The genetic signature of Neolithic in Greece

The Neolithic is characterized by the transition from a subsistence economy, based on hunting and gathering, to one based on food producing. This important change was paralleled by one of the most significant demographic increase in the recent history of European populations. The earliest Neolithic sites in Europe are located in Greece. However, the debate regarding the colonization route followed by the Middle-eastern farmers is still open. Based on archaeological, archaeobotanical, craniometric and genetic data, two main hypotheses have been proposed. The first implies the maritime colonization of North-eastern Peloponnesus from Crete, whereas the second points to an island hopping route that finally brought migrants to Central Greece. To test these hypotheses using a genetic approach, 206 samples were collected from the two Greek regions proposed as the arrival point of the two routes (Korinthian district and Euboea). Expectations for each hypothesis were compared with empirical observations based on the analysis of 60 SNPs and 26 microsatellite loci of Y-chromosome and mitochondrial DNA hypervariable region I. The analysis of Y-chromosome haplogroups revealed a strong genetic affinity of Euboea with Anatolian and Middle-eastern populations. The inferences of the time since population expansion suggests an earlier usage of agriculture in Euboea. Moreover, the haplogroup J2a-M410, supposed to be associated with the Neolithic transition, was observed at higher frequency and variance in Euboea showing, for both these parameters, a decreasing gradient moving from this area. The time since expansion estimates for J2a-M410 was found to be compatible with the Neolithic and slightly older in Euboea. The analysis of mtDNA resulted less informative. However, a higher genetic affinity of Euboea with Anatolian and Middle-eastern populations was confirmed. These results taken as a whole suggests that the most probable route followed by Neolithic farmers during the colonization of Greece was the island hopping route.

Implicit computational complexity and probabilistic classes

The thesis applies the ICC tecniques to the probabilistic polinomial complexity classes in order to get an implicit characterization of them. The main contribution lays on the implicit characterization of PP (which stands for Probabilistic Polynomial Time) class, showing a syntactical characterisation of PP and a static complexity analyser able to recognise if an imperative program computes in Probabilistic Polynomial Time. The thesis is divided in two parts. The first part focuses on solving the problem by creating a prototype of functional language (a probabilistic variation of lambda calculus with bounded recursion) that is sound and complete respect to Probabilistic Prolynomial Time. The second part, instead, reverses the problem and develops a feasible way to verify if a program, written with a prototype of imperative programming language, is running in Probabilistic polynomial time or not. This thesis would characterise itself as one of the first step for Implicit Computational Complexity over probabilistic classes. There are still open hard problem to investigate and try to solve. There are a lot of theoretical aspects strongly connected with these topics and I expect that in the future there will be wide attention to ICC and probabilistic classes.

Extending Implicit Computational Complexity and Abstract Machines to Languages with Control

The Curry-Howard isomorphism is the idea that proofs in natural deduction can be put in correspondence with lambda terms in such a way that this correspondence is preserved by normalization. The concept can be extended from Intuitionistic Logic to other systems, such as Linear Logic. One of the nice conseguences of this isomorphism is that we can reason about functional programs with formal tools which are typical of proof systems: such analysis can also include quantitative qualities of programs, such as the number of steps it takes to terminate. Another is the possiblity to describe the execution of these programs in terms of abstract machines. In 1990 Griffin proved that the correspondence can be extended to Classical Logic and control operators. That is, Classical Logic adds the possiblity to manipulate continuations. In this thesis we see how the things we described above work in this larger context.

Probabilistic Recursion Theory and Implicit Computational Complexity

In this thesis we provide a characterization of probabilistic computation in itself, from a recursion-theoretical perspective, without reducing it to deterministic computation. More specifically, we show that probabilistic computable functions, i.e., those functions which are computed by Probabilistic Turing Machines (PTM), can be characterized by a natural generalization of Kleene's partial recursive functions which includes, among initial functions, one that returns identity or successor with probability 1/2. We then prove the equi-expressivity of the obtained algebra and the class of functions computed by PTMs. In the the second part of the thesis we investigate the relations existing between our recursion-theoretical framework and sub-recursive classes, in the spirit of Implicit Computational Complexity. More precisely, endowing predicative recurrence with a random base function is proved to lead to a characterization of polynomial-time computable probabilistic functions.

Epigenetic signature in persons with Down Syndrome

Persons affected by Down Syndrome show a heterogeneous phenotype that includes developmental defects and cognitive and haematological disorders. Premature accelerated aging and the consequent development of age associated diseases like Alzheimer Disease (AD) seem to be the cause of higher mortality late in life of DS persons. Down Syndrome is caused by the complete or partial trisomy of chromosome 21, but it is not clear if the molecular alterations of the disease are triggered by the specific functions of a limited number of genes on chromosome 21 or by the disruption of genetic homeostasis due the presence of a trisomic chromosome. As epigenomic studies can help to shed light on this issue, here we used the Infinium HumanMethilation450 BeadChip to analyse blood DNA methylation patterns of 29 persons affected by Down syndrome (DSP), using their healthy siblings (DSS) and mothers (DSM) as controls. In this way we obtained a family-based model that allowed us to monitor possible confounding effects on DNA methylation patterns deriving from genetic and environmental factors. We showed that defects in DNA methylation map in genes involved in developmental, neurological and haematological pathways. These genes are enriched on chromosome 21 but localize also in the rest of the genome, suggesting that the trisomy of specific genes on chromosome 21 induces a cascade of events that engages many genes on other chromosomes and results in a global alteration of genomic function. We also analysed the methylation status of three target regions localized at the promoter (Ribo) and at the 5’ sequences of 18S and 28S regions of the rDNA, identifying differently methylated CpG sites. In conclusion, we identified an epigenetic signature of Down Syndrome in blood cells that sustains a link between developmental defects and disease phenotype, including segmental premature aging.

Identification of a molecular signature as potential biomarker in blood of symptomatic and asymptomatic patients with carotid atherosclerosis

Background and Objectives: Carotid revascularization to prevent future vascular events is reasonable in patients with high-grade carotid stenosis. Currently, several biomarkers to predict carotid plaque development and progression have been investigated, among which microRNAs (miRs) are promising tools for the diagnosis of atherosclerosis. Methods and Results: A total of 49 participants were included in the study, divided into two main populations: Population 1 comprising symptomatic and asymptomatic inpatients, and Population 2 comprising asymptomatic outpatients. The study consisted of two main phases: a preliminary discovery phase and a validation phase, applying different techniques. MiR-profiles were performed on plasma and plaque tissue samples obtained from 4 symptomatic and 4 asymptomatic inpatients. MiRs emerging from profiling comparisons, i.e. miR-126-5p, miR-134-5p, miR-145-5p, miR-151a-5p, miR-34b, miR-451a, miR-720 and miR-1271-5p, were subjected to validation through RT-qPCR analysis in the total cohort of donors. Comparing asymptomatic and symptomatic inpatients, significant differences were reported in the expression levels of c-miRs for miR-126-5p and miR-1271-5p in blood, being more expressed in symptomatic subjects. In contrast, simultaneous evaluation of the selected miRs in plaque tissue samples did not confirm data obtained by the miR profiling, and no significant differences were observed. Using Receiver-Operating Characteristic (ROC) analysis, a circulating molecular signature (mir-126-5p, miR-1271-5p, albumin, C-reactive protein, and monocytes) was identified, allowing the distinction of the two groups in Population 1 (AUC = 0.795). Conclusions: Data emerging from this thesis suggest that c-miRs (i.e. miR-126-5p, miR-1271-5p) combined with selected haemato-biochemical parameters (albumin, C-reactive protein, and monocytes) produced a good molecular 'signature' to distinguish asymptomatic and symptomatic inpatients. C-miRs in blood do not necessarily reflect the expression levels of the same miRs in carotid plaque tissues since different mechanism can influence their expression.