Patterns of long-term settlement and land exploitation in the region of the Nile First Cataract (Egypt)

The First Cataract region (Egypt) has always played a crucial role as a border area and a crossroads for cultures and people living in adjacent landscapes. The region has its central point in the modern city of Aswan, but it extends up to the Kom Ombo Plain in the north and reaches the Bab el-Kalabsha in the south. Its eastern and western limits cannot be defined with the same precision, given that they are located in deserts. This research focused on the landscape analysis of the region intended as a complex entanglement of archaeological evidence in a geographical and natural environment whose changes impacted and, simultaneously, were influenced by human activities. Settlement patterns and land use can give interesting information on how these relationships worked from a diachronic perspective and how they shaped the region’s characteristics. To understand the links between the human presence and its evidence and the landscape of the First Cataract region, the integration of various datasets was needed, from historical and archaeological ones to the remote sensing observation of large areas. An area corresponding to ca. 18.000 km2 has been selected for this research. The chronological framework has been chosen to cover a considerable period, from the beginning of the 5th millennium BCE to the 7th century AD. Multi-temporality and multifunctionality appear as two essential aspects when the archaeological evidence of the First Cataract region is considered in its geographical and topographical setting as a general context for settlement patterns and resource exploitation analyses. A combination of remote sensing data and topographical materials has been integrated with archaeological evidence to obtain information about resource exploitation strategies and settlement adaptation from a diachronic perspective.

Pathogenic mechanisms in mitochondrial optic neuropathies

Leber’s hereditary optic neuropathy (LHON) and Autosomal Dominant Optic Atrophy (ADOA) are the two most common inherited optic neuropathies and both are the result of mitochondrial dysfunctions. Despite the primary mutations causing these disorders are different, being an mtDNA mutation in subunits of complex I in LHON and defects in the nuclear gene encoding the mitochondrial protein OPA1 in ADOA, both pathologies share some peculiar features, such a variable penetrance and tissue-specificity of the pathological processes. Probably, one of the most interesting and unclear aspect of LHON is the variable penetrance. This phenomenon is common in LHON families, most of them being homoplasmic mutant. Inter-family variability of penetrance may be caused by nuclear or mitochondrial ‘secondary’ genetic determinants or other predisposing triggering factors. We identified a compensatory mechanism in LHON patients, able to distinguish affected individuals from unaffected mutation carriers. In fact, carrier individuals resulted more efficient than affected subjects in increasing the mitochondrial biogenesis to compensate for the energetic defect. Thus, the activation of the mitochondrial biogenesis may be a crucial factor in modulating penetrance, determining the fate of subjects harbouring LHON mutations. Furthermore, mtDNA content can be used as a molecular biomarker which, for the first time, clearly differentiates LHON affected from LHON carrier individuals, providing a valid mechanism that may be exploited for development of therapeutic strategies. Although the mitochondrial biogenesis gained a relevant role in LHON pathogenesis, we failed to identify a genetic modifying factor for the variable penetrance in a set of candidate genes involved in the regulation of this process. A more systematic high-throughput approach will be necessary to select the genetic variants responsible for the different efficiency in activating mitochondrial biogenesis. A genetic modifying factor was instead identified in the MnSOD gene. The SNP Ala16Val in this gene seems to modulate LHON penetrance, since the Ala allele in this position significantly predisposes to be affected. Thus, we propose that high MnSOD activity in mitochondria of LHON subjects may produce an overload of H2O2 for the antioxidant machinery, leading to release from mitochondria of this radical and promoting a severe cell damage and death ADOA is due to mutation in the OPA1 gene in the large majority of cases. The causative nuclear defects in the remaining families with DOA have not been identified yet, but a small number of families have been mapped to other chromosomal loci (OPA3, OPA4, OPA5, OPA7, OPA8). Recently, a form of DOA and premature cataract (ADOAC) has been associated to pathogenic mutations of the OPA3 gene, encoding a mitochondrial protein. In the last year OPA3 has been investigated by two different groups, but a clear function for this protein and the pathogenic mechanism leading to ADOAC are still unclear. Our study on OPA3 provides new information about the pattern of expression of the two isoforms OPA3V1 and OPA3V2, and, moreover, suggests that OPA3 may have a different function in mitochondria from OPA1, the major site for ADOA mutations. In fact, based on our results, we propose that OPA3 is not involved in the mitochondrial fusion process, but, on the contrary, it may regulate mitochondrial fission. Furthermore, at difference from OPA1, we excluded a role for OPA3 in mtDNA maintenance and we failed to identify a direct interaction between OPA3 and OPA1. Considering the results from overexpression and silencing of OPA3, we can conclude that the overexpression has more drastic consequences on the cells than silencing, suggesting that OPA3 may cause optic atrophy via a gain-of-function mechanism. These data provide a new starting point for future investigations aimed at identifying the exact function of OPA3 and the pathogenic mechanism causing ADOAC.

Studio caso-controllo multicentrico su distacco di retina e movimentazione manuale di carichi

Obiettivo Valutare l’ipotesi secondo cui la movimentazione manuale di carichi possa essere un fattore di rischio per il di distacco di retina. Metodi Si è condotto uno studio caso-controllo ospedaliero multicentrico, a Bologna, (reparto di Oculistica del policlinico S. Orsola Malpighi, Prof. Campos), e a Brescia (reparto di oculistica “Spedali Civili” Prof. Semeraro). I casi sono 104 pazienti operati per distacco di retina. I controlli sono 173 pazienti reclutati tra l’utenza degli ambulatori del medesimo reparto di provenienza dei casi. Sia i casi che i controlli (all’oscuro dall’ipotesi in studio) sono stati sottoposti ad un’intervista, attraverso un questionario strutturato concernente caratteristiche individuali, patologie pregresse e fattori di rischio professionali (e non) relativi al distacco di retina. I dati relativi alla movimentazione manuale di carichi sono stati utilizzati per creare un “indice di sollevamento cumulativo―ICS” (peso del carico sollevato x numero di sollevamenti/ora x numero di anni di sollevamento). Sono stati calcolati mediante un modello di regressione logistica unconditional (aggiustato per età e sesso) gli Odds Ratio (OR) relativi all’associazione tra distacco di retina e vari fattori di rischio, tra cui la movimentazione manuale di carichi. Risultati Oltre alla chirurgia oculare e alla miopia (fattori di rischio noti), si evidenzia un trend positivo tra l’aumento dell’ICS e il rischio di distacco della retina. Il rischio maggiore si osserva per la categoria di sollevamento severo (OR 3.6, IC 95%, 1.5–9.0). Conclusione I risultati, mostrano un maggiore rischio di sviluppare distacco di retina per coloro che svolgono attività lavorative che comportino la movimentazione manuale di carichi e, a conferma di quanto riportato in letteratura, anche per i soggetti miopi e per coloro che sono stati sottoposti ad intervento di cataratta. Si rende quindi evidente l’importanza degli interventi di prevenzione in soggetti addetti alla movimentazione manuale di carichi, in particolare se miopi.

Innovative therapeutic approaches for the atrophic Age-related Macular Degeneration (“dry” AMD)

Age related macular degeneration (AMD) is a major concern regarding blindness in the world. In western countries, where visual alterations due to minor pathologies as cataract and uncorrected refractive errors are easily resolved, AMD represent the main cause of blindness. Of the two existing forms of the disease, while the neovascular is more aggressive and progress quickly, geographic atrophy is the one still lacking an appropriate therapy. My PhD program was focused on investigating AMD features, trying to understand if some approaches I tested could be able to provide some suggestion about potential future therapies on “dry” AMD. In my research I developed three main projects. The most important part of the work regards the study of integrins and their fundamental role in cell adhesion in a context of interaction between retinal pigmented epithelium (RPE) and immune cells. I investigated how co-culture of these different cell lines can lead to simulate an inflammatory state inducing cell signaling, cytokine production and cell death. The use of integrin antagonists developed in our laboratory, showed how these effects can be reverted. A secondary approach regards the use of antioxidants and their role in epigenetic modifications in ARPE-19 cells to investigate how these compounds might exert their well-known protective role on AMD. Commonly used antioxidants as Lutein and Quercetin do not induce clear epigenetic modifications through histone H3 acetylation indicating only a limited involvement.

New perspectives of genetic disorders in cattle

In the last decades a negative trend in inbreeding has accompanied the evident improvement in productivity and performance of bovine domestic population, predisposing to the occurrence of recessively inherited disorders. The objectives of this thesis were: a) the study of genetic diseases applying a “forward genetic approach” (FGA); b) the estimation of the prevalence of deleterious alleles responsible for eight recessive disorders in different breeds; c) the collection of well-characterized materials in a Biobank for Bovine Genetic Disorders. The FGA allowed the identification of seven new recessive deleterious variants (Paunch calf syndrome - KDM2B; Congenital cholesterol deficiency - APOB; Ichthyosis congenita - FA2H; Hypotrichosis - KRT71; Hypotrichosis - HEPHL1; Achromatopsia - CNGB3; Hemifacial microsomia – LAMB1) and of seven new de novo dominant deleterious variants (Achondrogenesis type II - two variants in COL2A1; Osteogenesis imperfecta - COL1A1; Skeletal-cardio-enteric dysplasia - MAP2K2; Congenital neuromuscular channelopathy - KGNG1; Epidermolysis bullosa simplex - KRT5; Classical Ehlers-Danlos syndrome - COL5A2) in different breeds, associated with a large spectrum of phenotypes affecting different systems. The FGA was based on the sequence of a clinical, genealogical, gross- and/or histopathological and genomic study. In particular, a WGS trio-approach (patient, dam and sire) was applied. The prevalence of deleterious alleles was calculated for the Pseudomyotonia congenita, Paunch calf syndrome, Hemifacial microsomia, Congenital bilateral cataract, Ichthyosis congenita, Ichthyosis fetalis, Achromatopsia and Hypotrichosis. A particular concern resulted the allelic frequency of 12% for the Paunch calf syndrome in Romagnola cattle. In respect to the Biobank for Bovine Genetic Diseases, biological materials of clinical cases and their available relatives as well as controls used for the allelic frequency estimations were stored at -20 °C. Altogether, around 16.000 samples were added to the biobank.