Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD

Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure 1) on reactivity to novelty in an open-field (as an index of hyperarousal), and 2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86 mA, and 6 seconds per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5 minutes in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5 μg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30 ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results suggest that an increased noradrenergic activity in the amygdala contributes to the expression of hyperarousal in an animal model of PTSD.

A Historical Materialist Approach to the Eurozone Crisis: Fictitious Capital, States, and Capital Accumulation

This dissertation examines the ongoing European sovereign debt crises that began with Greece in 2009, in the wake of the US subprime mortgage crisis. Through the application of a historical materialist approach, I attempt to understand the on-going crisis in the European Monetary Union (EMU) by investigating root causes of sovereign debt crises, relations of power, and main beneficiaries of the policy responses. My theoretical framework hinges on three contradictions in capitalism: the tendency towards overaccumulation, the tension between fictitious capital and the productive base, and the contradiction inherent in capitalist states between their role as a national state and as a class state. In contrast to the dominant positions that locate the cause of the crisis within either: debtor states; creditor states; or the framework at the EMU, I argue that these sovereign debt crises are actually a broader crisis of crisis of capitalism within the EMU itself. In order to do so, I trace the evolution of the political economy of the Eurozone in the post-Bretton woods era, with a particularly focus on the credit system. More specifically, I argue that these crises are the result of an interaction between three meso-level contradictions that have developed within the EMU region: 1) Germany’s postwar accumulation regime, which has produced a deep crisis of overaccumulation; 2) the contradictory processes associated with the neoliberal logic of the EMU, by which I mean the rush to lower barriers to credit and finance at the expense of all else; and 3) credit-fueled, consumption-based EMU integration in the periphery; and. These three contradictions came together in the wake of the 2007-2008 US subprime crisis to form an overall crisis of capitalism in the Eurozone, expressed, as I suggest, as a crisis of fictitious capital. This dissertation aims to contribute to the ongoing project among critical political economists to de-naturalize and re-politicize money, while challenging the hegemony of monetarism within neoliberalism. Second, there has yet to be a comprehensive study that examines the EMU, Germany, and the crises in the periphery from a holistic, historical materialist analysis.

La concentración de calcio iónico se asocia a la presencia de fibrilación auricular post operatoria en pacientes llevados a revascularización miocardica

Objetivo. Determinar en un grupo de pacientes llevados a revascularización miocárdica si existió asociación entre la presencia de niveles de calcio iónico inferiores a 1,1 en las 24 horas del post operatorio y la ocurrencia de fibrilación auricular post operatoria. Metodología. Estudio observacional, analítico de casos y controles, en donde de manera consecutiva se incluyeron 110 sujetos (57 en el grupo de casos con presencia de fibrilación auricular post operatoria y 54 en el grupo de controles sin evidencia de fibrilación auricular) estos sujetos fueron llevados a revascularización miocárdica en la Fundación Cardioinfantil en los años 2010 a 2015. Resultados. Hubo 13 casos de fibrilación auricular post operatoria en pacientes con niveles de calcio iónico inferiores a 1,1 mmol/l en las primeras 24 horas del post operatorio OR: 0,5, IC (0,2-1,2) p: 0,1. Sin determinarse asociación por limitaciones del estudio, sin embargo un 29% de los pacientes con fibrilación auricular tuvieron niveles de calcio inferiores a 1,1 mmol/l en las primeras 24 horas del post operatorio, este valor aumenta a 31% cuando se analizan por separado los valores de calcio obtenidos a las 12 horas. Conclusiones. Aunque no se logró determinar asociación entre la fibrilación auricular post operatoria y las concentraciones de calcio iónico, de manera exploratoria se pudo establecer que un 29% de los pacientes con fibrilación auricular tuvieron concentraciones de calcio iónico inferiores a 1,1 mmol/l, este valor aumenta a 31% cuando se analizan los niveles de calcio iónico por separado.

La influencia del regionalismo post-liberal en la cooperación sur-sur dentro de la Unasur

El interés de este estudio de caso es analizar la influencia del regionalismo post-liberal en la cooperación sur-sur (CSS) de América Latina. Se analiza y explica cómo las dinámicas del regionalismo post-liberal del nuevo milenio, mediante esquemas de integración regional como la UNASUR, dieron paso al resurgimiento de la CSS en América Latina, no como una herramienta a favor de la integración, sino como un instrumento del liderazgo regional. Siguiendo finalmente la perspectiva neorrealista de Kenneth Waltz, con la cual se explican las transformaciones estructurales que dieron paso a un nuevo modelo de integración y los procesos de CSS que dentro de éste se desarrollan.

Índice acumulativo de riesgo (nice) como prueba diagnóstica con base en tomografía corneal por elevación en la prevención de ectasia corneal post-lasik

Antecedentes La ectasia corneal post-lasik (ECPL) es una complicación infrecuente, pero devastadora en la cirugía lasik (queratomileusis asistida con éxcimer láser) para el tratamiento de la miopía con o sin astigmatismo. Con base en la tomografía corneal por elevación por imágenes de Scheimpflug (Sistema Pentacam HR, Oculus Wetzlar, Alemania), se propone un novedoso índice acumulativo de riesgo para ser utilizado como prueba diagnóstica de tamizaje y así prevenir esta complicación. Metodología Se realizó un estudio observacional analítico, de corte transversal tipo pruebas diagnósticas, con el fin de evaluar las características operativas del índice NICE teniendo como estándar de referencia el módulo de Belin-Ambrosio (Pentacam HR) utilizando un modelo de regresión logística binaria, tablas de contingencia y estimando el área bajo la curva ROC. Resultados Se evaluaron 361 ojos de los cuales el 59,3% provenían de pacientes de sexo femenino, la edad media global fue de 30 años (RIC 11,0). El modelo logístico binario aplicado se construyó con base en cuatro variables independientes cuantitativas (K2, PAQUI, EP e I-S) y una cualitativa (SEXO), y se determinó su relación con la variable dependiente, NICE (puntaje final). Las variables predictoras fueron estadísticamente significativas clasificando adecuadamente el 92,9% de los ojos evaluados según presencia o ausencia de riesgo. El coeficiente de Nagelkerke fue de 74,4%. Conclusiones El índice acumulativo de riesgo NICE es una herramienta diagnóstica novedosa en la evaluación de candidatos a cirugía refractiva lasik para prevenir la ectasia secundaria.

Unraveling the pathophysiological mechanisms of visceral pain in the murine model of Fabry disease

Fabry disease (FD) is an X‐linked inherited, lysosomal storage disorder characterized by a deficient activity of the enzyme α-Galactosidase A (α-Gal A). This deficiency causes an accumulation of globotriaosylceramide 3 (Gb3), in nearly all organs. Gastrointestinal (GI) symptoms are among the earliest and most frequent symptoms of FD. It has been hypothesized that Gb3 accumulation is the leading cause of these, but their pathophysiology is complex and still poorly understood. Here, we aim at understanding the molecular mechanisms underpinning the GI symptoms of FD. For this purpose, we used the α‐Gal A (-/0) male mouse, a murine model of FD, to characterize morphological and molecular features of the colon tract. Our results show that α‐Gal A (-/0) mice display a thickening of the muscular layer due to a hypertrophic state of myenteric plexus ganglia, caused by an accumulation of Gb3 in neurons. Also, α-Gal A (-/0) mice present a decreased density of mucosal nerve fibres. Furthermore, α-Gal A (-/0) mice presented visceral hyperalgesia, by showing greater visceromotor response (VMR) values and obtaining higher abdominal withdrawal reflex (AWR) scores, following colorectal distension (CRD). Subsequently, the immunoreactivity of the pain-related ion channels TRPV1, TRPV4, TRPA1 and TRPM8 was detected at level of myenteric and submucosal plexus ganglia of both the genotypes. Further studies are required to assess differences of expression between α-Gal A (-/0) and control mice. Finally, we optimized the protocols to obtain three types of primary cultures from mouse intestine to be tested electrophysiologically: a mixed culture containing neurons and glia, an enriched culture of neurons, and one of glia. In summary, we revealed alterations that are likely to be part of the pathophysiological causes of FD GI symptoms. Therefore, together with further studies, this work could help identify new therapeutic targets for the treatment of visceral pain in FD.

Development and characterisation of a neurogenic model of brain cancer

Primary glioblastoma (GB), the most common and aggressive adult brain tumour, is refractory to conventional therapies and characterised by poor prognosis. GB displays striking cellular heterogeneity, with a sub-population, called Glioblastoma Stem Cells (GSCs), intrinsically resistant to therapy, hence the high rate of recurrence. Alterations of the tumour suppressor gene PTEN are prevalent in primary GBM, resulting in the inhibition of the polarity protein Lgl1 due to aPKC hyperactivation. Dysregulation of this molecular axis is one of the mechanisms involved in GSC maintenance. After demonstrating that the PTEN/aPKC/Lgl axis is conserved in Drosophila, I deregulated it in different cells populations of the nervous system in order to individuate the cells at the root of neurogenic brain cancers. This analysis identified the type II neuroblasts (NBs) as the most sensitive to alterations of this molecular axis. Type II NBs are a sub-population of Drosophila stem cells displaying a lineage similar to that of the mammalian neural stem cells. Following aPKC activation in these stem cells, I obtained an adult brain cancer model in Drosophila that summarises many phenotypic traits of human brain tumours. Fly tumours are indeed characterised by accumulation of highly proliferative immature cells and keep growing in the adult leading the affected animals to premature death. With the aim to understand the role of cell polarity disruption in this tumorigenic process I carried out a molecular characterisation and transcriptome analysis of brain cancers from our fly model. In summary, the model I built and partially characterised in this thesis work may help deepen our knowledge on human brain cancers by investigating many different aspects of this complicate disease.

Charge accumulation and transport in degenerately doped semiconducting polymers with mixed ionic and electronic conductivity

This thesis is part of the fields of Material Physics and Organic Electronics and aims to determine the charge carrier density and mobility in the hydrated conducting polymer–polyelectrolyte blend PEDOT:PSS. This kind of material combines electronic semiconductor functionality with selective ionic transport, biocompatibility and electrochemical stability in water. This advantageous material properties combination makes PEDOT:PSS a unique material to build organic electrochemical transistors (OECTs), which have relevant application as amplifying transducers for bioelectronic signals. In order to measure charge carrier density and mobility, an innovative 4-wire, contact independent characterization technique was introduced, the electrolyte-gated van der Pauw (EgVDP) method, which was combined with electrochemical impedance spectroscopy. The technique was applied to macroscopic thin film samples and micro-structured PEDOT:PSS thin film devices fabricated using photolithography. The EgVDP method revealed to be effective for the measurements of holes’ mobility in hydrated PEDOT:PSS thin films, which resulted to be <μ>=(0.67±0.02) cm^2/(V*s). By comparing this result with 2-point-probe measurements, we found that contact resistance effects led to a mobility overestimation in the latter. Ion accumulation at the drain contact creates a gate-dependent potential barrier and is discussed as a probable reason for the overestimation in 2-point-probe measurements. The measured charge transport properties of PEDOT:PSS were analyzed in the framework of an extended drift-diffusion model. The extended model fits well also to the non-linear response in the transport characterization and results suggest a Gaussian DOS for PEDOT:PSS. The PEDOT:PSS-electrolyte interface capacitance resulted to be voltage-independent, confirming the hypothesis of its morphological origin, related to the separation between the electronic (PEDOT) and ionic (PSS) phases in the blend.

Generare con transformer lineare spiegazioni di concept set medicali costituiti da termini correlati estratti da social post di pazienti

Le malattie rare pongono diversi scogli ai pazienti, ai loro familiari e ai sanitari. Uno fra questi è la mancanza di informazione che deriva dall'assenza di fonti sicure e semplici da consultare su aspetti dell'esperienza del paziente. Il lavoro presentato ha lo scopo di generare da set termini correlati semanticamente, delle frasi che abbiamo la capacità di spiegare il legame fra di essi e aggiungere informazioni utili e veritiere in un linguaggio semplice e comprensibile. Il problema affrontato oggigiorno non è ben documentato in letteratura e rappresenta una sfida interessante si per complessità che per mancanza di dataset per l'addestramento. Questo tipo di task, come altri di NLP, è affrontabile solo con modelli sempre più potenti ma che richiedono risorse sempre più elevate. Per questo motivo, è stato utilizzato il meccanismo di recente pubblicazione del Performer, dimostrando di riuscire a mantenere uno stesso grado di accuratezza e di qualità delle frasi prodotte, con una parallela riduzione delle risorse utilizzate. Ciò apre la strada all'utilizzo delle reti neurali più recenti anche senza avere i centri di calcolo delle multinazionali. Il modello proposto dunque è in grado di generare frasi che illustrano le relazioni semantiche di termini estratti da un mole di documenti testuali, permettendo di generare dei riassunti dell'informazione e della conoscenza estratta da essi e renderla facilmente accessibile e comprensibile al pazienti o a persone non esperte.

Best-practice model for technology enhanced learning in the creative arts

This paper presents a best-practice model for the redesign of virtual learning environments (VLEs) within creative arts to augment blended learning. In considering a blended learning best-practice model, three factors should be considered: the conscious and active human intervention, good learning design and pedagogical input, and the sensitive handling of the process by trained professionals. This study is based on a comprehensive VLE content analysis conducted across two academic schools within the creative arts at one Post-92 higher education (HE) institution. It was found that four main barriers affect the use of the VLE within creative arts: lack of flexibility in relation to navigation and interface, time in developing resources, competency level of tutors (confidence in developing online resources balanced against other flexible open resources) and factors affecting the engagement of ‘digital residents’. The experimental approach adopted in this study involved a partnership between the learning technology advisor and academic staff, which resulted in a VLE best-practice model that focused directly on improving aesthetics and navigation. The approach adopted in this study allowed a purposive sample of academic staff to engage as participants, stepping back cognitively from their routine practices in relation to their use of the VLE and questioning approaches to how they embed the VLE to support teaching and learning. The model presented in this paper identified a potential solution to overcome the challenges of integrating the VLE within creative arts. The findings of this study demonstrate positive impact on staff and student experience and provide a sustainable model of good practice for the redesign of the VLE within creative disciplines.

Integrating omics in prion diseases as a model to explore the strain paradigm in neurodegenerative diseases

This project aims at deepening the understanding of the molecular basis of the phenotypic heterogeneity of prion diseases. Prion diseases represent the first and clearest example of “protein misfolding diseases”, that are all the neurodegenerative diseases caused by the accumulation of misfolded proteins in the central nervous system. In the field of protein misfolding diseases, the term “strain” describes the heterogeneity observed among the same disease in the clinical and pathologic progression, biochemical features of the aggregated protein, conformational memory and pattern of lesions. In this work, the two most common strains of Creutzfeldt-Jakob Disease (CJD), named MM1 and VV2, were analyzed. This thesis investigates the strain paradigm with the production of new multi omic data, and, on such data, appropriate computational analysis combining bioinformatics, data science and statistical approaches was performed. In this work, genomic and transcriptomic profiling allowed an improved characterization of the molecular features of the two most common strains of CJD, identifying multiple possible genetic contributors to the disease and finding several shared impaired pathways between the VV2 strain and Parkinson Disease. On the epigenomic level, the tridimensional chromatin folding in peripheral immune cells of CJD patients at onset and of healthy controls was investigated with Hi-C. While being the first application of this very advanced technology in prion diseases and one of the first in general in neurobiology, this work found a significant and diffuse loss of genomic interactions in immune cells of CJD patients at disease onset, particularly in the PRNP locus, suggesting a possible impairment of chromatin conformation in the disease. The results of this project represent a novelty in the state of the art in this field, both from a biomedical and technological point of view.

Evaluation of the transcriptomic response of an Alzheimer's disease murine model induced at different ages: searching for predictors

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disease, characterized by the impairment of mnesic and cognitive functions, that represents the most frequent type of dementia in older people worldwide. Aging is the most important risk factor for the sporadic form of the pathology and it is associated to the progressive impairment of the proteostasis network. The endoplasmic reticulum (ER), the main cellular actor involved in proteostasis, appears significantly compromised in AD due to the accumulation of β-amyloid (Aβ) protein and phosphorylated-tau protein. Increasing proteins misfolding activates a specific cellular response known as Unfolded Protein response (UPR) which orchestrates the recovery of ER function. The aim of the present study was to investigate the role of UPR and aging process in a murine model of AD induced by intracerebroventricular (i.c.v.) injection of Aβ1-42 oligomers at 3 or 18 months. The oligomers injection in aged animals caused the increased of memory impairment, oxidative stress, and the depletion of glutathione reserve. Furthermore, the RNA-sequencing analysis was performed and the bioinformatic analysis showed the enrichment of several pathways involved in neurodegeneration and protein regulations. The following analysis highlighted the significant dysregulation of the three branches of the UPR, the protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF-6). In turn, ER stress affected the PI3K/Akt/Gsk3β and MAPK/ERK pathways, highlighting Mapkapk5 as a potential marker of the neurodegenerative process, which regulation could lead to the definition of new pharmacological and neuroprotective strategies to counteract AD.

Pathogenetic mechanisms of gastrointestinal symptoms in a mouse model of Fabry disease: insights on the microbiota-gut-brain axis

Fabry disease (FD), X-linked metabolic disorder caused by a deficiency in α-galactosidase A activity, leads to the accumulation of glycosphingolipids, mainly Gb3 and lyso-Gb3, in several organs. Gastrointestinal (GI) symptoms are among the earliest and most common, strongly impacting patients’ quality of life. However, the origin of these symptoms and the exact mechanisms of pathogenesis are still poorly understood, thus the pressing need to improve their knowledge. Here we aimed to evaluate whether a FD murine model (α-galactosidase A Knock-Out) captures the functional GI issues experienced by patients. In particular, the potential mechanisms involved in the development and maintenance of GI symptoms were explored by looking at the microbiota-gut-brain axis involvement. Moreover, we sought to examine the effects of lyso-Gb3 on colonic contractility and the intestinal epithelium and the enteric nervous system, which together play important roles in regulating intestinal ion transport and fluid and electrolyte homeostasis. Fabry mice revealed visceral hypersensitivity and a diarrhea-like phenotype accompanied by anxious-like behavior and reduced locomotor activity. They reported also an imbalance of SCFAs and an early compositional and functional dysbiosis of the gut microbiota, which partly persisted with advancing age. Moreover, overexpression of TRPV1 was found in affected mice, and partial alteration of TRPV4 and TRPA1 as well, identifying them as possible therapeutic targets. The Ussing chamber results after treatment with lyso-Gb3 showed an increase in Isc (likely mediated by HCO3- ions movement) which affects neuron-mediated secretion, especially capsaicin- and partly veratridine-mediated. This first characterization of gut-brain axis dysfunction in FD mouse provides functional validation of the model, suggesting new targets and possible therapeutic approaches. Furthermore, lyso-Gb3 is confirmed to be not only a marker for the diagnosis and follow-up of FD but also a possible player in the alteration of the FD colonic ion transport process.

The engagement of yugoslav technical cooperation experts in post-colonial Algeria (1962-1990). A global microhistory of east-south relations

The venture of socialist Eastern Europe in assisting the development efforts of the post-colonial countries opened up official migratory channels to the Global South for a specific labour group engaged under international technical cooperation programmes. By taking post-colonial Algeria as a space of East-South interactions and intense inter-socialist competition, the thesis studies labour mobility from socialist Yugoslavia of a heterogeneous group labelled “technical cooperation experts” in the period from 1962 to 1990. While CMEA members dispatched to the country personnel in great numbers, after 1965, Yugoslavia failed to do so. Tracing them beyond the institutional level, the thesis aims at detecting and exposing factors which inhibited the attempts to increase the presence of Yugoslav technical experts in Algeria. It argues that instead of building an alternative, solidarity-based aid model, Yugoslav technical cooperation with the developing countries was reduced to mediation in the employment of highly-skilled labour abroad. The cooperation scheme, which differed from one of its Eastern European counterparts, manifested in the employment and legal status as well as everyday life and work experiences of Yugoslav citizens. Relying on the methodological approach of global microhistory, which strongly favours the micro-historical analysis of primary sources in studying global processes, the thesis provides a more comprehensive and nuanced understanding of Yugoslav globalization endeavours. By shifting the focus to the experiences of ordinary people who were under the strong influence of globalization forces of the Cold War era, the thesis adds a “human” dimension to the history of East-South relations.

An Efficient Protocol For The Generation Of Monocyte Derived Dendritic Cells Using Serum-free Media For Clinical Applications In Post Remission Aml Patients.

Protocols for the generation of dendritic cells (DCs) using serum as a supplementation of culture media leads to reactions due to animal proteins and disease transmissions. Several types of serum-free media (SFM), based on good manufacture practices (GMP), have recently been used and seem to be a viable option. The aim of this study was to evaluate the results of the differentiation, maturation, and function of DCs from Acute Myeloid Leukemia patients (AML), generated in SFM and medium supplemented with autologous serum (AS). DCs were analyzed by phenotype characteristics, viability, and functionality. The results showed the possibility of generating viable DCs in all the conditions tested. In patients, the X-VIVO 15 medium was more efficient than the other media tested in the generation of DCs producing IL-12p70 (p=0.05). Moreover, the presence of AS led to a significant increase of IL-10 by DCs as compared with CellGro (p=0.05) and X-Vivo15 (p=0.05) media, both in patients and donors. We concluded that SFM was efficient in the production of DCs for immunotherapy in AML patients. However, the use of AS appears to interfere with the functional capacity of the generated DCs.