Proteomic analysis of redox-dependent AGR2 complexes reveals a novel mucin quality control system in oesophageal adenocarcinoma

Disulphide bonds covalently linking cysteine residues, intramolecularly or intermolecularly, are often essential in ensuring the stability of secreted and cell surface proteins as well as facilitating correct spatial positioning of protein active sites. The protein disulphide isomerase (PDI) family of proteins catalyse the oxidation, reduction and isomerisation of these disulphide bonds. PDI proteins are vital for protein quality control and most are found ubiquitously. Anterior gradient-2 (AGR2) is an unusual tissue-restricted member of the PDI family that has gained considerable attention in the last 15 years because of its overexpression in a variety of different cancer types, including oesophageal adenocarcinoma. In this thesis it has been demonstrated that the OE19 late stage oesophageal adenocarcinoma cell line strongly expresses AGR2, and that in this cell line AGR2 can form redox-inducible, disulphide bond dependent complexes. It has also been shown, through the development and use of a novel, unbiased trapping and immunoprecipitation approach, that these AGR2 interacting proteins can be identified and compared. This approach has identified mucin isoforms that AGR2 preferentially binds as its primary clients and has revealed a host of ER chaperones involved in this quality control complex. This thesis lays the groundwork for the elucidation and definition of an AGR2-mucin quality control system within oesophageal adenocarcinoma and provides biomarkers and potential therapeutic targets for identification and treatment of AGR2-positive cancers

Numerical investigation into the influence of cubicle positioning in large-scale explosive arena trials

In arena blast testing, a common and economical practice employed is to distribute several targets radially around a central charge. However, if these targets are positioned too proximally, reflections and diffractions of blast waves off neighbouring cubicles can affect the nature of expected blast loading. Computational fluid dynamics software has been used through an extensive series of simulations to identify the levels of interference in incident pressure–time histories with and without an obstructing target present. The data were post-processed to identify the Cartesian co-ordinates in which different levels of interference in peak incident overpressure and incident positive phase impulse were achieved. The results indicated that in all cases, there was a greater interference in peak incident overpressure than incident positive phase impulse values directly proximal to the target but, at greater separations, significant differences in incident positive phase impulse existed where peak incident overpressure had returned to free-field equivalent magnitudes. When compared with the established ‘rules of thumb’ for cubicle placement, for targets at different stand-off ranges, an angle of 45° to the rear cubicle still holds some practical relevance, although it is too acute to cover all interference effects. For targets positioned at the same stand-off range, a separation distance of two cubicle widths is generally too conservative and, in many cases, more cubicles can be positioned around the charge. A bespoke recommendation table has been presented for targets at stand-off ranges between 15 and 50 m to allow users to identify the minimum distance from a target at which obstructed-field peak incident overpressure and incident positive phase impulse values differ negligibly from free-field equivalents

Recommendations for cubicle separation in large-scale explosive arena trials

In large-scale arena blast testing, a common and economical practice undertaken is to position several cubicle targets radially around a central charge. To gain maximal benefit from this, targets should be positioned at their minimum permissible separation at which no blast wave interference is sustained from neighbouring obstructions. This interference typically occurs either when targets positioned at the same stand-off range are too close creating an amplification effect where a superposition forms between the incident blast wave and the reflected wave off the cubicle, or, where a target is positioned in the region behind another target, which causes a shadowing effect with decreased magnitudes of pressure and impulse. A comprehensive computational modelling study was undertaken using the hydrocode Air3D to examine the influence of cubicle positioning at different ranges on the surrounding blast wave pressure-time fields. A systematic series of simulations were conducted to show the differences in incident peak overpressure and positive phase impulse between free-field and obstructed-field simulation configurations. The predictions from the modelling study indicated that the presence of cubicle target obstructions resulted in differences in peak incident overpressure and positive phase impulse in nearby pressure waves. In all cases, at close separation distances, there were greater differences in peak pressure than positive phase impulse. However, with increased separation, peak pressure returned to free-field conditions sooner whilst differences in impulse remained significant, thus governing separation distance recommendations. The simulations showed that, for targets at the same stand-off range, clear separations of between 3.88 m and 6.92 m were required to achieve free-field equivalency, depending on the distance from the charge to the target. For targets at different stand-off ranges an angle greater than 54.2° from the front corner of the cubicle has been shown to ensure free-field equivalent conditions. A bespoke recommendation table has been generated to provide precise positioning for cubicles at different stand-off ranges in a look-up matrix format that can be readily used by engineers in the field

Stably non-synchronizable maps of the plane

Pecora and Carroll presented a notion of synchronization where an (n-1)-dimensional nonautonomous system is constructed from a given $n$-dimensional dynamical system by imposing the evolution of one coordinate. They noticed that the resulting dynamics may be contracting even if the original dynamics are not. It is easy to construct flows or maps such that no coordinate has synchronizing properties, but this cannot be done in an open set of linear maps or flows in $\R^n$, $n\geq 2$. In this paper we give examples of real analytic homeomorphisms of $\R^2$ such that the non-synchronizability is stable in the sense that in a full $C^0$ neighborhood of the given map, no homeomorphism is synchronizable

Symmetry groups, semidefinite programs, and sums of squares

We investigate the representation of symmetric polynomials as a sum of squares. Since this task is solved using semidefinite programming tools we explore the geometric, algebraic, and computational implications of the presence of discrete symmetries in semidefinite programs. It is shown that symmetry exploitation allows a significant reduction in both matrix size and number of decision variables. This result is applied to semidefinite programs arising from the computation of sum of squares decompositions for multivariate polynomials. The results, reinterpreted from an invariant-theoretic viewpoint, provide a novel representation of a class of nonnegative symmetric polynomials. The main theorem states that an invariant sum of squares polynomial is a sum of inner products of pairs of matrices, whose entries are invariant polynomials. In these pairs, one of the matrices is computed based on the real irreducible representations of the group, and the other is a sum of squares matrix. The reduction techniques enable the numerical solution of large-scale instances, otherwise computationally infeasible to solve.Comment: 38 pages, submitte

Universal high work function flexible anode for simplified ITO-free organic and perovskite light-emitting diodes with ultra-high efficiency

Flexible transparent electrode materials such as conducting polymers, silver nanowires, carbon nanotubes and graphenes are being investigated as possible replacements for conventional brittle inorganic electrodes. However, they have critical drawbacks of low work function (WF), resulting in a high hole injection barrier to an overlying semiconducting layer in simplified organic or organic-inorganic hybrid perovskite light-emitting diodes (OLEDs or PeLEDs). Here, we report a new anode material (AnoHIL) that has multifunction of both an anode and a hole injection layer (HIL) as a single layer. The AnoHIL has easy WF tunability up to 5.8 eV and thus makes ohmic contact without any HIL. We applied our anodes to simplified OLEDs, resulting in very high efficiency (62% ph el(-1) for single and 88% ph el(-1) for tandem). The AnoHIL showed a similar tendency in simplified PeLEDs, implying universal applicability to various optoelectronics. We also demonstrated large-area flexible lightings using our anodes. Our results provide a significant step toward the next generation of high-performance simplified indium tin oxide (ITO)-free light-emitting diodes.