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Adaptive changes of the gastrointestinal neuromuscolar function in a mouse model of Catechol-O-Methyl trasferase genetic reduction: implication in the pathogenesis of Irritable Bowel syndrome.
No full textEnteric neuronal circuitries display a considerable ability to adapt to a changing microenvironment, which comprises several cellular "players", including neurons, enteric glial cells, smooth muscle cells, interstitial cells of Cajal, immune cells and commensal bacteria (Giaroni et al., 1999). In particular, gut microbiota seems to be directly involved in modulating the development and function of enteric nervous system (ENS), supporting the concept that changes in commensal microbiome composition, induced by infections or antibiotics, can perturb ENS integrity and activity. Neuronal circuitries in the ENS are known to communicate with the Central Nervous System (CNS) via vagal and sympathetic extrinsic pathways: the so called brain-gut axis. Current cutting-edge research suggests that the enteric microbiota, by modifying enteric neuronal circuitries, may communicate with the brain, thus influencing cognitive and behavioural functions. However, early life perturbations of gut microbiota can potentially influence neurodevelopment leading to functional bowel disorders later in life (Ianiro et al., 2016). There is increasing evidence showing that an altered microbiota composition may be related to functional or psychiatric disorders such as irritable bowel syndrome (Bonfrate et al., 2013; Kennedy et al., 2014) and autism (Finegold, 2011; Mayer et al., 2014).
Irritable bowel syndrome (IBS) comprises a heterogeneous group of functional lower gastrointestinal tract disorders characterized by abdominal pain or discomfort associated with altered bowel habits and disordered defecation that may be exacerbated by emotional stress.
This gut disorder cannot be explained by specific pathophysiologic mechanisms, since it is not associated with any structural finding or biological marker (Mach, 2004). However, the symptoms of IBS are related to combinations of several known physiological determinants such as abnormal motor reactivity, enhanced visceral hypersensitivity, altered mucosal immune and inflammatory functions (which includes changes in bacterial flora), and altered brain-ENS regulation, which is influenced by psychosocial and socio-cultural factors (Drossman, 2006; Ohman and Simren, 2010; Simren et al., 2013). Recently, the association between gut functional disorders, such as IBS, and catechol-O-methyl-transferase (COMT), an enzyme protein which regulates catecholamines levels in mammalian brain (Lundstrom et al., 1995; Mannisto and Kaakkola, 1999) has been proposed. In this perspective, IBS can be described as a disorder of the gut–brain axis (Moloney et al., 2016). The aim of the study was to determine whether a genetic-driven defective COMT activity may affect the structural and functional integrity of murine ENS. Data obtained in the COMTtransgenic mouse model have been compared to those obtained in the gastrointestinal tract of antibiotic treated-mice in order to deplete the microbiota. Data showed that the partial deletion of COMT determined anomalies in the ENS architecture, with a marked increase in protein and mRNA expression of the glial marker S100β. Excitatory cholinergic transmission and inhibitory nitrergic neurotransmission, mainly through iNOS increased expression, led to impaired gut neuromuscular contractility. In addition, an increase of GluN1 glutamatergic subunit expression, affecting visceral hypersensitivity with critical effects on gut function, was also observed. The massive antibiotic treatment determined the same alterations in ENS structure and function observed in the COMT transgenic model. Interestingly, COMT partial genetic deletion induced changes in gut microbioma composition and some commensal intestinal microbial strains underwent drastic changes. In particular, in COMT+/- mice a significant increase of Firmicutes DNA in the ileum and colon and a significant decrease of Bacterioidetes DNA in the ileum were observed with respect to control animals, suggesting that host may affect gut microbial flora arrangement. These data confirmed the importance of studying the interplay between host and microbiota, reflecting alterations in motor and sensitive parameters which resemble some features of functional gastrointestinal disorders, such as Irritable Bowel Syndrome (IBS). In conclusion, this study showed that both COMT genetic deletion as well as dysbiosis may be critical factors involved in the pathogenesis of functional gut disorders, such as IBS
Morphological and ‘omics’ analysis of root systems in agronomics plant grown under biochar applications
Full text linkThe continued increase of the demand for agricultural crops is responsible of a strong environmental deterioration due to soil fragmentation as well as, to a massive use of fertilizers uses that pollute both water and terrestrial ecosystems. In the future, this demand will growth up more and more. This explain why is crucial to find a new approach and new technologies to achieve greater yields with a lower environmental impact. Biochar is a solid material obtained from a process called pyrolysis characterized by a thermal transformation of biomass at high temperature and in the absence of oxygen. This mineral transformation attributes to biochar a skeletal structure that looks like a carbon sponge, which allows a higher water retention. The addition of biochar to the soil reduces leaching of ammonium compared to untreated soil due to its characteristic sponge structure and recently, it has been observed that also the total nitrates/nitrites, ammonia and nitrogen content and the nitrogen fixation rate are affected. The aim of this work is investigate some morphological and molecular response of plants treated with biochar. For this purpose, two of the most important crop species and one model specie have been tested: 1) Solanum lycopersicum (Cherry tomato of Pachino vr), 2) Vitis vinifera (Chardonnay cv) and 3) Arabidopsis thaliana.
Concerning Cherry tomato cultivar, the plant treated with biochar has shown an interesting modification of seedling and fruit traits – especially in the case of fruit quality.
In regard to Vitis vinifera, positive effects have been detected in both experiments (pot and field treatments) with biochar, improving the root length in pot experiment while the radial root growth in field experiment. Finally, in Arabidopsis, biochar addition has induced positive effects in all the parameters measured under normal watering regime. In the case of seedlings affected by water stress, the presence of biochar seemed to inhibit strongly the plants growth.
Data obtained in this work throw light upon some of the most important aspects of plant nutrition and development. They indicate how those are modified in presence of biochar
Tanatologia e tecnologia. Metamorfosi del concetto e dei rituali di morte nella società post-umana e tecnofila. Thanatology and technology. Metamorphosis and the concept of death rituals In the post-human society and technophilic.
No full textrichiesto più brev
Il diritto alla terra dei popoli indigeni in prospettiva comparata. Il caso dell’America Latina. The right to traditional land of indigenous peoples in a comparative perspective. The Latin American case.
No full textThe dissertation aims to investigate the problematic question of the return of indigenous peoples in their historical lands and the deep connection between their culture and their political institutions with environment, nature and tradition, as it is actually introduced by international law and public law in the different countries where the indigenous presence is relevant.
The definition of "indigenous people" and its development in the international scenario in the last decades has characterized a new consideration about the rights of indigenous peoples, whose self-determination is otherwise connected to a specific land, occupied and translated from generations and synonymous of an unique identity (the so-called anthropological concept of "ancestral land"). It caused a re-interpretation of the relationship between lands and indigenous peoples, either providing the reintegration of indigenous in their ancestral lands (once expropriated by State authorities), either considering a unified point-of-view on land/earth as a common, in which natural resources should be managed by communities (referring to the concept of "Mother Earth").
The thesis investigates the international protection of the rights of indigenous peoples and its development in history, considering the protection extended by the ILO Conventions (1957/n.105 and 1989/n.169) and the UN Declaration on the Rights of Indigenous Peoples 2007 and the influence of the Cobo Report in international and national law. It also deals with some "virtuous" cases involving a special relation between national institutions and indigenous communities, in order to create a legal paradigm of protection to indigenous peoples and their historical rights (i.e., the cases of North-American natives, Australian aborigines, New Zealand maoris and Scandinavian saamis).
The protection of indigenous peoples and their traditional lands becomes a particularly relevant fact in the Latin-American contest for the peculiar complexity (historically based) of the relationship with natives and the important phase of political and democratic transition in '80s-'90s. New Constitutions (or constitutional reviews), elaborated in this period in the Latin-American region, have been affected by the theory of Nuevo Constitucionalismo, that totally disagrees with the western constitutionalism and with the theory of legal positivism. According to this new constitutional theory, indigenous customary law is considered among the basics of national law, granted and protected by the Constitution. It provides that the natives are seen as an entity per se, recognized by the State (and not forcedly integrated into the European inspired reality, as in the past years), entitled to possess their ancestral lands and to claim their own rights (even the cultural ones). In order to this renewal, the indigenous costumbre becomes law of the State. So on, the common managing on lands and natural resources are to be in accordance with the indigenous harmonic relationship with nature. Earth, or Mother Earth (Tierra Madre or, using a quechua term, Pacha Mama), becomes effectively a common.
The thesis deals with the political passage of transition to democracy in Latin-American region and with the construction of a new constitutionalism, affected by the consideration of collective rights and the protection of social and cultural minorities. It also provides to do a general framework of the recent Latin-American constitutions and their protection of indigenous rights and indigenous property of lands (with a specific consideration about the Andean constitutionalism in Bolivia and Ecuador and the revolutionary entrance of customary laws). Then, the analysis focuses on the case of Paraguay and Argentina, whereas the new constitutional laws (Constitution of Paraguay in 1992 and constitutional review in Argentina in 1994) have expressively contemplated the recognition and the protection of the indigenous right to historical lands, also considering the development of the protection in the political and legal history of the States.
Finally, the research aims to focus on the role of the Inter-American Court of Human Rights in creating a constitutional and international parameter of protection of indigenous land right and providing the return of indigenous communities in their traditional lands. The decisions of the Inter- American Court are actually a bridge for the incorporation of indigenous rights in national legislations, providing a constitutional-oriented jurisprudence and giving an important signal for the international debate
LA cura degli interessi dei centri storici. Il centro storico come sistema complesso e come bene comune.
Full text linkHistoric centers are characterized by a high degree of complexity. In the first part of the thesis, an overview of basic knowledge of the regulatory system is given to the reader, by mapping the norms involving the historical centers.
To further emphasize the fact that the historic center involves extremely varied interests, many different aspects are analyzed, for example the effects of gentrification, the problem of soil consumption, restructuring incentives, the norms regarding the circulation and parking in historic centers, antipollution measures, in addition to the great theme of the delicate relationship between a site's vitality and the trade protection in historic centers.
The second part of the thesis has a constructive and innovative approach. The aim is to induce the reader to look at the historical center from a new perspective, exploiting multidisciplinary concepts. It is required a new methodological approach for this topic, that is to describe the historical center as a complex adaptive system and as a Commons, trying to find a new model for the management of historical centers.
In the concluding part of the elaboration is carried out an empirical research of the administrative techniques of management of the historical centers, the research concerns the level of the Italian municipal administrations, in this context a great emphasis is devoted to the important model of the UNESCO Site Management Plans.
The UNESCO site reference rules are explained and later the Italian experience is analyzed, special attention is given to the Management Plans of Historic Centers UNESCO sites of the Municipalities of Florence and Siena. Based on these considerations, more general conclusions are taken. For more details, refer to the full text of the PhD thesis
L'alimentazione nell'anziano dal domicilio alla lungodegenza. Etica ed appropriatezza dell'apporto nutrizionale nei percorsi assistenziali. Feeding in the elderly from domicile to long term care. Ethics and appropriateness of nutritional support in care paths.
No full textBACKGROUND: The World Health Organization estimates that the population over the age of 60 is growing steadily and will double by the year 2050.
In the elderly there are physiological modifications but incorrect nutrition can produce a state of malnutrition that may result in excessive morbidity and mortality or an alteration in the quality of life. Therefore, the diagnosis and therapy of malnutrition are one of the key moments of elder care.
Recovery of at least 5% of body weight can reduce the incidence of morbidity and mortality in institutionalized patients.
There are several studies in the literature on the state of malnutrition in the elderly, but no one takes into account all the possible risk factors and variations that may arise in nutritional status prior to entering in long term care and later.
OBJECTIVE: To assess the state of nutrition and risk factors for malnutrition of patients at the time of entry into a long-term care. Monitor dietary intake during hospitalization and check for changes in nutritional status at a distance of one month from the beginning of institutionalization. This path is promoted:
1) as a means of improving the quality of care,
2) as a means to optimize the outcome of interventions on patients,
3) to discourage and detect ineffective or dangerous interventions,
4) to improve and ensure the adequacy of care,
5) to identify areas of clinical practice where there is insufficient evidence,
6) to help balance costs and results.
MATERIALS AND METHODS: A cohort study was developed on eight long term care in which were the same menu, raw materials and methodologies. The population of study is constituted by the new patients of more than 65 years, males or females indifferently and who have signed informed consent to the processing of their data in anonymous form for statistical purposes. People in enteral nutrition were excluded from the study. The collected data encompasses the characteristics of patients and their conditions at time 0, their eating behavior and conditions after a month in long term care (time 1). Data were extracted from clinical diaries, assessment scales and laboratory examinations.
RESULTS: The general characteristics of patients (sex, age, level of instruction and provenance), patient conditions at time 0 and time 1 (general conditions, state consciousness, most frequent pathologies, pharmacotherapy, oral cavity conditions, dysphagia, decubitus lesions, walking, cognitive level -MMSE-), nutritional evaluation at time 0 and time 1 (weight, body mass index, weight variations, use of a diet, use of dietary supplements, malnutrition risk -MUST-) and laboratory examinations evaluation at time 0 and time 1 (hemoglobin, absolute lymphocytes, serum iron, folic acid, vitamin B12, vitamin D, calcium, albumin, total cholesterol, glucose).
CONCLUSIONS: On the basis of analyzed data, it is concluded that proper nutrition in older people does not go through the construction of a pyramid process but by the creation of a harmonic gear consisting of doctors, chefs, nutritionists, professional educators, caregivers and institutions
Omyc analyzes reveal how plants respond to the symbiosis with the arbuscolar mycorrhizal fungi and symbiotic bacteria
No full textCurrently, there is an increasing body of evidence that the plant health depends on their tight associations with specialised soil microorganisms that have great effects on plant growth, protection and productivity. Among them, arbuscular mycorrhizal (AM) fungi (subphylum Glomeromycota, Schüßler et al., 2001) can establish a mutualistic association with most terrestrial plant species, including important agricultural and horticultural crops (Bonfante and Genre 2015). The AM symbiosis develops in roots, where the fungus colonizes the cortex supplying mineral nutrients to the plants in exchange of photosynthetic carbon compounds (Smith and Rweead, 2008). The exchanges between fungus and plant occur through specialized, branched and intracellular fungal structures called arbuscules (Bonfante and Anca 2009). Besides an improved mineral nutrition, plants colonized by AMF also receive other benefits, including an increased biomass, yield, and higher tolerance to biotic (pathogens) and abiotic (drought, salinity, heavy metals) stresses, leading to improved plant fitness (Gernns et al. 2001; Van der Heijden and Sanders 2002; Hildebrandt et al. 2007; Pozo and Azcón- Aguilar 2007; Aroca et al. 2008; Pozo et al., 2010; Lanfranco and Young 2012). Many plant roots also harbour a variety of soil beneficial bacteria that can benefit the plant by serving as plant-growth promoters. These bacteria, known as PGPR (plant-growth promoting rhizobacteria) can work as active rhizosphere components (Caballero-Mellado et al., 2007) or endophytic plant colonizers (Paungfoo-Lonhienne et al., 2014). The mechanisms that promote plant growth and development include: solubilization of minerals, nitrogen fixation, production of siderophores, plant growth regulators and organic acids, as well as protection by enzymes like chitinase, ACC-deaminase and glucanase (Berg, 2009; Glick et al., 2007; Hayat et al., 2010). These microorganisms can enhance biomass production and tolerance of the plants to several soil conditions as salinity, drought and heavy metals (Baharlouei et al., 2011). However, knowledge on the interaction of PGPR with many plants of agronomic interest is still scarce (Castanheira et al., 2015). Among plants colonized by AMF and PGPR is the bread wheat (Triticum aestivum), one of the most important food supply and the third-most widely grown crop worldwide, after rice and corn. Despite its economic and social importance, the effects of wheat symbiosis with the above microbes, considered individually or together, have never been investigated, in contrast to many other crop plants. Thanks to their benefits, AMF and PGPR can be used as natural biofertilizers and bioprotectors in integrated strategies for a sustainable and healthy wheat production. Furthermore, some AMF may contain endobacteria in their cytoplasm. These bacteria have a reduced genome, which lacks some crucial metabolic pathways and reveals dependence on the host for nutrients and energy (Ghignone et al. 2012). In exchange, they give many benefits to fungal host, sustaining its presymbiotic growth (Lumini et al., 2007; Salvioli et al., 2015), increasing the success of AMF sporulation and mechanisms for ROSdetoxification, and eliciting AMF innate immune responses (Salvioli et al., 2015). The beneficial effects of mycorrhizae in the rhizosphere are the result of synergistic interactions among all rhizosphere microbes, which are crucial for plant growth (Linderman, 1992). Thus, the relationship between AMF, their associated bacteria and plants provides a very interesting example of a metaorganism (Bosch and McFall-Ngai, 2011) and may be of great importance for sustainable agriculture.
In view of the above observations, during this thesis work three aims were pursued.
The first was the characterization of the molecular responses of wheat roots and leaves in presence of AMF alone and with a leaf pathogen to test whether AM fungi can be used as biofertilizer and bioprotector for enhancing plant growth and yield. We investigated the main pathways involved in enhancing plant biomass and mineral nutrition, and in promoting the bioprotective effect against a leaf pathogen. To address these issues, we combined phenotypic, metabolomic and molecular approaches, as detailed in Chapter 1.
The second aim was to analyze how proteome of wheat, in both roots and leaves, changes in response to colonisation by AMF and PGPR, considering single or double inocula. The purpose was to use these rhizosphere microbes in integrated strategies for a sustainable agriculture to improve plant health and yield. We wanted to achieve information about proteins that play pivotal roles in the molecular interactions of wheat with AMF and PGPR. In particular, this study has been set to obtain proteomic data providing a comprehensive picture of the intricate and yet mostly unknown cross-talk between wheat and AMF/PGPR. Methods and results of this study are reported in Chapter 2.
The third aim was to understand the effects of AMF endobacteria on both fungal and plant fitness. Thus, we analysed the proteomic profile of AMF spores with and without endobacteria, and after application of the synthetic strigolactone GR24 that, similarly to strigolactones produced by plant roots, is perceived by AM fungi, stimulating their energy metabolism and growth. The goal was to better explain with proteomics some morphological traits of the spore without bacteria. Moreover, we wanted to provide new insights into the molecular mechanisms mediating endosymbiosis and into how bacteria provide direct and/or indirect ecological benefits, not only for their fungal host, but also for the plant. A full account of this investigation is given in Chapter 3.
The research activities carried out during this thesis can be divided in the following three distinct, but interconnected parts.
In Chapter 1, we focused on the role of an AM fungus (Funneliformis mosseae) in the mineral nutrition of wheat, and on its potential protective effect against a leaf pathogen (Xanthomonas translucens). To address these issues, phenotypical, metabolomic and molecular approaches have been combined. Several studies have shown that both model and agricultural plants colonized by AMF often display an increased mineral nutrition and biomass, and higher tolerance to biotic and abiotic stresses. Despite wheat being one of the major global crops, its response to AM symbiosis has been poorly investigated so far. In this study, morphological observations indicated that AM wheat plants displayed a growth effect, in terms of biomass and grain yield, as well as a reduction of the lesions produced by the pathogen. To elucidate the molecular mechanisms underlying the mycorrhizal phenotype, we investigated the local and systemic changes of transcripts and proteins in roots and leaves during the bipartite (wheat-AM fungus) and tripartite (wheat-AM fungus-pathogen) interaction. Transcriptomic and proteomic profiling identified the main pathways (nutrient transport, primary metabolism, defence mechanisms, hormone regulation) involved in enhancing plant biomass, mineral nutrient content and in promoting the bio-protective effect against the leaf pathogen. Interestingly, the pathways were differentially regulated depending on the plant organ/microbe relationship. Mineral and amino-acid contents in roots, leaves and seeds, and protein oxidation profiles in leaves supported the omics data, providing new insightin the mechanisms exerted by AM symbiosis to confer stronger productivity and higher resistance to X. translucens in wheat.
In Chapter 2, we studied the mechanisms behind PGPR (Burkholderia graminis) - wheat interactions and the synergic interaction between B. graminis and F. mosseae on plant, through a proteomic analysis of wheat roots and leaves. Thus, we investigated the proteome alterations triggered in wheat by the dual inoculation PGPR + AMF compared to the sum of the effects elicited by single inocula. The main pathways identified concerned regulation of metabolic process, phytohormones, mineral transport and stress responses. In plants inoculated with B. graminis, the regulation of proteins involved in auxin pathways and the increase of N uptake efficiency may explain the observed root growth increase upon PGPR inoculation. Moreover, bacteria promoted the increase of several proteins involved in abiotic stress, in particular salt stress, and may contribute to improvement of the plant performance under stress conditions. Dual inoculation further led to the activation of many growth and defense-related proteins in roots and at systemic level. This result indicates that the dual inoculation in wheat enhances the biofertilizer and bioprotective effects of PGPR B. graminis and AMF F. mossae when co-inoculated. Phenotypic results also revealed that dual inoculation stimulates the growth of both roots and leaves of wheat plants with respect to the control.
Finally, in Chapter 3, we shed light on the interaction between AMF and their endosymbiont bacteria. RNA-seq analysis of the AMF Gigaspora margarita in the presence and absence of its endobacterium Candidatus Glomeribacter gigasporarum indicated that endobacteria are able to enhance fungal bioenergetics capacity. iTRAQ quantitative proteomics was used to identify differentially expressed proteins in G. margarita germinating spores with its endobacteria (B+), without endobacteria in the cured line (B-) and after application of the synthetic strigolactone GR24. Proteomic, transcriptomic and biochemical data identified several fungal and bacterial proteins involved in interspecies interactions. The greatest effects were on fungal primary metabolism and respiration, which was 50% higher in B+ than in B-. Quantification of carbonylated proteins indicated that the B- line had higher oxidative stress levels, which were also observed in two host plants. This study shows that endobacteria generate a complex interdomain network that affects AMF and fungal–plant interactions
L'altro. Uno studio sull'individuazione femminile.
Full text linkThe female psychology dominates this third and final year of research, with a particular focus on the development of the female awareness through time. The topic has been critically analysed starting from Jung’s studies and postulating its alterity from the western culture. Highly relevant in the research the analysis of Neumann’s works. The evolution of the male/patriarchal awareness leads to a complete perception of the western culture and, consequently, to set the link with its opposite: the East and the female. The dissertation aims at affirming the relevance of the identification of that part of the human psyche which was buried in the deep unconscious with no rational reason. Jung laid the foundations for the subject. Based on his own theories, the research focuses on the female perspective by comparing it with the male one and highlighting analogies and discrepancies. Moving on, psychology originates from the human need to balance its unconscious, along with the exacerbation of the rational perspective during the 19th century. Moreover today’s lack of emotional involvement in the Christian symbolism produced a sense of uncertainty typical of the weakening of the sacred world. The goal is to recover spirituality by revaluing the visceral dimension, inherent to both the East and the female, of the human existence. And to set it, an examination of psychology and a series of learnings widely tagged as obscure and obsolete is required: mythology, alchemy, shamanism and tantric-yoga. Revaluating the psyche as human’s entirety links the scientific method and the irrational which characterized the archaic rituals and plays a crucial role in human’s self and social balance. The research does not result in a finish line. It rather discloses an alternative perspective on the psychological analysis of the modern society, which can help in postulating the female future evolution. To sum up, a change in perspective seems essential to unlock classical issues
Preconditioned fast solvers for large linear systems with specific sparse and/or Toeplitz-like structures and applications
Full text linkIn this thesis, the design of the preconditioners we propose starts from applications instead of treating the problem in a completely general way. The reason is that not all types of linear systems can be addressed with the same tools. In this sense, the techniques for designing efficient iterative solvers depends mostly on properties inherited from the continuous problem, that has originated the discretized sequence of matrices. Classical examples are locality, isotropy in the PDE context, whose discrete counterparts are sparsity and matrices constant along the diagonals, respectively.
Therefore, it is often important to take into account the properties of the originating continuous model for obtaining better performances and for providing an accurate convergence analysis. We consider linear systems that arise in the solution of both linear and nonlinear partial differential equation of both integer and fractional type. For the latter case, an introduction to both the theory and the numerical treatment is given.
All the algorithms and the strategies presented in this thesis are developed having in mind their parallel implementation. In particular, we consider the processor-co-processor framework, in which the main part of the computation is performed on a Graphics Processing Unit (GPU) accelerator.
In Part I we introduce our proposal for sparse approximate inverse preconditioners for either the solution of time-dependent Partial Differential Equations (PDEs), Chapter 3, and Fractional Differential Equations (FDEs), containing both classical and fractional terms, Chapter 5. More precisely, we propose a new technique for updating preconditioners for dealing with sequences of linear systems for PDEs and FDEs, that can be used also to compute matrix functions of large matrices via quadrature formula in Chapter 4 and for optimal control of FDEs in Chapter 6. At last, in Part II, we consider structured preconditioners for quasi-Toeplitz systems. The focus is towards the numerical treatment of discretized convection-diffusion equations in Chapter 7 and on the solution of FDEs with linear multistep formula in boundary value form in Chapter 8
The role of the long non coding RNA HAS2-AS1 in breast cancer cells
Full text linkExtracellular matrix (ECM) is a network made by proteins and proteoglycans, whose structure is essential to maintain tissue architecture and to provide molecules diffusion and cellular communications. A deregulated synthesis of ECM components is often associated to a pathological status. Among various glycosaminoglycans, hyaluronan (HA) is a ubiquitous ECM component with a remarkable structural importance. It is able to modulate cell adhesion, motility, growth and inflammation after the binding with cellular receptors (CD44 and RHAMM) and the activation of different cellular pathways. In tumour microenvironment, the up-regulation of HAS2 and the overproduction of HA are often associated with tumour progression and metastasis. This also applies to breast cancer, where the accumulation of HA and the overexpression of hyaluronan synthases (HASes) in stromal and tumoral cells correlate with tumor malignancy and patients survival.
The study of the regulation of HAS2, the main enzyme in the production of HA, is very important to understand the development and the progression of breast cancer. Recently, it has been discovered that the lncRNA HAS2-AS1 can modulate the expression of HAS2 and the production of hyaluronan in aortic smooth muscle cells via epigenetic modifications [1]. Although the role of HA and HAS2 in breast cancer is widely described, little is known about HAS2-AS1.
Given this considerations, the aim of this project is to study the role of HAS2-AS1 in breast cancer. In particular, we compared the behaviour of MDA-MB-231 and MCF-7 cells after the modulation of HAS2-AS1 expression with functional assays evaluating cell proliferation, migration and invasion. In the same conditions, we analysed the expression of HA related genes and receptors in MDA-MB-231 cells. This analysis revealed that HAS2-AS1 knockdown stimulated the presence of a malignant phenotype, as its abrogation increased cell motility and invasion, as well as the expression of several HA related genes and the receptor CD44. These evidences suggested that HAS2-AS1 plays an important role breast tumor progression through alteration of HA metabolism.
Further analysis were conducted to understand the molecular mechanisms at the basis of the changes observed. LncRNAs can orchestrate gene expression through a variety of mechanisms, regulating transcription and translation, chromatin remodelling and the interaction with other RNA species, i.e. miRNAs. HAS2-AS1 transcript contains a putative binding site for miRNA 186, a negative regulator of the pro-apoptotic receptor P2X7 [2]. In our results we demonstrated that the overexpression of HAS2-AS1 decreased the abundance of miR-186, while the transcript of P2X7 and other targets of miRNA 186 (involved in cell cycle and autophagy) raised.
All together, these data suggest that the “sponge effect” of HAS2-AS1 is able to antagonise the function of miRNA 186 on its downstream targets and could explain the presence of a malignant phenotype after HAS2-AS1 silencing in MDA-MB-231.
1. Vigetti D, Deleonibus S, Moretto P, Bowen T, Fischer JW, Grandoch M, et al. Natural antisense transcript for hyaluronan synthase 2 (HAS2-AS1) induces transcription of HAS2 via protein O-GlcNAcylation. J. Biol. Chem. 2014;289:28816–26.
2. Zhou L, Qi X, Potashkin JA, Abdul-Karim FW, Gorodeski GI. MicroRNAs miR-186 and miR-150 down-regulate expression of the pro-apoptotic purinergic P2X7 receptor by activation of instability sites at the 3ʹ-untranslated region of the gene that decrease steady-state levels of the transcript. J. Biol. Chem. 2008;283:28274–86