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Abstract: BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response; however, selective small molecule inhibitors of defined mechanism are currently lacking. Here, we identify and characterise a specific inhibitor of BLM’s ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.

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Abstract: A detailed understanding of the local dynamics in ionic liquids remains an important aspect in the design of new ionic liquids as advanced functional fluids. Here, we use small-angle X-ray scattering and quasi-elastic neutron spectroscopy to investigate the local structure and dynamics in a model ionic liquid as a function of temperature and pressure, with a particular focus on state points (P,T) where the macroscopic dynamics, i.e., conductivity, is the same. Our results suggest that the initial step of ion transport is a confined diffusion process, on the nanosecond timescale, where the motion is restricted by a cage of nearest neighbors. This process is invariant considering timescale, geometry, and the participation ratio, at state points of constant conductivity, i.e., state points of isoconductivity. The connection to the nearest-neighbor structure is underlined by the invariance of the peak in the structure factor corresponding to nearest-neighbor correlations. At shorter timescales, picoseconds, two localized relaxation processes of the cation can be observed, which are not directly linked to ion transport. However, these processes also show invariance at isoconductivity. This points to that the overall energy landscape in ionic liquids responds in the same way to density changes and is mainly governed by the nearest-neighbor interactions.

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Abstract: Nicotinamide adenine dinucleotide (NAD) is a key molecule in cellular bioenergetics and signalling. Various bacterial pathogens release NADase enzymes into the host cell that deplete the host’s NAD+ pool, thereby causing rapid cell death. Here, we report the identification of NADases on the surface of fungi such as the pathogen Aspergillus fumigatus and the saprophyte Neurospora crassa. The enzymes harbour a tuberculosis necrotizing toxin (TNT) domain and are predominately present in pathogenic species. The 1.6 Å X-ray structure of the homodimeric A. fumigatus protein reveals unique properties including N-linked glycosylation and a Ca2+-binding site whose occupancy regulates activity. The structure in complex with a substrate analogue suggests a catalytic mechanism that is distinct from those of known NADases, ADP-ribosyl cyclases and transferases. We propose that fungal NADases may convey advantages during interaction with the host or competing microorganisms.

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Abstract: Porosity is the term used to describe the voids in a rock. This porosity is made up of many pores which form a pore network. Pore scale displacement in fluid flow is relevant to a number of industrial and environmental applications. The characteristics of the pore network control the way in which fluid flow occurs throughout the network. Carbonate rocks have particularly complex pore networks due a range of post-depositional processes that modify pore size, shape and connectivity. Although the contributions of factors such as pore throat size and pore network connectivity on fluid flow are reasonably well understood, there is a limited understanding of the effect of pore topology. This research aims to provide a pore-scale picture of the dynamics of fluid flow in both single and multiphase immiscible flow through the use of digital image analysis of fluid flow experiments. The dynamics and patterns of interface displacement as well as the size distribution of trapped oil ganglia were visualised using 2D microfluidic experiments. Different pore topologies resulted in different oil recoveries, however the effect of pore topology was not constant across fluid pairs with different viscosity ratios. Pore size was shown to be a key factor in the recovery efficiency of polymer flooding. This demonstrates that microfluidic experiments offer a methodology to quickly assess a number of different pore topologies under different fluid flow conditions. A range of rock types were imaged in 3D using X-Ray micro-computed tomography to visualise and quantify the range of pore topologies which exist in carbonates. These pore systems were used to assess the reliability of using 2D digital image analysis for permeability prediction, and show that 3D digital image analysis is a far superior technique for reliable pore topological characterisation and permeability prediction. A highly correlated multi-linear regression between permeability and pore topological parameters shows the relevance of pore topologies in predicting permeability. In addition to the investigation of single phase flow in a range of different carbonate pore systems, an investigation into multiphase immiscible displacement in a single carbonate pore system has been conducted. Through the use of synchrotron X-Ray tomographic imaging of an experimental core-flood (oil-brine drainage followed by imbibition) insights into the dynamics of multiphase flow have been gained. The pathway followed by the non-wetting fluid during drainage is strongly linked to the pore topological parameters measured during the analysis of the experiment. Oil initially invades simple pores with low elongation, which are aligned with the flow direction, before invading increasingly complex pores, less aligned to the flow direction. A channelization of flow occurs associated with an area of large, elongate pores. This research demonstrates that pore topology, particularly elongation and orientation to flow direction, has a clear influence on flow and warrants further investigation.

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Abstract: Water quality parameters such as salt content and various pH environments can alter the stability of gels as well as their rheological properties. Here, we investigated the effect of various concentrations of NaCl and different pH environments on the rheological properties of TEMPO-oxidised cellulose nanofibril (OCNF) and starch-based hydrogels. Addition of NaCl caused an increased stiffness of the OCNF:starch (1:1 wt%) blend gels, where salt played an important role in reducing the repulsive OCNF fibrillar interactions. The rheological properties of these hydrogels were unchanged at pH 5.0 to 9.0. However, at lower pH (4.0), the stiffness and viscosity of the OCNF and OCNF:starch gels appeared to increase due to proton-induced fibrillar interactions. In contrast, at higher pH (11.5), syneresis was observed due to the formation of denser and aggregated gel networks. Interactions as well as aggregation behaviour of these hydrogels were explored via ζ-potential measurements. Furthermore, the nanostructure of the OCNF gels was probed using small-angle X-ray scattering (SAXS), where the SAXS patterns showed an increase of slope in the low-q region with increasing salt concentration arising from aggregation due to the screening of the surface charge of the fibrils.