Reformation and society in Guernsey : c.1500-c.1640

The maintenance of civil order in Guernsey's pre-Reformation community was regulated by a variety of secular institutions, the most important of which was the Royal Court. Religious beliefs and practices helped to reinforce stability and legitimized traditional authority. Catholic practice, including charity and the activities of numerous fraternities - not hitherto noticed in Guernsey - engendered social cohesion. Any major changes in the island's religious life threatened this traditional polity. When religious alterations loomed in the wake of Henrician and Edwardian changes in England, the Guernsey authorities chose to conceal religious revenues and subvert English intentions. Traditional practices and institutions predominated until the reign of Elizabeth -a finding which contradicts previous studies. In the fifteen-sixties, however, the English Government appointed a series of commissions to seize Catholic dues and close down traditional institutions. The commissioners favoured local Protestants materially, and in 1565 elevated some of them to the Royal Court. The possibilities offered by a Calvinist system of social control appealed to the island's elite group. Calvinist organisation facilitated the enforcement of discipline, Catholic revenues were turned to private and secular purposes, and the elite retained power. The new Church depended on the secular authorities for its survival; it needed magistrates to allow foreign ministers to settle, to educate local ones, and to fend off the threat of an imposed settlement in line with the English settlement of 1559. The Church also repeatedly requested the Court to enact legislation in line with Calvinist principles, which it did. Although the records do not lend themselves to quantitative analysis, it is clear however that the Court often neglected to enforce such legislation. The Church's own remedies frequently were inadequate and ineffective. The secular power responded more positively in other areas. The Church's role in succouring the poor was encouraged, and the elite itself benefited materially as a consequence of Calvinist ideas. But the price paid for the retention of the elite's control and the material advantages it gained was the failure of the Calvinist dream and increased cultural differentiation in the community

Piloting a Community of Student Data Consultants that Supports and Enhances Research Data Services

Research ecosystems within university environments are continuously evolving and requiring more resources and domain specialists to assist with the data lifecycle. Typically, academic researchers and professionals are overcommitted, making it challenging to be up-to-date on recent developments in best practices of data management, curation, transformation, analysis, and visualization. Recently, research groups, university core centers, and Libraries are revitalizing these services to fill in the gaps to aid researchers in finding new tools and approaches to make their work more impactful, sustainable, and replicable. In this paper, we report on a student consultation program built within the University Libraries, that takes an innovative, student-centered approach to meeting the research data needs in a university environment while also providing students with experiential learning opportunities. This student program, DataBridge, trains students to work in multi-disciplinary teams and as student consultants to assist faculty, staff, and students with their real-world, data-intensive research challenges. Centering DataBridge in the Libraries allows students the unique opportunity to work across all disciplines, on problems and in domains that some students may not interact with during their college careers. To encourage students from multiple disciplines to participate, we developed a scaffolded curriculum that allows students from any discipline and skill level to quickly develop the essential data science skill sets and begin contributing their own unique perspectives and specializations to the research consultations. These students, mentored by Informatics faculty in the Libraries, provide research support that can ultimately impact the entire research process. Through our pilot phase, we have found that DataBridge enhances the utilization and openness of data created through research, extends the reach and impact of the work beyond the researcher’s specialized community, and creates a network of student “data champions” across the University who see the value in working with the Library. Here, we describe the evolution of the DataBridge program and outline its unique role in both training the data stewards of the future with regard to FAIR data practices, and in contributing significant value to research projects at Virginia Tech. Ultimately, this work highlights the need for innovative, strategic programs that encourage and enable real-world experience of data curation, data analysis, and data publication for current researchers, all while training the next generation of researchers in these best practices. [This paper is a conference pre-print presented at IDCC 2020 after lightweight peer review.

Cationic and PEGylated amphiphilic cyclodextrins: co-formulation opportunities for neuronal siRNA delivery

Optimising non-viral vectors for neuronal siRNA delivery presents a significant challenge. Here, we investigate a co-formulation, consisting of two amphiphilic cyclodextrins (CDs), one cationic and the other PEGylated, which were blended together for siRNA delivery to a neuronal cell culture model. Co-formulated CD-siRNA complexes were characterised in terms of size, charge and morphology. Stability in salt and serum was also examined. Uptake was determined by flow cytometry and toxicity was measured by MTT assay. Knockdown of a luciferase reporter gene was used as a measure of gene silencing efficiency. Incorporation of a PEGylated CD in the formulation had significant effects on the physical and biological properties of CD. siRNA complexes. Co-formulated complexes exhibited a lower surface charge and greater stability in a high salt environment. However, the inclusion of the PEGylated CD also dramatically reduced gene silencing efficiency due to its effects on neuronal uptake. The co-formulation strategy for cationic and PEGylated CDs improved the stability of the CD. siRNA delivery systems, although knockdown efficiency was impaired. Future work will focus on the addition of targeting ligands to the co-formulated complexes to restore transfection capabilities

Anisamide-targeted cyclodextrin nanoparticles for siRNA delivery to prostate tumours in mice

A hepta-guanidino-β-cyclodextrin (G-CD), its hepta-PEG conjugate (G-CD-PEG), and the corresponding anisamide-terminated PEG conjugate (G-CD-PEG-AA) have been synthesised and compared as delivery vectors for siRNA to prostate cancer cells and tumours in vivo. The G-CD-PEG-AA.siRNA formulations (in which anisamide targets the sigma receptor), but not the non-targeted formulations, induced prostate cell-specific internalisation of siRNA resulting in approximately 80% knockdown in vitro of the reporter gene, luciferase. Following intravenous administration of the anisamide-targeted formulation in a mouse prostate tumour model significant tumour inactivation with corresponding reductions in the level of vascular endothelial growth factor (VEGF) mRNA were achieved, without demonstrating enhanced toxicity. This data imply significant potential for anisamide-conjugated cyclodextrin vectors for targeted delivery of therapeutic siRNAs in the treatment of prostate cancer

A click chemistry route to 2-functionalised PEGylated and cationic beta-cyclodextrins: co-formulation opportunities for siRNA delivery

A new approach to the synthesis of amphiphilic beta-cyclodextrins has used 'click' chemistry to selectively modify the secondary 2-hydroxyl group. The resulting extended polar groups can be either polycationic or neutral PEGylated groups and these two amphiphile classes are compatible in dual cyclodextrin formulations for delivery of siRNA. When used alone with an siRNA, a cationic cyclodextrin was shown to have good transfection properties in cell culture. Co-formulation with a PEGylated cyclodextrin altered the physicochemical properties of nanoparticles formed with siRNA. Improved particle properties included lower surface charges and reduced tendency to aggregate. However, as expected, the transfection efficiency of the cationic vector was lowered by co-formulation with the PEGylated cyclodextrin, requiring future surface modification of particles with targeting ligands for effective siRNA delivery

Brain-Derived Neurotrophic Factor Expression and Respiratory Function Improve after Ampakine Treatment in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is thought to act as a transcriptional repressor of brain-derived neurotrophic factor (BDNF), Mecp2 null mice, which develop an RTT-like phenotype, exhibit progressive deficits in BDNF expression. These deficits are particularly significant in the brainstem and nodose cranial sensory ganglia (NGs), structures critical for cardiorespiratory homeostasis, and may be linked to the severe respiratory abnormalities characteristic of RTT. Therefore, the present study used Mecp2 null mice to further define the role of MeCP2 in regulation of BDNF expression and neural function, focusing on NG neurons and respiratory control. We find that mutant neurons express significantly lower levels of BDNF than wild-type cells in vitro, as in vivo, under both depolarizing and nondepolarizing conditions. However, BDNF levels in mutant NG cells can be increased by chronic depolarization in vitro or by treatment of Mecp2 null mice with CX546, an ampakine drug that facilitates activation of glutamatergic AMPA receptors. Ampakine-treated Mecp2 null mice also exhibit marked functional improvement, characterized by restoration of normal breathing frequency and minute volume. These data demonstrate that BDNF expression remains plastic in Mecp2 null mice and raise the possibility that ampakine compounds could be of therapeutic value in the treatment of RTT

Click-modified cyclodextrins as non-viral vectors for neuronal siRNA delivery

RNA interference (RNAi) holds great promise as a strategy to further our understanding of gene function in the central nervous system (CNS) and as a therapeutic approach for neurological and neurodegenerative diseases. However, the potential for its use is hampered by the lack of siRNA delivery vectors, which are both safe and highly efficient. Cyclodextrins have been shown to be efficient and low toxicity gene delivery vectors in various cell types in vitro. However, to date they have not been exploited for delivery of oligonucleotides to neurons. To this end, a modified β-cyclodextrin (CD) vector was synthesised, which complexed siRNA to form cationic nanoparticles of less than 200nm in size. Furthermore, it conferred stability in serum to the siRNA cargo. The in vitro performance of the CD in both immortalised hypothalamic neurons and primary hippocampal neurons was evaluated. The CD facilitated high levels of intracellular delivery of labelled siRNA, whilst maintaining at least 80% cell viability. Significant gene knockdown was achieved, with a reduction in luciferase expression of up to 68% and a reduction in endogenous glyceraldehyde phosphate dehydrogenase (GAPDH) expression of up to 40%. To our knowledge, this is the first time that a modified CD has been used as a safe and efficacious vector for siRNA delivery into neuronal cells