Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration

Modeling of convection, temperature distribution and dendritic growth in glass-fluxed nickel melts

Melt flow is often quoted as the reason for a discrepancy between experiment and theory on dendritic growth kinetics at low undercoolings. But this flow effect is not justified for glass-fluxed melts where the flow field is weaker. In the present work, we modeled the thermal history, flow pattern and dendritic structure of a glass-fluxed nickel sample by magnetohydrodynamics calculations. First, the temperature distribution and flow structure in the molten and undercooled melt were simulated by reproducing the observed thermal history of the sample prior to solidification. Then the dendritic structure and surface temperature of the recalescing sample were simulated. These simulations revealed a large thermal gradient crossing the sample, which led to an underestimation of the real undercooling for dendritic growth in the bulk volume of the sample. By accounting for this underestimation, we recalculated the dendritic tip velocities in the glass-fluxed nickel melt using a theory of three-dimensional dendritic growth with convection and concluded an improved agreement between experiment and theory

Dendritic growth velocities in an undercooled melt of pure nickel under static magnetic fields: A test of theory with convection

Dendritic growth velocities in an undercooled melt of pure nickel under static magnetic fields up to 6 T were measured using a high-speed camera. The growth velocities for undercoolings below 120 K are depressed under low magnetic fields, but are recovered progressively under high magnetic fields. This retrograde behavior arises from two competing kinds of magnetohydrodynamics in the melt and becomes indistinguishable for higher undercoolings. The measured data is used for testing of a recent theory of dendritic growth with convection. A reasonable agreement is attained by assuming magnetic field-dependent flow velocities. As is shown, the theory can also account for previous data of dendritic growth kinetics in pure succinonitrile under normal gravity and microgravity conditions. These tests demonstrate the efficiency of the theory which provides a realistic description of dendritic growth kinetics of pure substances with convection

Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines

Background and Aim Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient-derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting. Methods Patient-derived colorectal cancer organoids were derived from tissue obtained from treatment-naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor. Results We created a bio-resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor. Conclusions Patient-derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting

Turbulence modelling and its impact on CFD predictions for cooling of electronic components

This paper will discuss Computational Fluid Dynamics (CFD) results from an investigation into the accuracy of several turbulence models to predict air cooling for electronic packages and systems. Also new transitional turbulence models will be proposed with emphasis on hybrid techniques that use the k-ε model at an appropriate distance away from the wall and suitable models, with wall functions, near wall regions. A major proportion of heat emitted from electronic packages can be extracted by air cooling. This flow of air throughout an electronic system and the heat extracted is highly dependent on the nature of turbulence present in the flow. The use of CFD for such investigations is fast becoming a powerful and almost essential tool for the design, development and optimization of engineering applications. However turbulence models remain a key issue when tackling such flow phenomena. The reliability of CFD analysis depends heavily on the turbulence model employed together with the wall functions implemented. In order to resolve the abrupt fluctuations experienced by the turbulent energy and other parameters located at near wall regions and shear layers a particularly fine computational mesh is necessary which inevitably increases the computer storage and run-time requirements. The PHYSICA Finite Volume code was used for this investigation. With the exception of the k-ε and k-ω models which are available as standard within PHYSICA, all other turbulence models mentioned were implemented via the source code by the authors. The LVEL, LVEL CAP, Wolfshtein, k-ε, k-ω, SST and kε/kl models are described and compared with experimental data

Mathematical modelling of a compressible oxygen jet entering a hot environment using a pressure-based finite volume code

A procedure for solving compressible flow within a finite volume, pressure-correction-type scheme, has been devised and successfully implemented in two test cases: a de Laval nozzle and an oxygen jet enteringa heated furnace. Both cases have been validated with the analytical solution for the nozzle case and experimental data for the oxygen jet case. The method was successful in predicting the axial variables of the jet, and used to develop a modified turbulence model for such jets

Thermoelectric effects on alloy solidification microstructure

Thermoelectric currents in the presence of a magnetic field generate Lorentz forces which can drive fluid flow. In the case of dendritic growth a naturally occurring thermoelectric current exists and in the presence of a high magnetic field micro convections are generated. Experimental evidence has attributed changes in microstructure to this effect. A numerical model has been developed to study the flow field around an unconstricted equiaxed dendrite growing under these conditions. The growth is modeled in 2D and 3D by an enthalpy based method and a complex flow structure has been predicted. Using a pseudo-3D approximation for economy, realistic 2D simulations are obtained where a fully coupled transient scheme reveals significant changes to the dendrite morphology reflecting experimental evidence. There is a rotation of the preferred direction of growth and increased secondary branching