Investigation into [4+6] porous organic cages and their use in porous liquids

The field of porous liquids is relatively new compared to other porous materials but is rapidly developing and gaining interest. There is a diverse range of strategies in the literature to achieve porosity in the liquid state, including using porous organic cages as either soluble pores or neat liquid hosts. However, there are not enough examples to draw a comparison, so little is known about the design and limitations associated with these systems. In this thesis, we show how high-throughput automation can be applied to streamline discovery and expand the area of porous liquids with two different approaches. Firstly, the focus was on improving current systems and finding highly soluble porous organic cages in cavity-excluded solvents. This resulted in a library of porous liquids with increased cavity concentrations that allowed the exploration into how changing the solvent and cage components effects overall properties, such as gas uptake and viscosity. One problem associated with these soluble cages was the use of solvents with associated vapour pressure, which limits their study using gas sorption methods. Therefore, a second strategy was devised to explore low melting cage salts with large cavity-excluded anions. A high-throughput screen was developed that generated a small cage salt library with varying cages and counterions. The thermal behaviour of these systems was studied to determine the effect of changing these components on melting. Overall, the work carried out in this thesis developed high-throughput workflows that can be applied to larger screens and presented a series of design considerations for future systems

The clinical features of polymerase proof-reading associated polyposis (PPAP) and recommendations for patient management

Pathogenic germline exonuclease domain (ED) variants of POLE and POLD1 cause the Mendelian dominant condition polymerase proof-reading associated polyposis (PPAP). We aimed to describe the clinical features of all PPAP patients with probably pathogenic variants. We identified patients with a variants mapping to the EDs of POLE or POLD1 from cancer genetics clinics, a colorectal cancer (CRC) clinical trial, and systematic review of the literature. We used multiple evidence sources to separate ED variants into those with strong evidence of pathogenicity and those of uncertain importance. We performed quantitative analysis of the risk of CRC, colorectal adenomas, endometrial cancer or any cancer in the former group. 132 individuals carried a probably pathogenic ED variant (105 POLE, 27 POLD1). The earliest malignancy was colorectal cancer at 14. The most common tumour types were colorectal, followed by endometrial in POLD1 heterozygotes and duodenal in POLE heterozygotes. POLD1-mutant cases were at a significantly higher risk of endometrial cancer than POLE heterozygotes. Five individuals with a POLE pathogenic variant, but none with a POLD1 pathogenic variant, developed ovarian cancer. Nine patients with POLE pathogenic variants and one with a POLD1 pathogenic variant developed brain tumours. Our data provide important evidence for PPAP management. Colonoscopic surveillance is recommended from age 14 and upper-gastrointestinal surveillance from age 25. The management of other tumour risks remains uncertain, but surveillance should be considered. In the absence of strong genotype–phenotype associations, these recommendations should apply to all PPAP patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10689-021-00256-y

Early Mississippian evaporites of coastal tropical wetlands

Extensive evaporites in Lower Mississippian successions from palaeoequatorial regions are commonly used as evidence for an arid to semi‐arid palaeoclimate. However, in this article, detailed studies of evaporites and their context refute this interpretation. Detailed sedimentological and petrographical analysis of the Lower Mississippian of northern Britain, is combined with archived log data from more than 40 boreholes across southern Scotland, northern England and Northern Ireland, and published literature from Canada. Two key cores from the Tweed Basin and the northern margin of the Northumberland – Solway Basin contain 178 evaporite intervals and reveal twelve distinct forms of gypsum and anhydrite across seven facies that are associated with planar laminated siltstone and intercalated thin beds of ferroan dolostone. Nodular gypsum and anhydrite, typically in intervals <1 to 2 m thick, are integral components of the succession. Nodular evaporite occurs within about 1 m of a palaeosurface, but most evaporite deposits represent ephemeral brine pans to semi‐permanent hypersaline lakes or salinas on a floodplain that was subjected periodically to storm surges introducing marine waters. Formation of evaporites under a strongly seasonal climate in a coastal wetland is supported by palaeosol types and geochemical proxies, and from palaeobotanical evidence published previously. Although 65% of modern equatorial areas experience a strongly seasonal climatic regime, salinas and sabkhas are a minor component today in comparison with the evidence from these Lower Mississippian successions. This implies that the earliest terrestrial environments were complex and dynamic, providing a diverse range of habitats in which the early tetrapods became terrestrialized and represent a setting that is rarely preserved in the geological record

Cdt1 proteolysis is promoted by dual PIP degrons and is modulated by PCNA ubiquitylation

Cdt1 plays a critical role in DNA replication regulation by controlling licensing. In Metazoa, Cdt1 is regulated by CRL4Cdt2-mediated ubiquitylation, which is triggered by DNA binding of proliferating cell nuclear antigen (PCNA). We show here that fission yeast Cdt1 interacts with PCNA in vivo and that DNA loading of PCNA is needed for Cdt1 proteolysis after DNA damage and in S phase. Activation of this pathway by ultraviolet (UV)-induced DNA damage requires upstream involvement of nucleotide excision repair or UVDE repair enzymes. Unexpectedly, two non-canonical PCNA-interacting peptide (PIP) motifs, which both have basic residues downstream, function redundantly in Cdt1 proteolysis. Finally, we show that poly-ubiquitylation of PCNA, which occurs after DNA damage, reduces Cdt1 proteolysis. This provides a mechanism for fine-tuning the activity of the CRL4Cdt2 pathway towards Cdt1, allowing Cdt1 proteolysis to be more efficient in S phase than after DNA damage

Accelerated Robotic Discovery of Type II Porous Liquids

Porous liquids are an emerging class of materials and to date little is known about how to best design their properties. For example, bulky solvents are required that are size-excluded from the pores in the liquid, along with high concentrations of the porous component, but both of these factors may also contribute to higher viscosities, which are undesirable. Hence, the inherent multivariate nature of porous liquids makes them amenable to high-throughput optimisation strategies. Here we develop a high-throughput robotic workflow, encompassing the synthesis, characterisation and property testing of highly-soluble, vertex-disordered porous organic cages dissolved in a range of cavity-excluded solvents. As a result, we identified 29 cage-solvent combinations that combine both higher cage-cavity concentrations and more acceptable carrier solvents than the best previous examples. The most soluble materials gave three times the pore concentration of the best previously reported scrambled cage porous liquid, as demonstrated by increased gas uptake. We were also able to explore alternative methods for gas capture and release, including liberation of the gas by increasing the temperature. We also found that porous liquids can form gels at higher concentrations, trapping the gas in the pores, which could have potential applications in gas storage and transportation

Competitive Aminal Formation during the Synthesis of a Highly Soluble, Isopropyl-Decorated Imine Porous Organic Cage

The synthesis of a new porous organic cage decorated with isopropyl moieties (CC21) was achieved from the reaction of triformylbenzene and an isopropyl functionalised diamine. Unlike structurally analogous porous organic cages, its synthesis proved challenging due to competitive aminal formation, rationalised using control experiments and computational modelling. The use of an additional amine was found to increase conversion to the desired cage

Competitive aminal formation during the synthesis of a highly soluble, isopropyl-decorated imine porous organic cage

The synthesis of a new porous organic cage decorated with isopropyl moieties (CC21) was achieved from the reaction of triformylbenzene and an isopropyl functionalised diamine. Unlike structurally analogous porous organic cages, its synthesis proved challenging due to competitive aminal formation, rationalised using control experiments and computational modelling. The use of an additional amine was found to increase conversion to the desired cage