China's absorptive State: research, innovation and the prospects for China-UK collaboration

China's innovation system is advancing so rapidly in multiple directions that the UK needs to develop a more ambitious and tailored strategy, able to maximise opportunities and minimise risks across the diversity of its innovation links to China. For the UK, the choice is not whether to engage more deeply with the Chinese system, but how. This report analyses the policies, prospects and dilemmas for Chinese research and innovation over the next decade. It is designed to inform a more strategic approach to supporting China-UK collaboration

Integrated interpretation of 3D seismic data using seismic attributes to understand the structural control of methane occurrences at deep gold mining levels: West Wits Line Goldfield, South Africa

A thesis submitted to the Faculty of Science, University of the Witwatersrand in fulfilment of the requirements for the degree of Master of Science, School of Geosciences University of the Witwatersrand. 08 November 2017.At a number of gold mines in South Africa, the presence of methane gases has been encountered when drilling into faults and/or dyke structures extending to depths beyond 4.5 km. Methane gas has been reported to have migrated through structures from within the basin to the mine working environments (~3.0 km depths) and caused explosions. The Booysens Shale is considered one of the possible source rocks for hydrocarbons and it forms the footwall to the gold-bearing Ventersdorp Contact Reef (VCR, ~ 1.5 m thick). The Booysens Shale lies at depths between 3.5 km and 4.5 km below land surface and can be best described as the base of the divergent clastic wedge which thickens westward, hosting the quartzite and conglomerate units that sub-crop against the VCR towards the east of the gold mining areas. Geometric attributes (dip and dip azimuth) and instantaneous attributes (phase, frequency and envelope) computed for the Booysens Shale and Ventersdorp Contact Reef horizons (interpreted from 3D prestack time migrated data acquired in the Witwatersrand goldfields) provide insight into structures that extend from the Booysens Shale into the overlying mining level, the Ventersdorp Contact Reef. These attributes provide high-resolution mapping of the structures (faults, dykes, and joints) that have intersected both the Ventersdorp Contact Reef and Booysens Shale horizons. Volumetric fault analysis using the ant-tracking attribute incorporated with methane gas data also show the continuity and connections of the faults and fracture zones possibly linked to methane gas and fluid migration. Correlation between the known occurrence of fissure water and methane with geologically- and seismically-mapped faults show that steeply dipping structures (dip>60°) are most likely to channel fracture water and methane. δ13C and δ2H isotope results suggest that the methane gas (and associated H2 and alkanes) from the goldfields, particularly along seismically delineated faults and dykes, have an abiogenic origin produced by water-rock reactions. Isotopic data derived from adjacent goldfields also suggests the possibility of mixing between microbial hydrocarbons (characterized by highly depleted 2HCH4 values) and abiogenic gases. It is, therefore, possible that the propagation of these structures, as mapped by 3D seismics and enhanced volumetric attributes, between Booysens Shale and Ventersdorp Supergroup provide conduits for mixing of fluids and gases encountered at mining levels. The study may provide new evidence for the notion of hydrocarbons, particularly CH4, having migrated via faults and dykes from depth, within the Witwatersrand Basin, to where they are intersected at mining levels. The research gives new insight into mixing between microbial and abiogenic end-members within hydrogeologically isolated water pockets.LG201

The development and application of a ChIP and MeDIP assay to determine a link between epigenetics and metabolism in ovarian cancer progression

Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers globally. High-grade serous ovarian carcinomas (HGSOC) comprise 75% of EOCs and are characterised by diagnosis at advanced stages due to the late manifestation of non-specific symptoms. The majority of HGSOC cells are found to metastasise to the omentum, an adipocyte-rich membrane which can metabolise chemotherapeutic drugs. EOC patients develop malignant ascites, characterised by the high concentration of cytokines and the presence of multicellular aggregates of EOC cells known as spheroids. Both characteristics can facilitate EOC metastasis. EOC patients initially respond well to platinum-based chemotherapy, but the vast majority will relapse and eventually develop chemotherapy-resistant disease. Long-term survival for OC has shown no recent improvement which highlights the needs for new strategies that improve EOC prognosis. The dysregulation of the epigenetic landscape is a hallmark of EOC leading to the activation of oncogenes and suppression of anti-tumour genes. Ten-eleven translocation (TET) 2 is involved in DNA demethylation, playing a role in transcriptional regulation and gene expression. Oncometabolites present in EOC can inhibit TET2 which leads to aberrant gene regulation, contributing to malignant transformation and progression. Additionally, TET2 can be stabilised by metformin through activation of AMPK, a key regulator of cellular energy homeostasis. Metformin, a biguanide drug widely prescribed as first line treatment for diabetes, has shown promise as an anti-cancer drug. In EOC, metformin has been linked with an increased survival rate in addition to being able to decrease cytokine production and tumour formation in ovarian tumour cells. However, here metformin was found to increase cytokine (IL-6 and IL-8) production in chemosensitive EOC cells, under conditions of a physiological EOC tumour microenvironment (i.e., restricted glucose conditions), but not in chemoresistant EOC cells. This may be unfavourable if metformin was to be repurposed as treatment for EOC and may account for its inconsistent efficacy as a potential therapeutic drug in other cancers. Pathways including AMPK/TET2, and JAK/STAT were explored using techniques such as western Blot, Chromatin immunoprecipitation (ChIP) and methylated DNA immunoprecipitation (MeDIP) as possible mechanisms for this response. Cell viability and proliferation assays were used to explore the effect of oncometabolites on EOC cells. The results will provide insights into how metabolites affect EOC progression in addition to identifying potential therapeutic targets

G-quadruplexes in the HSV-1 and HHV-6 genomes as antiviral targets

Guanine-rich nucleic acids can fold into G-quadruplexes, four-stranded secondary structures which are implicated in important regulatory functions at the genomic level in humans, prokaryotes and viruses. Because the herpes simplex virus-1 (HSV-1) genome is remarkably rich in guanines, we aimed at investigating both the presence of G-quadruplex forming sequences at the viral genome level and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with novel mechanisms of action. Here we show that HSV-1 displays six clusters of repeated sequences that form very stable G-quadruplexes. These sequences are located in the inverted repeats and in two gene-coding regions (ICP0 and UL36) of the HSV-1 genome. One G-quadruplex repeat is located in the promoter region of the multifunctional protein γ134.5. Treatment of HSV-1 infected cells with the G-quadruplex ligands BRACO-19 and TMPyP4 induced significant inhibition of virus production and reduction of viral transcripts. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and caused a decreased intracellular viral DNA in infected cells. The last step targeted by BRACO-19 was viral DNA replication, while no effect on virus entry in the cells was observed. A different TMPyP4-mediated mechanism of action was on the contrary observed. Despite its capability to affect Taq polymerase processing, TMPyP4 did not inhibit intracellular viral DNA and it appeared to prevent HSV-1 maturation/egress by stimulating the autophagy process. As a second part of the study, we extended this innovative antiviral approach to human herpes virus-6 (HHV-6). One of the main HHV-6 features is the presence of tandem repeats of the telomeric sequence (TTAGGG)n at the genome termini (DR). This peculiarity is thought to be responsible for the viral integration in specific human chromosomes, occurring in the 1-2% of the world population. To date, the telomeric G-quadruplex structure had been extensively characterized. We showed that BRACO-19 and TMPyP4 displayed a great antiviral activity against both HHV-6A and HHV-6B. In the third part of this study, by using specific DNA G-quadruplex-interacting antibodies, for the first time we visualized viral DNA G-quadruplexes in infected cells at crucial time points for the viral replication cycle, in which viral DNA is likely in a single-stranded state. This work, besides presenting the first evidence of extended G-quadruplex sites in key regions of the HSV-1 and HHV-6 genomes, points out G-quadruplexes as innovative potential antiviral targets in novel therapeutic interventions, based on the use of G-quadruplex ligands