The theology of judgement in the Fourth Gospel: christology and eschatology in John 5

This thesis addresses the apparent puzzle of the theology of judgement in the Fourth Gospel. Throughout John’s Gospel, Jesus is presented as both judging and not judging while eschatological scenarios are presented and alluded to in which humanity will be judged at the last day and also in which will be no final judgement. This puzzling theology is particularly apparent in John 5 as has been noted many times in Johannine scholarship. In order to resolve this puzzle a hypothesis in initially proposed and the remainder of the study is devoted to affirming that the hypothesis does, in fact, provide a resolution. The hypothesis which is proposed at the beginning of this thesis is that John 5 presents a unified theology of judgement which is bicameral in that it consists of two eschatological compartments – one for Christian believers and one for the rest of humanity. The eschatology which John 5 presents for Christian believers is one in which they have been exempted from any end-time judgement process, but have already obtained the salvific benefit of eternal life which they shall continue to enjoy in a heavenly realm following bodily death. In parallel, John 5 presents a more traditional eschatology of a judgement tribunal for the rest of humanity at the eschaton where Christ, as God’s appointed judge, will sit in judgement of those who have rejected him and those who have not had the opportunity to accept him. The salvific benefits of such a bicameral eschatology are directed entirely in favour of Christian believers. In addition, the hypothesis proposes that the Christology of the Fourth Gospel has developed specifically to empower the Johannine Christ to act as the bringer of life to Christian believers and as the deliverer of Judgement to the non-Christian portion of humanity. This thesis seeks to substantiate the validity of the hypothesis by firstly establishing three prerequisites for its applicability to the text of John 5. Firstly, it is necessary to establish that the Christology and eschatology which the hypothesis addresses are indeed to be found in the Gospel and in John 5 in particular. Secondly, it is necessary to search through Johannine scholarship to establish how the problem has been addressed before and whether any proposed solutions can successfully stand as obstacles to the application of the hypothesis. Thirdly, the hypothesis requires that John 5 is a unified text with no redactional insertions by secondary editors. All three of these prerequisites are addressed and a case is made for proceeding with the application of the hypothesis

Cross Sector Service Coordination for People with High and Complex Needs: Harnessing Existing Evidence and Knowledge

People with high and complex needs will generally need an array of supports to enable social and economic participation as envisaged by the National Disability Insurance Scheme (NDIS). As participants, these people will receive funding from the NDIS to purchase services and supports from a range of different disability sector providers, but will also need to access various 'mainstream’ services including health, education, housing, justice and transport in order to pursue the life they choose. The complexity of the services system, and the interfaces between sectors, create gaps and barriers that are challenging for participants, service providers and for policy makers alike to navigate. Cross-sector coordination is a critical scheme design element to ensure that NDIS participants get the range of services and supports they need to pursue their goals and participate in society and the economy. Any failure of other sectors to provide access to quality services will increase the costs of disability support and risk the sustainability of the NDIS. Coordination can thus also be seen as a way of addressing this fundamental risk facing the NDIS. For these reasons cross-sector coordination should be a core element in NDIS design. The disability field is actively discussing these challenges and this paper aims to provide evidence to inform policy directions now being developed.The Centre for Disability Research and Policy at the University of Sydney and the Young People in Nursing Homes National Alliance were partners in a project, supported by the NDIACentre for Disability Research and Polic

Copy-number variations in DISC1 and DISC1-interacting partners in major mental illness

Robust statistical, genetic and functional evidence supports a role for DISC1 in the etiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy-number variants (CNVs) are suspected to play an important causal role in these disorders. In this study CNV-analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification (MAQ). We report finding rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the etiology of these devastating diseases

Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder

Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role of glutamate receptors and their interacting scaffold proteins, the exons of ten glutamatergic ‘hub’ genes in 1304 individuals were re-sequenced in case and control samples. No significant difference in the overall number of non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases and controls. However, cluster analysis of nsSNPs identified two exons encoding the cysteine-rich domain and first transmembrane helix of GRM1 as a risk locus with five mutations highly enriched within these domains. A new splice variant lacking the transmembrane GPCR domain of GRM1 was discovered in the human brain and the GRM1 mutation cluster could perturb the regulation of this variant. The predicted effect on individuals harbouring multiple mutations distributed in their ten hub genes was also examined. Diseased individuals possessed an increased load of deleteriousness from multiple concurrent rare and common coding variants. Together, these data suggest a disease model in which the interplay of compound genetic coding variants, distributed among glutamate receptors and their interacting proteins, contribute to the pathogenesis of schizophrenia and bipolar disorders

Immunocompetent 3D Model of Human Upper Airway for Disease Modeling and In Vitro Drug Evaluation

The development of more complex in vitro models for the assessment of novel drugs and chemicals is needed because of the limited biological relevance of animal models to humans as well as ethical considerations. Although some human-cell-based assays exist, they are usually 2D, consist of single cell type, and have limited cellular and functional representation of the native tissue. In this study, we have used biomimetic porous electrospun scaffolds to develop an immunocompetent 3D model of the human respiratory tract comprised of three key cell types present in upper airway epithelium. The three cell types, namely, epithelial cells (providing a physical barrier), fibroblasts (extracellular matrix production), and dendritic cells (immune sensing), were initially grown on individual scaffolds and then assembled into the 3D multicell tissue model. The epithelial layer was cultured at the air–liquid interface for up to four weeks, leading to formation of a functional barrier as evidenced by an increase in transepithelial electrical resistance (TEER) and tight junction formation. The response of epithelial cells to allergen exposure was monitored by quantifying changes in TEER readings and by assessment of cellular tight junctions using immunostaining. It was found that epithelial cells cocultured with fibroblasts formed a functional epithelial barrier at a quicker rate than single cultures of epithelial cells and that the recovery from allergen exposure was also more rapid. Also, our data show that dendritic cells within this model remain viable and responsive to external stimulation as evidenced by their migration within the 3D construct in response to allergen challenge. This model provides an easy to assemble and physiologically relevant 3D model of human airway epithelium that can be used for studies aiming at better understanding lung biology, the cross-talk between immune cells, and airborne allergens and pathogens as well as drug delivery

Integration of robotic surgery into routine practice and impacts on communication, collaboration, and decision making: A realist process evaluation protocol

Background: Robotic surgery offers many potential benefits for patients. While an increasing number of healthcare providers are purchasing surgical robots, there are reports that the technology is failing to be introduced into routine practice. Additionally, in robotic surgery, the surgeon is physically separated from the patient and the rest of the team, with the potential to negatively impact teamwork in the operating theatre. The aim of this study is to ascertain: how and under what circumstances robotic surgery is effectively introduced into routine practice; and how and under what circumstances robotic surgery impacts teamwork, communication and decision making, and subsequent patient outcomes. Methods and design: We will undertake a process evaluation alongside a randomised controlled trial comparing laparoscopic and robotic surgery for the curative treatment of rectal cancer. Realist evaluation provides an overall framework for the study. The study will be in three phases. In Phase I, grey literature will be reviewed to identify stakeholders' theories concerning how robotic surgery becomes embedded into surgical practice and its impacts. These theories will be refined and added to through interviews conducted across English hospitals that are using robotic surgery for rectal cancer resection with staff at different levels of the organisation, along with a review of documentation associated with the introduction of robotic surgery. In Phase II, a multi-site case study will be conducted across four English hospitals to test and refine the candidate theories. Data will be collected using multiple methods: the structured observation tool OTAS (Observational Teamwork Assessment for Surgery); video recordings of operations; ethnographic observation; and interviews. In Phase III, interviews will be conducted at the four case sites with staff representing a range of surgical disciplines, to assess the extent to which the results of Phase II are generalisable and to refine the resulting theories to reflect the experience of a broader range of surgical disciplines. The study will provide (i) guidance to healthcare organisations on factors likely to facilitate successful implementation and integration of robotic surgery, and (ii) guidance on how to ensure effective communication and teamwork when undertaking robotic surgery

Rare coding variants in ten genes confer substantial risk for schizophrenia

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, PPeer reviewe

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination