A Yeast Chemical Genetic Screen Identifies Inhibitors of Human Telomerase

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Highlights? Growth arrest induced by human telomerase in yeast is chemically reversible ? Readout is sensitive to telomerase catalytic activity and telomere recruitment ? Three cell-permeable compounds also inhibit purified human telomerase ? Yeast can be successfully used to screen for human telomerase inhibitors     

QMX: A versatile environment for hybrid calculations applied to the grafting of Al2Cl3Me3 on a silica surface

We present a new software to easily perform QM:MM and QM:QM' calculations called QMX. It follows the subtraction scheme and it is implemented in the Atomic Simulation Environment (ASE). Special attention is paid to couple molecular calculations with periodic boundaries approaches. QMX inherits the flexibility and versatility of the ASE package: any combination of methods namely force field, semiempirical, first principle, and ab initio, can be used as hybrid potential energy surface (PES). Its ease of use is demonstrated by considering the adsorption of Al₂Cl₃Me₃ on silica surface and by combining different levels of theory (from standard DFT to MP2 calculations) for the so‐called High Level cluster with standard PW91 density functional theory calculations for the Low Level environment. It is shown that the High Level cluster must contain the silanol group close to the aluminum atoms. The bridging adsorption is favored by 58 kJ mol^?1 at the MP2:PW91 level with respect to the terminal position. Using large clusters at the MP2:PW91 level, it is shown that PW91 calculations are sufficient for structure optimization but that embedded methods are required for accurate energy profiles. © 2013 Wiley Periodicals, Inc.     

Apolar 2‐alkoxyalkoxy‐substituted nematic liquid crystals

The synthesis is reported of a series of apolar nematic liquid crystals incorporating an alkoxyalkoxy chain attached in a terminal position to the molecular core. The dependence of the mesomorphism and phase transition temperatures on the nature of the terminal chain with one, two or three oxygen atoms was studied. Some compounds with a completely alicyclic molecular core and a terminal 2‐methoxyethoxy chain exhibit a nematic phase with a low melting point, birefringence and viscosity and a relatively high clearing point in the absence of smectic phases. They do not to absorb light in the near UV and may be useful as components of UV‐stable nematic mixtures for use in photoluminescent liquid crystal displays. The presence of the methoxyethoxy chain leads to a relatively large dipole moment perpendicular to the molecular long axis.     

The effect of terminal chain modifications on the mesomorphic properties of 4,4′-disubstituted diphenyldiacetylenes

The typical sidewalls produced in the fabrication of protrusion electrodes are proposed to create a low voltage (4.5 V_rms) and high transmittance (93%) blue-phase liquid crystal display (BP-LCD). The tilted electrodes produce a strong horizontal electrical field that reduces the operating voltage considerably. The common problem of the ‘dead zones’ is solved by reflecting the light onto the electrodes. In order to estimate the phase retardation of the reflected light, a ray tracing simulation program for anisotropic mediums has been developed. The proposed device is more competitive than vertical field switching based BP-LCD and also, has the advantages of protruded in-plane-switching structures. These facts make this technology a potential candidate for the next generation of BP-LCDs.     

Development of ultra-high-performance supercritical fluid chromatography-mass spectrometry assays to analyze potential biomarkers in sweat

Liquid chromatography-mass spectrometry methods were required to afford the rapid separation and detection of purines and small organic acids. These compounds are found in sweat and sebum and are potential biomarkers for the early detection of pressures sores. Two ultra-high-performance supercritical fluid chromatography-mass spectrometry assays have been successfully developed for both classes of compounds. Separation for purines was achieved using a gradient of supercritical carbon dioxide and methanol with a 1-aminoanthracene sub 2 μm particle size column followed by positive ion electrospray ionization. Separation for organic acids was achieved using a gradient of supercritical carbon dioxide and methanol (50 mM ammonium acetate 2% water) with a Diol sub 2 μm particle size column followed by negative ion electrospray ionization. Calibration curves were created in the absence of internal standards and R² values > 0.96 were achieved using single ion monitoring methods for the protonated purines and the deprotonated acids. The two new assays afford rapid analytical methods for the separation and detection of potential biomarkers in human sweat leading to the early detection and prevention of pressure sores.     

Small-scale fracture toughness of ceramic thin films: the effects of specimen geometry,ion beam notching and high temperature on chromium nitride toughness evaluation

For the implementation of thin ceramic hard coatings into intensive application environments, the fracture toughness is a particularly important material design parameter. Characterisation of the fracture toughness of small-scale specimens has been a topic of great debate, due to size effects, plasticity, residual stress effects and the influence of ion penetration from the sample fabrication process. In this work, several different small-scale fracture toughness geometries (single-beam cantilever, double-beam cantilever and micro-pillar splitting) were compared, fabricated from a thin physical vapour-deposited ceramic film using a focused ion beam source, and then the effect of the gallium-milled notch on mode I toughness quantification investigated. It was found that notching using a focused gallium source influences small-scale toughness measurements and can lead to an overestimation of the fracture toughness values for chromium nitride (CrN) thin films. The effects of gallium ion irradiation were further studied by performing the first small-scale high-temperature toughness measurements within the scanning electron microscope, with the consequence that annealing at high temperatures allows for diffusion of the gallium to grain boundaries promoting embrittlement in small-scale CrN samples. This work highlights the sensitivity of some materials to gallium ion penetration effects, and the profound effect that it can have on fracture toughness evaluation.     

Accumulation of endogenous and exogenous nucleic acids in “Touch DNA” components on hands

Successful forensic DNA profiling from handled items is increasingly routine in casework. This “touch DNA” is thought to contain both cellular and acellular nucleic acid sources. However, there is little clarity on the origins or characteristics of this material. The cellular component consists of anucleate, terminally differentiated corneocytes (assumed to lack DNA), and the occasional nucleated cell. The acellular DNA source is fragmentary, presumably cell breakdown products. This study examines the relative contributions each component makes to the hand-secretions (endogenous) and hand-accumulations (exogenous) by recovering rinses from the inside and outside of worn gloves. Additionally, cellular and acellular DNA was measured at timepoints up to 2 h after hand washing, both with and without interim contact. Microscopic examination confirmed cell morphology and presence of nucleic acids. Following the novel application of a hair keratinocyte lysis method and plasma-DNA fragment purification to hand rinse samples, DNA profiles were generated from both fractions. Exogenous cell-free DNA is shown to be a significant source of touch DNA, which reaccumulates quickly, although its amplifiable nuclear alleles are limited. Endogenous DNA is mostly cellular in origin and provides more allelic information consistently over time.     

The ortho‐Substituent Effect on the Ag‐Catalysed Decarboxylation of Benzoic Acids

A combined experimental and computational investigation on the Ag‐catalysed decarboxylation of benzoic acids is reported herein. The present study demonstrates that a substituent at the ortho position exerts dual effects in the decarboxylation event. On one hand, ortho‐substituted benzoic acids are inherently destabilised starting materials compared to their meta‐ and para‐substituted counterparts. On the other hand, the presence of an ortho‐electron‐withdrawing group results in an additional stabilisation of the transition state. The combination of both effects results in an overall reduction of the activation energy barrier associated with the decarboxylation event. Furthermore, the Fujita–Nishioka linear free energy relationship model indicates that steric bulk of the substituent can also exert a negative effect by destabilising the transition state of decarboxylation.