This diploma thesis called Internet and the Holy See deals with a specific question concerning relationship between the Catholic Church and media. It examines development of the attitude of the Holy See to the Internet in context of its attitude to mass media on the basis of exploration of ecclesiastical documents related to media and analysis of Internet and mass media use in practice. It takes the Internet as the latest fundamental milestone in development of human communication and probes how the Catholic Church represented by the Holy See deals with this phenomenon. Name of this thesis begins with the word Internet, to indicate perspective chosen on this topic. In the last chapter there are conclusions emerging from analysis of ecclesiastical documents compared with actual use of the Internet by the Holy See.

The aim of this study was to contribute to the comprehension of the connection of element uptake in trees at the Laacher See in Germany and climatic parameters on different time scales. Understanding the relationship of certain elements in trees and temperature might enable the assignment of extraordinary high peaks in the elemental concentration, which cannot be explained by temperature, to another process as CO2 degassing of the mofettes, which are relics of the volcanic past of the lake. Beech and oak trees at the Laacher See are not growing close to their climatic distribution limit. The relationship between tree-ring width and temperature might be not distinct enough and therefore insufficient to reconstruct climate back in time based on typical dendrochronological methods. Increasing temperatures affect the production of biomass and the release of elements in the soil. These elements are taken up by roots of trees and are implemented in yearly forming tree-rings. Using elements in tree-rings is discussed to be an alternative method for the reconstruction of climate back in time. However, there is an ongoing debate about dendrochemical methods as it is still not clear how much the resolution of the results is affected by translocation of elements between tree-rings. In this study, tree-cores of living beech and oak trees, sampled 2020, have been measured using an energy dispersive x-ray fluorescence technique (ED-XRF), which is a non-destructive method for multi-element analysis. Eleven elements (Ca, Co, Cu, Cr, Ge, Fe,K, Mn, Ni, Sc, Zn) and three elemental ratios (K/Ca, Ca/Mn, Fe/Mn) have been found to show significant positive or negative correlations in the time period from 1901 to 2018 between their concentration in tree-rings and temperature. Since Cu, Ge and K also show significant correlations with temperature in 10-year periods, higher mobility between tree-rings is assumed for those elements. Low mobility is suggested for the elements Ca and Mn as their concentration in the bark and in the wood shows little correlation. Low mobility indicated by significant correlations between elements and yearly temperature or a lack ofcorrelation between the concentration in the bark and in the wood, makes elements more suitable as indicators for temperature. However, the explanation of element concentration in tree-rings is complex, as elements are influencing each other. Antagonistic behaviour has especially been observed for the elements Ca, Co, Ge, Fe, K, Mn, Ni and Sc. These elements are showing significant correlations with temperature as well, which reveals the dependency of elemental concentrations on more than one variable. Furthermore, acidic soil at the study site might be caused by elevated CO2 concentrations, which originate from mofettes. Increasing concentrations of Fe and Ca in tree-rings give indication for decreasing soil pH. Acidification is a contrary process to temperature increase, as it generally reduces the microbial activity and therefore the availability of nutrients.

Galactic-cosmic-rays (GCR) exist in space from unknown origins. A cosmic ray is a very high energy electron, proton, or heavy ion. As a GCR transverses a power semiconductor device, electron-hole-pairs (ehps) are generated along the ion track. Effects from this are referred to as single-event-effects (SEEs). A subset of a SEE is single-event burnout (SEB) which occurs when the parasitic bipolar junction transistor is triggered leading to thermal runaway. The failure mechanism is a complicated mix of photo-generated current, avalanche generated current, and activation of the inherent parasitic bipolar transistor. Current space-borne power systems lack the utility and advantages of terrestrial power systems. Vertical-double-diffused MOSFETs (VDMOS) is by far the most common power semiconductor device and are very susceptible to SEEs by their vertical structure. Modern space power switches typically require system designers to de-rate the power semiconductor switching device to account for this. Consequently, the power system suffers from increased size, cost, and decreased performance. Their switching speed is limited due to their vertical structure and cannot be used for MHz frequency applications limiting the use of modern digital electronics for space missions. Thus, the Power Semiconductor Research Laboratory at the University of Central Florida in conjunction with Sandia National Laboratories is developing a rad-hard by design lateral-double-diffused MOSFET (LDMOS). The study provides a novel in-depth physical analysis of the mechanisms that cause the LDMOS to burnout during an SEE and provides guidelines for making the LDMOS rad-hard to SEB. Total dose radiation, another important radiation effect, can cause threshold voltage shifts but is beyond the scope of this study. The devices presented have been fabricated with a known total dose radiation hard CMOS process. Single-event burnout data from simulations and experiments are presented in the study to prove the viability of using the LDMOS to replace the VDMOS for space power systems. The LDMOS is capable of higher switching speeds due to a reduced drain-gate feedback capacitance (Miller Capacitor). Since the device is lateral it is compatible with complimentary-metal-oxide-semiconductor (CMOS) processes, lowering developing time and fabrication costs. High switching frequencies permit the use of high density point-of-load conversion and provide a fast dynamic response.

This article provides reflections on the role of ecological expertise as a tool of environmental governance. It examines the importance of State Ecological Expertise (SEE) in maintaining the ecological balance and its influence on the decision-making process for various activities. The article examines the principles and considerations underlying SEE, its impact on sustainable development and the potential implications of its assessments. By examining the relationship between ecological expertise and environmental conservation, the article aims to contribute to a deeper understanding of the instrumental role of SEE in environmental governance and sustainable resource management. In this article we reflect on the concept, importance and functioning of the State Ecological Expertise (SEE) as an independent legal institution. SEE plays an important role in monitoring the preservation of the ecological balance of the environment and in providing preliminary state control to prevent potential negative impacts on the environment. We discuss the factors considered in SEE assessments, the activities subject to mandatory SEE and the implications of the opinions issued as a result of SEE. We also examine the procedural aspects of SEE, including the requirements for the composition of the documentation submitted for the State Environmental Impact Assessment. Through this reflection, we aim to improve the understanding of the role and importance of SEE in the system of expert activity of public authorities to prevent negative impacts on the environment. This abstract is based on the concept, meaning and functioning of State Ecological Expertise (SEE) as described in the provided search results.

Aggregations of fused in sarcoma (FUS), a multifunctional RNA processing protein, define a pathological subtype of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), whilst mutations in the FUS gene are causative for ALS. To model the impact of FUS mutations, expression vectors containing the entire genomic sequence of FUS, up and downstream regions, and native promoter sequences have been generated. The constructs have been tagged with an mCherry fluorescent tag, and three separate pathological mutations (R244C, R521C, and P525L) have been separately inserted. Transgenic mice have been generated using the WT and P525L FUS vectors to provide a highly physiological model of FUS in disease. Within transfected HEK293 cells, insertion of the P525L and R521C FUS mutations leads to relocalisation of FUS from the nucleus to the cytoplasm. R521C and P525L mutant FUS incorporates into cytoplasmic aggregations of untranslated mRNA and RNA binding proteins known as stress granules. The strong relocalisation seen with P525L-FUS is associated with a gain of cytotoxicity. Reversal of this cytoplasmic relocalisation by demethylation of FUS rescues this cytotoxicity, suggesting a toxic gain of cytoplasmic function in the majority of FUS mutations. By contrast, insertion of the R244C mutation leads to neither relocalisation, stress granule association, nor cytotoxicity. Notably the R244C mutation, located away from the nuclear localization domain in which the majority of FUS mutations are found, leads to the presence of smaller FUS fragments in western blot analyses. These fragments appear not to be due to splicing defects in FUS but rather are due to post-translational modifications or aberrant protein cleavage. These data suggest an alternative pathway for FUS toxicity based upon a nuclear loss of function.

Breast cancer type 1 susceptibility protein (BRCA1) has been established as an important tumour suppressor protein and its loss of function is associated with hereditary breast and ovarian cancer. An emerging body of work suggests that BRCA1 is involved in sporadic cases of breast and ovarian cancers and may also have a role in other cancers, indicating a more global role in tumourigenesis. BRCA1-mutated cancers can be early-onset and are characterised by being highly aggressive with a propensity to metastasize, thus from a clinical perspective there is a requirement to understand the molecular mechanisms in order to be able to tailor treatments and develop therapeutics. BRCA1 has numerous cellular functions, many ascribed to its role in maintenance of genome integrity, transcription and checkpoint control. More recently, a number of extra-nuclear roles have been established. An interesting novel function is the role of the E3 ubiquitin ligase activity on cell motility. Abrogation of the ubiquitin ligase activity of BRCA1 results in cells exhibiting a hypermotile, invasive phenotype which may help to account for the metastatic nature of BRCA1-mutated tumours. Our aim was to further elucidate BRCA1’s role in cell motility, starting with the identification of relevant candidate ubiquitin ligase substrates. To date, there has yet to be a systematic approach to identify BRCA1’s ubiquitin ligase substrates. Thus we undertook an unbiased proteomic approach to identify extra-nuclear candidates by comparing the profiles of ubiquitinated proteins in breast cancer epithelial cells expressing either functional BRCA1 or ubiquitin ligase-dead BRCA1. We identified 55 candidates which were differentially enriched between the two cell lines and through pathway analysis we determined a significant proportion were cytoskeletal and translation related proteins. Using an ubiquitin-remnant profiling approach, we also identified the site(s) of ubiquitination for many of the candidates. To assess the role of these candidates in cell motility initially we adopted an in silico approach. We used existing time-lapse movies from the online database (www.mitocheck.org) which systematically siRNA knocked down every single gene in the human genome. We developed a series of algorithms which track cell motility from these movies and used these to analyse 192,000 movies containing 3.5 billion cell steps. We have produced a complete database containing motility information after siRNA knockdown of every gene in the human genome, which has been annotated with gene ontologies, KEGG families, Gene Descriptions, SwissProt, Ensembl IDs and siRNA information. In addition to providing motility data of our candidates, we also carried out gene set enrichment analysis on the whole dataset to uncover structural or functional families that may be involved in up-regulating motility when knocked down by siRNA. This is the first report of a genome-wide motility database. Based on overlaps between the results from these two large-scale unbiased proteomic and in silico datasets, we selected 4 candidates, namely, ezrin, moesin, fermitin-2 and delta-catenin. Through monolayer wound healing, cell spreading and single cell motility assays, we determined that ezrin was a particularly relevant and informative candidate. The hypermotile phenotype observed in cells expressing ubiquitin ligase dead BRCA1 was rescued through siRNA knockdown of ezrin and thus we suggest that BRCA1 may regulate cell motility through effects on ezrin. This thesis has investigated candidate BRCA1’s role in cell motility, identified candidate substrates for the E3 ubiquitin ligase activity, established a genome-wide motility database and proposed a possible pathway through which BRCA1 may mediate cell motility and by extension metastasis.

This thesis examines the relationship between environmental stress and human mobility with a view to understanding the impacts of climate change on human migration. Using a conjuncture of political ecology and migration theory, it firstly explores the literature on 'environmental refugees' identifying a distinction between general agreement on the existence of a relationship between environmental stress and migration, and debate over the appropriateness of the 'environmental refugee' as a suitable means for representing that relationship. Secondly this conjuncture is used to examine accounts from farmers and migrants in northern Ethiopia, with a focus on understanding how environmental and non-environmental factors interact to shape mobility decisions in a context of environmental stresses, thought analogous to those predicted to accompany future climate change. The principal finding of the study is that although environmental stress matters in mobility decisions, it does so due to the context of non-environmental factors in which it occurs, not in spite of them. With this in mind the work provides a framework of additive, vulnerability, enabling and barrier effects as a means for elaborating our understanding of how environmental and non-environmental factors interact to determine mobility strategies in a context of environmental stress. Focussing on the role of non-environmental factors, the work reveals that while biophysical features operate at a macro-scale to shape mobility decisions, these decisions are determined by non-environmental features operating at a micro-scale. The research then traces differences in the existence of these micro-scale, non-environmental, factors across two field sites, finding that their origins lie in both historical and contemporary forces of regional and global political economy. As such, the work concludes that understanding the relationship between climate change and human migration will require a contextualisation of that relationship within this broader framework.

Mucolipidosis type IV (MLIV) is a rare, autosomal recessive, neurodegenerative, lysosomal storage disorder. MLIV is caused by mutations in a gene (MCOLN1) encoding a TRP channel family member known as Mucolipin 1 or TRPML1. TRPML1 is a lysosomal transmembrane protein that appears to be required for normal lysosomal pH regulation, recycling of molecules and membrane reorganisation including lysosomal biogenesis, fusion and exocytosis. The exact function of the channel is unknown but it is permeable to multiple ions including Ca²⁺, Na⁺ and K⁺, possibly also Fe²⁺ and Zn²⁺. How normal TRPML1 function regulates lysosomal processes is not clearly understood. Mutations in the MCOLN1 gene can lead to complete loss of TRPML1 function, partial loss of function or mislocalisation, all of which lead to lysosomal dysfunction, lysosomal lipid storage and ultimately neurodegeneration. The disease processes that lead to neurodegeneration are poorly understood and at present no therapy exists for MLIV. We have discovered that TRPML1 results in regulating lysosomal Ca²⁺ homeostasis that is the opposite of the Ca²⁺ dysregulation associated with Niemann-Pick type C disease (NPC). Our findings indicate that disrupted function of TRPML1 leads to enhanced Ca²⁺ release via the NAADP receptor, recently shown to be the lysosomal two-pore channel TPC2. This indicates that TRPML1 is not the NAADP receptor as suggested by others, indeed NAADP mediated Ca²⁺ release is enhanced with multiple NAADP induced lysosomal Ca²⁺ release events occurring in TRPML1 null cells compared to single releases in normal cells. This phenotype appears to be responsible for the cellular dysfunction associated with MLIV disease cells, enhanced lysosomal fusion, defective endocytosis and potentially even altered lysosomal pH. Several of these phenotypes are normalised by the NAADP receptor specific antagonist Ned-19. These findings illustrate that the NAADP receptor is central to MLIV disease pathology and may be a novel candidate for disease therapy.

Environmental governance is a challenging topic in development contexts. On the one hand, the traditional development paradigm is based on economic growth through environmental exploitation; on the other, environmental degradation reduces vulnerable populations’ options for development. In the last thirty years numerous attempts to integrate environmental concerns in development policies have proved unsuccessful, raising questions as to whether the current governance system can address the challenge. The literature on environmental management has focused on identifying rules for successful governance, leaving little space to explore the complexities of the interactions between actors and their environments, wherein the reasons for sustained degradation might lie. The questions that this thesis asks are: How do diverse groups of actors rationalize and interact with degraded ecosystems? And what role does the governance system play in codifying these interactions? To answer these questions, the thesis engages in an institutional study of Lake Titicaca, between Peru and Bolivia. The lake has witnessed a degradation of its bay in the last thirty years, as a result of urban and mining development in the region. A complex web of organizations that go from the bi-national to the community level manages Lake Titicaca. The investigation of the questions asked is particularly relevant in the current context, as the countries to which the lake belongs put forward significantly different visions of the environment. By drawing on the strengths of social-ecological systems frameworks proposed by the two mains schools – the Resilience Alliance and Bloomington Workshop – and filling some of their deficiencies using insights from the sociological literatures on negotiation and justification, I hope to have created a composite framework with which to give an insightful account of the complexity and diversity at play in the field. The thesis adopts a broad range of qualitative methods (observation, interviews, document analysis) completed with descriptive statistics for budget analysis. The thesis argues that the actors’ approaches to the ecosystem are complex, diverse and constitutive of social-ecological systems wherein relationships are negotiated between actors, between actors and the ecosystem and ‘within’ actors as they hold competing visions and strategies. Some of the variables shaping these negotiations are crafted through the interaction between social and ecological elements, which also influence the actors’ understanding of the system. Others are determined by parameters crafted in the social sphere, and the ways in which social-ecological interactions fit with those. Policy interventions to improve the condition of Lake Titicaca need a more sophisticated understanding of these social-ecological systems.

The CCCTC-binding factor (CTCF) is a versatile, multifunctional zinc-finger protein involved in a broad spectrum of cellular functions. In mammalian cells, CTCF functions together with the Cohesin complex, an essential regulator of sister chromatid cohesion. Together, CTCF and Cohesin have been shown to regulate gene expression at a genome-wide level in mammalian cells. In the yeast Saccharomyces pombe, Cohesin has been implicated in transcription termination of convergently transcribed genes, in a cell cycle dependent manner. The aim of this thesis was to investigate the possibility of direct transcriptional involvement of CTCF and Cohesin in human cells. The first model system applied for this experimental purpose was the β-globin gene with introduced canonical CTCF-binding sites replacing the endogenous Co- Transcriptional Cleavage (CoTC) element downstream of β-globin. The results obtained indicate that recruitment of CTCF to the β-globin 3` flanking region does not prevent read-through transcription. However, CTCF-binding does mediate RNA Polymerase II (Pol II) pausing at the site of recruited CTCF. This results in more efficient pre-mRNA 3` end processing and therefore rescues β-globin mRNA to wild type levels. Cohesin was not detected at the introduced CTCF-binding sites. These results are a contribution to our understanding of the spatio-temporal requirements for cotranscriptional events like 3` end pre-mRNA processing and Pol II kinetics. The second part of my thesis presents an investigation on the involvement of CTCF and Cohesin in lipopolysaccharide (LPS)-induced Tumor Necrosis Factor α (TNFα) gene expression regulation in human monocytes and differentiated M1- and M2-type macrophages. These studies provide first evidence of Cohesin recruitment to the TNFα gene body and its regulatory NFκB-binding sites. Differences in the recruitment profiles obtained indicate potential regulatory differences of TNFα among the three cell types. Preliminary data provide an insight into the effects on TNFα mRNA levels upon down-regulation of Cohesin subunits.