Flash vacuum pyrolysis of some sulphonyl and sulphinyl stabilised phosphorous ylides

The reaction between alkylidene or arylmethylene triphenyl phosphoranes and sulphonyl fluorides or sulphonic anhydrides has been used to give a variety of α-sulphonyl stabilised phosphorus ylides. Flash Vacuum Pyrolysis (FVP) of alkyl- and arylsulphonyl alkylidene triphenyl phosphoranes leads to two fractions. The first fraction is made up of up to 20 phosphorus containing products, the major one being Ph₃PO. The second fraction is a liquid at low temperature which forms a white, insoluble polymeric material on warming to room temperature. Trapping reactions of the liquid with Diels-Alder dienes or chlorine gives unknown and unstable compounds except with anthracene where an unidentified complex is formed. FVP of benzyl- and substituted-benzylsulphonyl alkylidene and phenylmethylene triphenyl phosphoranes proceeds by loss of Ph₃P followed by intramolecular insertion of the resulting carbene to form episulphones which lose SO₂ to give stilbene or styrene derivatives. In the cases where the phosphorane is an α-sulphonyl ethylidene triphenyl phosphorane, a 1,2-H shift of the carbene can occur to form a vinyl sulphone, which decomposes to vinyl and benzyl radicals and SO₂ with formation of bibenzyl products. Where the phosphorane is an α-sulphonyl ortho-substituted-benzylidene triphenyl phosphorane, a second carbene insertion pathway occurs to give eventually benzofuran or benzothiophene and bibenzyl. The Ph₃P group reacts with the liberated SO2 to give some conversion to a 2:1 mixture of Ph₃PO and Ph₃PS, a previously unrecognised reaction. The initially formed stilbene or styrene products can react to a certain extent to form cross over products under the reaction conditions used. A number of α-sulphinyl alkoxycarbonylmethylene triphenyl phosphoranes have been made from alkoxycarbonylmethylene triphenyl phosphoranes, sulphinyl chlorides and Et₃N. These ylides exhibit broadening in their ¹H and ¹³C NMR spectra, variable temperature NMR studies indicating the presence of cis and trans rotamers. FVP of these compounds gave Ph₃P, Ph₃PO, vinyl or substituted vinyl sulphides, alkyl sulphides and an as yet unidentified carbonyl compound. The vinyl or substituted vinyl sulphides are obtained via loss of Ph₃PO from the starting ylide followed by insertion of the carbene form of the initially formed thia-acetylene and loss of CO₂ from the resulting β-lactone. The other products are obtained from a variety of insertion, rearrangement and elimination reactions of the initially formed carbenes some of which have been elucidated with the help of ¹³C labelling. Isopropylsulphinyl benzylidene triphenyl phosphorane was synthesised and upon FVP gave Ph₃P, isopropyl thiobenzoate and thiobenzoic acid. The formation of isopropyl thiobenzoate is rationalised via an S to C oxygen transfer mechanism of the initially formed carbene, involving the intermediacy of the previously unknown λ⁴-oxathiirene ring system. A β-keto tri-n-butyl phosphorane, benzoyl butylidene tri-n-butyl phosphorane was synthesised and its FVP performed at room temperature, 300°C and 500°C. The almost complete extrusion of Buⁿ₃PO from the ylide at 300°C indicates that much lower temperatures are required for loss of Bun₃PO as compared to loss of Ph₃PO

Identification of a selective G1-phase benzimidazolone inhibitor by a senescence-targeted virtual screen using artificial neural networks

Cellular senescence is a barrier to tumorigenesis in normal cells and tumour cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. 147 virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase (SA-β-gal) assays. Among the found hits a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced SA-β-gal activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1 and CDC25C. Additionally, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long term treatments. Preliminary structure-activity and structure clustering analyses are reported and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells

A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB

Small GTPases regulate many key cellular processes and their role in human disease validates many proteins in this class as desirable targets for therapeutic intervention. Reliable recombinant production of GTPases, often in the active GTP loaded state, is a prerequisite for the prosecution of drug discovery efforts. The preparation of these active forms can be complex and often constricts the supply to the reagent intensive techniques used in structure base drug discovery. We have established a fully automated, multidimensional protein purification strategy for the parallel production of the catalytic G-domains of KRas, Rac1 and RalB GTPases in the active form. This method incorporates a four step chromatography purification with TEV protease-mediated affinity tag cleavage and a conditioning step that achieves the activation of the GTPase by exchanging GDP for the non-hydrolyzable GTP analogue GMPPnP. We also demonstrate that an automated method is efficient at loading of KRas with mantGDP for application in a SOS1 catalysed fluorescent nucleotide exchange assay. In comparison to more conventional manual workflows the automated method offers marked advantages in method run time and operator workload. This reduces the bottleneck in protein production while generating products that are highly purified and effectively loaded with nucleotide analogues

E-cigarette manufacturers' compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.

BACKGROUND: Electronic cigarettes (e-cigarettes) are a frequently debated topic in public health. It is essential that clinical trials examining e-cigarettes are fully and accurately reported, especially given long-standing concerns about tobacco industry research. We assess the reporting of clinical trials sponsored by Juul Labs, the largest e-cigarette company in the USA, against accepted reporting standards. METHODS: We searched ClinicalTrials.gov for all trials sponsored by Juul Labs and determined those with registry data consistent with coverage by the Food and Drug Administration (FDA) Amendments Act 2007 (FDAAA). For trials with a primary completion date more than 1 year earlier, we searched ClinicalTrials.gov, the academic literature and a Juul-funded research database (JLI Science) for results. For located results, we compared reported outcomes with registered outcomes in line with Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. RESULTS: We located five registered trials sponsored by Juul Labs that appeared covered by the FDAAA 2007 in the public data. All five trials did not have results available on ClinicalTrials.gov. We found one publication and four poster presentations reporting results for four of the five covered trials outside of ClinicalTrials.gov. Of 61 specified outcomes, 28 were CONSORT compliant. Specific outcome reporting issues are detailed. DISCUSSION: Our findings raise substantial concerns regarding these trials. Clinicians, public health professionals, and the public cannot make informed choices about the benefits or hazards of e-cigarettes if the results of clinical trials are not completely and transparently reported. Clarification and potential enforcement of reporting laws may be required

Reactive and Additive Modifications of Styrenic Polymers with Phosphorus Containing Compounds and Their Effects on Fire Retardance

Polystyrene, despite its high flammability, is widely used as a thermal insulation material for buildings, for food packaging, in electrical and automotive industries, etc. A number of modification routes have been explored to improve the fire retardance and boost the thermal stability of commercially important styrene-based polymeric products. The earlier strategies mostly involved the use of halogenated fire retardants. Nowadays, these compounds are considered to be persistent pollutants that are hazardous to public and environmental health. Many well-known halogen-based fire retardants, regardless of their chemical structures and modes of action, have been withdrawn from built environments in the European Union, USA, and Canada. This had triggered a growing research interest in, and an industrial demand for, halogen-free alternatives, which not only will reduce the flammability but also address toxicity and bioaccumulation issues. Among the possible options, phosphorus-containing compounds have received greater attention due to their excellent fire-retarding efficiencies and environmentally friendly attributes. Numerous reports were also published on reactive and additive modifications of polystyrene in different forms, particularly in the last decade; hence, the current article aims to provide a critical review of these publications. The authors mainly intend to focus on the chemistries of phosphorous compounds, with the P atom being in different chemical environments, used either as reactive, or additive, fire retardants in styrene-based materials. The chemical pathways and possible mechanisms behind the fire retardance are discussed in this review

The Book of Mick: A Collaboration Chapter 17

Eighteen international ceramic authors were approached to be involved in this collaborative novel, exploring the history of wood firing in Australia, New Zealand, Japan and the United States. It was published as part of the proceedings of the Smoke on the Water 2017 Australian Woodfired Ceramics Conference, Cooroy, Queensland, Australia. The Book of Mick utilises the creative medium of the novel to explore the unique experiences of Australian woodfired ceramics, along with the associated educational, cultural, governmental and personal experiences that have shaped the development of this art form over the last 50 years

FLYSNPdb: a high-density SNP database of Drosophila melanogaster

FLYSNPdb provides high-resolution single nucleotide polymorphism (SNP) data of Drosophila melanogaster. The database currently contains 27 367 polymorphisms, including >3700 indels (insertions/deletions), covering all major chromsomes. These SNPs are clustered into 2238 markers, which are evenly distributed with an average density of one marker every 50.3 kb or 6.6 genes. SNPs were identified automatically, filtered for high quality and partly manually curated. The database provides detailed information on the SNP data including molecular and cytological locations (genome Releases 3–5), alleles of up to five commonly used laboratory stocks, flanking sequences, SNP marker amplification primers, quality scores and genotyping assays. Data specific for a certain region, particular stocks or a certain genome assembly version are easily retrievable through the interface of a publicly accessible website (http://flysnp.imp.ac.at/flysnpdb.php)

Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents

Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Structure-based elaboration of these compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies

Locating oneself in the past to influence the present: Impacts of Neolithic landscapes on mental health well-being

There are well-established links between mental health and the environment. Mental illness is a global issue, and international policies increasingly focus on promoting mental health well-being through community-based approaches, including non-clinical initiatives such as therapeutic landscapes and the use of heritage assets. However, the empirical evidence-base for the impact of such initiatives is limited. This innovative study, known as Human Henge, used a mixed-methods approach to investigate the impact of immersive experiences of prehistoric landscapes on the well-being of participants with mental health issues. Uniquely, the study followed participants for a year after their participation in the project to explore the long-term impact of their experiences on their mental well-being. Findings highlight that, overall, participants experienced improved mental health well-being from baseline to mid- and end-of programme (p = 0.01 & 0.003), as well as one-year post-programme (p = 0.03). Qualitative data indicated the reconnection of participants with local communities, and with other people, in ways that improved their mental health well-being. These data highlight the effectiveness of using heritage as a means of improving the well-being of people with mental health issues