Residual function, spontaneous reorganisation and treatment plasticity in homonymous visual field defects

This thesis will focus on the residual function and visual and attentional deficits in human patients, which accompany damage to the visual cortex or its thalamic afferents, and plastic changes, which follow it. In particular, I will focus on homonymous visual field defects, which comprise a broad set of central disorders of vision. I will present experimental evidence that when the primary visual pathway is completely damaged, the only signal that can be implicitly processed via subcortical visual networks is fear. I will also present data showing that in a patient with relative deafferentation of visual cortex, changes in the spatial tuning and response gain of the contralesional and ipsilesional cortex are observed, which are accompanied by changes in functional connectivity with regions belonging to the dorsal attentional network and the default mode network. I will also discuss how cortical plasticity might be harnessed to improve recovery through novel treatments. Moreover, I will show how treatment interventions aimed at recruiting spared subcortical pathway supporting multisensory orienting can drive network level change.

Caring Minds

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Prepared for a Symposium on Country Development at the European Meeting on Cybernetics and Systems Research, Vienna, Austria, April 2012 (Untitled). ACES Working Papers, April 2012

In Kazakhstan doctoral students are not expected to make a contribution to knowledge, as is required at Western universities. Rather, their task is to become familiar with what is known and then make policy recommendations for Kazakhstan. For example, how can the human capital in Kazakhstan be improved? This is a very broad subject for a PhD dissertation. However, it does require a holistic perspective, and such dissertation topics may create an opportunity for systems scientists. When Russell Ackoff created the Social Systems Sciences PhD program at the Wharton School of the University of Pennsylvania, he had his students solve practical problems for business or government managers. That program graduated a large number of people who became consultants. A few became academics in several countries. The program created a philosophy and methods for holistic management. Large issues in developing countries may be a source of clients for systems scientists who want to further develop philosophy, theories and methods by working with large social systems.

Distinct mechanisms eliminate mother and daughter centrioles in meiosis of starfish oocytes

Centriole elimination is an essential process that occurs in female meiosis of metazoa to reset centriole number in the zygote at fertilization. How centrioles are eliminated remains poorly understood. Here we visualize the entire elimination process live in starfish oocytes. Using specific fluorescent markers, we demonstrate that the two older, mother centrioles are selectively removed from the oocyte by extrusion into polar bodies. We show that this requires specific positioning of the second meiotic spindle, achieved by dynein-driven transport, and anchorage of the mother centriole to the plasma membrane via mother-specific appendages. In contrast, the single daughter centriole remaining in the egg is eliminated before the first embryonic cleavage. We demonstrate that these distinct elimination mechanisms are necessary because if mother centrioles are artificially retained, they cannot be inactivated, resulting in multipolar zygotic spindles. Thus, our findings reveal a dual mechanism to eliminate centrioles: mothers are physically removed, whereas daughters are eliminated in the cytoplasm, preparing the egg for fertilization.

Unraveling the molecular underpinnings of Philadelphia-negative myeloproliferative neoplasms: implications for future therapeutic strategies

The present thesis encompasses the two researches projects I conducted during my PhD program in Molecular Biology and Pathology. The common thread is represented by the analysis of the signaling pathways implicated in the pathophysiology of the two most aggressive Philadelphia-negative myeloproliferative neoplasms, namely, atypical chronic myeloid leukemia (aCML) and primary myelofibrosis (PMF). In the last decade, since the description of the JAK2V617F mutation in 2005, the field of the molecular characterization of Philadelphia-negative myeloproliferative neoplasms has experienced an astonishing implementation that led to the discovery of 16 new mutations involving signal transduction, epigenetic modifiers, cell cycle regulators. Nevertheless, their pathogenetic relevance and whether they could represent good “druggable” candidates have to be proved yet. In the first section I provide the first report of the signaling cascade down-stream the rare cytogenetic lesion t(8;9)(p22;p24)/PCM1-JAK2 associated with aCML, finding that it selectively activates the ERK1/2 signaling without affecting JAK/STAT phosphorylation. In the second part, I investigated the implication of the ε isoform of novel Protein kinase Cs (PKCs) in the pathophysiology of the aberrant megakaryocytopoiesis in PMF, concluding that the over-expression of PKCε detains a crucial relevance in the aberrant behavior of PMF megakaryocytes and its inhibition is capable to restore their normal differentiation and abrogate the anti-apoptotic signaling. Both results are discussed in the view of their therapeutic implications. In case PCM1/JAK2-related hematologic neoplasms, ERK-inhibitors rather than JAK-inhibitors (i.e. ruxolitinib) should be considered as a “tailored” drugs. In case of PMF, PKCε-inhibitors (i.e. εV1-2 peptide) configure as an appealing strategy to re-direct the megakaryocytic neoplastic clone.

Adaptive Signal Processing for Power Line Communications

This thesis represents a significant part of the research activity conducted during the PhD program in Information Technologies, supported by Selta S.p.A, Cadeo, Italy, focused on the analysis and design of a Power Line Communications (PLC) system. In recent times the PLC technologies have been considered for integration in Smart Grids architectures, as they are used to exploit the existing power line infrastructure for information transmission purposes on low, medium and high voltage lines. The characterization of a reliable PLC system is a current object of research as well as it is the design of modems for communications over the power lines. In this thesis, the focus is on the analysis of a full-duplex PLC modem for communication over high-voltage lines, and, in particular, on the design of the echo canceller device and innovative channel coding schemes.

Interventions for nurses caring for a child who has an unexpected acute life threatening event (ALTE) in hospital

Introduction: Caring for a child who has an unexpected ALTE in hospital can be stressful. An ALTE may include a cardiac arrest, respiratory arrest or call for immediate assistance. An international survey of practice was conducted to identify any existing interventions to inform a PhD program of work aimed at reducing the stress from these events through preparation and support. Purpose: The purpose of the survey was threefold: (1) Describe ‘normal’ practice when it comes to preparing staff or providing psychological support after caring for a child who has had an ALTE. (2) Determine if there are any interventions to prepare clinical staff for potential psychological effects of caring for a child who has an ALTE. (3) Determine if there are any interventions to provide support for clinical staff after caring for a child who has an ALTE. Material - Methods: An 18 item semi structured questionnaire was designed for the study to allow respondent to describe practices within their institution and outline their opinions and professional experiences. Clinicians from selected children’s and adult hospitals in Australia, Canada, New Zealand, United Kingdom and the United States of America were contacted by telephone. Following consent they were given the option to complete the survey via the telephone, by post or online. Results: Of the 61 hospitals approached 44 (72%) clinicians responded. Eighteen (41%) respondents identified interventions in place to prepare nurses for an ALTE ranging from (but not limited to) ad hoc discussions during life support training through to structured simulation training. Thirty-six (82%) respondents identified that they had interventions in place to support nurses after an ALTE ranging from (but not limited to) debriefing through to structured case reviews. Conclusions: Interventions varied across institutions, with no outcome or evaluation data for the interventions published to date.

Progresser dans la formation doctorale en sciences de l’humain et du social : individus et structure en tension

La présente thèse porte sur les enjeux de la progression dans la formation doctorale en sciences de l’humain et du social (SHS). Dans la plupart des pays occidentaux, les administrations universitaires se disent préoccupées par les délais d’achèvement et les faibles taux de diplomation au doctorat. S’il est admis que les aptitudes intellectuelles ne suffisent pas pour progresser dans les études doctorales, les recherches menées jusqu’ici montrent que les modalités de la formation, ainsi que le milieu et le contexte d’études dans lesquels celle-ci s’inscrit ont des répercussions sur l’expérience doctorale. Peu d’études portent toutefois sur la façon dont l’interaction de facteurs individuels et structurels peut affecter la progression dans ce processus de formation. En nous appuyant sur la théorie de la structuration de Giddens (2005), nous postulons dès lors que certaines valeurs, traditions et pratiques propres au monde académique – perpétuées, volontairement ou non, par les acteurs universitaires – peuvent nuire à la progression des doctorant-e-s. Afin d’examiner la question, une étude de cas instrumentale à visée compréhensive (Stake, 1994) a été réalisée. Six facultés des SHS d’une université canadienne ont été ciblées pour constituer le cas à l’étude. Outre l’analyse d’un ensemble de documents institutionnels relatif à la formation doctorale dans le contexte étudié, 36 doctorant-e-s issus de 19 disciplines ainsi que quatorze professeur-e-s et cinq administrateurs universitaires (directions de programmes/doyens/vices-doyens) ont été rencontrés dans le cadre d’entretiens semi-directifs. Nos résultats ont dans un premier temps permis de tracer un portrait descriptif détaillé du cas à l’étude. Les particularités de l’organisation formelle et tacite de la formation doctorale en SHS dans le contexte étudié ainsi que les défis qu’elle sous-tend ont été circonscrits, de même que les stratégies à privilégier – du point de vue des participant-e-s – pour progresser dans la formation. Dans un deuxième temps, il a été possible de montrer, d’une part, que c’est bien à la jonction de facteurs individuels et structurels que se situe la problématique de la progression dans la formation doctorale en SHS et des faibles taux de diplomation qui la caractérisent. D’autre part, la portée systémique d’une telle problématique a été mise au jour : à travers leurs choix, leurs attitudes et leurs pratiques, les acteurs universitaires contribuent à la reproduction de façon de faire et de penser « attendues » ou « admises » dans leur milieu, dont certaines ont le potentiel de nuire à la progression dans la formation doctorale.

Adaptive and Maladaptive Implications of Reinforcement Learning Processes: Fronto-Striatal Loops and Behavioural Correlates

That humans and animals learn from interaction with the environment is a foundational idea underlying nearly all theories of learning and intelligence. Learning that certain outcomes are associated with specific actions or stimuli (both internal and external), is at the very core of the capacity to adapt behaviour to environmental changes. In the present work, appetitive and aversive reinforcement learning paradigms have been used to investigate the fronto-striatal loops and behavioural correlates of adaptive and maladaptive reinforcement learning processes, aiming to a deeper understanding of how cortical and subcortical substrates interacts between them and with other brain systems to support learning. By combining a large variety of neuroscientific approaches, including behavioral and psychophysiological methods, EEG and neuroimaging techniques, these studies aim at clarifying and advancing the knowledge of the neural bases and computational mechanisms of reinforcement learning, both in normal and neurologically impaired population.

Integration of Multiple Simultaneous Stimuli within and between Somatosensory sub-Modalities

Psychological characterisation of the somatosensory system often focusses on minimal units of perception, such as detection, localisation, and magnitude estimation of single events. Research on how multiple simultaneous stimuli are aggregated to create integrated, synthetic experiences is rarer. This thesis aims to shed a light on the mechanisms underlying the integration of multiple simultaneous stimuli, within and between different sub-modalities of the somatosensory system. First, we investigated the ability of healthy individuals to perceive the total intensity of composite somatosensory patterns. We found that the overall intensity of tactile, cold, or warm patterns was systematically overestimated when the multiple simultaneous stimuli had different intensities. Perception of somatosensory totals was biased towards the most salient element in the pattern. Furthermore, we demonstrated that peak-biased aggregation is a genuine perceptual phenomenon which does not rely on the discrimination of the parts, but is rather based on the salience of each stimulus. Next, we studied a classical thermal illusion to assess participants’ ability to localise thermal stimuli delivered on the fingers either in isolation, or in uniform and non-uniform patterns. We found that despite a surprisingly high accuracy in reporting the location of a single stimulus, when participants were presented with non-uniform patterns, their ability to identify the thermal state of a specific finger was completely abolished. Lastly, we investigated the perceptual and neural correlates of thermo-nociceptive interaction during the presentation of multiple thermal stimuli. We found that inhibition of pain by warmth was independent from both the position and the number of thermal stimuli administered. Our results suggest that nonlinear integration of multiple stimuli, within and between somatosensory sub-modalities, may be an efficient way by which the somatosensory system synthesises the complexity of reality, providing an extended and coherent perception of the world, in spite of its deep bandwidth limitations.

Innovative therapeutic approaches for the atrophic Age-related Macular Degeneration (“dry” AMD)

Age related macular degeneration (AMD) is a major concern regarding blindness in the world. In western countries, where visual alterations due to minor pathologies as cataract and uncorrected refractive errors are easily resolved, AMD represent the main cause of blindness. Of the two existing forms of the disease, while the neovascular is more aggressive and progress quickly, geographic atrophy is the one still lacking an appropriate therapy. My PhD program was focused on investigating AMD features, trying to understand if some approaches I tested could be able to provide some suggestion about potential future therapies on “dry” AMD. In my research I developed three main projects. The most important part of the work regards the study of integrins and their fundamental role in cell adhesion in a context of interaction between retinal pigmented epithelium (RPE) and immune cells. I investigated how co-culture of these different cell lines can lead to simulate an inflammatory state inducing cell signaling, cytokine production and cell death. The use of integrin antagonists developed in our laboratory, showed how these effects can be reverted. A secondary approach regards the use of antioxidants and their role in epigenetic modifications in ARPE-19 cells to investigate how these compounds might exert their well-known protective role on AMD. Commonly used antioxidants as Lutein and Quercetin do not induce clear epigenetic modifications through histone H3 acetylation indicating only a limited involvement.

Environmental assessment of industrial chemical and primary sector processes from a life cycle perspective

During the PhD program in chemistry at the University of Bologna, the environmental sustainability of some industrial processes was studied through the application of the LCA methodology. The efforts were focused on the study of processes under development, in order to assess their environmental impacts to guide their transfer on an industrial scale. Processes that could meet the principles of Green Chemistry have been selected and their environmental benefits have been evaluated through a holistic approach. The use of renewable sources was assessed through the study of terephthalic acid production from biomass (which showed that only the use of waste can provide an environmental benefit) and a new process for biogas upgrading (whose potential is to act as a carbon capture technology). Furthermore, the basis for the development of a new methodology for the prediction of the environmental impact of ionic liquids has been laid. It has already shown good qualities in identifying impact trends, but further research on it is needed to obtain a more reliable and usable model. In the context of sustainable development that will not only be sector-specific, the environmental performance of some processes linked to the primary production sector has also been evaluated. The impacts of some organic farming practices in the wine production were analysed, the use of the Cereal Unit parameter was proposed as a functional unit for the comparison of different crop rotations, and the carbon footprint of school canteen meals was calculated. The results of the analyses confirm that sustainability in the industrial production sector should be assessed from a life cycle perspective, in order to consider all the flows involved during the different phases. In particular, it is necessary that environmental assessments adopt a cradle-to-gate approach, to avoid shifting the environmental burden from one phase to another.

Neuroprotective role of nutraceutical and phytochemical components

Neurodegenerative diseases (NDs) are characterized by a multifactorial etiology, in which oxidative stress and inflammation are the main causative factors. For this reason, increasing attention is being paid to the characterization and the identification of nutraceuticals and phytochemicals with intrinsic pleiotropic activity. Moreover, in a Circular Economy perspective, these natural compounds can be obtained also from renewable resources derived from the food industry by-products and can be used for both preventive and therapeutic purposes. The aim of this PhD program was to identify nutraceuticals and phytochemicals, both as extracts and pure compounds, and obtained from both plant and renewable sources, which due to their antioxidant and anti-inflammatory properties, were able to counteract cellular and molecular alterations that characterize NDs. Their neuroprotective potential has been evaluated in an in vitro model of neuroinflammation (the LPS-activated BV-2 microglial cell line), and/or in an in vitro model of neuronal oxidative stress (the neuron-like SH-SY5Y cell line differentiated with retinoic acid and exposed to H2O2). Four different projects, although deeply linked by the aforementioned common goal, have been discussed in this thesis: 1_ Impact of phenolic profile of different cherry cultivars on the potential neuroprotective effect in SH-SY5Y cells. 2_Anti-inflammatory activities of Spilanthol-rich essential oil from Acmella oleracea (L.). 3_Study of the anti-inflammatory activity of novel tacrine derivatives with lipids extracted from cashew nutshell liquid. 4_Coffee Silverskin (CSS) and Spent Coffee Grounds (SCG): coffee industry by-products as a promising source of neuroprotective agents. In general, it is, therefore, possible to conclude that the natural compounds studied in this thesis have been proven, due to their antioxidant and/or anti-inflammatory properties, to be valid preventive and therapeutic strategies for the treatment of NDs, to improve the life quality of these patients and of the general population by preventing and combating the onset of these deleterious diseases.