Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase a1

Choline kinase (CK) catalyses the transfer of the ATP gamma-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the a isoforms (HsCK alpha) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCK alpha biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4-(N-methylaniline) pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low mM range to HsCK alpha 1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCK alpha 1

New simulants for martian regolith: Controlling iron variability

Existing martian simulants are predominantly based on the chemistry of the average ‘global’ martian regolith as defined by data on chemical and mineralogical variability detected by orbiting spacecraft, surface rovers and landers. We have therefore developed new martian simulants based on the known composition of regolith from four different martian surface environments: an early basaltic terrain, a sulfur-rich regolith, a haematite-rich regolith and a contemporary Mars regolith. Simulants have been developed so that the Fe2+/Fe3+ ratios can be adjusted, if necessary, leading to the development of four standard simulants and four Fe-modified simulants. Characterisation of the simulants confirm that all but two (both sulfur-rich) are within 5 wt% of the martian chemistries that they were based on and, unlike previous simulants, they have Fe2+/Fe3+ ratios comparable to those found on Mars. Here we outline the design, production and characterisation of these new martian regolith simulants. These are to be used initially in experiments to study the potential habitability of martian environments in which Fe may be a key energy source

Adverse selection under ignorance

We examine an adverse selection relationship in which the principal may ignore the ex ante distribution of the agent's types. The principal's behavior is described by a disutility function that covers the standard minimax regret and minimax loss criteria. We show that the incentive compatible and individually rational mechanism, which minimizes the maximal (or the minimal) principal's disutility over a set of priors, requires the efficient agents to realize the corresponding first-best actions and may demand actions lower than the first-best ones from less efficient agents. We also analyze the qualitative differences between the case in which the principal considers regrets and the case in which he considers losses.Principal-agent problem, Adverse selection, Minimax regret criterion, Minimax loss criterion.

Scratch Fracture of Polycrystalline Silicon Wafers

Fracture of silicon wafers is responsible for lower than desirable manufacturing yields in the photovoltaic industry. This study investigates the fracture response of polycrystalline silicon wafers under sliding contacts at different length scales, by means of macro and microscratch tests which simulate cutting processes. The dominant fracture modes were found to be partial cone cracking (macro) and radial cracking (micro). Statistical analysis of the critical loads for crack initiation showed that polycrystalline wafers are weaker than their single-crystal counterparts, that is, they crack at lower applied loads under comparable conditions. Moreover, the Weibull modulus of polycrystalline silicon was found to be the average of the relevant single-crystal directions. Subsequent microscopic observations and flexure tests reveal that the lower resistance of polycrystalline silicon to scratch fracture is due mainly to the presence of relatively large polishing defects, and not to the weakness of its grain boundaries. Alternatives are proposed to minimize damage during ingot cutting, with a view to minimizing wafer breakages during wafer handling and machining

Cyano-Functionalized Triarylamines On Au(111): Competing Intermolecular Versus Molecule/Substrate Interactions

The self-assembly of cyano-substituted triarylamine derivatives on Au(111) is studied with scanning tunneling microscopy and density functional theory calculations. Two different phases, each stabilized by at least two different cyano bonding motifs are observed. In the first phase, each molecule is involved in dipolar coupling and hydrogen bonding, while in the second phase, dipolar coupling, hydrogen bonding and metal-ligand interactions are present. Interestingly, the metal-ligand bond is already observed for deposition of the molecules with the sample kept at room temperature leaving the herringbone reconstruction unaffected. It is proposed that for establishing this bond, the Au atoms are slightly displaced out of the surface to bind to the cyano ligands. Despite the intact herringbone reconstruction, the Au substrate is found to considerably interact with the cyano ligands affecting the conformation and adsorption geometry, as well as leading to correlation effects on the molecular orientation

Cyano-Functionalized Triarylamines On Coinage Metal Surfaces: Interplay Of Intermolecular And Molecule-Substrate Interactions

The self-assembly of cyano-functionalized triarylamine derivatives on Cu(111), Ag(111) and Au(111) was studied by means of scanning tunnelling microscopy, low-energy electron diffraction, X-ray photoelectron spectroscopy and density functional theory calculations. Different bonding motifs, such as antiparallel dipolar coupling, hydrogen bonding and metal coordination, were observed. Whereas on Ag(111) only one hexagonally close-packed pattern stabilized by hydrogen bonding is observed, on Au(111) two different partially porous phases are present at submonolayer coverage, stabilized by dipolar coupling, hydrogen bonding and metal coordination. In contrast to the self-assembly on Ag(111) and Au(111), for which large islands are formed, on Cu(111), only small patches of hexagonally close-packed networks stabilized by metal coordination and areas of disordered molecules are found. The significant variety in the molecular self-assembly of the cyano-functionalized triarylamine derivatives on these coinage metal surfaces is explained by differences in molecular mobility and the subtle interplay between intermolecular and molecule-substrate interactions