 canine specific). To confirm the data obtained from the array, quantitative real-time PCR of miR-183, miR-155, miR-146a, miR-129, miR-29b, and miR-19a was performed. Future research will be directed to real-time PCR validation of additional DE miRNAs, in vitro analysis at the protein level, integration with recently published transcriptomic data10, and comparison with other similar retinal degenerative diseases (e.g. rcd1) in order to determine if the DE miRNAs are disease-specific, or common to several early onset retinal degenerations.

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Baldissera, Antonella <1963&gt. "Focalità e clonalità nei carcinomi in situ ed invasivo mammari, studio genetico e nuove tecniche di radioterapia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/2143/1/tesi_dottorato_antonella_baldissera.pdf.

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Baldissera, Antonella <1963&gt. "Focalità e clonalità nei carcinomi in situ ed invasivo mammari, studio genetico e nuove tecniche di radioterapia." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2009. http://amsdottorato.unibo.it/2143/.

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11

Marian, Marco. "Studio e progettazione di un meccanismo per l’estrazione di pacchetti in una macchina automatica." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2017. http://amslaurea.unibo.it/12895/.

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Il presente elaborato di tesi descrive lo studio di fattibilità di un meccanismo articolato come organo spingitore di pacchetti in una macchina automatica. Sfruttando la teoria degli algoritmi genetici, sono state effettuate sintesi di quadrilateri articolati ed esalateri articolati aventi un tratto di traiettoria rettilinea. Infine è stato scelto il migliore meccanismo per gli scopi desiderati e di questo è stata effettuata una progettazione basata su di un processo iterativo di analisi delle tensioni e conseguenti modifiche. In questo modo si è giunti alla configurazione finale del meccanismo.

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SARDINA, Maria Teresa. "Studio del gene della β-lattoglobulina in razze ovine e caprine autoctone siciliane." Doctoral thesis, Università degli Studi Mediterranea di Reggio Calabria, 2009. http://hdl.handle.net/10447/208220.

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Zizzo, Maurizio. "Colite acuta da raggi dopo radioterapia preoperatoria short-course per il cancro del retto: uno studio morfologico, immunoistochimico e genetico." Doctoral thesis, Università degli studi di Modena e Reggio Emilia, 2021. http://hdl.handle.net/11380/1246166.

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Background: La radioterapia preoperatoria con o senza chemioterapia si è dimostrata utile nel ridurre i tassi di recidiva locale e nel migliorare la sopravvivenza globale nel cancro del retto. I cambiamenti indotti dalle radiazioni nel tumore sono ben descritti, mentre è stata prestata meno attenzione agli effetti delle stesse nella mucosa non neoplastica. Il nostro scopo è fornire un'analisi dettagliata delle caratteristiche morfologiche, immunoistochimiche e genetiche presenti nella mucosa non neoplastica. E’ necessario che i patologi acquisiscano familiarità con le suddette caratteristiche morfologiche, quando valutano campioni di cancro del retto di pazienti trattati con radioterapia preoperatoria, in particolare con schema short-course, al fine di evitare diagnosi errate. Metodi e risultati: Abbiamo confrontato 2 gruppi di 95 pazienti con cancro del retto trattati con radioterapia preoperatoria short-course (25 Gy somministrati in 5 giorni consecutivi, seguiti da intervento chirurgico pochi giorni dopo; 45 pazienti) o radioterapia long-course (45-50 Gy in 4-6 settimane, seguito da intervento chirurgico 4 settimane dopo; 50 pazienti). A seconda del tipo di protocollo, sono state osservate diverse caratteristiche istopatologiche, in termini di infiammazione, anomalie ghiandolari e differenziazione endocrina nella mucosa non neoplastica all'interno del volume irradiato. Da notare che le caratteristiche che imitano la displasia come la distorsione della cripta, l'atipia nucleare e citoplasmatica dell'epitelio ghiandolare, sono state identificate solo nel gruppo short-course. L'analisi della mutazione del DNA, utilizzando un pannello di 56 geni frequentemente mutati nel cancro del colon-retto, e l'immunocolorazione con p53 sono state eseguite sia su mucosa neoplastica che su mucosa non neoplastica e danneggiata da radiazioni in un sottogruppo di pazienti short-course. Mutazioni somatiche sono state identificate solo nella mucosa neoplastica, supportando il concetto che i tessuti con caratteristiche "displasiche" indotte dalle radiazioni non sono geneticamente trasformati. Conclusioni: I patologi dovrebbero essere consapevoli dei caratteristici cambiamenti morfologici indotti dalle radiazioni. La presenza di caratteristiche che simulano la displasia nel gruppo trattato con radioterapia short-course può portare a gravi errori diagnostici, se interpretata erroneamente. L'analisi NGS ha ulteriormente convalidato il concetto morfologico secondo cui le anomalie indotte dalle radiazioni non rappresentano lesioni pre-neoplastiche.
Background: Preoperative radiotherapy with or without chemotherapy has been demonstrated of value in reducing local recurrence rates and improving overall survival in rectal cancer. Radiation-induced changes in the tumor are well described, whereas less attention has been given to the non-neoplastic mucosa. Our aim is to provide a detailed analysis of morphological, immunohistochemical and genetic features present in non-neoplastic mucosa. Pathologists need to be familiar with aforementioned morphological features, when evaluating rectal cancer specimens of patients preoperatively treated with radiotherapy, especially with short-course regimen, in order to avoid misdiagnosis. Methods and Results: We compared 2 groups of 95 rectal cancer patients treated preoperatively with either short-course (25 Gy administered in 5 consecutive days, followed by surgery a few days after; 45 patients) or long-course radiotherapy (45-50 Gy in 4-6 weeks, followed by surgery 4 weeks later; 50 patients). Depending on the type of protocol, different histopathological features, in terms of inflammation, glandular abnormalities and endocrine differentiation were seen in the non-neoplastic mucosa within the irradiated volume. Of note, features mimicking dysplasia, such as crypt distortion, nuclear and cytoplasmic atypia of glandular epithelium, were identified only in the short-course group. DNA mutation analysis, using a panel of 56 genes frequently mutated in colorectal cancer, and p53 immunostaining were performed on both neoplastic and radiation-damaged non-neoplastic mucosa in a subset of short-course cases. Somatic mutations were identified only in neoplastic mucosa, supporting the concept that tissues with radiation-induced “dysplastic-like” features are not genetically transformed. Conclusions: Pathologists should be aware of the characteristic morphological changes induced by radiation. The presence of features simulating dysplasia in the group treated with short-course radiotherapy may lead to serious diagnostic mistakes, if erroneously interpreted. NGS analysis further validated the morphological concept that radiation-induced abnormalities do not represent pre-neoplastic lesions.

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Vincis, Claudia. ""L'ordre comme règle" uno studio genetico, analitico e estetico sull'Octuor pour instruments à vents (1919-23) e sul Concerto pour piano suivi d'orchestre d'harmonie (1923-24) di Igor Strawinsky /." [S.l.] : [s.n.], 2005. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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TRAMONTANA, SIMONA. "MammOmics™ in Sus scrofa: Studio degli adattamenti genomici alla base dello sviluppo della ghiandola mammaria durante la gravidanza e la lattazione." Doctoral thesis, Università Cattolica del Sacro Cuore, 2009. http://hdl.handle.net/10280/403.

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La comprensione dei geni che controllano la crescita, lo sviluppo, e il metabolismo della ghiandola mammaria suina può rivelare potenziali vie metaboliche o di segnale per migliorare l'efficienza di sintesi del latte. Un microarray suino costituito da 13.263 oligonucleotidi (mer 70) è stato utilizzato per lo studio del profilo di trascrizione del tessuto mammario da 4.5 scrofe a -34, -14, -4, 0, 7, 14, 21, e 28 giorni rispetto alla data del parto. ANOVA (FDR ≤ 0.10) ha individuato 2664 geni differenzialmente espressi (DEG) in relazione allo stato fisiologico. L’analisi dei network e delle vie metaboliche ha identificato come funzioni molecolari più affette dallo stato fisiologico: crescita e proliferazione cellulare (548 geni) cellule di segnale(612 geni).La qPCR rimane il metodo migliore per la misurazione dell’ abbondanza mRNA ad alta precisione e per la validazione di dati array. Essenziale per assicurare l'affidabilità della qPCR è la normalizzazione dei dati con l’utilizzo di geni di controllo interno (ICG). Un analisi sulla stabilità dei geni ha identificato, tra i 19 potenziali ICG, API5, VABP, e MRPL39 come i più stabili ICG nel tessuto mammario suini e ha inoltre stabilito che l'uso di tali 3 geni è il più appropriato per il calcolo di un fattore di normalizzazione. I risultati sottolineano l'importanza di una corretta validazione dei controlli interni per qPCR ed evidenziano le limitazioni di utilizzo dell’assenza dell’effetto tempo come unico criterio per la selezione di CIG.
Elucidating genes controlling growth, development, and metabolism of swine mammary glands can reveal potential metabolic or signalling pathways that might help improve efficiency of milk synthesis. A swine microarray consisting of 13,263 oligonucleotides (70 mer) was used for transcript profiling of mammary tissue from 4-5 sows at -34, -14, -4, 0, 7, 14, 21, and 28 d relative to parturition. ANOVA (FDR ≤ 0.10) identified 2,664 differentially expressed genes (DEG) dueto physiological state. Gene network/pathway analysis revealed that cell growth and proliferation (548 genes) and cell signaling (612 genes) were among the most affected molecular functions due to physiological state in DEG. QPCR remains the chosen method for high-precision mRNA abundance analysis and for array data validation. Essential for reliability of qPCR data is normalization using appropriate internal control genes (ICG). Gene stability analysis identified , among 19 potential ICG, API5, VABP, and MRPL39 as the most stable ICG in porcine mammary tissue and indicated that the use of those 3 genes was most appropriate for calculating a normalization factor. Results underscore the importance of proper validation of internal controls for qPCR and highlight the limitations of using absence of time effects as the criteria for selection of appropriate ICG.

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Balciuniene, Jorune. "Genetic studies of two inherited human phenotypes : Hearing loss and monoamine oxidase activity." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4917-4/.

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17

Nordquist, Niklas. "Genetic Studies of Rheumatoid Arthritis using Animal Models." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5117-9/.

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18

VAJANA, ELIA. "Studio della storia evoluzionistica e conservazione delle specie zootecniche attraverso analisi di genomica del paesaggio e modelli di nicchia ecologica." Doctoral thesis, Università Cattolica del Sacro Cuore, 2017. http://hdl.handle.net/10280/19085.

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Attività antropiche e pressioni di mercato stanno rapidamente riducendo la biodiversità. Per questa ragione, conservare il patrimonio ecosistemico, tassonomico e genetico risulta fondamentale al fine di garantire potenziale adattativo alle specie, e, in ultima analisi, un futuro sostenibile per il pianeta. Al fine di minimizzare la perdita di biodiversità, numerosi metodi sono stati proposti per priorizzare ecosistemi, specie e popolazioni. Il presente lavoro di tesi fornisce in primo luogo una revisione di tali approcci, proponendo un albero decisionale volto a favorirne un corretto utilizzo. Secondariamente, la variabilità genomica neutrale del bufalo d’acqua (Bubalus bubalis L.) è investigata per mezzo di un pannello di marcatori SNP a media densità, rivelando due centri di domesticazione (India Nord-occidentale, Cina-Indocina) e possibili rotte di migrazione per gli ecotipi ‘river’ e ‘swamp’. L’adattamento locale ad East Coast Fever, patologia endemica delle popolazioni bovine in Africa Sub-sahariana, è stato inoltre studiato in bovini autoctoni Ugandesi (Bos taurus L.) combinando tecniche di modellizzazione delle nicchie ecologiche e di genomica del paesaggio. L’approccio ha portato ad indentificare PRKG1 e SLA2 come possibili geni di adattamento. I risultati sono discussi alla luce delle possibili implicazioni nella conservazione del bufalo e nella gestione delle risorse genetiche animali Ugandesi.
Biodiversity is quickly disappearing due to human impact on the biosphere, and to market pressure. Consequently, the protection of both wild and domestic species needs to become a priority in order to preserve their evolutionary potential and, ultimately, guarantee a sustainable future for coming human generations. To date, tens of methods have been proposed to prioritize biodiversity for conservation purposes. Here, an ontology for priority setting in conservation biology is provided with the aim of supporting the selection of the most opportune methodologies given specific conservation goals. Further, two case studies are presented characterizing neutral and adaptive genomic diversity in water buffalo (Bubalus bubalis L.) and indigenous Ugandan cattle (Bos taurus L.), respectively. In particular, two independent domestication centres (North-western India and Indochina) and separate migration routes are suggested for the ‘river’ and ‘swamp’ water buffalo types. In the case of indigenous Ugandan cattle, the integration of species distribution modelling and landscape genomics techniques allowed the identification of PRKG1 and SLA2 as candidate genes for local adaptation to East Coast Fever, a vector-borne disease affecting bovine populations of Sub-Saharan Africa. Results are discussed for their implications in water buffalo conservation and Ugandan cattle adaptive management.

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Mayans, Sofia. "Genetic studies of diabetes in northern Sweden." Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1920.

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Diabetes mellitus represents a group of metabolic disorders caused by both environmental and genetic factors. The two most common forms of diabetes are type 2 diabetes (T2D) and type 1 diabetes (T1D). T2D is associated with obesity and the disease is caused by insulin resistance and pancreatic b-cell dysfunction. T1D is an autoimmune disease in which the insulin- producing b-cells in the pancreas are destroyed by infiltration of lymphocytes. The aim of this thesis was to identify genes conferring susceptibility to diabetes. This was approached using genetic methods, both linkage and association studies, within the population of northern Sweden. The northern Swedish population is well suited for genetic studies of familial forms of disease, since an internal expansion of the northern Swedish population, coupled with a low frequency of immigration and a high frequency of consanguineous marriages, has resulted in a relatively homogeneous gene pool. This simplified genetic background increases the probability of identifying genes contributing to disease. The family-based material used for the type 2 diabetes studies (papers I and II) consisted of 231 individuals from 59 families originating in northern Sweden. The type 2 diabetes case-control material (papers I and II) consisted of 872 cases and 857 matched controls, all from northern Sweden. In paper I we performed a genome-wide linkage scan, seeking T2D susceptibility loci. Linkage to the previously identified Calpain-10 region was found, however, association studies in the case-control material revealed no association to the CAPN10 gene. Using both the family-based and the case-control material, we were able to confirm the association of polymorphisms in the TCF7L2 gene to T2D in the population of northern Sweden (paper II). CTLA-4 is a negative regulator of T cell activity, belonging to the CD28 co-stimulatory receptor family. Numerous reports, including our own, have associated CTLA-4 variants with T1D as well as other autoimmune diseases, such as autoimmune thyroid disease (AITD). Allelic variation in the 3ÚTR of the CTLA-4 gene was associated to human T1D and this variant has also been suggested to affect the level of mRNA encoding the soluble form of the molecule (sCTLA-4). We confirmed the association of allelic variation in the 3ÚTR of the CTLA-4 gene in a T1D/AITD case-control material from northern Sweden, consisting of 104 individuals with ATID, 149 individuals with T1D and 865 matched controls. However, we were unable to identify any correlation between allelic variants in the 3ÚTR of the CTLA-4 gene and expression of sCTLA-4 (paper III). Based on recently published genome-wide association (GWA) scans, 33 single-nucleotide polymorphisms (SNPs) located within 16 genes were selected for an association analysis in T1D/AITD families from northern Sweden. The T1D/AITD family-based material consisted of 253 cases and 206 healthy individuals from 97 northern Swedish families. Analysis revealed association to T1D for SNPs in PTPN22, COL1A2, IL-2Ra and INS. In addition, SNPs in CTLA-4, IL-2 and C12orf30 were shown to be associated to AITD (paper IV). Together, these results underpin the notion that the population of northern Sweden is well suited for the detection of genes involved in complex diseases. The use of our more restricted patient material, compared to materials used in published GWA scans, enables the discovery of disease associated genes in a more cost effective manner and show that our population is capable of detecting general susceptibility genes.

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Leach, Carolyn R. "Studies on self-incompatibility in grasses /." Title page, contents and summary only, 1987. http://web4.library.adelaide.edu.au/theses/09PH/09phl4341.pdf.

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CACCIATORE, GIULIA. "«Il romanzo multiplo». Etude génétique des oeuvres de Gesualdo Bufalino." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/545737.

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The thesis is a genetic study of the works of the Sicilian writer Gesualdo Bufalino (1920-1996). Through the analysis of the writing process, this study reconstructs the genesis of all the works completed by Bufalino during his youth and up until his debut in 1981, with the novel Diceria dell'untore. The research carried out in the archives which hold the genetic materials of Bufalino enabled us to date the creative phase of Bufalino in the period 1955-65. In particular, we have identified in an unpublished novel, Il guazzabuglio, dating back to 1977, a kind of canvas or reservoir, from which the writer drew themes or narrative sequences for other works. This novel, still considered unfinished, was not only completed by Bufalino, but was also closely linked to the genesis of the first two novels, Diceria dell'untore (1981) and Argo il cieco (1984), on the one hand, and to Qui pro quo (1991) and Tommaso e il fotografo cieco (1996), Bufalino’s last novel which can be considered its rewriting. The works completed and published from 1981 until his death in 1996, were the result of a creative process begun during his youth and continued throughout his life. The reconstruction of the genesis of the works written before 1981 is accompanied by the reconstruction of the intellectual biography of Bufalino through the investigation of sources and archive documents.

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MARULLO, Letizia. "Dissection of pleiotropic effects in genome-wide association studies of phenotypes related to cardiometabolic health." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2388968.

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In the past seven years, Genome-Wide Association Studies (GWAS) have identified hundreds of variants associated with cardiometabolic quantitative traits and diseases. Many genetic loci appear to harbour variants associated with multiple phenotypes (cross-phenotype associations, CP). CP associations highlight that phenotypes may share common underlying genetic mechanisms that might, or might not, be consistent with epidemiological expectations and, therefore, add complexity to the relationships between human phenotypes. Pleiotropy occurs when the same genetic causal element affects more than one phenotype “in parallel” and can explain the presence of CP associations. It can appear at a single variant level, where a single causal variant is related to multiple phenotypes, or at a locus level, that is when multiple variants in the same gene or locus are associated with different phenotypes by affecting the same functional element. However, other potential genetic mechanisms, that can explain CP associations, exist. Among them, mediation occurs when a genetic variant is directly associated with a phenotype and that phenotype is itself causal for a second phenotype or more phenotypes; multi-phenotype allelic heterogeneity is a phenomenon which involves independent uncorrelated variants within the same locus which cause changes in multiple phenotypes, by affecting them through independent pathways related to distinct functional elements. The identification and characterisation of CP associations across the genome may help uncovering the mechanistic basis of physiological processes that underlie variability of cardiometabolic quantitative traits, and of pathogenetic processes leading to metabolic disorders. The definition of specific patterns of effect combinations on cardiometabolic phenotypes will highlight novel biological pathways, targets for translational research, for therapeutic intervention, and for the understanding of the pathophysiology of human metabolism. Based on this hypothesis, and in collaboration with the Cross-Consortia pleiotropy group and with the European Network for Genetic and Genomic Epidemiology (ENGAGE) consortium, my PhD project focused on dissection of CP effects, pleiotropy in particular, at common variants across the genome in association with cardiometabolic phenotypes. The objective was to improve our understanding of the extent of shared genetics between cardiometabolic phenotypes and of the influences of DNA sequence variation on risk of metabolic diseases, considering phenotypes as a range of inter-related manifestations of biological mechanisms rather than as isolated events. My research has been divided into three sub-projects: Project 1: Clustering and pathway analysis of univariate GWAS results for the detection of pleiotropic effects. We explored multi-phenotype effects at hundreds of established cardiometabolic genetic variants from published univariate GWAS meta-analyses on more than 20 respective phenotypes, by defining clusters of loci with similar multiple effects, comparing them to known epidemiological expectations, and identifying enriched biological networks within the most interesting groups of loci. Our results highlighted that many variants at cardiometabolic loci have multiple associations that characterise different aspects of metabolism. Cardiometabolic loci can be grouped according to their shared multi-phenotype effects and metabolic syndrome represents just one possible combination; in fact, several other unexpected combinations might be observed, for example healthy obesity/unhealthy leanness. We also highlighted that genetic loci with similar cardiometabolic effects are involved in shared biological pathways. Some of these may be expected, for instance, regulation of lipids metabolism or cholesterol transport for groups of loci with strong effects on lipids, and circulatory system processes for genes near blood pressure-association signals. Sometimes groups of loci affected fundamental cell functions, such as regulation of cellular processes, for the loci with effects on obesity and anthropometric traits. The enriched connectivity within pathway networks revealed new potential candidate genes and tissues of action that are more likely to have causal effect on phenotypes. Project 2: Validating pleiotropy and analysis of locus architecture in potential pleiotropic regions. We aimed to dissect the architecture of established cardiometabolic loci showing multiple associations for a better definition of the underlying mechanisms of multi-phenotype effects and for the discernment of potential pleiotropy from allelic heterogeneity. To this aim, we applied an approximate conditional analysis, based on observed linkage disequilibrium patterns, which led us to the discovery of multiple associations at adjacent variants that underlie the same genetic cause for variability of different phenotypes. Our results also highlighted that a substantial proportion of metabolic loci incorporate complex patterns of multi-phenotype allelic heterogeneity, thus suggesting an important contribution of this mechanism into cross-phenotype effects. Project 3: Application of a multivariate statistical approach for the study of pleiotropy within cardiometabolic phenotypes. We developed and applied a statistical strategy for joint multivariate analysis of multiple correlated phenotypes using individual genetic data from the ENGAGE consortium to discover new uncovered multiple associations and to follow-up GWAS meta-analysis at two loci, FTO and FADS1. Using this approach we were able to take into account correlation between phenotypes, and we achieved a boost in power; moreover, we improved precision of parameter estimates and of the identification of novel candidate genes. Our results allowed us to identify several variants jointly associated with multiple lipid traits and body mass index. Our approach was useful for the identification of mediation: we, in fact, confirmed mediation underlying causal relationship between adiposity and other cardiometabolic phenotypes at the FTO locus. Additionally, we demonstrated that multiple effects on cardiometabolic phenotypes attributable to the FADS1 locus are mediated by its independent, thus pleiotropic, effect on total cholesterol and triglycerides. In conclusion, we applied several statistical approaches which allowed dissecting suggestive CP effects and their mechanisms, including pleiotropy, mediation and allelic heterogeneity. Our analyses have demonstrated the complexity of the relationships between cardiometabolic phenotypes related to the variability of both, underlying genetic mechanisms and genetic loci architecture.

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23

Huson, Susan Mary. "Clinical and genetic studies of von Recklinghausen neurofibromatosis." Thesis, University of Edinburgh, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236157.

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A population-based study in South East Wales (population 668,100) identified 69 families with 135 affected members with von Recklinghausen neurofibromatosis (NF-1), giving a disease prevalence of 20/105 of population. In these families penetrance of the NF-1 gene was 100% by the age of five years. 41/135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1x10-5 and 10.4x10-5. A parental age effect for new mutations was not demonstrated, nor was a maternal effect on disease severity. The clinical features and natural history of NF-1 in this cohort were used to derive data for genetic counselling and recommendations for the management of affected individuals. For counselling purposes the complications of NF-1 can be usefully divided into 4 categories (the frequency of each, based on this study, are shown in parentheses): intellectual handicap (33% overall, moderate/severe retardation 3.2%, minimal retardation/ learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity, e. g. facial plexiform neurofibromas, scoliosis, pseudoarthrosis (8.5%); 'treatable' complications which can develop at any age, e. g. benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis (15.7%) and malignant or CNS tumours (4.4-5.2%). The study population indicates that sufferers are not being diagnosed sufficiently early, nor receiving appropriate follow-up and counselling. It is recommended that patients with NF-1 have regular clinical assessments to monitor for the development of complications, although none occur often enough to warrant biochemical or radiological screening. As many of the complications develop early in life, children should have biannual review; in adults, unless a particular complication indicates more frequent review,annual clinical examination is sufficient. Alongside the population survey, genetic linkage studies were undertaken in selected large families to determine the chromosomal localisation of the NF-1 gene. At the outset of this work, two families had been reported in which NF-1 and Myotonic Dystrophy (DM) appeared to co-segregate, suggesting that the two genes were closely linked and on chromosome 19. However, linkage studies of 3 chromosome 19 markers linked to DM showed significantly negative lod scores, therefore excluding this possibility. Other chromosomes were then studied using random unique sequence DNA probes and samples from the largest families were made available to collaborators in the USA for linkage studies using possible candidate genes (ß nerve growth factor and oncogenes). No marker studied showed evidence of linkage. The negative data were used to produce an exclusion map for NF-1, using the computer program 'EXCLUDE'. The presentation of this work was one of the factors which precipitated the formation of an international consortium for NF-1 linkage in February 1987; the first task of the consortium was to produce an expanded exclusion map. A small positive lod score for a marker on chromosome 17, taken with the exclusion data, showed that NF-1 was seven times more likely to be on chromosome 17 than any other chromosome; this was rapidly confirmed by two North American groups, one of which was using samples from the 5 largest families presented in the thesis. Subsequent linkage analysis of pericentromeric chromosome 17 markers in the Welsh family panel showed no evidence of non-allelic heterogeneity and identified closely linked flanking markers for the NF-1 gene suitable for prenatal/presymptomatic diagnosis. The chromosomal localisation of NF-1 represents a major step towards the eventual understanding of the disease pathogenesis and the development of possible treatments.

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24

Dibbens, Justin Andrew. "Studies on the control of late gene transcription in coliphage 186 /." Title page, contents and summary only, 1990. http://web4.library.adelaide.edu.au/theses/09PH/09phd543.pdf.

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25

Wong, Chi-sun, and 黃志新. "Molecular studies of the heat shock protein 60 gene of Trichinella spp(Nematoda)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31226826.

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關仲天 and Chung-tin Kwan. "Studies of the regulation of mouse Hoxb-3 gene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B31237150.

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27

Kotova, Irina. "Purification of general RNA polymerase II transcription factors from mouse for studies of proliferation-specific transcription." Doctoral thesis, Umeå : Department of Medical BIochemistry and Biophysics, Umeå University, 2003. http://publications.uu.se/umu/theses/abstract.xsql?dbid=91.

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28

Mulley, John Charles. "Genetic marker studies in humans /." Title page, contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09phm958.pdf.

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29

Zhou, Chen, and 周辰. "Genome-informed studies on Penicillium marneffei: horizontal gene transfer survey and differentialsecretomics." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41633672.

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30

Entesarian, Miriam. "Molecular Genetic Studies of ALSG, Kostmann Syndrome and a Novel Chromosome 10 Inversion." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-100598.

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In summary, this thesis presents the localisation and identification of genetic variants of which some are disease associated and some considered to be neutral. Knowledge of the basic mechanisms behind human disorders is important both from a biological and medical point of view. The thesis is based on four papers of which the first two clarify the genetic basis of autosomal dominant aplasia of lacrimal and salivary glands (ALSG). ALSG is a rare disorder with high penetrance and variable expressivity characterized by dry mouth and eyes. In paper I, we located the ALSG gene to a 22 centiMorgan region on chromosome 5 through a genome-wide linkage scan with microsatellite markers in two families. Mutations were found in the gene encoding fibroblast growth factor 10 (FGF10) situated in the linked chromosome 5 region. Mice having only one copy of the FGF10 gene (Fgf10+/- mice) have a phenotype similar to ALSG, providing an animal model for the disorder. In paper II, we describe two additional patients with ALSG and missense mutations in FGF10, providing further genotype-phenotype correlations. The aim of paper III was to identify a gene involved in autosomal recessive severe congenital neutropenia (SCN), also referred to as Kostmann syndrome. The disease is characterized by a very low absolute neutrophil count and recurrent bacterial infections. Affected individuals from the family with SCN originally described by Dr Kostmann were genotyped with whole-genome SNP arrays. Autozygosity mapping identified a shared haplotype spanning 1.2 Mb on chromosome 1q22. This region contained 37 known genes, of which several were associated with myelopoiesis. Our finding contributed to the identification of the gene mutated in Kostmann syndrome. In paper IV a cytogenetic inversion on chromosome 10 was mapped and characterized. Sequence- and haplotype analysis of carriers from four non-related Swedish families revealed identical inversion breakpoints and established that the rearrangement was identical by descent. A retrospective study of karyotypes together with screening of large sample sets established that the inversion is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. No consistent phenotype was found associated with the inversion. Genetic research increases the understanding of our genomes and makes it possible to discover variants contributing to disease. Identification of such genetic variants further enables studies of gene function and pathogenesis. The finding of the disease associated variants in this thesis will eventually contribute to improved diagnosis, prognosis, risk assessment and a future treatment of patients.

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31

Kantidakis, Theodoros. "In vivo studies of repressors of RNA polymerase III transcription." Thesis, Thesis restricted. Connect to e-thesis to view abstract, 2008. http://theses.gla.ac.uk/161/.

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Thesis (Ph.D.) - University of Glasgow, 2008.
Ph.D. thesis submitted to the Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, 2008. Includes bibliographical references. Print version also available.

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32

Jansson, Mattias. "Molecular Genetic Studies of Genes Predisposing for Glaucoma." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4142.

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33

Prokunina, Ludmila. "Strategies for Identification of Susceptibility Genes in Complex Autoimmune Diseases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4138.

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34

Scoville, Alison G. "Phenotypic Plasticity and the Post-Modern Synthesis: Integrating Evo-Devo and Quantitative Genetics in Theoretical and Empirical Studies." DigitalCommons@USU, 2008. https://digitalcommons.usu.edu/etd/212.

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Mainstream evolutionary biology lacks a mature theory of phenotype. Following from the Modern Synthesis, researchers tend to assume an unrealistically simple mapping of genotype to phenotype, or else trust that the complexities of developmental architecture can be adequately captured by measuring trait variances and covariances. In contrast, the growing field of evolutionary developmental biology (evo-devo) explicitly examines the relationship between developmental architecture and evolutionary change, but lacks a rigorous quantitative and predictive framework. In my dissertation, I strive to integrate quantitative genetics and evo-devo, using both theoretical and empirical studies of plasticity. My first paper explores the effect of realistic development on the evolution of phenotypic plasticity when there is migration between two discrete environments. The model I use reveals that nonadditive developmental interactions can constrain the evolution of phenotypic plasticity in the presence of stabilizing selection. In my second paper, I examine the manner in which the genetically controlled responsiveness of traits to each other is shaped by selection and can in turn shape the phenotypic response to selection. Here, results indicate that developmental entanglement through plasticity can facilitate rapid multivariate adaptation in response to a novel selective pressure. In my final paper, I examine patterns of gene expression underlying ancestral plasticity and adaptive loss of melanin in Daphnia melanica. My results indicate that the developmental mechanism underlying ancestral plasticity has been co-opted to facilitate rapid adaptation to an introduced predator.

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35

Zhang, Xiao-Qun. "Functional Studies on the PDGFR α gene promoter and effects of autocrine PDGF-A stimulation in vivo." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1455.

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Platelet-derived growth factor receptor α (PDGFRα) plays an important role during embryogenesis. After implantation, the patterns of expression of Pdgfrα and its ligand Pdgf-A undergo an "autocrine-paracrine transition", in that Pdgf-A becomes expressed in the ectoderm and epithelia, while Pdgfrα is expressed in the adjacent mesenchymal tissue. In human tumors, such as malignant glioma, both PDGF and PDGFRα are overexpressed within the same tissue, indicating that an autocrine PDGF loop is generated in the tumors. This thesis is focused on the in vivo functionality of the PDGFRα gene (PDGFRA) promoter, arid on the effect of autocrine PDGF-A stimulation in transgenic n-iice during embryogenesis. To test the in vivo promoter function of a human PDGFRA 2.2 kb 5' flanking fragment, we generated transgenic mouse lines and found that the 2.2 kb fragment was able to promote lacZ reporter gene expression in most of the endogenous Pdgfra expressing tissues. Absence of expression and "ectopic" expression of the transgenic lacZ were also observed. To investigate the autocrine PDGF effect, we produced autocrine PDGF-As (A short-chain) transient transgenic embryos. These transgenic embryos carried a 6 kb mouse Pdgfra 5' flanking sequence linked to a human PDGF-As cDNA. The pattern of expression of the PDGF-As transgene mRNA was similar to that of lacZ. Some of the transgenic embryos exhibited severe abnormal phenotypes, such as midline fusion defects in the cephalic and craniofacial region and small body size, and these embryos die at mid-gestation stage. These findings indicate that a paracrine pattern of expression and the dosage of PDGF are important for sustaining normal embryo development, especially with regard to the middline fusion in craniofacial regions. The possible signaling pathways that may be involved in regulating Pdgfra activity were also studied by comparison of patterns of mRNA expression of Gli, Ptc, and Paxl with that of Pdgfra. The results pointed to the possibility that the Shh signaling pathway may be involved in the regulation of Pdgfra expression for example during early bone and foregut development. The specific regulatory mechanisms may vary for different tissues.

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36

Heller, Susanne. "Molecular mechanisms involved in glioma cell interactions in vitro and studies of PDGF B transcript variants." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1252.

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Glioblastoma multiforme is a malignant brain tumor characterized by heterogeneity.Interactions between heterogeneous tumor cells are supposed to affect the behavior of awhole tumor cell population. In this thesis an in vitro model system of clonal glioma celllines originating from one glioblastoma tumor was used, and the behavior of cells incocultures was studied and compared the behavior of cells grown separately. The resultsindicate the presence of two types of interactions. In one, paracrine signals acted via extra-cellular media. This was associated with increased growth of the whole co-culture followedby a selective force driving one clone to dominance. In the other type, the cell clones grewside by side without signs of paracrine signalling, in a balance resulting in an increasedterminal cell density. Further investigations focused on mechanisms of interactions in thiscombination.

Two cell clones were chosen, a GFAP⁺ and a GFAP^-, for further experiments. Withdifferential display PCR it was possible to investigate their specific gene expressionpatterns. Seventeen cDNA fragments were differentially expressed, among them twocorresponded to known transcription factors, ATF3 and prox-1, one to a cytoskeletal protein,α-tropomyosin. The collection also contained eight ESTs (Expressed Sequence Tags) wherethe corresponding genes are unknown at present. Expression of the isolated sequences werealso analyzed in a panel of 12 different glioma cell lines and the results illustrate thecomplexity of gene expression and of tumor heterogeneity. Genes, the expression levels ofwhich were modulated in co-cultures and/or were cell density dependent, were alsoidentified.

PDGF B is suggested to play a role in sarcomas. The gene codes for an mRNA transcriptwith long UTRs, parts of which are deleted in the homologous oncogene v-sis. The UTRs ofPDGF B mRNAs in human sarcomas were investigated for deletions similar to v-sis thatmight result in increased protein levels. A new transcript variant was identified, lacking a149 base region in the 3'UTR, but its presence was not associated with increased levels ofprotein. Alterations in the 5'UTR were found more likely to be associated with increasedprotein levels.

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37

Matsson, Hans. "Studies of the Ribosomal Protein S19 in Erythropoiesis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4283.

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38

Wirdefeldt, Karin. "Studies of genetic and environmental influences on Parkinson's disease /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-771-1/.

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39

Magnusson, Veronica. "Genetic studies on Systemic Lupus Erythematosus : A fine mapping and candidate gene approach." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2869.

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Linkage in the 2q37 region was evaluated using microsatellite markers in multi-case families from Sweden, Iceland and Norway. Both the two-point and the multipoint linkage analysis show highly significant LOD scores (Z=4.51 and 6.03, respectively). Linkage disequilibrium mapping indicates that some association exists in this region. The PDCD1 gene was suggested as a candidate gene within the 2q37 locus due to its importance in immune regulation. Indeed, one haplotype, described by the presence of allele A of the PD1.3 SNP located within intron 4 of this gene, shows linkage to SLE in the Nordic families. The PD1.3A allele is also found to be strongly associated in familiar and sporadic cases of SLE in Europeans and Mexicans. Functional studies further support PD1.3A to be a susceptibility allele for SLE.

The 1q23 region, containing the genes for the low affinity Fcγ receptors, was fine mapped using single- and multi- case families of various origins. Genetic variants of those genes were analysed and association is found to both the risk alleles of FcγRIIA and FcγRIIIA in all families. In these families, a single haplotype carrying both risk alleles is predominantly transmitted to patients with SLE, suggesting a presence of linkage disequilibrium between those two genes. FcγRIIA and FcγRIIIA are also found to be associated to SLE and lupus nephritis in a case-control cohort from Sweden. In the same cohort, the PD1.3A allele shows strong association to lupus nephritis. We suggest that there may be an additive effect between FcγRIIA and PDCD1, since having the disease-associated genotypes at both loci gives an increased risk for developing lupus nephritis.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disorder with a complex multifactorial aetiology. Genetic studies suggest that several genes are involved in disease pathogenesis and that extended genetic heterogeneity is present.

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40

MARICA, MONICA. "Malattie rare in genetica clinica: variabilità e distribuzione nella popolazione sarda, applicazione di test genetici, studio delle nuove prospettive terapeutiche." Doctoral thesis, Università degli Studi di Cagliari, 2006. http://hdl.handle.net/11584/265943.

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Le distrofie muscolari sono un gruppo di disordini degenerativi del muscolo geneticamente eterogeneo, caratterizzato da progressiva perdita della forza e dell’integrità muscolare. Distrofia muscolare è un termine generico che descrive un gruppo di disordini miogenici ereditari, caratterizzati da una progressiva disorganizzazione e atrofia del muscolo con variazione dello spessore delle fibre muscolari, aree di necrosi con incremento della quantità di grasso e di tessuto connettivo. La malattia muscolare riguarda l’anello terminale dell’unità motoria. La debolezza muscolare, o difetto di forza, colpisce la muscolatura prossimale dei cingoli scapolare e pelvico e, in certe forme in modo suggestivo, quella del collo e della faccia. Negli ultimi due decenni, il notevole sviluppo delle ricerche di genetica molecolare ha consentito di identificare molti dei geni coinvolti in tali malattie e ha fornito così la chiave per decifrarne la patogenesi molecolare; attualmente sono stati mappati 29 differenti loci che danno origine a 34 distinti disordini che variano per l’età di inizio, grado di severità, modo di ereditarietà, e gruppi muscolari che sono primariamente coinvolti. La membrana delle fibre muscolari (sarcolemma) è la vera responsabile di questo gruppo di malattie e la sua composizione proteica, ora molto più nota, risulta straordinariamente complessa.

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41

Olsen, Jeffrey B. "Genetic interpretation of microsatellite polymorphism in Pacific salmon : case studies in population genetics and kinship analysis /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/5285.

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42

Hellborg, Linda. "Evolutionary Studies of the Mammalian Y Chromosome." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4126.

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43

Kalionis, Bill. "The early control region of temperate coliphage 186 : sequence and transcription studies /." Title page, contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09phk14.pdf.

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44

Olsson, Malin. "Familial amyloidosis with polyneuropathy : studies of genetic factors modifying the phenotype of the disease." Doctoral thesis, Umeå universitet, Medicin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-34128.

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Background. Familial Amyloidosis with Polyneuropathy (FAP) is an autosomal dominantly inherited systemic amyloid disease. The disease is caused by mutations in the transthyretin (TTR) gene, where close to 100 different amyloidogenic mutations have been identified. FAP is found worldwide, but endemic areas with a high frequency of patients are found in Portugal, Japan and northern Sweden. Cases from these endemic areas all share the same TTR c.148G>A, p.V50M ("V30M") mutation, but the phenotype of the disease varies between the areas, and also within the endemic areas. The mean onset of the disease is two decades earlier in Portugal and Japan compared to Sweden, but late as well as early age at onset cases occur within all the populations. Interestingly, the different populations all display a maternal anticipation, where an earlier onset is observed for those individuals who inherit the trait from their mother. Since substantial variation in the phenotype is observed for different populations, epigenetic/genetic and/or environmental factors must exert a significant impact on the penetrance of the disease. Amyloid formation is caused by conformational changes of proteins, which facilitates their assembly into fibrils, amyloid. Oxidative stress can mediate conformational changes of proteins and since the mitochondria regulate oxidative processes within the cell, mitochondrial function may affect amyloid formation. The mitochondrial DNA is a non-nuclear DNA, which is entirely maternally inherited, and therefore could be related to the observed maternal anticipation of the disease. In addition, differences within the surrounding regions of the TTR gene may have an impact on the transcription of the gene and thereby on the expression of the different alleles. Material and methods. DNA from early and late onset V30M cases and from non-carriers (the latter utilised as controls) from Swedish, French, Japanese and Portuguese populations were analysed. In addition, DNA from healthy Swedish V30M carriers was analysed. Conventional analytical methods were employed, such as PCR, sequencing and genotyping. Conventional statistical methods used were t-test, Chi-squared test and maximum likelihood. Results. The study of V30M carrier frequency in two counties (Lycksele and Skellefteå) within the Swedish endemic area revealed a carrier frequency of 2.14% and 2.54%, respectively. The mitochondrial haplogroup analysis showed that in populations with generally late onset (French and Swedish), the haplogroup distribution of late onset cases resembled that of the controls derived from the same area, whereas haplogroup distribution for early onset patients was significantly different. The most pronounced difference was for the rare haplogroup K, of which early onset cases had a higher frequency than the controls. Analysis of the Portuguese population, with predominantly early onset, showed that haplogroup distribution for early onset cases were similar to the Portuguese control group, which had a different distribution than the Swedish control group. By analysis of pedigrees from Swedish and Portuguese patients it could be shown that mitochondrial genetic variation entirely could explain maternal anticipation in the Portuguese patients, whereas for Swedish patients, an additional parent of origin effect is present. Our analysis of the TTR gene disclosed a polymorphism (rs62093482) in the 3'UTR region of the Swedish patients. This polymorphism was found in all V30M carriers, irrespective of symptoms. In addition, homozygous TTR V30M carriers were homozygous also for the polymorphism. Since Swedish patients share a common founder this polymorphism thus is localised on the V30M allele. This polymorphism was found in only 4% of the Swedish controls. French controls showed the same frequency, but none of the French V30M patients displayed the polymorphism. In the Japanese population the polymorphism was not present at all. Interestingly, this polymorphism generates a potential binding site for microRNA and thereby possibly could down-regulate the expression of the mutated TTR allele. Conclusions. The carrier frequency in the endemic area is remarkably high, above 2% in the Lycksele and Skellefteå areas. The prevailing haplogroup distributions in the different endemic areas are consistent between the general population and the patient group with the predominant phenotype of that area. Mitochondrial genetic differences may explain maternal anticipation in Portuguese patients, and have an influence in Swedish patients. A polymorphism in the 3'UTR regulatory region of the mutated TTR allele is found in all Swedish patients. This polymorphism may down-regulate TTR V30M expression and thereby contribute to the late onset of the disease noted in the Swedish population.

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45

Eriksson, Jesper. "Structure-Function Studies of Bacteriophage P2 Integrase and Cox protein." Doctoral thesis, Stockholm University, Department of Genetics, Microbiology and Toxicology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-683.

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Probably no group of organisms has been as important as bacteriophages when it comes to the understanding of fundamental biological processes like transcriptional control, DNA replication, site-specific recombination, e.t.c.

The work presented in this thesis is a contribution towards the complete understanding of these organisms. Two proteins, integrase, and Cox, which are important for the choice of the life mode of bacteriophage P2, are investigated. P2 is a temperate phage, i.e. it can either insert its DNA into the host chromosome (by site-specific recombination) and wait (lysogeny), or it can produce new progeny with the help of the host protein machinery and thereafter lyse the cell (lytic cycle). The integrase protein is necessary for the integration and excision of the phage genome. The Cox protein is involved as a directional factor in the site-specific recombination, where it stimulates excision and inhibits integration. It has been shown that the Cox protein also is important for the choice of the lytic cycle. The choice of life mode is regulated on a transcriptional level, where two mutually exclusive promoters direct whether the lytic cycle (Pe) or lysogeny (Pc) is chosen. The Cox pro-tein has been shown to repress the Pc promoter and thereby making tran-scription from the Pe promoter possible, leading to the lytic cycle. Further, the Cox protein can function as a transcriptional activator on the parasite phage, P4. P4 has gained the ability to adopt the P2 protein machinery to its own purposes.

In this work the importance of the native size for biologically active integrase and Cox proteins has been determined. Further, structure-function analyses of the two proteins have been performed with focus on the protein-protein interfaces. In addition it is shown that P2 Cox and the P2 relative Wphi Cox changes the DNA topology upon specific binding. From the obtained results a mechanism for P2 Cox-DNA interaction is discussed.

The results from this thesis can be used in the development of a gene delivery system based on the P2 site-specific recombination system.

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46

Frisén, Louise. "Genetic studies of hypospadias /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-397-x/.

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47

Moffatt, Miriam Fleur. "Genetic studies of atopy." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358577.

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Lynex, Clare Nadine. "Genetic studies of neurodevelopment." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.410764.

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Andersson, Anna-Carin. "Postglacial Population History of the Common Shrew (Sorex araneus) in Fennoscandia : Molekylära studier av återkolonisation, könsbundet genflöde och kromosomrasbildning." Doctoral thesis, Uppsala universitet, Naturvårdsbiologi och genetik, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4289.

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The common shrew, Sorex araneus, has one of the most variable karyotypes among mammals, displaying numerous chromosomes races throughout its distribution, which can be categorized into different karyotypic groups. The objective of this thesis was to examine the postglacial population history of Fennoscandian common shrews using autosomal microsatellites, mitochondrial DNA (mtDNA) and a Y chromosome specific microsatellite (L8Y). Autosomal microsatellites and mtDNA revealed weak genetic structure over a hybrid zone between the karyotypically divergent Northern and Western karyotypic groups. However, the genetic structure displayed by the Y chromosome microsatellite was orders of magnitude higher. Hence, considerable chromosomal differences between the groups do not prevent female gene flow, while male gene flow is reduced (cf. Haldane's rule). Further, the results suggest that the Haldane effect may be caused by the chromosomal differences between the karyotypic groups. No mtDNA differentiation was observed either between chromosome races or between the Northern and Western karyotypic groups in Fennoscandia. The combined pattern of karyotypic and mtDNA variation of Fennoscandian common shrews, suggest bi-directional postglacial recolonisation from a single refugium in Europe. The variation of the Y-linked microsatellite supported this conclusion. In contrast, significant mtDNA structure, discordant with the karyotypic variation, revealed that common shrews in southern Finland belong to a different lineage than remaining Fennoscandian regions, implying postglacial recolonisation from a different source. MtDNA variation of the chromosome races in Sweden supports the hypothesis that three races of the Western karyotypic group have been formed through whole arm reciprocal translocations (WARTs), as suggested by their mutual karyotypic variation. The variation of the molecular markers supports the theory of rapid karyotypic evolution in the common shrew.

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Cohen, Francisca. "Studies on regulation of the plantaricin 423 gene." Thesis, Stellenbosch : Stellenbosch University, 2004. http://hdl.handle.net/10019.1/50111.

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Thesis (MSc) -- University of Stellenbosch, 2004.
ENGLISH ABSTRACT: Lactic acid bacteria play an essential role in the majority of fermented foods by producing organoleptic compounds and increasing the shelf life. The best-studied antimicrobial compounds are bacteriocins, i.e. ribosomally synthesized peptides. Most of these peptides have a narrow spectrum of activity and are usually only active against bacteria from the same ecological niche. The fact that all bacteriocins are degraded by proteolytic enzymes enlarges their potential use as natural food preservatives. The ideal would be to replace or reduce chemical preservatives such as sulfur dioxide, nitrates and nitrites. Bacteriocins are classified into four groups according to their structural and functional characteristics. Plantaricin 423, produced by Lactobacillus plantarum 423, is heat stable, plasmid encoded, relatively small (3.5 kDa) and is classified as a class Iia bacteriocin. The peptide is active from pH 1.0 to 10.0 and inhibits Gram-positive bacteria, including Lactobacillus spp., Leuconostoc spp., Oenococcus oeni, Pediococcus spp., Enterococcus spp., Propionibacterium spp. and pathogens such as Bacillus cereus, Clostridium spp. and Listeria monocytogenes. Production of bacteriocins may occur constitutively or may be regulated by a cell-density dependent system called quorum sensing. Plantaricin 423 is produced throughout logarithmic growth, with no apparent change in production levels when the producer strain is cultured in the presence of plantaricin 423 or Listeria innocua and Lactobacillus sakei. This led us to believe that plantaricin 423 may be produced constitutively. A reporter system was constructed which consisted of the plantaricin 423 promoter, P423, fused to the luxAB genes and cloned into a shuttle vector, pTRKH2. The newly constructed plasmid, pTAB4, was transformed to a bacteriocin-negative mutant of L. plantarum (423 B} Despite several repeats, no luciferase activity was recorded and no RNA homologous to the luxAB genes was detected. The region necessary for expression of plantaricin 423 may be located stream-up of the -80 region homologous to the -80 and -40 conserved repeats of regulated class II bacteriocins. Inclusion of the latter region in the reporter construct may result in the successful expression of luxAB.
AFRIKAANSE OPSOMMING: Melksuurbakteriee speel 'n belangrike rol in die meeste gefermenteerde voedselsoorte deur die produksie van organoleptiese komponente en die verlenging van rakleeftyd. Van aile antimikrobiese komponente is bakteriosiene (ribosomaal gesintetiseerde peptiede) die beste bestudeer. Hierdie peptiede het gewoonlik 'n nou spektrum van antimikrobiese werking en is meestal aktief teen bakteriee in dieselfde ekologiese nis. Die feit dat bakteriosiene deur proteolitiese ensieme in die spysverteringskanaal vernietig word, verhoog die potensiele gebruik van bakteriosiene as preserveermiddels. Die ideaal sal wees om die konsentrasie van chemiese preserveermiddels soos swaweldioksied, nitrate en nitriete te verlaag of rnoontlik te vervang met bakteriosiene. Bakteriosiene word in vier groepe op grond van hul strukturele en funksionele karaktereienskappe geklassifiseer. Plantarisien 423, geproduseer deur Lactobacillus plantarum 423, is hitte-stabiel, word deur 'n plasmied gekodeer, is relatief klein (3.5 kDa) en sorteer onder die klas Iia bakteriosiene. Die peptied is aktief oor 'n wye pH-reeks (pH 1.0-10.0) en inhibeer Gram-positiewe bakteriee, insluitend Lactobacillus spp., Leuconostoc spp., Oenococcus oeni, Pediococcus spp., Enterococcus spp., Propionibacterium spp. en patogene soos Bacillus cereus, Clostridium spp. en Listeria monocytogenes. Produksie van bakteriosiene kan konstitutief plaasvind of kan gereguleer word deur 'n seldigtheids- afhanklike sisteem naamlik "quorum sensing". Plantarisien 423 word regdeur logaritmiese groei geproduseer, met geen verandering in produksievlakke wanneer die produserende stam in die teenwoordigheid van plantarisien 423 of Listeria innocua en Lactobacillus sakei gekweek word nie. Dit het gelei tot die hipotese dat plantarisien 423 moontlik konstitutief geproduseer word. 'n Verklikkersisteem bestaande uit 'n fusie van die plantarisien 423 promoter, P423, aan die luxAB gene is gekonstrueer en in die pendelplasmied pTRKH2 gekloneer. Die nuutgekonstrueerde plasmied, pTAB4, is na 'n bakteriosien-negatiewe mutant van L. plantarum (stam 423 B-) getransfonneer. Ten spyte van etlike herhalings kon geen lusiferase-aktiwiteit opgespoor word nie en kon ook geen homologie in die RNA met die luxAB gene opgespoor word nie. Dit is moontlik dat die area nodig vir uitdrukking van plantarisien 423 verder stroom-op van die -80 area, homoloog aan die -80 en -40 gekonserveerde herhalings van reguleerbare klas II bakteriosiene, gesetel is. Insluiting van laasgenoemde area in die verklikker-konstruk mag lei tot die suksesvolle uitdrukking van luxAB.

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Dissertations / Theses on the topic 'Studio genetico'

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