Interaction between mechanism of attention selection in space and time: Behavioural and electrophysiological evidence

I meccanismi attentivi consentono di selezionare dall'ambiente circostante le informazioni utili allosvolgimento di un determinato compito. Negli ultimi trenta anni, i processi coinvolti nella selezionedi informazioni di natura spaziale sono stati ampiamente investigati, mentre rimangono ancora dachiarire i meccanismi coinvolti negli aspetti di selezione temporale. I tre esperimenti riportatiall'interno di questa tesi sono volti ad indagare alcuni degli aspetti legati alla capacit\ue0 di selezionaregli eventi nel tempo ed in che modo gli aspetti temporali e quelli spaziali interagiscono tra loro.Nel primo esperimento \ue8 stato impiegato un compito di Giudizio di Ordine Temporale (TOJ) perinvestigare la relazione esistente tra disturbi di selezione nello spazio e nel tempo in pazienti coneminegligenza spaziale unilaterale. Una forte compromissione dei meccanismi di selezione neltempo \ue8 stata rilevata per le coppie di stimoli presentate in porzioni dello spazio in cui il deficitspaziale \ue8 pi\uf9 marcato, suggerendo l'esistenza una relazione tra gli aspetti spaziali e quelli temporalinella modulazione del deficit.Nel secondo e nel terzo esperimento \ue8 stato investigato l'orientamento dell'attenzione nel tempoutilizzando stimoli che, grazie ad un movimento con velocit\ue0 regolare o irregolare, rendonopossibile il generarsi di aspettative temporali e di verificare cosa avviene quando tali aspettativevengono disattese. La regolarit\ue0 del movimento si \ue8 rivelato essere un indice importante nelgenerare aspettative temporali che a loro volta influenzano profondamente la performancediminuendo sensibilmente la velocit\ue0 di risposta del soggetto. Inoltre, la registrazione dei potenzialievocati ha evidenziato come aspettative spaziali e temporali interagiscano influenzando l'analisidello stimolo fin dalle prime fasi di elaborazione.The study of mechanisms involved in spatial attention is one of the most investigated field inmodern neuroscience, but in the last years a growing interest has been devoted to unveil themechanisms concerning also the temporal aspects of attention. In this thesis three experiment arereported that tried to cast more light on the temporal aspects of attention and on the relationshipbetween spatial and temporal attentional mechanisms.In the first experiment the relationship between spatial and temporal deficit in selective visualattention has been investigated in a group of neglect patients using a temporal order judgement task(TOJ). The main finding is a stronger impairment in temporal selection for spatial position in whichthe attention selection is more impaired, suggesting an interaction between the two aspects in themodulation of the deficit.The second and the third experiment investigated temporal expectations generated by a regularrhythm. In particular, the impact of exogenous and endogenous temporal expectation has beencompared in a discrimination task, revealing the pervasive effect of regularity of movement andspeed in orienting attention in time. Moreover, it has been confirmed the combined effect of spatialand temporal expectations in modulation of electrophysiological response.These results suggest the existence of an interaction between spatial and temporal mechanisms ofattention

A SVM-based method to classify RBM20 affected and not affected exons

Mutations of RNA binding motif protein 20 (RBM20) have been recently reported to cause Human dilated cardiomyopathy (DCM) (Brauch et al., 2009, Li et al., 2010). DCM is the major cause of heart failure and mortality around the world (Jefferies and Towbin, 2010). Overall, 25\u201350% of DCM cases are familiar and causative mutations which have been described in more than 50 genes encoding mostly for structural components of cardiomyocytes. RBM20 belongs to the family of the SR and SR-related RNA binding proteins which assemble in the spliceosome taking part in the splicing of pre-mRNA. RBM20 is mainly expressed in striated muscle, with the highest levels in the heart (Guo et al., 2012). Due to its involvement in DCM, RBM20 was studied a lot to unveil its mechanism of action and its RNA targets (Guo et al., 2012, Li et al., 2013). Guo and colleagues reported a set of 31 genes showing a RBM20 dependent splicing from a whole transcriptome analysis in rats and humans (Guo et al., 2012). More recently, Maatz and colleagues reported an additional set of 18 rat genes and observed that RNA sequences recognized by RBM20 are likely to be located in the 400 nucleotides flanking the exons whose alternative splicing is regulated by RBM20 (Maatz et al., 2014). However, both the suggested RNA sequence which is recognized by RBM20 and its over-representation over the flanking regions of affected exons remain poor predictors to target genes presenting splicing events regulated by RBM20. The aim of this work was, thus, to characterize, through a bioinformatic approach, the sequence motifs of the exons whose alternative splicing was affected by RBM20, in order to ameliorate the prediction of the genes (exons) affected by RBM20. A differential expression analysis was performed to select the dataset of RBM20 affected exons; a further dataset was retrieved from literature data (Maatz et al., 2014). A Support Vector Machine (SVM) approach evaluating more kinds of genetic elements binding in the flanking regions of our target exons was used. A SVM method was chose to classify RBM20 affected and not affected exons, but other machine learning algorithms could have been used as well; however, SVM is among the most commonly used ones. From the analyses, our model resulted to well discriminate RBM20 affected from not affected exons. From a biological and functional point of view, this approach helps us to target novel candidate genes associated to diseases depending on a dysregulation of RBM20. This study provided additional information about RBM20 regulation of target exons, based not only on the RNA binding site, but also on other genetic elements associated to the binding site. Furthermore, we proposed the first model based on a SVM algorithm for the classification of RBM20 affected and not affected exons

A mediação como método de solução construtiva de conflitos entre franqueador e franqueado

A relação de franquia comercial (ou franchising) gera considerável quantidade de riqueza e empregos no Brasil e pode ser fonte de prosperidade para franqueador e franqueado. Tratando-se de uma relação humana, contudo, não está livre de conflitos. Estes podem ter consequências destrutivas ou construtivas, a depender do tipo de interação existente entre os envolvidos e dos métodos de processamento da controvérsia. A mediação propõe-se, como método autocompositivo, a oferecer aos mediandos, por meio do diálogo e da intermediação de terceiro imparcial, oportunidade para investigar soluções mutuamente benéficas ante a existência de interesses (aparentemente) conflitantes. A pergunta que este trabalho visa a responder é se (e como) a mediação pode se caracterizar como um método de resolução construtiva de conflitos entre franqueador e franqueado, sendo o objetivo geral responder a esse questionamento. O primeiro objetivo específico é conceituar o que se entende por “resolução construtiva de conflitos” conforme o referencial teórico adotado. O estudo da relação de franquia, de sua dinâmica de incentivos e dos conflitos existentes entre franqueador e franqueado é o segundo objetivo específico do trabalho e culmina na propositura de um caso hipotético-exemplificativo de conflito entre franqueador e franqueada. O terceiro e último objetivo específico é o estudo do método da mediação de conflitos e da descrição de algumas das técnicas/ferramentas à disposição do mediador na condução da negociação entre os envolvidos, utilizando o caso criado como ilustração de sua aplicação. A metodologia utilizada para realização do trabalho foi a exploratória. A partir da estrutura de estudo proposta, pode-se concluir que a existência de interesses objetivamente conflitantes e/ou de alternativas à negociação que superem as vantagens que podem ser auferidas por meio do diálogo torna menos provável a cooperação entre franqueador e franqueado. Contudo, nas demais situações, as técnicas de mediação descritas têm potencial para aumentar as chances de desenvolvimento de dinâmicas cooperativas entre os mediandos e, com isto, reduzir as chances de que seus conflitos se tornem destrutivos. Em qualquer dos casos, por meio de mecanismos que incentivem o endereçamento de emoções, necessidades e interesses dos envolvidos no conflito, a mediação pode permitir maior objetividade no tratamento das questões negociais e aumento da criatividade na geração de soluções que atendam mutuamente aos interesses de franqueador e franqueado. Pode diminuir, assim, as chances de escalada do conflito, polarização de interesses e perecimento (parcial ou total) da relação social pré-existente.Commercial franchising generates a considerable amount of wealth and job places in Brazil and can be a source of prosperity for franchisor and franchisee. As any human relationship, however, it is not free of conflicts. These conflicts can have destructive or constructive consequences, depending on the type of interaction between those involved and the methods of processing the controversy. Mediation is a consensual dispute resolution method that aims to grant the parties involved in the conflictual situation, through dialogue and intermediation of an impartial third party (the mediator), the opportunity to investigate mutually beneficial solutions to the existence of (apparently) conflicting interests. This paper aims to answer whether (and how) mediation can be characterized as a method of constructive resolution of conflicts between franchisor and franchisee and its general objective is to answer this research question. Its first specific objective is to conceptualize what the expression "constructive resolution of conflicts" means according to the adopted theoretical framework. The study of the franchise relationship, its incentive dynamics and the existing conflicts between franchisor and franchisee is the second specific objective of this paper and culminates with the proposition of a hypothetical case-example of a conflict between franchisor and franchisee. The third and final specific objective of the paper is the study of the method of conflict mediation and the description of some of the techniques/tools available to the mediator in conducting the negotiation among the participants, using the case created as an illustration of their application. The methodology used to perform the work was the exploratory method. From the proposed study structure, it is possible to conclude that the existence of objectively conflicting interests and/or alternatives to a negotiated agreement that overcome the advantages that can be obtained through dialogue makes it less likely for cooperation to arise between franchisor and franchisee. However, in other scenarios, the described mediation techniques have the potential to increase the chances of developing cooperative dynamics between the participants and reduce the chances that their conflicts become destructive. In any case, through mechanisms that encourage the addressing of the emotions, needs and interests of those involved in the conflict, mediation can allow greater objectivity in the treatment of business issues and increase creativity in generating solutions that mutually meet the franchisor's and the franchisee’s interests. Mediation can thus diminish the chances of escalating the conflict, the polarization of interests and the partial or complete perishment of the preexisting social relation

CircRNAs are here to stay: A perspective on the MLL recombinome

Chromosomal translocations harbored by cancer genomes are important oncogenic drivers. In MLL rearranged acute leukemia (MLLre) MLL/KMT2A fuses with over 90 partner genes. Mechanistic studies provided clues of MLL fusion protein leukemogenic potential, but models failed to fully recapitulate the disease. Recently, expression of oncogenic fusion circular RNAs (f-circ) by MLL-AF9 fusion was proven. This discovery, together with emerging data on the importance and diversity of circRNAs formed the incentive to study the circRNAs of the MLL recombinome. Through interactions with other RNAs, such as microRNAs, and with proteins, circRNAs regulate cellular processes also related to cancer development. CircRNAs can translate into functional peptides too. MLL and most of the 90 MLL translocation partners do express circRNAs and exploration of our RNA-seq dataset of sorted blood cell populations provided new data on alternative circular isoform generation and expression variability of circRNAs of the MLL recombinome. Further, we provided evidence that rearrangements of MLL and three of the main translocation partner genes can impact circRNA expression, supported also by preliminary observations in leukemic cells. The emerging picture underpins the view that circRNAs are worthwhile to be considered when studying MLLre leukemias and provides a new perspective on the impact of chromosomal translocations in cancer cells at large

Whole-genome sequencing and SNV genotyping of 'Nebbiolo' (Vitis vinifera L.) clones

'Nebbiolo' (Vitis vinifera) is among the most ancient and prestigious wine grape varieties characterised by a wide genetic variability exhibited by a high number of clones (vegetatively propagated lines of selected mother plants). However, limited information is available for this cultivar at the molecular and genomic levels. The whole-genomes of three 'Nebbiolo' clones (CVT 71, CVT 185 and CVT 423) were re-sequenced and a de novo transcriptome assembly was produced. Important remarks about the genetic peculiarities of 'Nebbiolo' and its intra-varietal variability useful for clonal identification were reported. In particular, several varietal transcripts identified for the first time in 'Nebbiolo' were disease resistance genes and single-nucleotide variants (SNVs) identified in 'Nebbiolo', but not in other cultivars, were associated with genes involved in the stress response. Ten newly discovered SNVs were successfully employed to identify some periclinal chimeras and to classify 98 'Nebbiolo' clones in seven main genotypes, which resulted to be linked to the geographical origin of accessions. In addition, for the first time it was possible to discriminate some 'Nebbiolo' clones from the others

West Nile virus spread in Europe: phylogeographic pattern analysis and key drivers

BACKGROUND: West Nile virus (WNV) outbreaks in birds, humans, and livestock have occurred in multiple areas in Europe and have had a significant impact on animal and human health. The patterns of emergence and spread of WNV in Europe are very different from those in the US and understanding these are important for guiding preparedness activities.METHODS: We mapped the evolution and spread history of WNV in Europe by incorporating viral genome sequences and epidemiological data into phylodynamic models. Spatially explicit phylogeographic models were developed to explore the possible contribution of different drivers to viral dispersal direction and velocity. A "skygrid-GLM" approach was used to identify how changes in environments would predict viral genetic diversity variations over time.FINDINGS: Among the six lineages found in Europe, WNV-2a (a sub-lineage of WNV-2) has been predominant (accounting for 73% of all sequences obtained in Europe that have been shared in the public domain) and has spread to at least 14 countries. In the past two decades, WNV-2a has evolved into two major co-circulating clusters, both originating from Central Europe, but with distinct dynamic history and transmission patterns. WNV-2a spreads at a high dispersal velocity (88km/yr-215 km/yr) which is correlated to bird movements. Notably, amongst multiple drivers that could affect the spread of WNV, factors related to land use were found to strongly influence the spread of WNV. Specifically, the intensity of agricultural activities (defined by factors related to crops and livestock production, such as coverage of cropland, pasture, cultivated and managed vegetation, livestock density) were positively associated with both spread direction and velocity. In addition, WNV spread direction was associated with high coverage of wetlands and migratory bird flyways.CONCLUSION: Our results suggest that-in addition to ecological conditions favouring bird- and mosquito- presence-agricultural land use may be a significant driver of WNV emergence and spread. Our study also identified significant gaps in data and the need to strengthen virological surveillance in countries of Central Europe from where WNV outbreaks are likely seeded. Enhanced monitoring for early detection of further dispersal could be targeted to areas with high agricultural activities and habitats of migratory birds.</p

Metabolite and lipoprotein profiles reveal sex-related oxidative stress imbalance in de novo drug-naive Parkinson's disease patients

Parkinson's disease (PD) is the neurological disorder showing the greatest rise in prevalence from 1990 to 2016. Despite clinical definition criteria and a tremendous effort to develop objective biomarkers, precise diagnosis of PD is still unavailable at early stage. In recent years, an increasing number of studies have used omic methods to unveil the molecular basis of PD, providing a detailed characterization of potentially pathological alterations in various biological specimens. Metabolomics could provide useful insights to deepen our knowledge of PD aetiopathogenesis, to identify signatures that distinguish groups of patients and uncover responsive biomarkers of PD that may be significant in early detection and in tracking the disease progression and drug treatment efficacy. The present work is the first large metabolomic study based on nuclear magnetic resonance (NMR) with an independent validation cohort aiming at the serum characterization of de novo drug-naive PD patients. Here, NMR is applied to sera from large training and independent validation cohorts of German subjects. Multivariate and univariate approaches are used to infer metabolic differences that characterize the metabolite and the lipoprotein profiles of newly diagnosed de novo drug-naive PD patients also in relation to the biological sex of the subjects in the study, evidencing a more pronounced fingerprint of the pathology in male patients. The presence of a validation cohort allowed us to confirm altered levels of acetone and cholesterol in male PD patients. By comparing the metabolites and lipoproteins levels among de novo drug-naive PD patients, age- and sex-matched healthy controls, and a group of advanced PD patients, we detected several descriptors of stronger oxidative stress

Heterogeneity of prodromal Parkinson symptoms in siblings of Parkinson disease patients

Abstract: A prodromal phase of Parkinson’s disease (PD) may precede motor manifestations by decades. PD patients’ siblings are at higher risk for PD, but the prevalence and distribution of prodromal symptoms are unknown. The study objectives were (1) to assess motor and non-motor features estimating prodromal PD probability in PD siblings recruited within the European PROPAG-AGEING project; (2) to compare motor and non-motor symptoms to the well-established DeNoPa cohort. 340 PD siblings from three sites (Bologna, Seville, Kassel/Goettingen) underwent clinical and neurological evaluations of PD markers. The German part of the cohort was compared with German de novo PD patients (dnPDs) and healthy controls (CTRs) from DeNoPa. Fifteen (4.4%) siblings presented with subtle signs of motor impairment, with MDS-UPDRS-III scores not clinically different from CTRs. Symptoms of orthostatic hypotension were present in 47 siblings (13.8%), no different to CTRs (p = 0.072). No differences were found for olfaction and overall cognition; German-siblings performed worse than CTRs in visuospatial-executive and language tasks. 3/147 siblings had video-polysomnography-confirmed REM sleep behavior disorder (RBD), none was positive on the RBD Screening Questionnaire. 173/300 siblings had <1% probability of having prodromal PD; 100 between 1 and 10%, 26 siblings between 10 and 80%, one fulfilled the criteria for prodromal PD. According to the current analysis, we cannot confirm the increased risk of PD siblings for prodromal PD. Siblings showed a heterogeneous distribution of prodromal PD markers and probability. Additional parameters, including strong disease markers, should be investigated to verify if these results depend on validity and sensitivity of prodromal PD criteria, or if siblings’ risk is not elevated