1359 research outputs found
Sort by
Electrodeposition of Nb, Ta, Zr and Cu from Ionic Liquid for Nanocomposites Preparation
Get PDFMultilayer metal materials with nanometric scale are important in modern engineering applications. Composite materials based on metals with different characteristics give rise to new materials with unique properties. Among the others, nanostructured composites constituted by immiscible metals can present interfaces able to control defects produced by high doses of radiation, stress and temperature: their properties can be exploited in nuclear power reactor. Immiscible systems constituted by Cu/Nb or Cu/Ta multilayers exhibit higher thermal stability and improved mechanical properties with respect to bulk Nb, bulk Ta and bulk Cu. Refractory metals present high melting point, high hardness and high resistance against strong acids and bases. The electrodeposition of these metals presents several limitations: the most important is the very negative deposition potential that makes difficult the deposition of metals such as niobium, tantalum and zirconium. Since both oxygen reduction and hydrogen evolution from water splitting occur at potential values much less cathodic than the metals reduction, at the low potential requested to obtain niobium, tantalum and zirconium in metal form it is necessary the use of electrolytes free of water and oxygen and characterized by high stability in large potential windows. To overcome this limitation, the electrodeposition from molten salts or ionic liquids as solvents have been proposed.
In the present project the electrochemical coating of niobium, tantalum zirconium and copper has been investigated in 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl) imide([BMP][TFSA]) on both boron doped diamond (BDD) and metal substrates in order to determine the reduction path for both single metal and nanometric composites electrodeposition.
Electrochemical experiments have been performed at different temperatures in a glove box, under nitrogen atmosphere. Galvanostatic runs and cyclic voltammograms performed at different scan rates and different potential windows have been carried out in order to determine the behaviour of the systems employed. Potentiostatic experiments were performed at the potential values corresponding to the voltammetric peaks and the samples obtained were analysed by SEM-EDX analyses.
Regarding the electrodeposition of refractory metals nanometric crystallites have been obtained at 125 °C.
Cu/Nb and Cu/Ta composites have been prepared by a dual bath deposition technique; the deposits were constituted by fine crystallites with average sizes in the range 50-100 nm. The elemental maps indicate a different distribution of Cu/Nb and Cu/Ta in the composites obtained with the different substrates
Electromagnetic compatibility issues of electrical and electronic devices
Get PDFThe PhD dissertation addresses EMC issues of electrical and electronic devices. In the first part of this work
(Part_01), EMC fundamentals are briefly resumed and discussed, particularly focusing on EMC susceptibility
and conducted/radiated emissions. Subsequently, attention is moved to both intentional and nonintentional
EMI sources, particularly on RFID devices and power electronic converters respectively. These
last are very widespread in several application fields, such as battery chargers, personal computers,
electrical drives and grid interfaces. They consists of passive elements (inductors, capacitors, etc.), which
are appropriately coupled by means of switching devices in order to guarantee appropriate voltage and/or
current supply. The inherent switching nature of power electronic converters make them non-intentional
EMI sources, may leading to high levels of conducted and/or radiated emissions. Particularly, conducted
emissions are mainly due to unsuitable coupling among heat sinks, wires and printed circuits. Whereas
radiated emissions are due to the switching devices, which behave as antenna when operate at high
frequency value. Thus, the second part of this PhD dissertation (Part_02) deals with modelling and
simulation of power electronic converters, whose switching frequencies generally lie within several
hundred kilohertz. Then, several experimental results are presented regarding EMC tests performed in an
RF anechoic chamber, highlighting the most critical EMC issues in terms of both conducted and radiated
emission levels.
The last part of this work (Part_03) is devoted to EMC susceptibility/immunity of implantable medical
devices. At the present time these kinds of electrical and electronic devices are implanted even from a very
young age, allowing more people to live a normal life. Consequently, EMC issues related to them are
becoming increasingly relevant for both researcher and manufacturer, international standards being
slightly outdated. In this context, an Implantable Cardioverter Defibrillator (ICD) have been considered with
the aim of determining an EMC characterization in terms of sensing performances. This goal is achieved by
developing a suitable sensing test procedure, which allows the evaluation of the ICD susceptibility level at
different patient state of health. The proposed testing procedure has been validated through several
experimental tests, which have been performed in the RF anechoic chamber above-mentioned. It assures
pre-compliance of the tests in accordance with international standards, shielding against uncontrolled EMI
sources. Experimental results are finally reported and discussed, highlighting the effectiveness of the
proposed procedure
Valutazione dei rischi ambientali con particolare riferimento alle zone colpite da problemi di dissesto idrogeologico e dal ripetuto passaggio di incendi boschivi.
Get PDFWildfires are one of the most widespread factors of ecosystem degradation around the
world. The degree of change in both chemical and biological properties of soil inducted
by forest fires depends on the temperature and the persistence of the fire as well as on
the soil moisture content of fuel.
This research, in a first step, deals the study of the stability variation of a hill slope
crossed by a forest fire. The first site of investigation is located at western boundary of
the rift of Campidano, south-western Sardinia, Italy, to the North-West of the urban
area of Villacidro. The geological features are constituted by metamorphic rocks
(Hercynian basement) overlying granitoid rocks with a sub-horizontal and weakly wavy
contact surface. In order to perform the stability analysis, two geotechnical models
were derived by the integration of the results of geotechnical surveys (NSPT
measurements and direct shear tests) with electrical resistivity tomographies. Classical
approach based on Limit Equilibrium Method is used to determine the safety
coefficient. Furthermore, the effects of the forest fire on the slope stability have been
discussed modifying the 2D models and introducing an ultra-shallow thin layer with the
shear strength parameters determined on burned soil samples, collected after the fire
crossing. In particular, this analysis has shown a marked reduction of safety factor at
the interface between the burned soil layer and the underlying material for both
geotechnical models, considering the infinite slope method with several saturation
conditions of the shallow layer.
In this study also were determined the concentrations of geochemical components in
the soils affected by forest fires. The fire-burn severity was medium, but the effect of
geochemical variation on soil is evident. We observe the variation of total content of
Mn that increase in soils affected by a forest fires, respect the control soils. Moreover
the C,N and P contents of soil decrease in the time, according with most of the
international bibliography. Mapping the values of the geochemical components it was
possible to see their mobilization after the rains. With these data we will try in the
future to build a model of mobilization of contaminants that is able to predict the
decrease in the concentration of the element considering the time elapsed from the
fire, the intensity of rainfall and slope.
In a third step the study aim is to develop methods for the analysis and the collection
of field data, by means of a multidisciplinary approach, to evaluate land erosion hazard. The second experimental area is located also in Mediterranean basin, on a
steep slope in a hilly area of north-western Sardinia (Municipality of Ittiri, province of
Sassari, Italy),where a human caused fire occurred in august 2013. The area is mainly
covered by the typical Mediterranean vegetation.
Precipitations were recorded using tipping bucket rain gauge installed at the site.
Soil erosion rates from experimental plots were measured and estimated with silt
fences technique taking into account different slopes and vegetation distribution. The
study aims to compare the results obtained by ERMiT (Erosion Risk Management
Tool) model application and post-fire sediment yields measured in the study area.
The application of the model shows that the area experienced most of erosion after the
first rain events after fire occurring. Comparing experimental and model estimated
data, there is evidence of ERMiT model overestimating in respect of sampled data for
the first year. Future experimental data are needed to confirm this assumption and to
contribute to calibrate ERMiT in a Mediterranean typical vegetation and climate
environment
Grid and high performance computing applied to bioinformatics
Get PDFRecent advances in genome sequencing technologies and modern biological data
analysis technologies used in bioinformatics have led to a fast and continuous increase
in biological data. The difficulty of managing the huge amounts of data currently
available to researchers and the need to have results within a reasonable time have
led to the use of distributed and parallel computing infrastructures for their analysis.
In this context Grid computing has been successfully used. Grid computing is based
on a distributed system which interconnects several computers and/or clusters to
access global-scale resources. This infrastructure is
exible, highly scalable and can
achieve high performances with data-compute-intensive algorithms.
Recently, bioinformatics is exploring new approaches based on the use of hardware
accelerators, such as the Graphics Processing Units (GPUs). Initially developed as
graphics cards, GPUs have been recently introduced for scientific purposes by rea-
son of their performance per watt and the better cost/performance ratio achieved in
terms of throughput and response time compared to other high-performance com-
puting solutions.
Although developers must have an in-depth knowledge of GPU programming and
hardware to be effective, GPU accelerators have produced a lot of impressive results.
The use of high-performance computing infrastructures raises the question of finding
a way to parallelize the algorithms while limiting data dependency issues in order
to accelerate computations on a massively parallel hardware.
In this context, the research activity in this dissertation focused on the assessment
and testing of the impact of these innovative high-performance computing technolo-
gies on computational biology. In order to achieve high levels of parallelism and, in
the final analysis, obtain high performances, some of the bioinformatic algorithms
applicable to genome data analysis were selected, analyzed and implemented. These
algorithms have been highly parallelized and optimized, thus maximizing the GPU
hardware resources. The overall results show that the proposed parallel algorithms
are highly performant, thus justifying the use of such technology.
However, a software infrastructure for work
ow management has been devised to
provide support in CPU and GPU computation on a distributed GPU-based in-
frastructure. Moreover, this software infrastructure allows a further coarse-grained
data-parallel parallelization on more GPUs. Results show that the proposed appli-
cation speed-up increases with the increase in the number of GPUs
Information management and multivariate analysis techniques for metabolomics data
Get PDFAmong the so-called "omics" disciplines,metabolomics has been receiving considerable attention
over the last few years. Metabolomics is the large-scale study ofmetabolites that are
smallmolecules within cells, biofluids and tissues, produced as a result ofmetabolism.
The growing interest inmetabolomics has been encouraged by rapid advances inmetabolic
profiling techniques and by technological developments of the diverse analytical platforms,
including proton NucleicMagnetic Resonance (1H NMR), Gas Chromatography-Mass Spectrometry
(GC-MS) and Liquid Chromatography-Mass Spectrometry (LC-MS), used for extracting
metabolic profiles. The output generated from these experimental techniques results
in the production of a huge amount of data and information.
This thesis attempts to provide an overview of the analytical technologies, the resources
and databases employed in this emerging discipline, and ismainly focused on the following
two aspects: (i) the challenges of handling the large amounts of data generated and managing
the complex experimental processes needed to produce them; (ii) the techniques for the
multivariate analysis of metabolomics data, with a special emphasis on methods based on
the randomforest algorithm.
To this aim, a detailed description and explanation of QTREDS, a software platform designed
for managing, monitoring and tracking the experimental processes and activites of
"omics" laboratories is provided.
In addition, a thorough elucidation of the software package RFmarkerDetector, available
through the Comprehensive R Archive Network (CRAN), and a description of the multivariate
analysis techniques it implements, is also given
‘Poche parole ma significanti’: quando la traduzione va in scena – con due case studies
Get PDFThis doctoral dissertation focuses on the dramatic text, whose long neglected theatrical nature is
more volatile and harder to analyze if compared to the literary text.
The difficulty lies in reproducing a language whose final outcome is not completely in the hands of
the translator, as it happens with narrative. The dramatic text, once translated, will pass to the actors,
who will embrace it and use it in the performance; in order to be performable, there are some key
elements which cannot be overlooked. First, the dramatic text is not meant to be independent and
complete, but finds its utmost realization on stage, fused with all the other theatrical elements –
acting included- converging into the performance. The incompleteness of the dramatic text has to be
preserved in the passage to a new language, to allow the same chemistry of the original (or to make
it better) and to allow the actors to infuse their art in it. The dramatic translation must also consider
the so called ‘playable speakability’, that is, writing in a way which sounds natural to the ear and to
the acting; this implies a deep knowledge of the practical dimension, that of rehearsals.
To clarify these theoretical points, two authors and three plays have been taken into consideration.
Shakespeare’s Hamlet and Much Ado About Nothing, and Michael Frayn’s Noises Off. Shakespeare
allowed to verify how radically different is the approach of translators who treat Shakespeare’s texts
as ‘literature’ and those who treat them as theatrical text; moreover, the weight of the author’s name
revealed itself to be a powerful dominant as well: the translators, intimidated by the importance of
the text in the Canon, usually feared to strand from the source-text to find more suitable solutions in
the target language. Frayn’s Noises Off offered an insight on how the translation slowly turns into a
play, with all modifications that seemed necessary, showing also that the best results in theatrical
translation come when the theatrical perspective is allowed to take hold
Conservazione e gestione del paesaggio attraverso percorsi storici, geografici e strumentali
Get PDFThe concept of landscape has evolved through a process of reconsideration and redefinition in the past seven decades. This concept has been used in a broader scope of action and intervention. Particularly during the last ten years the importance of landscape definition has gone hand in hand with the debate about resource management planning. The analyses and regulation of human activities on landscape has been largely discussed in Europe from several points of view. The word landscape indicates all the visible features of an area that can be seen in a single view. The meaning of this word identifies a link between the object and the viewer. Being the image filtered by the audience, a correct representation of landscape should consider both the aspects of the land characteristics of a particular region and of the people’s point of view. A inter-disciplinary approach is essential in order to register the features of land-cover and to combine them with the values assigned by the community. The complexity increases if we think about the difference between the perspectives of insiders and outsiders and about the fact that they must be seen obviously as collective entities and not as individuals. The quality of natural resources, as well as historical heritage, is conditional on their management. The heritage is therefore an irreplaceable resource for mankind and it is often a synonym of identity, which must be preserved for current and future generations if our goal is sustainable development. Every single element belonging to a specific area takes part to the same complex system that has to be fully managed in a sustainable perspective: the challenge is managing all sources in a way that economic, social and aesthetic needs can be fulfilled while maintaining cultural heritage and biological diversity. In order to improve life-quality the management of the territory must consider not separately economic, social/cultural and environmental perspective. Such shift relates to the managing skills of local institutions and of entrepreneurs if the goal is the stability and success of a long-term collective action for a sustainable resource management, in terms of tax revenues, jobs, additional sources of income to support conservation and valorization strategies
Letteratura e identità irlandese nell'opera di Bram Stoker
Get PDFThis research project stems from two different sources: an interest in the connection between literature and identity (both personal and national) and an interest in the recent desire of reappropriating Bram Stoker as an Irish author that can be noticed both in academia and in the wider public. In the past, Stoker was often included in anthologies of British writers without mentioning his being Irish, sometimes being even explicitly described as an English writer. In fact, he was a hundred percent Irish, in spite of the long time spent in London and of being continuously in touch with British social elites (most of all thanks to his work at the Lyceum Theatre with Sir Henry Irving): his Irishness is evident both in his self-declared interest in Irish themes (he described himself as a “philosophical Home-Ruler”) and in some of his fiction. This research concentrates on finding Irish elements and themes in his novels, short stories, articles and personal diaries, using them for a threefold purpose: first of all shedding more light on his Irishness; secondly, connecting his work to his biography; and, last but not least, expanding the knowledge academia has of his work, both fictional and non fictional, so that he may be seen as a full-rounded author, not just as the author of Dracula.
Three novels and other materials have been selected for the analysis. The novels are The Snake’s Pass (1890), which is Stoker’s first and the only one to be set in Ireland; Dracula (1897), an unavoidable milestone in his literary production; and The Lady of the Shroud (1909), more overtly political and written towards the end of his life. Finding Irish elements and themes in The Snake’s Pass is not difficult, as it is full of Irish characters, legends, place names, customs, etc. In addition to these easy-to-spot elements, this novel also offers a first glimpse of Stoker’s idea of community and of what steps should be taken for the development of a rural area. In The Lady of the Shroud, similar solutions are applied to an imaginary land in the Balkans, which can be identified with Stoker’s homeland, since the ideas about culture, identity and development here presented are quite similar to the ones expressed in The Snake’s Pass and in some articles about Ireland written in the same years as The Lady of the Shroud. As regards Dracula, the connections, similarities and differences with the other two novels may help understand this famous novel more deeply than in the past and keep under scrutiny the development of Stoker’s political ideas over time, since these
three novels cover the two decades in which he devoted himself to writing on a more regular basis.
Together with the novels, a short story has been selected (‘The Primrose Path’, which deals with emigration and alcoholism), two long articles dealing with Ireland (‘The Great White Fair in Dublin’ and ‘The World’s Greatest Shipbuilding Yard’), Stoker’s private diaries, which have been recently made available through print, and other writings (e.g. an address to the Philosophical Society at Trinity College Dublin). Reference is also made to other novels, short stories, articles and private correspondence. All these materials provide more material for the analysis, which means not only collecting more evidence of his Irishness but also improving the analysis of the novels with factual information from his non fictional writings.
As for methodology, major texts have been adopted for each topic (e.g. Diarmuid Ó Giolláin’s Locating Irish Folklore. Tradition, Modernity, Identity for folklore or Roy Foster’s Modern Ireland. 1600-1972 for history), but also texts, like for instance Benedict Anderson’s Imagined Communities and Homi K. Bhabha’s Nation and Narration, that are not directly related to Ireland but provide the tools to compare the ways in which communities and identities are formed in the real world with the ways they are formed in Stoker’s fiction.
One last tool used for the analysis of his fiction is his biography, which has been recently investigated (for instance by Paul Murray in 2004) more closely than in the past. As we know, Stoker was immersed in Irish life until he left for London, working for public administration at Dublin Castle and being a prominent member of Dublin’s social life (for instance, he was one of the few people in the history of Trinity College Dublin to hold both the position of President of the Philosophical Society and that of Auditor of the Historical Society, he was a regular at the Wildes’ literary salon on Merrion Square, he was a well-known athlete in local sports competitions, etc.). After he left Ireland, he continued being interested in Irish life and politics, as is clear from his discussing Irish problems with W. E. Gladstone, his participation in the National Literary Society founded in London, and so on. Together with his personal diaries, his biography, in addition to performing the obvious task of providing information about Irish aspects in his life, can also be a useful tool for shedding more light on his fiction
Joint whole exome sequencing and linkage analysis in a multigenerational family segregating Type 1 Diabetes
Get PDFBackround: Type 1 diabetes (T1D) is a complex autoimmune disease with a
strong familial segregation. On the other hand, the recent and rapid increase
in incidence is a proof of the importance of environmental factor in the
etiology of disease. Linkage and Genome-wide association studies had
revealed almost 60 loci associated with the risk of T1D, explaining about 80%
of the total heritability, mostly due to HLA locus. However, many familial T1D
cases remains unexplained.
Objective: To identify rare variants contributing to T1D susceptibility, we
studied a Sardinian family with 9 individuals affected across 3 generations.
Methods: We performed exome sequencing in 3 affected members and a
healthy individual. In addition, all samples were extensively genotyped using
Illumina OmniExpress beadchips for about 750K SNPs. A combined linkage
analysis was carried out.
Results: This combined approach identified three variants predicted to be
damaging that are very rare in the general population (frequency <1%) and
that are likely causing the disease
Primary hyperoxalurias in Italy and Europe
Get PDFPrimary Hyperoxalurias (PH) are a group of rare disease caused by mutations in genes encoding
hepatic enzymes of the glyoxalate detoxification pathway, causing the formation and deposition of
calcium oxalate crystals at first in the urinary tract (nephrolithiasis and nephrocalcinosis) and, after
end stage renal failure, in the whole body.
At present, 3 PH types are known, with autosomal recessive inheritance: PH1, due to lack of
function of the hepatic alanine-glioxylate aminotransferase (AGT) enzyme; PH2, due to lack of
function of the glioxylate-reductase/hydroxypiruvate-reductase (GRHPR) enzyme; PH3, associated
with HOGA1 gene mutations. HOGA1 encodes the 4hydroxy2oxoglutarate aldolase, a
mitochondrial enzyme responsible for the final step of the mitochondrial hydroxyproline
metabolism.
The only two treatments available for PH are pyridoxine therapy, which is effective in a minority of
patients, and liver transplantation, which is a very invasive and problematic procedure. Thus,
approaches aimed at a deeper knowledge of genotype/phenotype correlations as well as at the
development of new treatment strategies, appear to be desirable.
The San Luigi Hospital is the only Italian Centre offering the genetic testing for primary
Hyperoxaluria in Italy;, our Centre is part of the OxalEurope group, the European Hyperoxaluria
Consortium.
Aim of the PhD project was to refine the current knowledge on genotype/phenotype correlations, to
better define the therapeutic strategy in patients and to extend the molecular analysis to HOGA1
gene.
At the end of 2014 the Italian database includes 80 PH1 patients (28 females and 52 males) and 2
PH2 patient. Median age of the cohort is 22 years old (I-III quartile: 11-35,3). Symptoms at onset
are mainly nephrolithiasis (52,5%) and nephrocalcinosis (35,2%), as generally reported in PH
patients. Three patients were diagnosed at family screening before symptoms development. Median
age at onset is age 4 years (0.5-11,5), median age at diagnosis is 11 years old (4-30). 55 patients
have had ESRF. Median age at ESRD is 14 years of age (4-31). Ten patients had a kidney-only
transplant and, among them, 2 had a second kidney-only transplant. In other 6 cases the second
kidney transplant was combined with liver transplant. Some recurrent mutations are present; as
reported in literature, also in the Italian cohort the most common mutation is p.Gly170Arg (28% of
the alleles), in 14 patients in homozygosis, in 11 in heterozygosis with a missense mutation and in 4
with a null mutation.
We set up the analysis of the AGXT promoter, of GRHPR and HOGA1 genes.
In 15 patients with clinical diagnosis of PH, who resulted negative for pathogenic variants in the
entire coding sequence and exon-intron boundaries of AGXT gene, we extended the analysis to
GRHPR and HOGA1 genes. One patient was homozygous for a novel HOGA1 variant of undefined
pathogenicity in intron 2 (c.341-81delT), that in silico tools predicted to affect splicing. However, a
minigene splicing assay did not identify any abnormal splicing product. In two patients we detected
heterozygosity for novel variants in the AGXT promoter (c.-647C>T, c.-424C>T), whose
pathogenicity however remained uncertain, since they lay outside of known transcription regulatory
sites.
A genotype-phenotype study was conducted in the OxalEurope Consortium database. This
retrospective report is based on 526 patients (410 with AGXT genotype). We grouped mutations by
the predicted effect as null (N), missense leading to mistargeting (G170R) and other missense (M)
and analyzed their phenotypic correlations. Median age of End-stage Renal Disease increased from
9.9 to 11.5, 16.9, 25.1, 31.2 and 33.9 years for the NN (n=88), MN (n=42), MM(n=116),
G170RN(n=61), G170R/M(n=32) and G170R/G170R(n=71) respectively. The outcome of some
recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an
unprecedented number of G170R homozygotes is described in detail.
In collaboration with Prof. Borri-Voltattorni’s group (University of Verona) we developed a
Telethon project (GGP10092), aiming to improve the clinical management of patients affected by
PH1 by exploiting the knowledge on the genotype-enzymatic phenotype-clinical phenotype relationships to develop new specific and non-invasive treatment strategies. We focused our
attention on the molecular defects underlying AGT deficiency in compound heterozygous patients.
Until now, only “single protein” studies have been undertaken to investigate the molecular
pathogenesis of PH1, and the possible interplay between two different pathogenic mutations at
clinical and enzyme level has never been analysed. We started from the clinical data on two PH1
patients, one hemizygous for the S81L mutation associated with the major allele, and the other
compound heterozygous for the S81L mutation on the major allele and the most common mutation
in Caucasian patients, i.e. the G170R associated with the minor allele. With in vitro studies we
demonstrated a phenomenon of positive interallelic complementation between the S81L and G170R
monomers, mimicking heterozygous and heterozigous compound patients.
In an attempt to identify molecules acting as pharmacological chaperones for AGT variants showing
folding defects, the Telethon project was focused on aminoxyacetic acid (AOA) a known
competitive inhibitor of AGT. The interaction of AOA with AGT and the pathogenic variants G41R,
G170R and I244T were studied in CHO-GO cells stably expressing AGT, demonstrating that AOA
behaves as a competitive inhibitor and is able to act as a pharmacological chaperone for the
pathogenic variants because it decreases the aggregation propensity of G41R and promote the
peroxisomal localization of G170R and I244T. These results provide the proof-of-principle that an
enzyme enhancement therapy for PH1 could be possible and constitute the base for the
identification of molecules more specific for AGT. In this regard, large scale in silico screening of
libraries of commercially available compounds are ongoing.
In conclusion, in this PhD thesis some contributions were made to the general understanding of this
disease, both as regards the genotype-phenotype correlations and as functional characterization of
AGXT mutations.
A grey zone of cases in which suspicions based on clinical and biochemical findings are not
confirmed by genetic testing is recognized in the diagnostic practice of most rare genetic diseases
and in PH1 as well. To clarify the inconclusive diagnoses in our historical series of cases referred
for genetic diagnosis of PH we selected 15 patients with primary oxaluria, AGXT mutationnegative,
to address to the analysis of the AGXT-promoter and the additional known genes GRHPR
and HOGA1. Our analyses did not provide evidence of pathogenic mutations of these genes in any
of the 15 patients. Since oxalate metabolism is complex and not fully described, it is possible that
other genes are presently uncovered and even a multiallelic PH inheritance has been suggested. In
the future, next generation sequencing could be a useful tool to both discover novel genes involved
in glyoxalate metabolism and PH phenotype modifiers.
Thanks to the collaboration with Prof. Borri-Voltattorni's group, we were able, for the first time, to
understand the effects of the S81L mutation on the major allele and the G170R on the minor allele
under homozygous and heterozygous conditions. This work constitutes a valid example of an
approach useful to understand the enzymatic phenotype in compound heterozygous PH1 patients,
with potential applications to the study of the interaction between other pathogenic mutations.
Besides providing a better knowledge of the disease pathogenesis, the results obtained could allow
to develop proper therapeutic treatments, as the hybrid protein could have defects different from
those of the parental enzymes.
The genotype-phenotype studies were made possible by the collaboration with several European
Centres, all being part of the OxalEurope group. This study of an unprecedented number of PH1
patients showed geno-phenotype associations that have not been previously described. These
findings may have important implications for the management of PH1 patients and underline the
necessity of genotyping PH patients. We also identified considerable diagnostic delay in this
disease, which may partly explain the overall adverse outcome in some patients