NEW SYNTHETIC STRATEGIES FOR THE PREPARATION OF HETEROCYCLIC AND HETEROPOLYCYCLIC COMPOUNDS

The aim of the project of this doctoral thesis is the development of new synthetic strategies for the preparation of heterocyclic and heteropolycyclic compounds of potential interest in biological and pharmacological fields. In particular, we studied new general, flexible and regioselective synthetic approaches to oxygen and nitrogen heterocycles. We showed the versatility of nucleophilic addition/annulation domino reactions of alkyne compounds bearing a proximate nucleophile in the synthesis of heterocyclic systems, such as dihydroisobenzofurans, isoquinolines and naphthyridines. These approaches have been successfully transformed in Pd-catalysed multicomponent processes involving a one-pot coupling/addition/cyclisation sequence starting from the simple building blocks, such as ortho-bromoarylaldehydes, terminal alkynes and methanol or ammonia. In some cases, the reactivity of less reactive alkyne substrates has been enhanced by the catalysis of alkynophilic transition metals, such as gold and silver. In particular, we reported a new silver-catalysed approach to 2-methylisoquinolines and 5-methyl-1,6-naphtyridines by tandem addition/cyclisation of \u3b3-ketoalkynes with ammonia. The domino approach has been also extended to 2-acetyl-N-propargylpyrroles for the synthesis of pyrrolo[1,2-a]pyrazine. In this case TiCl4 revealed to be the best promoter. Microwave heating demonstrated to be able to improve the efficiency of both domino and multicomponent processes. Finally, the project developed at the Institut f\ufcr Organische und Biomolekulare Chemie in the Georg-August-Universit\ue4t G\uf6ttingen (Germany), under the supervision of Prof. L. Ackermann, concerned with the direct arylations of indoles and pyrroles with differently substituted diaryliodonium salts in the absence of metal catalysts. The protocol proved broadly applicable, thereby enabling C-H bond functionalisations of free (NH)- as well as N-substituted indoles and pyrroles

Progetto Terra più Sicura: i rischi geologici e la loro prevenzione spiegati agli studenti delle scuole secondarie di primo grado

L'associazione Geologia Senza Frontiere onlus (www.gsf.it) è nata nel 2003 dalla volontà di un gruppo di geologi, ambientalisti e naturalisti di dare una prospettiva comune alle competenze conseguite nell'ambito della ricerca universitaria, dell'attività professionale e della cooperazione. Durante l'anno scolastico 2013-2014 Geologia Senza Frontiere ha ideato e realizzato il progetto Terra più Sicura (TpS), volto all'insegnamento dei rischi geologici in scuole secondarie di primo grado di Lazio, Toscana e Veneto. Gli obiettivi del progetto sono stati in particolare l'avvicinamento di studenti ed insegnanti ai problemi della sicurezza del territorio, dei rischi in esso presenti, oltre a come prevenire ed affrontare in maniera consapevole e corretta le emergenze naturali

High-density molecular characterization and association mapping in Ethiopian durum wheat landraces reveals high diversity and potential for wheat breeding

Durum wheat (Triticum turgidum subsp. durum) is a key crop worldwide, and yet, its improvement and adaptation to emerging environmental threats is made difficult by the limited amount of allelic variation included in its elite pool. New allelic diversity may provide novel loci to international crop breeding through quantitative trait loci (QTL) mapping in unexplored material. Here, we report the extensive molecular and phenotypic characterization of hundreds of Ethiopian durum wheat landraces and several Ethiopian improved lines. We test 81 587 markers scoring 30 155 single nucleotide polymorphisms and use them to survey the diversity, structure, and genome-specific variation in the panel. We show the uniqueness of Ethiopian germplasm using a siding collection of Mediterranean durum wheat accessions. We phenotype the Ethiopian panel for ten agronomic traits in two highly diversified Ethiopian environments for two consecutive years and use this information to conduct a genome-wide association study. We identify several loci underpinning agronomic traits of interest, both confirming loci already reported and describing new promising genomic regions. These loci may be efficiently targeted with molecular markers already available to conduct marker-assisted selection in Ethiopian and international wheat. We show that Ethiopian durum wheat represents an important and mostly unexplored source of durum wheat diversity. The panel analysed in this study allows the accumulation of QTL mapping experiments, providing the initial step for a quantitative, methodical exploitation of untapped diversity in producing a better wheat

Which wheat for smallholder Ethiopian farmers? Joining traditional knowledge with metric phenotypes

Africa hosts approximately 33 million smallholder farms, which account for 80% of the continent's farming system. Subsistence farming systems face highly variable climatic conditions that threaten locally-adapted, low-input agriculture. For the near future, they are among the most seriously affected by changing climatic conditions, posing additional risks to these systems. The benefits of modern breeding benefits may fail to reach small farming communities when broadly adapted material does not address specific local requirements. To date, participatory variety selection has only scratched the surface of the exploitability of farmers' knowledge in breeding. Yet, considering that over 80% of the farmers receive seeds from informal systems, making sure that well adapted material is available in production systems, seems to be a reasonable solution to quickly affect a large populations. Ethiopia is one of the most populous countries in Africa, with more than 96 million inhabitants, 80% of whom are engaged in small-scale agriculture, and often subsistence farming. We involved 60 smallholder farmers in two locations in Ethiopia to evaluate traits of their interest in 400 wheat accessions, producing 230,400 data points. We couple this information with metric measurements of 10 agronomic traits, breaking down farmers' preferences on quantitative phenotypes. We found that the relative importance of wheat traits is gender- and locality- dependent, and produced a ranking of the 400 varieties identifying the combination of traits most desired by farmers. The study scale and methods lead to a better understanding of smallholder farmer needs, broadening the discussion for the future of local, sustainable breeding efforts accommodating farmers' knowledge

A forward genetics approach integrating genome-wide association study and expression quantitative trait locus mapping to dissect leaf development in maize (Zea mays)

The characterization of the genetic basis of maize (Zea mays) leaf development may support breeding efforts to obtain plants with higher vigor and productivity. In this study, a mapping panel of 197 biparental and multiparental maize recombinant inbred lines (RILs) was analyzed for multiple leaf traits at the seedling stage. RNA sequencing was used to estimate the transcription levels of 29\ua0573 gene models in RILs and to derive 373\ua0769 single nucleotide polymorphisms (SNPs), and a forward genetics approach combining these data was used to pinpoint candidate genes involved in leaf development. First, leaf traits were correlated with gene expression levels to identify transcript\u2013trait correlations. Then, leaf traits were associated with SNPs in a genome-wide association (GWA) study. An expression quantitative trait locus mapping approach was followed to associate SNPs with gene expression levels, prioritizing candidate genes identified based on transcript\u2013trait correlations and GWAs. Finally, a network analysis was conducted to cluster all transcripts in 38 co-expression modules. By integrating forward genetics approaches, we identified 25 candidate genes highly enriched for specific functional categories, providing evidence supporting the role of vacuolar proton pumps, cell wall effectors, and vesicular traffic controllers in leaf growth. These results tackle the complexity of leaf trait determination and may support precision breeding in maize

A crowdsourcing approach to detect farmers’ preferences: evidences from Ethiopia for adapting to climate change

Climate change is severely affecting production systems all over Africa. Ethiopia will face an increase in temperature and changes in rainfall patterns. One solution for long term management of climate related risks is to introduce new traits into production systems. We present an approach to quickly deliver to farmers a selected number of preferred accessions of durum wheat using a crowdsourcing approach. After having completed a phenotypic and genotypic characterisation of 400 accessions of Ethiopian landraces and asked farmers to evaluate them, we distributed seeds of preferred varieties to a large number of farmers using a crowdsourcing approach. In two sites representing different agroecological zones, we distributed 20 superior varieties and one check, an improved variety very common in both areas to 200 farmers in 12 villages per site, covering an area of roughly 350 km 2. We repeated the experiment for 2 years. Each farmer was given 3 blind varieties and the check, each variety being equally represented in the sample. In addition, in each village we included 2 i-buttons, measuring temperature and humidity every 3 hours throughout the growing season. This allowed to analyse the data on critical climatic parameters. Results clearly indicate farmers’ preferences: a) Landraces were preferred over improved varieties for their multiple uses; b) By considering farmers as citizen scientists, we have a better understanding of the criteria farmers use to select their preferred varieties (in our case straw and grain yield, drought tolerance, uniformity, long and dense spikes). In conclusion: • This process has been very effective in quickly disseminating seeds that match farmers’ needs. After 2 years several hundred farmers can use better adapted material. • It shows the potential of landraces to provide immediate option for managing climate related risks and calls for broader use of material conserved in gene banks. • It indicates the need to strengthen local seed systems to better manage these resources. • It indicates how farmers can provide very valuable scientific information that can be translated into research as well as development potential in other areas of research

White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Genome wide association study to identify the genetic base of smallholder farmer preferences of Durum wheat traits

Smallholder agriculture involves millions of farmers worldwide. A methodical utilization of their traditional knowledge in modern breeding efforts may help the production of locally adapted varieties better addressing their needs. In this study, a combination of participatory approaches, genomics, and quantitative genetics is used to trace the genetic basis of smallholder farmer preferences of durum wheat traits. Two smallholder communities evaluated 400 Ethiopian wheat varieties, mostly landraces, for traits of local interest in two locations in the Ethiopian highlands. For each wheat variety, farmers provided quantitative evaluations of their preference for flowering time, spike morphology, tillering capacity, and overall quality. Ten agronomic and phenology traits were simultaneously measured on the same varieties, providing the means to compare them with farmer traits. The analysis of farmer traits showed that they were partially influenced by gender and location but were repeatable and heritable, in some cases more than metric traits. The durum wheat varieties were genotyped for more than 80,000 SNP markers, and the resulting data was used in a genome wide association (GWA) study providing the molecular dissection of smallholder farmers' choice criteria

Role of the Cysteine in R3 Tau Peptide in Copper Binding and Reactivity

Tau is a widespread neuroprotein that regulates the cytoskeleton assembly. In some neurological disorders, known as tauopathies, tau is dissociated from the microtubule and forms insoluble neurofibrillary tangles. Tau comprises four pseudorepeats (R1-R4), containing one (R1, R2, R4) or two (R3) histidines, that potentially act as metal binding sites. Moreover, Cys291 and Cys322 in R2 and R3, respectively, might have an important role in protein aggregation, through possible disulfide bond formation, and/or affecting the binding and reactivity of redox-active metal ions, as copper. We, therefore, compare the interaction of copper with octadeca-R3-peptide (R3C) and with the mutant containing an alanine residue (R3A) to assess the role of thiol group. Spectrophotometric titrations allow to calculate the formation constant of the copper(I) complexes, showing a remarkable stronger interaction in the case of R3C (log K-f = 13.4 and 10.5 for copper(I)-R3C and copper(I)-R3A, respectively). We also evaluate the oxidative reactivity associated to these copper complexes in the presence of dopamine and ascorbate. Both R3A and R3C peptides increase the capability of copper to oxidize catechols, but copper-R3C displays a peculiar mechanism due to the presence of cysteine. HPLC-MS analysis shows that cysteine can form disulfide bonds and dopamine-Cys covalent adducts, with potential implication in tau aggregation process

The ATLAS Simulation: an LHC Challenge

The simulation program for the ATLAS experiment at CERN is currently in a full operational mode and integrated into the ATLAS common analysis framework, Athena. The OO approach, based on GEANT4, and in use during the DC2 data challenge has been interfaced within Athena and to GEANT4 using the LCG dictionaries and Python scripting. The robustness of the application was proved during the DC2 data challenge. The Python interface has added the flexibility, modularity and interactivity that the simulation tool requires in order to be able to provide a common implementation of different full ATLAS simulation setups, test beams and cosmic ray applications. Generation, simulation and digitization steps were exercised for performance and robustness tests. The comparison with real data has been possible in the context of the ATLAS Combined Test Beam (2004) and ongoing cosmic ray studies