ATG based combination therapy - a novel clinically relevant approach to promote regulation and induce long-term allograft survival

Regulatory T cells (Treg) actively regulate alloimmune responses and promote transplantation tolerance. Polyclonal anti-thymocyte globulin (ATG), a widely used induction therapy in clinical organ transplantation, depletes peripheral T cells. However, resistance to tolerance induction is seen with certain T cell depleting strategies and is attributed to alterations in the balance of naïve, memory and regulatory T cells. Here we report a novel reagent, murine ATG (mATG), depletes T cells but preferentially spares CD25+ natural Tregs which limit skewing of T cell repertoire toward T-effector-memory (Tem) phenotype among the recovering T cells. T-cell depletion with mATG combined with CTLA4Ig and Sirolimus synergize to prolong graft survival by tipping the Treg/Tem balance further in favor of Tregs by preserving Tregs, facilitating generation of new Tregs by a conversion mechanism and limiting Tem expansion in response to alloantigen and homeostatic proliferation. These results provide the rationale for translating such novel combination therapies to promote tolerance in primate and human organ transplantation.

Physical model of PD behavior and relevant damage growth from micro-cavities in polyethylene-based material under AC voltage

In the framework of developing defect-based life models, in which breakdown is explicitly associated with partial discharge (PD)-induced damage growth from a defect, ageing tests and PD measurements were carried out in the lab on polyethylene (PE) layered specimens containing artificial cavities. PD activity was monitored continuously during aging. A quasi-deterministic series of stages can be observed in the behavior of the main PD parameters (i.e. discharge repetition rate and amplitude). Phase-resolved PD patterns at various ageing stages were reproduced by numerical simulation which is based on a physical discharge model devoid of adaptive parameters. The evolution of the simulation parameters provides insight into the physical-chemical changes taking place at the dielectric/cavity interface during the aging process. PD activity shows similar time behavior under constant cavity gas volume and constant cavity gas pressure conditions, suggesting that the variation of PD parameters may not be attributed to the variation of the gas pressure. Brownish PD byproducts, consisting of oxygen containing moieties, and degradation pits were found at the dielectric/cavity interface. It is speculated that the change of PD activity is related to the composition of the cavity gas, as well as to the properties of dielectric/cavity interface.

Cyclic alternating pattern in sleep and its relationship to creativity

Background/Objectives: Sleep has been shown to enhance creativity, but the reason for this enhancement is not entirely known. There are several different physiological states associated with sleep. In addition to rapid (REM) and non-rapid eye movement (NREM) sleep, NREM sleep can be broken down into Stages (1-4) that are characterized by the degree of EEG slow wave activity. In addition, during NREM sleep there are transient but cyclic alternating patterns (CAP) of EEG activity and these CAPs can also be divided into three subtypes (A1-A3) according to speed of the EEG waves. Differences in CAP ratios have been previously linked to cognitive performances. The purpose of this study was to learn the relationship CAP activity during sleep and creativity. Methods: The participants were 8 healthy young adults (4 women), who underwent 3 consecutive nights of polysomnographic recording and took the Abbreviated Torrance Test for Adults (ATTA) on the 2 and 3rd mornings after the recordings. Results: There were positive correlations between Stage 1 of NREM sleep and some measures of creativity such as fluency (R= .797; p=.029) and flexibility ( R=.43; p=.002), between Stage 4 of Non-REM sleep and originality (R= .779; p=.034) and a global measure of figural creativity (R= .758; p=.040). There was also a negative correlation between REM sleep and originality (R= -.827; p= .042) . During NREM sleep the CAP rate, which in young people is primarily the A1 subtype, also correlated with originality (R= .765; p =.038). Conclusions: NREM sleep is associated with low levels of cortical arousal and low cortical arousal may enhance the ability of people to access to the remote associations that are critical for creative innovations. In addition, A1 CAP activity reflects frontal activity and the frontal lobes are important for divergent thinking, also a critical aspect of creativity.

Innovation and economic performance of the firms in the service sector: relevant issues and open problems

This thesis is a collection of essays related to the topic of innovation in the service sector. The choice of this structure is functional to the purpose of single out some of the relevant issues and try to tackle them, revising first the state of the literature and then proposing a way forward. Three relevant issues has been therefore selected: (i) the definition of innovation in the service sector and the connected question of measurement of innovation; (ii) the issue of productivity in services; (iii) the classification of innovative firms in the service sector. Facing the first issue, chapter II shows how the initial width of the original Schumpeterian definition of innovation has been narrowed and then passed to the service sector form the manufacturing one in a reduce technological form. Chapter III tackle the issue of productivity in services, discussing the difficulties for measuring productivity in a context where the output is often immaterial. We reconstruct the dispute on the Baumol’s cost disease argument and propose two different ways to go forward in the research on productivity in services: redefining the output along the line of a characteristic approach; and redefining the inputs, particularly analysing which kind of input it’s worth saving. Chapter IV derives an integrated taxonomy of innovative service and manufacturing firms, using data coming from the 2008 CIS survey for Italy. This taxonomy is based on the enlarged definition of “innovative firm” deriving from the Schumpeterian definition of innovation and classify firms using a cluster analysis techniques. The result is the emergence of a four cluster solution, where firms are differentiated by the breadth of the innovation activities in which they are involved. Chapter 5 reports some of the main conclusions of each singular previous chapter and the points worth of further research in the future.

Poverty and Mental Health. Tangible and Intangible Aspects of Microcredit

Microcredit, a small lending system, invests on an individual's creativity by stimulating the development of their own potential. This process leads to the attainment of various objectives which in turn allow individuals to develop their skill awareness. Consequently, this process also increases an individual’s self-esteem and self-confidence. These factors play an important role in the aetiology of a number of mental disorders. Namely, those characterized by a series of psychological conditions which impede the full development of a person’s personal, relational and social sphere. Furthermore, since Microcredit is thought to produce tangible goods, such as income, and intangible goods, such as self-esteem and mutual trust, it could also represent an innovative socio-economic tool. We therefore also hypothesize that, Microcredit would be valuable in maximizing abilities/skills in those subjects who are financially excluded and rarely perceived as a ‘resource’ for the Community The longitudinal study set the impact of the Grameen Bank microcredit program on new borrowers women from Noakhali District at the south Bangladesh. The impact evaluation assessment has been structured to detect individual, family and social changes. Manova Analysis allowed distinguishing from women with positive or negative outcomes related to the loan performance. Data revealed consistent differences in terms of economical outcomes and psychological well being amongst the groups of subject analyzed. The data gathered in relation to the changes arisen in the individuals should be looked into through future, continuous and systematic, monitoring.

Das moderne Buch: Harry Graf Kesslers Ästhetik der Lebenskunst im Spiegel der Großherzog Wilhelm Ernst Ausgabe deutscher Klassiker

Die Großherzog Wilhelm Ernst Ausgabe deutscher Klassiker wurde seit 1904 bis in die Zwanziger Jahre hinein im Insel Verlag in Leipzig publiziert. Die Buchreihe hat nicht nur für den Verlag und die Druckerei Poeschel in der sie gedruckt wurde eine ganze Reihe von Neuerungen nach sich gezogen, auch für den deutschen Buchmarkt hat die Klassikerausgabe einen Meilenstein bedeutet. Sie hat einige Eigenschaften des Taschenbuches vorweggenommen. Sie orientierte sich an der Qualität bibliophiler Buchpublikationen, aber war dennoch preislich erschwinglich. Zeitgenössische Klassikerausgaben erschienen zumeist mit einem Kommentar. Nicht so die Großherzog Wilhelm Ernst Ausgabe. Der Text wurde zwar von führenden Wissenschaftlern editiert, aber sie war dennoch unkommentiert. Der Text war in einer Jenson-Antiqua gesetzt obwohl die Debatte um individuell gestaltete Künstlerschriften und die Diskussion um die als deutsche Schrift begriffene Fraktur unter den wichtigsten Protagonisten des deutschen Buchgewerbes ihren Höhepunkt noch nicht erreicht hatte. Ziel für die Klassikerausgabe war darüber hinaus, das zur Jahrhundertwende leicht angestaubte Image der Stadt Weimar aufzupolieren. Über das Patronat des Großherzogs hinaus hätte man die Gewinne aus dem Verkauf der Bücher der Permanenten Ausstellung für die Anschaffung von modernen Kunstobjekten zur Verfügung stellen wollen, die unter der Leitung von Harry Graf Kessler stand. Sieht man den Inhalt der Werke der in der Klassikerreihe erschienen Dichter Goethe, Schiller und Körner in einem ästhetischen Kontext mit dem der Philosophen Schopenhauer und Kant, wird im Spiegel der Formalästhetik der Klassikerausgabe Graf Kesslers Bildungs- und Kulturbegriff erkennbar, der sich in den Jahren nach der Jahrhundertwende zu seinem Lebenskunstideal verdichtete. Der zerrütteten Existenz der Zeitgenossen, wie Friedrich Nietzsche sie beschrieben hatte, sollte der Inhalt der Ausgabe in seiner modernen Form eine moderne Wertehaltung entgegensetzen. Die Lektüre der Klassiker sollte den deutschen Philister „entkrampfen“ und ihm ein Stück der verloren geglaubten Lebensfreude wieder zurück bringen, in dem dieser auch die Facetten des Lebensleids als normal hinnehmen und akzeptieren lernte. Die Klassikerausgabe repräsentierte aus diesem Grund auch den kulturellen und politischen Reformwillen und die gesellschaftlichen Vorstellungen die der Graf für ein modernes Deutschland als überfällig erachtete. Die Buchreihe war aus diesem Grund auch ein politisches Statement gegen die Beharrungskräfte im deutschen Kaiserreich. Die Klassikerreihe wurde in der buchhistorischen Forschung zwar als bedeutender Meilenstein charakterisiert und als „wichtiges“ oder gar „revolutionäres“ Werk der Zeit hervorgehoben, die Ergebnisse der Forschung kann man überspitzt aber in der Aussage zusammenfassen, dass es sich bei der Großherzog Wilhelm Ernst Ausgabe um einen „zufälligen Glückstreffer“ deutscher Buchgestaltung zu handeln scheint. Zumindest lassen die Aussagen, die bisher in dieser Hinsicht gemacht wurden, keine eindeutige Einordnung zu, außer vielleicht der, dass die Klassiker von der englischen Lebensreform inspiriert wurden und Henry van de Velde und William Morris einen Einfluss auf ihre äußere Form hatten. Gerade die Gedankenansätze dieser Beiden nutzte Graf Kessler aber für eigene Überlegungen, die ihn schließlich auch zu eigenen Vorstellungen von idealer Buchgestaltung brachten. Da für Kessler auch Gebrauchsgegenstände Kunst sein konnten, wird das Konzept der Klassikerausgabe bis zur Umsetzung in ihrer `bahnbrechenden´ Form in das ideengeschichtliche und ästhetische Denken des Grafen eingeordnet. Die Klassiker werden zwar in buchhistorischen Einzeluntersuchungen bezüglich ihrer Komponenten, dem Dünndruckpapier, ihrem Einband oder der Schrifttype exponiert. In buchwissenschaftlichen Überblicksdarstellungen wird ihr Einfluss hingegen weniger beachtet, denn verschiedene Kritiker bezogen sie seit ihrem ersten Erscheinen nicht als deutsches Kulturgut mit ein, denn sie lehnten sowohl die englischen Mitarbeiter Emery Walker, Edward Johnston, Eric Gill und Douglas Cockerell wie auch ihre Gestaltung als „welsche“ Buchausgabe ab. Richtig ist, die Großherzog Wilhelm Ernst Ausgabe hatte dieselbe Funktion wie die von Graf Kessler in Weimar konzipierten Kunstausstellungen und die dortige Kunstschule unter der Leitung seines Freundes Henry van de Velde. Auch das für Weimar geplante Theater, das unter der Leitung von Hugo von Hofmannsthal hätte stehen sollen und die Großherzog Wilhelm Ernst Schule, hätten dieselben Ideen der Moderne mit anderen Mitteln transportieren sollen, wie die Großherzog Wilhelm Ernst Ausgabe deutscher Klassiker.

Identification and genetic diversity in phytoplasmas associated with diseases of cassava and other agronomic relevant crops in south-east Asia and Latin America

Identification and genetic diversity of phytoplasmas infecting tropical plant species, selected among those most agronomically relevant in South-east Asia and Latin America were studied. Correlation between evolutionary divergence of relevant phytoplasma strains and their geographic distribution by comparison on homologous genes of phytoplasma strains detected in the same or related plant species in other geographical areas worldwide was achieved. Molecular diversity was studied on genes coding ribosomal proteins, groEL, tuf and amp besides phytoplasma 16S rRNA. Selected samples infected by phytoplasmas belonging to diverse ribosomal groups were also studied by in silico RFLP followed by phylogenetic analyses. Moreover a partial genome annotation of a ‘Ca. P. brasiliense’ strain was done towards future application for epidemiological studies. Phytoplasma presence in cassava showing frog skin (CFSD) and witches’ broom (CWB) diseases in Costa Rica - Paraguay and in Vietnam – Thailand, respectively, was evaluated. In both cases, the diseases were associated with phytoplasmas related to aster yellows, apple proliferation and “stolbur” groups, while only phytoplasma related to X-disease group in CFSD, and to hibiscus witches’ broom, elm yellows and clover proliferation groups in CWB. Variability was found among strains belonging to the same ribosomal group but having different geographic origin and associated with different disease. Additionally, a dodder transmission assay to elucidate the role of phytoplasmas in CWB disease was carried out, and resulted in typical phytoplasma symptoms in periwinkle plants associated with the presence of aster yellows-related strains. Lethal wilt disease, a severe disease of oil palm in Colombia that is spreading throughout South America was also studied. Phytoplasmas were detected in symptomatic oil palm and identified as ‘Ca. P. asteris’, ribosomal subgroup 16SrI-B, and were distinguished from other aster yellows phytoplasmas used as reference strains; in particular, from an aster yellows strain infecting corn in the same country.

A multiparental cross population for mapping QTL for relevant agronomic traits in durum wheat (Triticum durum Desf.)

Multiparental cross designs for mapping quantitative trait loci (QTL) in crops are efficient alternatives to conventional biparental experimental populations because they exploit a broader genetic basis and higher mapping resolution. We describe the development and deployment of a multiparental recombinant inbred line (RIL) population in durum wheat (Triticum durum Desf.) obtained by crossing four elite cultivars characterized by different traits of agronomic value. A linkage map spanning 2,663 cM and including 7,594 single nucleotide polymorphisms (SNPs) was produced by genotyping 338 RILs with a wheat-dedicated 90k SNP chip. A cluster file was developed for correct allele calling in the framework of the tetraploid durum wheat genome. Based on phenotypic data collected over four field experiments, a multi-trait quantitative trait loci (QTL) analysis was carried out for 18 traits of agronomic relevance (including yield, yield-components, morpho-physiological and seed quality traits). Across environments, a total of 63 QTL were identified and characterized in terms of the four founder haplotypes. We mapped two QTL for grain yield across environments and 23 QTL for grain yield components. A novel major QTL for number of grain per spikelet/ear was mapped on chr 2A and shown to control up to 39% of phenotypic variance in this cross. Functionally different QTL alleles, in terms of direction and size of genetic effect, were distributed among the four parents. Based on the occurrence of QTL-clusters, we characterized the breeding values (in terms of effects on yield) of most of QTL for heading and maturity as well as yield component and quality QTL. This multiparental RIL population provides the wheat community with a highly informative QTL mapping resource enabling the dissection of the genetic architecture of multiple agronomic relevant traits in durum wheat.

Cancer and aging: a multidisciplinary medicinal chemistry approach on relevant biological targets such as proteasome, sirtuins and interleukin 6

It is well known that ageing and cancer have common origins due to internal and environmental stress and share some common hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury. Moreover, ageing is involved in a number of events responsible for carcinogenesis and cancer development at the molecular, cellular, and tissue levels. Ageing could represent a “blockbuster” market because the target patient group includes potentially every person; at the same time, oncology has become the largest therapeutic area in the pharmaceutical industry in terms of the number of projects, clinical trials and research and development (R&D) spending, but cancer remains one of the leading causes of mortality worldwide. The overall aim of the work presented in this thesis was the rational design of new compounds able to modulate activity of relevant targets involved in cancer and aging-related pathologies, namely proteasome and immunoproteasome, sirtuins and interleukin 6. These three targets play different roles in human cells, but the modulation of its activity using small molecules could have beneficial effects on one or more aging-related diseases and cancer. We identified new moderately active and selective non-peptidic compounds able to inhibit the activity of both standard and immunoproteasome, as well as novel and selective scaffolds that would bind and inhibit SIRT6 selectively and can be used to sensitize tumor cells to commonly used anticancer agents such gemcitabine and olaparib. Moreover, our virtual screening approach led us also to the discovery of new putative modulators of SIRT3 with interesting in-vitro and cellular activity. Although the selectivity and potency of the identified chemical scaffolds are susceptible to be further improved, these compounds can be considered as highly promising leads for the development of future therapeutics.

Innovative asymmetric organocatalytic processess: en route to the synthesis of biologically relevant compounds

This doctoral thesis deals with the development of novel organocatalytic strategies for asymmetric transformation. The intrinsic versatility of organocatalysis and the use of different activation modes have been exploited to achieve new catalytic enantioselective processes, towards the synthesis of biologically relevant scaffolds. The most investigated organocatalytic system have been those based on H-bond interaction (such as chiral thioureas or phosphoric acids) as well as the ones based on aminocatalysis. Despite conceptually distinct, the transformations detailed in this Thesis are linked together by simple and recurring modes of activation, induction and reactivity, promoted by the catalysts employed. The chemical diversity of the challenges encountered allows to get a precious overall view on organocatalysis, highlighting that enormous chemical diversity can be created by judicious choice of select catalyst.

Brand formative design - development and assessment of product design from a future, brand and consumer perspective

With this dissertation research we investigate intersections between design and marketing and in this respect, which factors do contribute that a product design becomes brand formative. We have developed a Brand Formative Design (BFD) framework, which investigates individual design features in a holistic, comparable, brand relevant, and consumer specific context. We discuss what kinds of characteristics contribute to BFD but also illuminate how they should be applied and examine: rnA holistic framework leading to Brand Formative Design. Identification and assessment of BFD Drivers. The dissection of products into three Distinctive Design Levels. The detection of surprising design preferences. The appropriate degree of scheme deviation with evolutionary design. Simulated BFD development processes with three different products and the integration of consumers. Future oriented objectification, comparability and assessment of design. Recommendations for the management of design in a brand specific context. Design is a product feature, which contributes significantly to the success of products. However, the development of new design contains challenges. Design can hardly be objectified; many people have an opinion concerning the attractiveness of new products but cannot formulate their future preferences. Product design is widely developed based on intuition, which can be difficult for the management of design. Here the concept of Brand Formative Design can provide a framework which contributes to structure, objectify, develop and assess new evolutionary design in brand and future relevant contexts, but also integrates consumers and their preferences without restricting creativity too much.

Bleaching of nonvital teeth: a clinically relevant literature review

Today, the bleaching of nonvital, discolored teeth is a low-risk routine treatment for improving esthetics. This review article focuses on the etiology of tooth discolorations, different treatment techniques, and risks of bleaching procedures. Some tooth discolorations in endodontically treated teeth are caused by dental treatments. The three most popular techniques for nonvital tooth bleaching are the walking bleach technique, inside/outside bleaching, and in-office bleaching. The walking bleach technique is a relatively reliable, fairly simple technique for dentists and patients. Inside/outside bleaching can be used additionally when internal and external bleaching must be combined. Inoffice bleaching seems to be a short-term solution, the effects of which can largely be attributed to dehydration of the teeth. There are still some open questions concerning the bleaching agents. Improved safety seems desirable with regard to adding thiourea as a scavenger of radicals or newer materials such as sodium percarbonate. The thermocatalytic technique, insufficient cervical sealing, and high concentrations of bleaching agents should be avoided, as this can increase the risk of cervical root resorptions. Patients should be informed about the low predictability of bleaching success and the risk of recurrent discoloration. The risk of cervical root resorption should be discussed with the patient. There is a strong correlation between root resorption and dental trauma.

Emergency skill training--a randomized controlled study on the effectiveness of the 4-stage approach compared to traditional clinical teaching

The "4-stage approach" has been widely accepted for practical skill training replacing the traditional 2 stages ("see one, do one"). However, the superior effectiveness of the 4-stage approach was never proved.

Oropharyngeal lesions and cervical lymphadenopathy: syphilis is a differential diagnosis that is still relevant

Syphilis (lues), a chronic infectious disease caused by Treponema pallidum, has been increasing in incidence during the last few years. Therefore, while clinically it is often not suspected, syphilis is increasingly becoming a differential diagnosis in routine pathology.