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Strong, water-resistant adhesion between aggregate chip and the bitumen binder is vital for achieving effective chipsealing and pavement waterproofing. However, mineral aggregates are hydrophilic, while bitumen is hydrophobic, so the two systems are fundamentally poorly compatible. Chemically this means that the aggregate surface/water (S/W) interface is energetically favoured over the aggregate surface/bitumen (S/B) interface. The presence of water on the aggregate surface or infiltration of water into the S/B interface can therefore destroy the adhesion of bitumen to aggregate surfaces. In this study the surface of chipsealing aggregates has been rendered hydrophobic by treatment with alkyl phosphonate (A-Phon) or alkyl phosphate (A-Phos) surface modifiers. Following this treatment, the interfacial free energy of the S/B interface becomes favoured over that of the S/W interface. Using this method, the adhesion mechanism changes from one where discrete polarisation forces dominate to one where more general dispersive forces dominate. Vibrational spectroscopy was used to probe the mode of binding of the alkylating species to the mineral surface, identifying a mixture of binding modes and tenacity of the bound molecules towards hydrolysis and physical attrition. The surface spreading factor of water and hence the surface free energies for water sorption on the aggregate surface was probed via contact angle analysis. The hydrolytic stability of the treatment was further tested via accelerated weathering in boiling water followed by contact angle analysis. Various physical and rheological bitumen tests and adhesion tests were performed and compared with both non-modified chips and adhesion agent-modified bitumen systems and indicated very strong aggregate/bitumen adhesion that resisted de-bonding by water. The method would be equally applicable to asphalt concrete aggregates.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12Cmutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12Cinhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Nanoclay/bitumen nanocomposites have been prepared using a commercial organically modified nanoclay (Nanomer), and two different penetration grade bitumens under a range of different blending conditions. Simple paddle stirring and high-shear mixing for different times at different shear speeds were investigated in order to determine whether expensive and time-consuming blending was necessary to achieve significant changes in the properties of the bitumen composites. Longer blending times and/or higher shearing speeds resulted in increased dispersion and exfoliation of the Nanomer particles, but this was not necessarily beneficial to the physico-chemical properties of the final material. Rheological analyses showed insignificant differences in properties between the samples blended for different times and speeds of shear mixing. Simple paddle mixing was sufficient to disperse the Nanomer to generate nanocomposites with improved physical properties. Dispersion of Nanomer into the softer of the two bitumen grades caused larger apparent changes than blending into the stiffer grade. These results suggest that the use of simple, low-cost blending techniques should be possible to manufacture effective clay-bitumen nanocomposites.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel “MTA-cooperative” compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivolead compound, 28(“AZ-PRMT5i-1”), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivoefficacy in several MTAP-deficient preclinical cancer models.

A new borohydride, [CH3NH3]+[BH4]−, has been synthesized through the metathesis of CH3NH3F and NaBH4in methylamine. Room-temperature X-ray diffraction studies have shown that [CH3NH3]+[BH4]−adopts a tetragonal unit cell with considerable hydrogen mobility similar to that observed in NH3BH3. The kinetics and thermodynamics of hydrogen release have been investigated and were found to follow a similar pathway to that of [NH4]+[BH4]−. Decomposition of [CH3NH3]+[BH4]−occurred slowly at room temperature and rapidly at ca. 40 °C to form [BH2(CH3NH2)2]+[BH4]−, the methylated analogue of the diammoniate of diborane. The decomposition has been investigated by means of in situX-ray diffraction and solid state 11B NMR spectroscopy and occurred in the absence of any detectable intermediates to form crystalline [BH2(CH3NH2)2]+[BH4]−. [(CH3)2NH2]+[BH4]−and [BH2{(CH3)2NH}2]+[BH4]−have also been synthesized through analogous routes, indicating a more general applicability of the synthetic method.

B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.

Current crop protection chemicals span an array of chemistry classes and modes of action. Typically, within each chemistry class, there are multiple chemically distinct active ingredients competing with each other for market position. In this competition, the first product to market in a new class or mode of action may or may not have an advantage depending upon a number of parameters, including relative efficacy against the target pests, pest resistance, regulatory pressures, synthetic complexity, and marketing effectiveness. The number of companies involved in the discovery of new crop protection compounds has been declining, and patenting strategies have become more sophisticated, making it more challenging to break into an existing area of chemistry. One result is new classes of chemistry tend to be smaller, making first to market more beneficial than in the past. Additionally, the first into a market with a new class of chemistry has the opportunity to set positioning and expectations.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans.

Well-defined Au–TiO2materials were synthesized by deposition of triphenylphosphine-protected Au9clusters on TiO2(Aeroxide P-25), pre-treated in eight different ways and subsequently exposed to two post-treatments. X-ray photoelectron spectroscopy and UV–vis diffuse reflectance spectroscopy studies showed that in most cases the PPh3ligand shell was removed upon deposition even before post-treatment, coinciding with some cluster aggregation. However, clusters deposited on TiO2treated using H2SO4and H2O2showed remarkable resistance to aggregation, even after high-temperature calcination, while clusters on H2-treated TiO2showed the greatest resistance to aggregation under ozonolysis.

Abstract:The current study uses affective disposition theory and the schema-triggered affect model to examine the process of forming affiliations with media characters. In the current study, disposition formation was examined within the nonfiction context of sports news. Individual levels of sports fanship and religiosity were used to examine associations between existing cognitive schema and the disposition toward an unknown athlete and the appreciation of a sports news story. A sample of 195 individuals read a sports magazine article in which a fictitious athlete either expressed a religious affiliation or no religious affiliation. Respondents evaluated the article containing statements of religious affiliation more positively than the similar article containing no expression of religious affiliation. Compared to general and specific sport interest, religiosity was the best predictor of disposition formation toward the athlete and appreciation of the article. This study expands the disposition literature by examining media coverage surrounding sports events and extending our knowledge of how cognitive constructs are related to disposition formation and enjoyment.

The grain growth kinetics of Al-doped ZnO nanocrystalline powders have been studied using in situ, real-time synchrotron X-ray diffraction measurements during calcination at various temperatures (400–800 °C) from sol–gels with varying levels of Al dopant (0–4 mol %). Development of the crystallite size versus time was described using a relaxation model. A grain growth activation energy of 24 ± 3 kJ/mol was obtained for undoped ZnO, while for all of the Al-doped ZnO experiments the activation energy was 43 ± 4 kJ/mol. This difference is attributed to the segregation of Al to the crystallite interfaces, where it interferes with the ZnO grain growth, by inhibiting the motion of atoms across the grain boundaries.

The settling of marine diatoms Amphora coffeaeformis onto a photocatalytic titanium dioxide surface was monitored by ATR-IR. Attachment of the diatoms via their mucilaginous secretions was monitored via observation of protein amide I and II linkages, carboxylate linkages from a uronic acid polysaccharide, and sulfate ester groups. Exposure to UV-A light resulted in the rapid removal of the groups attached to the photocatalyst surface, demonstrating the potential antifouling capability of a TiO2 anatase surface.

We report the discrimination of Al doping sites in sol–gel-formed ZnO powders by solid-state 27Al nuclear magnetic resonance (NMR) spectrometry. A degree of control of dopant placement is demonstrated by modifying sol precursors and processing parameters. ZnO powders containing 1–8 at. % aluminum ions were prepared from aqueous citrate-amino-alcohol-based gels calcined at 500 °C. The powders were characterized using 27Al NMR spectrometry, X-ray diffraction (XRD), and scanning electron microscopy (SEM). Solid-state 27Al NMR spectrometry clearly distinguished between different Al environments and was effective in determining the relative amounts of incorporation of Al dopant ions into the Zn lattice sites in the zincite structure. This allowed a synthesis protocol to be developed to optimize the doping effectiveness. Relatively minor variations in processing conditions could influence the degree and mode of Al incorporation. Optimal conditions were found to include a 90 °C drying step, followed by placement in a preheated (500 °C) furnace for 1 h. An ethanolamine-containing precursor was shown to perform much better than precursors containing alternative amino alcohols.

This is the latest edition of Baker & McKenzie’s column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside web sites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is the latest edition of Baker & McKenzie’s column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside web sites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is a summary of the Baker & McKenzie columns on developments in EU law relating to IP, IT and telecommunications. This summarises the principal developments in 2009 that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas and which were reported on in this column in 2009. It seeks also to update any further development which may have taken place in relation to the specific topics since originally reported. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside websites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is the latest edition of Baker & McKenzie's column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside websites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is the latest edition of Baker & McKenzie's column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside web sites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is the latest edition of Baker & McKenzie's column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside websites are included where possible. No responsibility is assumed for the accuracy of information contained in these links

This is a summary of the Baker & McKenzie columns on developments in EU law relating to IP, IT and telecommunications. This summarises the principal developments in 2008 that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas and which were reported on in this column in 2008. It seeks also to update any further development which may have taken place in relation to the specific topics since originally reported. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside web sites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This is the latest edition of Baker & McKenzie's column on developments in EU law relating to IP, IT and telecommunications. This article summarises recent developments that are considered important for practitioners, students and academics in a wide range of information technology, e-commerce, telecommunications and intellectual property areas. It cannot be exhaustive but intends to address the important points. This is a hard copy reference guide, but links to outside web sites are included where possible. No responsibility is assumed for the accuracy of information contained in these links.

This paper examines processes for the preparation and characterisation of new ceramic membrane materials with potential for gas purification, based on nanostructured anodic alumina. The ultimate research goal is to develop a membrane capable of separating hydrogen from hot synthesis gas so a key factor is the ability of the membrane to operate successfully at temperatures in excess of 800°C. Two membrane materials are compared and contrasted: a commercial Whatman product and a membrane prepared in our laboratory. We have demonstrated that the fabrication conditions, most particularly the acid environment used during membrane fabrication, controls and directs the high temperature behaviour of the membranes. Membranes prepared using sulphuric acid electrolytes have been shown to withstand 800°C without distortion and without compromising their nanostructured pore array.