I nemici del popolo a Bologna (1274-1306)

In questa tesi di dottorato ci si propone di indagare i conflitti politici che sconvolsero la Bologna di fine Duecento e dei primissimi anni del Trecento. Analizzando l'evoluzione del linguaggio politico e delle tecniche di esclusione utilizzate dal gruppo dirigente bolognese, sar\ue0 possibile illustrare come la creazione di un nemico pubblico fosse parte della strategia politica del popolo e della pars geremea per consolidare il proprio potere sulla citt\ue0 felsinea. L'esclusione degli avversari politici dalla citt\ue0, il conferimento di ampi privilegi e prerogative ai membri del gruppo dirigente e l'emanazione di una legislazione estremamente favorevole ai soli esponenti del popolo bolognese venivano appunto giustificati affermando che tali interventi erano necessari per difendere la citt\ue0 dai nemici interni e dai traditori. Per una puntuale analisi di questa strategia sar\ue0 fondamentale osservare, seppure per somme linee, l'influenza esercitata dalle potenze straniere sullo spazio politico bolognese. Se da una parte il gruppo dirigente bolognese aveva messo in atto una vera e propria demonizzazione dei propri avversari, dall'altra manteneva con molti di loro rapporti pi\uf9 o meno intensi. I banditi spesso rientravano stringendo accordi vantaggiosi per entrambe le parti o con la promessa di difendere la loro patria con la vita, mentre i confinati, a distanza di decenni, mantenevano vivi i loro rapporti con Bologna. Tali indagini saranno estese anche al contado bolognese, territorio poco studiato, dove si muovevano i famigerati signori territoriali. Questi soggetti, spesso identificati con i cosiddetti "lupi rapaci" e tratteggiati come principali fautori della debolezza del controllo della citt\ue0 sul contado bolognese, svolgevano in realt\ue0 importantissime funzioni sia nell'amministrazione del distretto sia nella sua difesa. I casati magnatizi del contado, certamente violenti e spesso coinvolti in sanguinose faide, venivano dotati di una sostanziale autonomia e impunit\ue0 fino a che riconoscevano l'autorit\ue0 cittadina e utilizzavano la loro potenza per combattere i nemici esterni di Bologn

IKK promotes naïve T cell survival by repressing RIPK1-dependent apoptosis and activating NF-κB

The inhibitor of κB kinase (IKK) complex regulates the activation of the nuclear factor κB (NF-κB) family of transcription factors. In addition, IKK represses extrinsic cell death pathways dependent on receptor-interacting serine/threonine-protein kinase 1 (RIPK1) by directly phosphorylating this kinase. Here, we showed that peripheral naïve T cells in mice required the continued expression of IKK1 and IKK2 for their survival; however, the loss of these cells was only partially prevented when extrinsic cell death pathways were blocked by either deleting Casp8 (which encodes the apoptosis-inducing caspase 8) or inhibiting the kinase activity of RIPK1. Inducible deletion of Rela (which encodes the NF-κB p65 subunit) in mature CD4+ T cells also resulted in loss of naïve CD4+ T cells and in reduced abundance of the interleukin-7 receptor (IL-7R) encoded by the NF-κB target Il7r, revealing an additional reliance upon NF-κB for the long-term survival of mature T cells. Together, these data indicate that the IKK-dependent survival of naïve CD4+ T cells depends on both repression of extrinsic cell death pathways and activation of an NF-κB-dependent survival program

La proper generalized decomposition appliquée à la théorie variationnelle des rayons complexes pour le calcul des vibrations moyennes fréquences dans une bande de fréquence

De nos jours, les problèmes d'acoustique pour les vibrations moyennes fréquences suscitent un grand intérêt de la part des industriels. Néanmoins, leur prédiction numérique reste toujours un problème ouvert dans le monde de la recherche scientifique, car les méthodes classiques (telle que FEM, SEA) ne fonctionnent pas dans cette gamme de fréquences. La méthode appelée Théorie Variationnelle des Rayons Complexes (TVRC), qui sera présentée, est une méthode numérique qui permet de le faire. L'accent sera en particulier mis sur sa capacité à calculer les solutions sur des bandes de fréquences, gr

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL

Hedgehog Signalling in the Embryonic Mouse Thymus

T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC)-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC) development, and thymocyte–TEC cross-talk in the embryonic mouse thymus during the last week of gestation

Integrated Cognitive and Neuromotor Rehabilitation in Multiple Sclerosis: A Pragmatic Study

Background: Few studies examined the effects of combined motor and cognitive rehabilitation in patients with multiple sclerosis (MS). The present prospective, multicenter, observational study aimed to determine the efficacy of an integrated cognitive and neuromotor rehabilitation program versus a traditional neuromotor training on walking, balance, cognition and emotional functioning in MS patients.Methods: Sixty three MS patients were selected and assigned either to the Integrated Treatment Group (ITG; n = 32), receiving neuropsychological treatment (performed by ERICA software and paper–pencil tasks) complemented by conventional neuromotor rehabilitation, or to the Motor Treatment Group (n = 31) receiving neuromotor rehabilitation only. The intervention included two 60-min sessions per week for 24 weeks. At baseline and at end of the training all patients underwent a wide-range neuropsychological, psychological/emotional, and motor assessment.Results: At baseline the two groups did not differ for demographic, neuropsychological, psychological/emotional, and motor features significantly. After rehabilitation, only ITG group significantly (p-corrected for False Discovery Rate) improved on test tapping spatial memory, attention and cognitive flexibility, as well as on scales assessing depression and motor performance (balance and gait). A regression analysis showed that neuropsychological and motor improvement was not related to improvements in fatigue and depression.Conclusion: The present study demonstrated positive effects in emotional, motor, and cognitive aspects in MS patients who received an integrated cognitive and neuromotor training. Overall, results are supportive of interventions combining motor and cognitive training for MS

Neural correlates of anosognosia in Alzheimer\u2019s disease and mild cognitive impairment: A multi-method assessment

Patients with Alzheimer\u2019s Disease (AD) and Mild Cognitive Impairment (MCI) may present anosognosia for their cognitive deficits. Three different methods have been usually used to measure anosognosia in patients with AD and MCI, but no studies have established if they share similar neuroanatomical correlates. The purpose of this study was to investigate if anosognosia scores obtained with the three most commonly used methods to assess anosognosia relate to focal atrophy in AD and MCI patients, in order to improve understanding of the neural basis of anosognosia in dementia. Anosognosia was evaluated in 27 patients (15 MCI and 12 AD) through clinical rating (Clinical Insight Rating Scale, CIRS), patient-informant discrepancy (Anosognosia Questionnaire Dementia, AQ-D), and performance discrepancy on different cognitive domains (self-appraisal discrepancies, SADs). Voxel-based morphometry correlational analyses were performed on magnetic resonance imaging (MRI) data with each anosognosia score. Increasing anosognosia on any anosognosia measurement (CIRS, AQ-D, SADs) was associated with increasing gray matter atrophy in the medial temporal lobe including the right hippocampus. Our results support a unitary mechanism of anosognosia in AD and MCI, in which medial temporal lobes play a key role, irrespectively of the assessment method used. This is in accordance with models suggesting that anosognosia in AD is primarily caused by a decline in mnemonic processes

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

JNK signalling in cancer: In need of new, smarter therapeutic targets

Copyright © 2013 The British Pharmacological Society. This is the accepted version of the following article: Bubici, C. and Papa, S. (2014), JNK signalling in cancer: in need of new, smarter therapeutic targets. British Journal of Pharmacology, 171: 24–37, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/bph.12432/abstract.The JNKs are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs is involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumour suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and, more importantly, what effect small molecule inhibitors of JNKs have on physiological processes, are essential. A number of ATP-competitive and ATP-non-competitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review, we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and haematological malignancies, and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.Kay Kendall Leukemia Fund, Italian Association for Cancer Research and Foundation for Liver Research