Around 100 kya, H. sapiens started its colonization of the world, gradually adapting to new environmental conditions and to extremely different alimentary resources. Interaction between the human genome and nutritional/climatic conditions is regulated by physiological mechanisms that modulate body temperature and the energetic balance. Genes involved in these processes are thus considered as one of the principal targets of biomedical research focused on chronic metabolic diseases. The aim of this project is to investigate micro-evolutionary processes that shaped metabolic variability among human populations through the description of patterns of genetic diversity and their potential association with phenotypes linked to nutrition and thermoregulation. Particularly the identification of potential adaptation processes was carried on through three major research projects. The first one focused on European populations, which have experienced several migration and adaptation processes during their recent evolutionary history. Through an in silico approach, it was possible to analyse the pattern of genetic variability in Europe for genes involved in different metabolic processes and to find multiple signals of local adaptation to climate. In the second study, thanking advantage from previous researches carried on by our research group on Italian samples and by means of genome-wide approaches, we investigate patterns of genetic variability at three genes associated to metabolic phenotypes along Italy. A targeted analysis has been conducted on samples from several Italian provinces, highlighting a different pattern of variability among distinct macro-areas of the peninsula thus indicating that different adaptation processes may have acted on such loci. Finally, in the last project, taking advantage from data generated for a probiotic treatment case study on individual affected by celiac disease, it was possible to evaluate the influence of this pathologic condition on gut microbiota composition and thus to get evolutionary insights into the complex interplay between gut microbiota and celiac disease susceptibility.

The present work aimed to synthesizing new biologically active small molecules as innovative antitumor lead candidates and to the total synthesis of a natural compound with selectivity towards cancer hypoxia. In this context, a first project involved the design and synthesis of N-acylhydrazone based inhibitors of lactate dehydrogenase A (LDH-A). The structures of the new molecules where designed by means of virtual screening and synthesized to obtain a library of analogs which were evaluated on the enzyme. Active compounds were also screened on cells of non-Hodgkins lymphoma and one of them proved to be a promising inhibitor, suggesting that the N-acylhydrazone as suitable scaffolds for LDH-A inhibitors. The second project aimed to the synthesis of Galloflavin (GF) analogs and to the study of the compound’s SAR. GF is an LDH-A inhibitor which was previously identified and synthesized by our group. Its poor solubility and stability prevented us from studying its SAR maintaining the core structure. Therefore, the synthesis of three potential classes of structural analogs was devised and carried out. One compound was found to reproduce GF’s behaviour on the enzyme and in cell, therefore being a good starting point for the study. A small library of analogs was synthesized and biological tests are ongoing to acquire in-depth knowledge about the key pharmacophores of this interesting inhibitor. The third project was carried out at Aarhus University in the group of Prof. Thomas Poulsen. The work focused on the total synthesis of Rakicidin A, a macrolide of natural origin which was identified and isolated from soil samples and is known for its interesting properties in selectively inducing cell death in hypoxic environments and being also active on cancer stem cells. The total synthesis involved several steps including key enantioselective reactions to build the 5 stereocenters on the molecule.

One of the main problems in reconstructing the biological profile of unidentified human remains is the reliability of the methods used. These methods are normally developed on modern identificated human skeletal collections, but human variability can introduce problematic biases when applied on osteological collections from different geografical and cronological contexts. This study test the reliability of selected macroscopic methods for sex determination: the index of sexualization of Acsadi and Nemeskeri, the Phenice method and for the age estimation: the synostosis of cranial sutures (Meindl and Lovejoy), the morphological variations at the pubic symphysis (Suchey and Brooks), the morphological variations at ileum surface (Lovejoy, et al.), the modifications of the sternal end of the fourth rib (Iscan et al.) and the variations of the degree of sacral vertebral body fusion (Belcastro et al.) on a large sample (n.489) of know sex and age from Certosa Cemetery of Bologna and “Colecção Esqueletos Identificados" of Coimbra. Regarding age, for each method was calculated the standard values of bias and inaccuracy. The method of pubic symphysis might be the most reliable for age estimation but we must consider the width of age ranges considered by the method. The values of inaccuracy are over 10 years in individuals older than 50 and 27 years in individuals older than 60. The index of sexualization confirm in more than 99% of cases the known sex and the Phenice method gave good results with the 87% of confirm. The reliability of the tested methods in the two european populations was confirmed, with the pelvis as the most diagnostic district, in particular the pubic symphysis. Nevertheless, the dramatic increase in values of bias and inaccuracy with increasing age confirms the need for new or revised age estimation methods that better suits the study of the remains of older individuals.

Plants, animals and micro-organisms represent a reservoir of natural products, the so called “natural source-derived compounds”. This is particularly true for the plant kingdom, as it offers a variety of species still used as remedies for several diseases in many parts of the world. Nevertheless, the bioactive potential of many plant species remains largely unexplored. Thus, biodiversity represents an unlimited source of chemical entities with potential beneficial effects on human health. These compounds are usually secondary metabolites often present in low quantity in plant material and their extraction, purification and quantitation still remain a great challenge for analytical scientists. The research activity carried out during these three years of PhD Programme was focused on the development, validation and application of original methods aimed at the quali-quantitative analysis of compounds with potential bioactive interest in plant matrices, foods, drinks and related products, as well as the analytical screening of plant by-products from cosmetic manufacture. Bioactive substances, belonging to the classes of polyphenols, aminoacids, coumarins, triterpenes and phytohormones, have been investigated as authenticity markers, in order to identify high quality products and to valorise niche products. The study regarded herbs (Argania spinosa), fruits (Citrus × myrtifolia, Punica granatum) and berries (Myrtus communis) mainly used as folk medicines for their broad spectrum of supposed pharmacological and therapeutic effects. The analytical methods developed within this study are based on high performance liquid chromatography and ultra-high performance liquid chromatography coupled to spectrofluorometric detection, triple quadrupole and high-resolution triple quadrupole mass spectrometry (HPLC-F, LC-MS/MS and UHPLC-HRMS). Significant efforts have been put also into the development and optimisation of miniaturised sample pretreatment strategies, such as micro-solid phase extraction (µSPE) and micro-extraction by packed sorbent (MEPS), able to purify complex matrices of natural origin (whole fruits, fruit parts, leaves and their extracts) and derived commercial products.

The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (γH2AX), marker of DNA damage and genomic instability. Constitutive γH2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL. The second part of this work is the clinical, molecular and functional description of a paradigmatic case of primary refractory Burkitt lymphoma characterized by spatial intratumor heterogeneity for the TP53 mutational status, high expression levels of genomic instability and DDR activation markers, primary resistance to chemotherapy and exquisite sensitivity to DDR inhibitors.

L’obiettivo del lavoro di ricerca consiste nell’analisi dei dati archeologici della sinagoga di Bova marina (RC). Dopo una veloce descrizione della presenza ebraica in Italia, attraverso i reperti archeologici, si è passati ad analizzare i dati degli scavi degli anni ’80 del Novecento e successivamente si è proceduto a delle nuove analisi stratigrafiche per definire la cronologia della sinagoga e dell’intero sito di S. Pasquale. Nella tesi sono riportati i nuovi dati inerenti il rilievo della sinagoga, le nuove ipotesi interpretative delle due aree sepolcrali e la lettura di un nuovo edificio collegabile alla stessa fase di vita della sinagoga. / The target of the research is the analysis of archaeological data of the Bova Marina (RC) synagogue. After a quick description of the Jewish presence in Italy, through the archaeological finds, it moved to analyze the data of the excavations of the 80s of the twentieth century and then we proceeded in the new stratigraphic analysis to define the history of the synagogue and the entire site of St. Pasquale. The thesis shows the new data concerning the importance of the synagogue, the new possible interpretations of the two burial grounds and reading a new building connected to the same phase of life of the synagogue.

La tesi ha per oggetto la cultura ebraica cretese nei secoli XIV-XVI e, in particolare, l’influsso esercitato su di essa dalla cultura e dalle tradizioni degli ebrei sefarditi e ashkenaziti che cominciarono a stabilirsi sull’isola a partire dalla metà del Trecento. La tesi si basa da un lato su fonti amministrative e notarili e, dall’altro, sui manoscritti ebraici prodotti o portati a Candia nel periodo considerato. Il primo capitolo tratta della comunità ebraica nel primo Cinquecento e porta nuove notizie a proposito della geografia della zudeca, delle sue sinagoghe, della sua composizione sociale, dell’entità della sua popolazione e della biografia del principale leader spirituale e culturale attivo a Candia a quell’epoca: Elia Capsali. Il secondo capitolo offre una panoramica sull’immigrazione ebraica a Candia nei secoli XIV-XV. Il terzo capitolo esplora alcune particolarità della liturgia sinagogale elaborata dagli ebrei candioti sotto l’influsso della tradizione ashkenazita. Il quarto capitolo tratta di due liste di libri databili alla seconda metà del Quattrocento (Bologna, Biblioteca Universitaria, ms. 3574 B) e suggerisce di considerarle come indicative del peso che ebbero alcuni immigrati ebrei catalani nella diffusione della cultura medica sefardita a Candia. Il quinto capitolo è dedicato al medico, filosofo e astronomo Mosheh ben Yehudah Galiano, il quale visse a Candia tra la seconda metà degli anni Venti del Cinquecento e il 1543. L’ultimo capitolo tratta degli effetti provocati dall’epidemia di peste del 1592-95 all’interno della zudeca di Candia. / The thesis investigates the culture of the Cretan Jews in the XIV-XVI centuries and concentrates on how the Sephardi and Ashkenazi immigrants who began to settle on the island around mid-XIV century contributed in shaping a shared culture. The thesis is based both on the administrative and notarial documents preserved in the State Archive in Venice and on the Hebrew manuscripts produced by Candiote Jews or brought there by the new settlers. The first chapter offers a reconnaissance of the Jewish community of Candia in the early XVI century and brings new information on the geography of the zudeca, its administration, its social composition, the amount of its population, and the biography of its main leader at the time: Elijah Capsali (d. 1550). The third chapter illustrates some of the peculiarities that the Candiote synagogal liturgy developed under the influence of Ashkenazi settlers. The fourth chapter deals with two lists of books found in a manuscript preserved in the University Library of Bologna, and shows how they can be viewed as a testimony of the role played by Catalonian immigrants in the spread of Sephardi medical lore among Candiote Jews. The fifth chapter is dedicated to Mosheh ben Judah Galiano, a physician, philosopher and astronomer who settled in Candia in the late ’20s of the Sixteenth century and left the island on 1543. The sixth chapter offers an examination of the plague that struck Candia in 1592 and its impact on the Jewish community.

Geochemical mapping is a valuable tool for the control of territory that can be used not only in the identification of mineral resources and geological, agricultural and forestry studies but also in the monitoring of natural resources by giving solutions to environmental and economic problems. Stream sediments are widely used in the sampling campaigns carried out by the world's governments and research groups for their characteristics of broad representativeness of rocks and soils, for ease of sampling and for the possibility to conduct very detailed sampling In this context, the environmental role of stream sediments provides a good basis for the implementation of environmental management measures, in fact the composition of river sediments is an important factor in understanding the complex dynamics that develop within catchment basins therefore they represent a critical environmental compartment: they can persistently incorporate pollutants after a process of contamination and release into the biosphere if the environmental conditions change. It is essential to determine whether the concentrations of certain elements, in particular heavy metals, can be the result of natural erosion of rocks containing high concentrations of specific elements or are generated as residues of human activities related to a certain study area. This PhD thesis aims to extract from an extensive database on stream sediments of the Romagna rivers the widest spectrum of informations. The study involved low and high order stream in the mountain and hilly area, but also the sediments of the floodplain area, where intensive agriculture is active. The geochemical signals recorded by the stream sediments will be interpreted in order to reconstruct the natural variability related to bedrock and soil contribution, the effects of the river dynamics, the anomalous sites, and with the calculation of background values be able to evaluate their level of degradation and predict the environmental risk.

Per comprendere le vicende di una famiglia illustre e nobile il cui ruolo politico e sociale in Sicilia si data alle soglie del XIV secolo, non possiamo astenerci dal ricordare i fatti e gli eventi che hanno dominato la storia siciliana e determinato l’ascesa di Castelvetrano come centro signorile per eccellenza. E’ necessario, quindi, collocare geograficamente e storicamente l’isola per inserirla all’interno di un preciso quadro socio-politico. All’origine della sua storia sono sicuramente da individuare sia il legame intercorso nei secoli tra l’Asia e l’Europa, in particolare tra l’Asia Minore bizantina e l’area mediterranea unificata proprio dall’impero di Bisanzio, sia le lotte per l’egemonia tra Chiesa e Impero, (che abbastanza presto sarà impero d’Occidente) lotte che vedono entrambe le parti impegnate a contendersi il ruolo di guida politica, morale e spirituale dell’intera cristianità medievale, ritenendo ogni altro potere subordinato al proprio. / To understand the story of a noble and illustrious family whose political and social role in Sicily date is on the threshold of the fourteenth century, we can not refrain from remembering facts and events that have dominated the history of Sicily and led to the rise of Castelvetrano as a center for aristocratic excellence. E 'therefore necessary to place geographically and historically the island to slip into a specific socio-political context. At the origin of its history are definitely identify both the bond in the centuries that elapsed between Asia and Europe, in particular between the Byzantine Asia Minor and the area Mediterranean Unified own empire of Byzantium, and the struggles for hegemony between Church and Empire, (which will be soon enough empire of the West) that struggles see both sides committed to contend for the role of political leadership, moral and spiritual whole of Christianity medieval, considering all other powers subject to their own.

Peripheral T-cell lymphomas-not otherwise specified (PTCL/NOS) are the most common T-cell neoplasms. This study sought to reshape the PTCL/NOS sub-classification (including its two main morphological variants, Lennert lymphoma, LL, and Follicular variant, F-PTCL) based on the correspondence between their molecular features and those of different functional T-cell subsets, also assessing the clinical impact of such an approach. We found that PTCLs/NOS could be divided into groups corresponding to T-cell subsets differently reliant on transcription regulators including mTOR and FOXP3, and identified minimal gene sets discriminating among these groups. Notably, by grouping tumors according to their dependency on master regulators of T-lymphocyte fate, we identified three groups (T-cytotoxic, Treg/TFH, and other-T-helper) characterized by specific genetic patterns and significantly different clinical outcomes. Immunohistochemistry partially substituted for the molecular analysis by consistently recognizing only Treg and TFH cases. Finally, targeted inhibition of MTOR in T-helper cases (that were characterized by genetic lesions targeting the pathway) was proved to be effective ex vivo. We conclude that PTCL/NOS can be divided into subgroups corresponding to different cellular counterparts, characterized by different genetic patterns and possibly sensitivity to specific therapeutic approaches. Furthermore, we identified different gene and microRNA signatures for LL capable of differentiating it from other PTCL/NOS and enriched in cytotoxic function. Moreover, PI3K/Akt/mTOR pathway emerged as novel therapeutic targets for LL. Additionally, LL showed some differences with other PTCL/NOS in terms of clinical features, all supporting its recognition as a distinct entity. Besides, we found that F-PTCL has a distinct molecular signature more similar to PTCL/NOS rather than AITL, and therefore cannot be included among AITLs at least based on GEP, although this necessities more genetic studies. Overall, these results may impact on PTCL classification as well as on future studies aimed to define the more appropriate therapeutic strategy for each identified subgroup/entity.