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The effect of the addition of ethanol (2% and 6%) during the Fischer-Tröpsch (FT) synthesis has been investigated using a 10%Co/TiO2 catalyst in a stirred basket reactor (T = 220°C, P = 8 bar, H2/CO = 2). The transformation of ethanol vapour (2% and 6% in nitrogen) over the Co/TiO2 catalyst was also studied in the absence of the synthesis gas under FT reaction conditions. Ethanol was observed to be incorporated in the growing chain and was found to (i) increase the selectivity to light products, (ii) increase the olefin to paraffin ratio and (iii) significantly decrease the catalyst activity. These effects were almost completely reversed when the ethanol in the feed was removed. Thermodynamic predictions, TPR and XRD analysis have shown that cobalt metal particles were oxidised to CoO by ethanol but that re-reduction to Co metal was possible when ethanol was removed from the feed stream allowing the catalyst to recover most of its initial performance, in particular when high flow rates were used. The effect of the cobalt carboxylate chain length (C2, C5 and C9) used in the preparation of alumina supported cobalt catalysts has been studied by TPR, XRD and hydrogen chemisorption techniques. The activity and selectivity of the prepared catalysts have been evaluated for the Fischer-Tröpsch (FT) reaction in a stirred basket reactor. It is shown that for catalysts with Co content of 10 wt.% the activity increases as the carboxylate chain length increases while the selectivity towards methane and light hydrocarbons decreases with the carboxylate chain length. The catalyst prepared using cobalt acetate was found to present the highest metal-support interaction and the poorest performance for the Fischer-Tröpsch reaction. When the metal content was increased to 15 wt.% Co and 20 wt.% Co respectively, the metal-support interaction for the catalyst prepared from cobalt acetate significantly decreased making it a better catalyst for the FT reaction compared to the catalysts prepared from C5 and C9 cobalt carboxylates. The effect of the addition of Au to a Co FT catalyst supported on titania, alumina and silica respectively, has been investigated by varying the amount of Au (0.2 to 5 wt.%) added to the catalyst. The catalysts were characterized by atomic absorption spectroscopy, XRD, XPS and TPR analysis. The catalyst evaluation for the Fischer- Tröpsch reaction activity and selectivity was achieved in a fixed bed micro-reactor (H2:CO = 2; 20 bar; 220°C). Addition of Au to supported Co catalysts improved the catalyst reduction and the cobalt dispersion on the catalyst surface. The catalyst activity for the FT reaction and the methane and light product selectivity increased with Au loading in the catalyst.

The first transplantable hematopoietic stem cells (HSC) arise in the aorta-gonad mesonephros region (AGM) during early stages of embryo development. Specifically, ventral aspect of embryonic dorsal aorta (DA) contains HSC that upon transplantation into irradiated recipients can reconstitute all lineages of the haematopoietic system [Medvinsky et al. 1993; Muller and Medvinsky, 1994; Medvinsky and Dzierzak, 1996; Cumano et al., 1996; Tavian et al., 1996; Peault and Tavian, 2003; Taoudi and Medvinsky, 2007; Ivanovs et al., 2011, 2014]. The ventral aspect of DA bears so-called intra-aortic cell clusters (IAC), the appearance of which coincides with the emergence of HSC [Babovic and Eaves, 2014; Bhatia, 2007; Boisset et al., 2010, 2011; Bollerot et al., 2005; de Bruijin et al., 2002; Bertrand et al., 2010]. According to recent reports, HSC are a heterogeneous population of cells [Dykstra et al., 2007; Seita and Weissman, 2010; Muller-Sieburg et al., 2012]. It is unclear whether all HSC precursors originate from the same location, for example, DA lining, IAC or sub-aortic tissues; or HSC precursors migrate into DA lining from other parts of the embryo [Tavian et al., 1999; Yoder et al., 1997; Oberlin et al., 2002; Peault and Tavian, 2003; Dzierzak, 2003; Samokhvalov et al., 2007; Medvinsky et al., 2011]. To elucidate ontogeny of early HSC precursors (pro-HSC), two approaches were applied in this PhD project. First, we mapped potential pro-HSC in pre-circulation mouse embryos (embryonic day 6-8.5, E6-E8.5). We defined potential pro-HSC as cells co-expressing the transcription factor Runx1, endothelial markers (VE-Cad or CD31) and/or haematopoietic markers (CD45, CD41) [Oberlin et al., 2002; de Bruijn and Dzierzak, 2012; Liakhovitskaia et al., 2009, 2014]. In E6-E8 mouse embryo, prospective pro-HSC were found to be located in chorionic plate, yolk sac and in allantoic core domain. In early somitic mouse embryo (E8-8.5) cells with pro-HSC phenotype (Runx1+CD31+CD41+) were found to be in cell clusters in forming vessel of confluence and in nascent dorsal aortae lining. Pro-HSC are not directly transplantable [Cumano et al., 1996., 2001; Godin et al., 1993; 1995; Batta et al., 2016; Matsuoka et al., 2001; Nishikawa et al., 1998]. Therefore, cells and tissues containing prospective pro-HSC were initially matured using several in-vitro culture systems. According to our results, E8 mouse embryo pro-HSC are only preserved in explant cultures, but not in co-aggregate cultures with stroma cells. After culture, cells were transplanted into sub-lethally irradiated recipients. Six weeks after transplantation 19 out of 82 transplanted recipients had donor derived blood cells' chimerism at the level of 0.1-0.3%. Forty six percent of these grafts were derived from rostral part of the embryo tissues (head, heart, upper somites). Only one out of 82 recipients had donor cells contribution above 1% (1.2 %). This recipient was engrafted with cells derived from the E8 mouse embryo head and heart region. Recipients having blood chimerism at the range of 0.1-0.3% had mainly lymphoid donor derived cells in their peripheral blood. The only recipient showing the high donor cells contribution (1.2%) had contribution mainly to myeloid lineage. Recorded low levels of blood chimersims are in line with those reported by Rybtsov et al. (2014) for early E9 mouse embryos. Donor derived cells formed clearly distinguishable populations on cytometry plots. This population of cells were absent from control engraftment experiments with carrier cells only. Previously, lymphoid potential was detected in paraaortic spnanchnopleura (P-Sp) of E8.5-9 mouse embryos, but not in E8 mouse embryos (0-5 somites, pre-circulation) and later in yolk sac [Cumano et al., 1996; Nishikawa et al., 1998; Fraser et al., 2002; Yokota et al., 2006]. However, prior works used different criteria to establish recipient reconstitution. Therefore, it is possible that recipients repopulated with E8 derived cells at the level of 0.1% were not considered as repopulated and hence, presence of lymphoid lineage precursors was overlooked in early somitic mouse embryos. The only recipient showing substantial myeloid cells contribution (73% Mac1+Gr1+ cells of donor derived cells) received engrafted cells from an older (6-13 sp) embryo and therefore potentially has yolk sac derived myeloid cells. Yolk sac cell contribution to myeloid lineage, specifically to the brain microglia was reported in prior works [Samokhvalov et al., 2007]. Our data show that early E8 AGM cells do not expand in in vitro conditions. While in AGM, cells from E9 mouse embryo expand in culture [Rybtsov et al., 2014]. We have analysed Runx1 expression pattern and dorsal aorta morphology at the time when E9 HSC precursors acquire ability to expand in in vitro culture. Runx1 expression becomes clearly polarised at the time point (22-26 sp), when paired dorsal aortae fusion is initiated. We envision that intimate connection between DA fusion events and induction of pro-HSC maturation exists. According to prior reports, Bmp, Shh and VEGF signalling regulate DA fusion [Garriock et al., 2010]. Thereofore, to enhance in vitro HSC maturation system, DA fusion triggers (for example, Bmp4) might be added to culture. Since, pro-HSC maturation methods established to date are not efficient to expand and differentiate E8 pro-HSC into potent HSC, another approach had to be implemented to study HSC ontogeny. The second approach we utilized was to trace the origin of HSC in chicken embryo, starting from the very beginning of cell fate specification, i.e. from gastrulation stages. Chick embryo haematopoiesis is similar in both human and mouse: precursors of HSC arise in the embryo proper in AGM, and IAC are formed in DA ventral aspect [Dieterlen-Lièvre, 1975; Dieterlen-Lièvre and Martin, 1981; Dieterlen-Lièvre and Jaffredo, 2009; Jaffredo et al., 2000; Le Douarin and Dieterlen-Lièvre, 2013]. In contrast to mammals, chick embryo develops ex vivo, making direct labelling and cell tracing possible. We aimed to identify cells giving rise to regions of DA that produce IAC. Therefore, segments of primitive streak (PS) were labelled with lipophilic dyes or by substituting segments of host PS with PS sections derived from transgenic (GFP+) stage matched chicken embryos. Our results show that in an 18-25h chicken embryo (Hamburger and Hamilton developmental stage 4-6, HH4-6) cells giving rise to DA ingress through the wide region of PS (35-60% of its length) [Hamburger and Hamilton, 1951]. We identified that the section of DA producing HSC is formed by cells ingressing through PS in region of 40-55% of its length at 18-25h of chick embryo development. Regardless of the embryo development stage (HH4-6), in chimeras grafted at 40-55% of PS length, GFP+ cells contributed to DA and to the IAC. Within GFP+ labelled areas, we observed clusters consisting entirely of GFP+ and clusters having a mixture of GFP+ and GFP- cells. Entirely GFP+ clusters were found in the stretch of DA that had the entire aortic endothelial lining labelled. Clusters formed on the mosaic (GFP+/GFP-) aortic endothelium also had mosaic nature. According to our data, multiple descendants of PS contribute to the same stretch of dorsal aorta. This explains mosaicity of dorsal aorta lining and IAC labelling. Since we encountered clusters with mixture of GFP+ and GFP- cells, we conclude that IAC are not clonal formations. Mosaicity of IAC also does not exclude a scenario when cells migrate in and out of a cluster. Further tracing experiments are required to establish HSC nature of cells within a cluster.

Theory of mind refers to the ability to attribute mental states to others and to predict their behaviour based on inferences about their mental states, for example their perception, desires, or beliefs. Forty years ago, research on theory of mind originated from the question of whether or not chimpanzees (Pan troglodytes) have a theory of mind, a question that – after all this time – is still debated. In the present thesis, I investigate theory of mind and its precursors in birds of the crow family, specifically Eurasian jays (Garrulus glandarius), California scrub-jays (Aphelocoma californica), and carrion crows (Corvus corone corone). Corvids have been reported to possess theory of mind-like abilities. This qualification reflects the fact that most research on theory of mind in these birds has revolved around the ability to respond to perceptual and desire states of conspecifics, and so far has not produced evidence for or against an ability to also respond to others’ beliefs. Further, it is unclear which mechanisms could be the basis of corvids’ abilities. Thus, there are two open questions in regard to corvid theory of mind my thesis aims to address. To address these questions, first, I investigated the ability of Eurasian jays to respond to the false belief of a conspecific in a caching paradigm, where the knowledge of a conspecific observer about the accessibility of two caching sites was manipulated (Chapter 2). In Chapter 3 I explore which behavioural cues might present the basis of the jays’ ability to respond to the desire of a conspecific in a caching context. In Chapter 4, I report a study on biological motion perception in scrub-jays, a phenomenon suggested to be crucial for the detection of social agents. In Chapter 5, I assess scrub-jays’ sensitivity to gaze of a human and a conspecific. Finally, in Chapter 6, I report a study investigating the face inversion effect in carrion crows, an effect that is indicative of a ‘special’ relevance of faces. I conclude by discussing how the presented studies could help us inform our understanding of corvid theory of mind-like abilities.

Until now, few rigorous studies of the precursors in structures exhibiting superluminal group velocities have been performed. One dimensional photonic crystals(1DPC) and active Lorentzian media are among the ones which are able to exhibit superluminal propagation. In the first part of the thesis we have studied the evolution of the precursors in active Lorentzian media and 1DPC. The problem of the propagation of the precursors in active Lorentzian media is addressed, by employing the steepest descent method to provide a detailed description of the propagation of the pulse inside the dispersive medium in the time domain. The problem of the time and frequency evolution of the precursors in 1DPC is studied, using the finite-difference time-domain (FDTD) techniques in conjunction with joint time-frequency analysis (JTFA). Our study clearly shows that the precursor fields associated with superluminal pulse propagation travel at subluminal speeds. It is also shown that FDTD analysis and JTFA can be combined to study the dynamic evolution of the transient and steady state pulse propagation in dispersive media. The second part of the thesis concentrates on the applications of the precursors. An interesting property of the precursors is their lower than exponential attenuation rate inside a lossy dielectric, such as water. This property of the precursors has made them an interesting candidate for applications such as ground penetrating radar and underwater communication. It was recently pointed out that a pulse which is generated inside of water and assumes the shape of the Brillouin precursor would be optimally suited for long range propagation in water (described by the single-pole Debye model). Here, we have considered the optimal pulse propagation problem, accounting for the interaction of the pulse with the air/water interface at oblique incidence. In addition, we argue that pulse excitations which are rough approximation of the Brillouin precursor will eventually evolve into the Brillouin precursor itself shortly after they enter water. Therefore, the excitation of a long-propagating pulse is not sensitive to its shape. Finally, we studied the performance of the optimized pulse in terms of the energy of the scattered field from an object inside water. Based on the simulation results the optimized pulse scattered field has higher energy compared to pulses with the same energy and different temporal distribution. The FDTD technique is employed in all the simulations.

Until now, few rigorous studies of the precursors in structures exhibiting superluminal group velocities have been performed. One dimensional photonic crystals(1DPC) and active Lorentzian media are among the ones which are able to exhibit superluminal propagation. In the first part of the thesis we have studied the evolution of the precursors in active Lorentzian media and 1DPC. The problem of the propagation of the precursors in active Lorentzian media is addressed, by employing the steepest descent method to provide a detailed description of the propagation of the pulse inside the dispersive medium in the time domain. The problem of the time and frequency evolution of the precursors in 1DPC is studied, using the finite-difference time-domain (FDTD) techniques in conjunction with joint time-frequency analysis (JTFA). Our study clearly shows that the precursor fields associated with superluminal pulse propagation travel at subluminal speeds. It is also shown that FDTD analysis and JTFA can be combined to study the dynamic evolution of the transient and steady state pulse propagation in dispersive media. The second part of the thesis concentrates on the applications of the precursors. An interesting property of the precursors is their lower than exponential attenuation rate inside a lossy dielectric, such as water. This property of the precursors has made them an interesting candidate for applications such as ground penetrating radar and underwater communication. It was recently pointed out that a pulse which is generated inside of water and assumes the shape of the Brillouin precursor would be optimally suited for long range propagation in water (described by the single-pole Debye model). Here, we have considered the optimal pulse propagation problem, accounting for the interaction of the pulse with the air/water interface at oblique incidence. In addition, we argue that pulse excitations which are rough approximation of the Brillouin precursor will eventually evolve into the Brillouin precursor itself shortly after they enter water. Therefore, the excitation of a long-propagating pulse is not sensitive to its shape. Finally, we studied the performance of the optimized pulse in terms of the energy of the scattered field from an object inside water. Based on the simulation results the optimized pulse scattered field has higher energy compared to pulses with the same energy and different temporal distribution. The FDTD technique is employed in all the simulations.

No description available.

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer related death worldwide. Chemo-therapy has been commonly used to treat unresectable HCC but with limited efficacy. Therefore, there is an urgent demand for the development of better therapeutic approaches. Granulin-epithelin precursor (GEP) is a novel growth factor with over-expression in more than 70% of HCCs and has been demonstrated as potential therapeutic target. The aims of this study are to examine the role of GEP in chemo-resistance and the therapeutic potential of GEP antibody therapy in combination with chemo-therapy in HCC. The role of GEP in HCC chemo-resistance has been examined by HCC in vitro models in the first part of the study and by in vivo human HCC xenograft models in immunocompromised mice in the second part of the study. It was shown that the chemo-therapeutic agents selected HCC cells in vitro and in vivo resulted in increased cellular expression of GEP, ABCB5, hepatic cancer stem cell (CSC) marker CD133/EpCAM positive populations and demonstrated enhanced CSCs properties including colony formation ability and chemo-resistance. Over-expression and knockdown of GEP expressions respectively demonstrated that GEP levels were important in conferring resistance to the chemo-therapeutic agents and the drug-induced apoptosis. GEP antibody therapy not only sensitized the parental HCC populations but also the chemo-resistant subpopulations to chemo-therapy induced apoptosis. Importantly, combination of GEP antibody therapy with chemo-therapy inhibited the chemo-therapy induced GEP, ABCB5 and heaptic CSCs marker over-expression through neutralization of the secretary GEP levels in the culture supernatant, and the serum GEP levels in the HCC orthotopic mice model. In human HCC xenograft models, GEP antibody treatment alone is consistently able to inhibit the tumor growth, but is unable to eliminate the established intrahepatic tumor. Cisplatin treatment, low and high dose respectively, was only able to eradicate a fraction of the intrahepatic tumor and the residual tumors grew aggressively after chemo-drug withdrawal. Combination of GEP antibody with low dose of cisplatin resulted in significant proliferation inhibition and apoptosis induction respectively. Importantly, combination of GEP antibody with high dose of cisplatin resulted in eradication of all established intrahepatic tumor. In addition, chemo-therapy induced the Akt/PKB and MEK/ERK prosurvival pathways, disturbed the balanced between the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2) member through the induction of Bcl-2. Nonetheless, combination GEP antibody therapy suppressed the chemo-therapy induced phosphorylation of PDK1, Akt, MEK, ERK, and Bcl-2 levels. It was shown that Wortmannin, the PI3K/Akt inhibitor, suppressed the expression of ABCB5 and Bcl-2 induced by chemo-therapy but showed no effect on GEP expression levels. In summary, the study demonstrated the chemo-therapy treatment alone induced the expression of growth factor GEP, drug transporter ABCB5, hepatic cancer stem cell markers expressions, and the residual cancer cells showed enhanced CSCs properties. Combination treatment with GEP antibody reversed the signaling and cancer stem cell properties induced by chemo-therapy alone. Therefore, further investigations of this combination treatment approach may lead to the development of novel therapeutic approach for the clinical treatment of chemo-resistant HCC. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy