S. cerevisiae as a model for studying mutations in the human gene OPA1 associated with dominant optic atrophy and for drug discovery

L’atrofia ottica dominante (ADOA) è una malattia mitocondriale caratterizzata da difetti visivi, che si manifestano durante l’infanzia, causati da progressiva degenerazione delle cellule gangliari della retina (RGC). ADOA è una malattia genetica associata, nella maggior parte dei casi, a mutazioni nel gene OPA1 che codifica per la GTPasi mitocondriale OPA1, appartenente alla famiglia delle dinamine, principalmente coinvolta nel processo di fusione mitocondriale e nel mantenimento del mtDNA. Finora sono state identificate più di 300 mutazioni patologiche nel gene OPA1. Circa il 50% di queste sono mutazioni missenso, localizzate nel dominio GTPasico, che si pensa agiscano come dominanti negative. Questa classe di mutazioni è associata ad una sindrome più grave nota come “ADOA-plus”. Nel lievito Saccharomyces cerevisiae MGM1 è l’ortologo del gene OPA1: nonostante i due geni abbiano domini funzionali identici le sequenze amminoacidiche sono scarsamente conservate. Questo costituisce una limitazione all’uso del lievito per lo studio e la validazione di mutazioni patologiche nel gene OPA1, infatti solo poche sostituzioni possono essere introdotte e studiate nelle corrispettive posizioni del gene di lievito. Per superare questo ostacolo è stato pertanto costruito un nuovo modello di S. cerevisiae, contenente il gene chimerico MGM1/OPA1, in grado di complementare i difetti OXPHOS del mutante mgm1Δ. Questo gene di fusione contiene una larga parte di sequenza corrispondente al gene OPA1, nella quale è stato inserito un set di nuove mutazioni trovate in pazienti affetti da ADOA e ADOA-plus. La patogenicità di queste mutazioni è stata validata sia caratterizzando i difetti fenotipici associati agli alleli mutati, sia la loro dominanza/recessività nel modello di lievito. A tutt’oggi non è stato identificato alcun trattamento farmacologico per la cura di ADOA e ADOA-plus. Per questa ragione abbiamo utilizzato il nostro modello di lievito per la ricerca di molecole che agiscono come soppressori chimici, ossia composti in grado di ripristinare i difetti fenotipici indotti da mutazioni nel gene OPA1. Attraverso uno screening fenotipico high throughput sono state testate due differenti librerie di composti chimici. Questo approccio, noto con il nome di drug discovery, ha permesso l’identificazione di 23 potenziali molecole attive.

The service dominant logic:an MC21 project view

Vargo and Lusch propose a very exciting framework that aims in expanding the boundaries of the marketing discipline by moving away from the existing exchange paradigm towards a Service Dominant (S-D) logic. This new S-D logic has the potential to strengthen the theoretical grounds of marketing by establishing links to other disciplines. This commentary attempts to discuss some aspects of the foundational premises of the S-D logic from the perspective of the MC21 group with special emphases on innovation, value creation, and resource allocation.

Q parameter scaling in scalar and vector models with dominant signal-noise and noise-noise beating terms

The Q parameter scales differently with the noise power for the signal-noise and the noise-noise beating terms in scalar and vector models. Some procedures for including noise in the scalar model largely under-estimate the Q parameter.

Genetics of ocular disease Part 1: Basic concepts: cells, chromosomes and inheritance

This series of articles describes the basic elements of genetics necessary to understand the new advances and the impact these advances will have on the study and treatment of ocular disease. The first article describes the patterns of inheritance of human characteristics, how they are transmitted between the generations and the structure of chromosomes.

Genetics of ocular disease Part 3: Patterns of inheritance of ocular disease

The objective of this article is to describe the patterns of inheritance exhibited in the human populations and to illustrate them with examples drawn from a variety of ocular diseases.

Defective peroxisomal proliferators activated receptor gamma activity due to dominant-negative mutation synergizes with hypertension to accelerate cardiac fibrosis in mice

Aims: Humans with inactivating mutations in peroxisomal proliferators activated receptor gamma (PPAR?) typically develop a complex metabolic syndrome characterized by insulin resistance, diabetes, lipodystrophy, hypertension, and dyslipidaemia which is likely to increase their cardiovascular risk. Despite evidence that the activation of PPAR? may prevent cardiac fibrosis and hypertrophy, recent evidence has suggested that pharmacological activation of PPAR? causes increased cardiovascular mortality. In this study, we investigated the effects of defective PPAR? function on the development of cardiac fibrosis and hypertrophy in a murine model carrying a human dominant-negative mutation in PPAR?. Methods and results: Mice with a dominant-negative point mutation in PPAR? (P465L) and their wild-type (WT) littermates were treated with either subcutaneous angiotensin II (AngII) infusion or saline for 2 weeks. Heterozygous P465L and WT mice developed a similar increase in systolic blood pressure, but the mutant mice developed significantly more severe cardiac fibrosis to AngII that correlated with increased expression of profibrotic genes. Both groups similarly increased the heart weight to body weight ratio compared with saline-treated controls. There were no differences in fibrosis between saline-treated WT and P465L mice. Conclusion: These results show synergistic pathogenic effects between the presence of defective PPAR? and AngII-induced hypertension and suggest that patients with PPAR? mutation and hypertension may need more aggressive therapeutic measures to reduce the risk of accelerated cardiac fibrosis. © The Author 2009.

Access Rights Inheritance in Information Systems Controlled by Metadata

All information systems have to be protected. As the number of information objects and the number of users increase the task of information system’s protection becomes more difficult. One of the most difficult problems is access rights assignment. This paper describes the graph model of access rights inheritance. This model takes into account relations and dependences between different objects and between different users. The model can be implemented in the information systems controlled by the metadata, describing information objects and connections between them, such as the systems based on CASE-technology METAS.

Quantity-setting games with a dominant firm

We consider a possible game-theoretic foundation of Forchheimer's model of dominant-firm price leadership based on quantity-setting games with one large firm and many small firms. If the large firm is the exogenously given first mover, we obtain Forchheimer's model. We also investigate whether the large firm can emerge as a first mover of a timing game.

On Forchheimer's Model of Dominant Firm Price Leadership

We show that in a simple price-setting game with one large firm and many small firms the large firm does not accept the role of the price leader.

Domináns vállalat versenyképességének hatása az ellátási láncban (Effects of competitiveness of the dominant company in the supply chain)

Beszállító, gyártó és vevő vállalatok alkotnak egy ellátási láncot. Optimális esetben a vállalatok integrált rendszerben működnek, az együttműködés bizal mi alapon nyugszik, így a közös stratégiai döntések révén versenyképes lesz a lánc. Az ellátási láncban lehet egy kulcsfontosságú vállalat, amelyik domináns hatalmi pozícióval rendelkezik. A kutatás célja, hogy feltárja a hatalommal rendelkező vállalat szerepét a partnercégek és az ellátási lánc versenyképességének alakulásában. A szakirodalom alapján a hipotézis feltételezi, hogy van kapcsolat a versenyképesség és a domináns vállalat szerepvállalása között. A szerzők elemzése primer kutatáson alapul, a kérdőív válaszait SPSS statisztikai kiértékeléssel végezték. Az eredmények azt mutatták, hogy a domináns vállalat versenyképességétől valóban függ a partnercégek versenyképessége. Szignifikáns kapcsolat megléte bizonyítja a hipotézist. A vizsgálatok kiemelik, hogy a verseny már egy szinttel feljebb, az ellátási lánc szintjén értelmezhető: globális ellátási láncok versenyeznek egymással. _____ Supplier, producer and buyer companies make up a supply chain. In an optimal case the companies are integrated, partnership rests on trust which results in common strategic decisions leading to competitiveness. Each supply chain has a key company with dominant power position. The objective of the research is to analyse how the company with power affects competitiveness of partner firms and the supply chain as a whole. Based on theories hypothesis assumes a link between competitiveness and power position and its influence. Methodology of the analysis is based on primary research; the authors used SPSS statistical analysis to evaluate the answers of questionnaire. Findings include that partner firms’ competitiveness rely on competitiveness of the company with dominant power position. Significant connections prove that the hypothesis is true. Results show that competitiveness is being moved up to supply chain level. Global supply chains compete with each other.

Mitochondrial inheritance during a parasexual cycle in {\it Fusarium oxysporum\/} forma specialis {\it cubense\/}

Fusarium oxysporum is a diverse, asexual fungal species composed of both saprophytic and pathogenic members. The destructive phytopathogens are classified into formae speciales based on the host species and into vegetative compatibility groups (VCGs) based on the ability of two individuals to form heterokaryons. Parasexuality, a non-sexual mode of genetic exchange unique to some fungi has been demonstrated in the laboratory in Fusarium oxysporum f. sp. cubense (FOC). The goals of this dissertation were threefold: to ascertain whether mitochondrial (mt) markers can distinguish race differences in FOC; to determine genetic relatedness of VCGs in FOC based on a mt marker; and to discover the mode of mt inheritance during a parasexual cycle.^ Band patterns produced by electrophoresis of Hae III digested genomic DNA indicated that VCG differences, not race, could be discerned by mtDNA analysis. Primers were designed to amplify a mt intergenic locus which served as a molecular marker to screen 55 strains of FOC in 16 VCGs using both single strand conformational polymorphism and DNA sequencing. Based on homogeneity of the locus, strains were assigned to seven mitotypes, a classification unit which I introduced and found informative for grouping related VCGs.^ To determine the mode of mt inheritance during a parasexual cycle, strains in different mitotypes were paired. Mitochondrial inheritance in all hybrid progeny was found to be uniparental. I speculated that if a parasexual cycle occurs in nature there would be greater variation in the nuclear genome than the mt. This could produce multiple VCGs within a mitotype, a phenomenon observed in FOC. Based on these data, I concluded that parasexuality in nature may contribute to the diversity observed in Fusarium oxysporum. ^

I want out of the labels : how Chuck Palahniuk's characters challenge the dominant discourse

The purpose of this study was to explore postmodern identity in the work of Chuck Palahniuk. The characters within Palahniuk's text Invisible Monsters realize the manner in which identity is a construct, and their response is to oppose and redefine it. In my research, I looked at how postmodern identity is defined by some of the leading critical thinkers in the field, and then I applied their thought to Palahniuk's characters. I showed how these characters come to understand the process by which society defines them, and with that realization, they oppose its totalizing definitions. The characters deconstruct the natural attitudes society has towards identity, and they reveal that it is in some way possible to create a unique identity that is not easily definable by the ruling discourse. I concluded that his attention to identity highlights Palahniuk's concern for the place, identity, and influence of his generation.