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Reactive oxygen species (ROS) are naturally produced compounds that play important roles in cell signaling, gene regulation, and biological defense, including involvement in the oxidative burst that is central to the anti-microbial actions of macrophages. However, these highly reactive, short-lived radical species also stimulate cells to undergo programmed cell death at high concentrations, as well as causing detrimental effects such as oxidation of macromolecules at more moderate levels. Imaging ROS is highly challenging, with many researchers working on the challenge over the past 10–15 years without producing a definitive method. We report a new fluorescence microscopy-based technique, Bullseye Analysis. This methodology is based on concepts provided by the FRAP (Fluorescence Recovery after Photobleaching) technique and refined to evidence the spatiotemporal production of ROS, and the subsequent consequences, on a subcellular scale. To exemplify the technique, we have used the ROS-reporter dye, CellROX, and the ROS-inducing photosensitizer, LightOx58, a potent source of ROS compared with UV irradiation alone. Further validation of the technique was carried out using differing co-stains, notably Mitotracker and JC-1.

The oxidation of diethyl 1,2-hydrazinedicarboxylate using a catalytic Cu(II)-oxazoline system occurs at RT in air, resulting in azo generation, which can then be trapped in situ via hetero-Diels-Alder (HDA) and competitive ene-reactions, with chemoselectivity being both temperature and solvent dependent. The procedure was extended to other azo systems and mechanism studies are reported.

We report the evaluation of density-functional-theory (DFT) based procedures for predicting

We report the evaluation of density-functional-theory (DFT) based procedures for predicting 19F NMR chemical shifts at modest computational cost for a range of molecules with fluorine bonds, to be used as a tool for assisting the characterisation of reaction intermediates and products and as an aid to identifying mechanistic pathways. The results for a balanced learning set of molecules were then checked using two further testing sets, resulting in the recommendation of the ωB97XD/aug-cc-pvdz DFT method and basis set as having the best combination of accuracy and computational time, with a RMS error of 3.57 ppm. Cationic molecules calculated without counter-anion showed normal errors, whilst anionic molecules showed larger errors, possibly due to omission of the counter-cation. The method was applied to the prediction of the conformationally averaged 19F chemical shifts of 2,2,3,3,4,4,5,5-octafluoropentan-1-ol, in which gauche stereoelectronic effects involving fluorine dominate and to determining the position of coordination equilibria of fluorinated boranes as an aid to verifying the relative energies of intermediate species involved in catalytic amidation reactions involving boron catalysts.

Boron‐substituted 1,3‐dienes participate in ene reactions to afford new functionalized synthetic intermediates. After evaluating several enophiles as partners, the resulting products have been engaged in multistep sequences involving first a Diels Alder/allyboration process. A variety of skeletally diverse and complex polycyclic heterocycles were thus synthesized, such as tetrahydro‐ 1H ‐isoindole‐1,3( 2H )‐diones, eight‐membered lactones or tricyclic spiro compounds.

A highly selective, green and sustainable chlorination of aliphatic C–H bonds is reported using MCln under the co-catalysis of visible light and nano-Cu@CuCl, which was synthesised via a one-step, hydrothermal strategy using copper(II) sulfate and D-glucose as the reducing agent in a KCl solution. A novel cascade method of producing Cl2 occurs in situ chlorinating C(sp3)–Hs, achieved through nano-Cu@CuCl catalysis using inorganic chloride MCln as a chlorine source under visible light and without the need for a strong oxidant. The reaction was applied to the chlorination of different alkylarene α-Hs and cyclic hydrocarbons C–HS and was developed for use in a photocatalytic serial reactor system which accomplished the chlorination of toluene α-Hs to give 92% conversion, 90% yield and 98% selectivity. Electron spin resonance (ESR) studies of DMPO-Cl. revealed that the reaction mechanism belonged to a free radical process.

We report the evaluation of density-functional-theory (DFT) based procedures for predicting 19F NMR chemical shifts at modest computational cost for a range of molecules with fluorine bonds, to be used as a tool for assisting the characterisation of reaction intermediates and products and as an aid to identifying mechanistic pathways. The results for a balanced learning set of molecules were then checked using two further testing sets, resulting in the recommendation of the ωB97XD/aug-cc-pvdz DFT method and basis set as having the best combination of accuracy and computational time, with a RMS error of 3.57 ppm. Cationic molecules calculated without counter-anion showed normal errors, whilst anionic molecules showed somewhat larger errors. The method was applied to the prediction of the conformationally averaged 19F chemical shifts of 2,2,3,3,4,4,5,5-octafluoropentan-1-ol, in which gauche stereoelectronic effects involving fluorine dominate and to determining the position of coordination equilibria of fluorinated boranes as an aid to verifying the relative energies of intermediate species involved in catalytic amidation reactions involving boron catalysts.

The B,N-bifunctional catalyst homoboroproline has been applied to a catalytic asymmetric nitroalkene-Michael addition to beta-nitrostyrene analogues, showing broad substrate tolerance, high conversions and moderate to good asymmetric induction. The ability of homoboroproline to act as an efficient catalyst based on enamine-formation of the secondary amine, coupled with intramolecular Lewis-acid chelation of the nitro function, in a non-FLP manner, to effect efficient and enantioselective catalysis via a proposed large 10-membered ring transition state is remarkable and reinforced by theoretical calculations.

The Prevent Duty mandates that public authorities must work to prevent people from being drawn into terrorism. In this article we review how 158 UK Higher Education Institutions have responded to this new duty by examining their public-facing webpages and Prevent policy documentation. In doing this we draw upon de Certeau’s notions of the everyday to highlight how such initiatives are presented publicly to viewing audiences, and how messages seep into and deepen security measures within UK Higher Education. In reviewing the performative element of Prevent, specifically how information is displayed, we find that the majority of UK Higher Education Institutions have approached their new roles through the prism of ‘compliance’ and/or ‘safeguarding’. The article argues presentations of safeguarding, reassurance and reluctance offer a telling insight into how the Duty has been adopted in Higher Education Institutions’ everyday practice.

Of numerous genes regulated by retinoic acid (RA), CYP26A1 is the most inducible gene by RA. In this study, we have used a shortened construct form, E4, of the CYP26A1 gene promoter, in a promoter-less vector with either luciferase or red fluorescent protein (RFP) as the reporter gene and have tested its responses to retinoids in transfected HepG2 and HEK293T cells. The promoter responded linearly to a wide concentration range of RA in cells cotransfected with retinoic acid receptors. It also responded quantitatively to retinol and other retinoids. An isolated clonal line of HEK293T cells permanently transfected with the promoter driving the expression of RFP responded to both RA and retinol, and the responses could be measured by fluorescence microscopy and flow cytometry. The promoter was used to assess the retinoid activity of 3 novel synthetic retinoid analogues, as well as of the intact serum samples of rats. Among the synthetic retinoid analogues tested, EC23 is more potent than RA at lower concentrations and was more stable than RA. The retinoid activities could be measured in control rat serum samples and were increased in the serum of RA-treated rats. This system offers a biologically-based alternative to mass-based retinoid analysis.

The poultry industry generates a large quantity of litter, which consists of a mixture of manure, waste bedding and feathers, and can be used for recovery of energy. Recent studies suggest that gasification is a promising technology for an effective conversion of poultry litter to energy. This paper aims to assess the environmental impacts of generating electricity from the gasification of poultry litter in a small-scale integrated gasification combined cycle (IGCC) plant. Gasification of poultry litter has been simulated with ASPEN Plus® software and life cycle assessment has been used to determine the carbon footprint and primary energy demand of the system. The following life cycle stages have been considered: collection and storage of poultry litter, its gasification, syngas cleaning, production of electricity and co-production of ash as a fertiliser. The carbon footprint and primary energy demand of generating 1 kWh of energy by poultry litter gasification plant are estimated at 42 g CO2 eq./kWh and 0.14 MJ/kWh, respectively. Compared to electricity from fossil fuels, this system has 91%-96% smaller carbon footprint and 98%-99% lower primary energy demand. The energy payback period is estimated at 1.5 years. © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Ketonic decarboxylation has gained significant attention in recent years as a pathway to reduce the oxygen content within biomass-derived oils, and to produce sustainable ketones. The reaction is base catalysed, with MgO an economic, accessible and highly basic heterogeneous catalyst. Here we use MgO to catalyse the ketonic decarboxylation of dodecanoic acid to form 12-tricosanone at moderate temperatures (250 degrees C, 280 degrees C and 300 degrees C) with low catalyst loads of 1% (w/w), 3% (w/w) and 5% (w/w) with respect to the dodecanoic acid, with a reaction time of 1 hour under batch conditions. Three different particle sizes for the MgO were tested (50 nm, 100 nm and 44 mu m). Ketone yield was found to increase with increasing reaction temperature, reaching approximately 75% yield for all the samples tested. Temperature was found to be the main control on reaction yield, rather than surface area or particle size.

This chapter focuses on understandings and debates around cyberterrorism as well as the effect particular representations of this phenomenon have upon assessing its threat. The chapter begins by introducing various understandings of cyberterrorism and differentiates between narrow and broad conceptions as well as effects and intent based definitions. Moving on to consider the threat of cyberterrorism the chapter identifies an ongoing debate between “concerned” and “sceptical” voices as well as those that contest whether cyberterrorism has ever taken place. The chapter then introduces a range of broadly constructivist studies which question the orthodox approach to cyberterrorism as an ontological reality and highlight the importance of media representations of this threat. To illustrate this, the chapter concludes by highlighting findings from a recent study of global news media coverage. It shows that this media is frequently apprehensive in tone, despite the existence of diverse understandings of cyberterrorism and cybersecurity.

Fluorescent probes are increasingly used as reporter molecules in a wide variety of biophysical experiments, but when designing new compounds it can often be difficult to anticipate the effect that changing chemical structure can have on cellular localisation and fluorescence behaviour. To provide further chemical rationale for probe design, a series of donor-acceptor diphenylacetylene fluorophores with varying lipophilicities and structures were synthesised and analysed in human epidermal cells using a range of cellular imaging techniques. These experiments showed that, within this family, the greatest determinants of cellular localisation were overall lipophilicity and the presence of ionisable groups. Indeed, compounds with high log D values (>5) were found to localise in lipid droplets, but conversion of their ester acceptor groups to the corresponding carboxylic acids caused a pronounced shift to localisation in the endoplasmic reticulum. Mildly lipophilic compounds (log D = 2-3) with strongly basic amine groups were shown to be confined to lysosomes i.e. an acidic cellular compartment, but sequestering this positively charged motif as an amide resulted in a significant change to cytoplasmic and membrane localisation. Finally, specific organelles including the mitochondria could be targeted by incorporating groups such as a triphenylphosphonium moiety. Taken together, this account illustrates a range of guiding principles that can inform the design of other fluorescent molecules but, moreover, has demonstrated that many of these diphenylacetylenes have significant utility as probes in a range of cellular imaging studies.

Structures of Homo sapiens cellular retinoic acid-binding proteins I and II in the presence of natural and synthetic ligands are presented, demonstrating canonical binding activity for these new molecules and relating the structure and function of these novel retinoid signalling modulators., A detailed understanding of the interactions between small-molecule ligands and their proposed binding targets is of the utmost importance for modern drug-development programs. Cellular retinoic acid-binding proteins I and II (CRABPI and CRABPII) facilitate a number of vital retinoid signalling pathways in mammalian cells and offer a gateway to manipulation of signalling that could potentially reduce phenotypes in serious diseases, including cancer and neurodegeneration. Although structurally very similar, the two proteins possess distinctly different biological functions, with their signalling influence being exerted through both genomic and nongenomic pathways. In this article, crystal structures are presented of the L29C mutant of Homo sapiens CRABPI in complex with naturally occurring fatty acids (1.64 Å resolution) and with the synthetic retinoid DC645 (2.41 Å resolution), and of CRABPII in complex with the ligands DC479 (1.80 Å resolution) and DC645 (1.71 Å resolution). DC645 and DC479 are two potential drug compounds identified in a recent synthetic retinoid development program. In particular, DC645 has recently been shown to have disease-modifying capabilities in neurodegenerative disease models by activating both genomic and nongenomic signalling pathways. These co-crystal structures demonstrate a canonical binding behaviour akin to that exhibited with all-trans-retinoic acid and help to explain how the compounds are able to exert an influence on part of the retinoid signalling cascade.

Neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and currently lack effective treatments that block the degenerative process. It has been suggested that retinoids, a class of vitamin A-derived compounds, may hold potential as future therapeutics for these disorders.In this review, we explore the role of retinoids in modulating various signaling pathways in the brain which influence pathologically relevant processes such as cellular differentiation, immune and antioxidant response, neurite outgrowth and neurite regeneration. These actions are predominantly mediated by the retinoic acid receptors and we discuss the developmental history of ligands for these receptors, assessing how refinements in receptor binding specificity and improved pharmacokinetic properties may influence the management of off-target effects.New approaches to understanding retinoid's mechanisms of action, including non-genomic pathways, and how these mechanisms interact may prove vital in the development of future retinoid-based neurodegenerative disease treatments.

Raman spectroscopy has been used to observe uptake, metabolism and response of single-cells to drugs. Photodynamic therapy is based on the use of light, a photosensitiser and oxygen to destroy tumour tissue. Here, we used single-cell Raman spectroscopy to study the uptake and intracellular degradation of a novel photosensitiser with a diphenylacetylene structure, DC473, in live single-cells from colorectal adenocarcinoma cell lines SW480, HT29 and SW620. DC473 was seen to predominantly accumulate in lipid droplets, showing higher accumulation in HT29 and SW620 cells than in SW480 cells, with a broader DC473 peak shifted to higher wavenumbers. DC473 activation and effects were tracked on live single-cells for 5 minutes. Upon exposure to UV light, the DC473 signal intensity dropped, with remaining DC473 shifting towards higher wavenumbers and widening, with a lifetime of approximately 50 seconds. Morphologically, SW480 and SW620 cells showed changes upon photodynamic therapy, whereas HT29 cells showed no changes. Morphological changes correlated with higher remaining DC473 signal after UV exposure. Our research suggests that DC473 forms aggregates within the cells that disaggregate following activation, showing the potential of Raman spectroscopy for the study of time-dependent single-cell pharmacodynamics.

The retinoic acid (RA) signaling pathway is crucial for the control of embryonic development and also regulates function of several organ systems in the adult, including the central nervous system. The retinoic acid receptors (RARs) that mediate the majority of the functions of RA can promote proliferation, differentiation, morphogenesis and cell survival. Dysregulation of this signaling pathway has been considered in the pathophysiology of various diseases including neurodegenerative disorders such Alzheimer's disease and amyotrophic lateral sclerosis. Thus, drugs targeted to the RARs have been proposed as treatments for such diseases. Understanding how these drugs distribute in the body is essential to determine their potential effectiveness. However measuring tissue levels of what are often lipophilic drugs can be difficult. Here we describe an indirect measurement of RAR ligand tissue distribution after intraperitoneal injection into rodents that uses a sensitive RA reporter cell line.

Assays for identifying the activity of retinoic acids and retinoic acid derivatives, have become increasingly accessible in the 21st century. Movement away from complex in cellulo expression and radiological systems toward accessible FRET or fluorescent compound led studies has increased the accessibility and high-throughput capabilities of the field. The improvement in assaying technologies will lead to both increased and faster screening of retinoids and related compounds, improving drug discovery workflows and implementation pipelines. This enabling technology will allow better understanding of the huge range of phenotypes closely linked to retinoid signaling, and through the development of improved treatments improve outlooks for diagnoses in these cases and those of closely related diseases. In this chapter we present an examination of historical and modern techniques for assaying the activity of retinoic acid derivatives against their binding proteins.

This chapter has been conceived as an introductory text to aid in the understanding of the key design strategies for the development of synthetic analogs of endogenous retinoids as ligands for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The structure and binding characteristics of the endogenous retinoids are first explained to put the main chemical design challenges in context. Existing biochemical and structural data is then used to describe the guiding principles used to develop agonists and antagonists of the RARs and RXRs. In light of the increasing proliferation of biophysical methods that employ fluorescence measurements or molecular tags, we also examine the application of retinoids as probes and the chemical principles required to develop these tools.

This chapter has been conceived as an introductory text to aid in the understanding of the key design strategies for the development of synthetic analogs of endogenous retinoids as ligands for the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). The structure and binding characteristics of the endogenous retinoids are first explained to put the main chemical design challenges in context. Existing biochemical and structural data is then used to describe the guiding principles used to develop agonists and antagonists of the RARs and RXRs. In light of the increasing proliferation of biophysical methods that employ fluorescence measurements or molecular tags, we also examine the application of retinoids as probes and the chemical principles required to develop these tools.

Assays for identifying the activity of retinoic acids and retinoic acid derivatives, have become increasingly accessible in the 21st century. Movement away from complex in cellulo expression and radiological systems toward accessible FRET or fluorescent compound led studies has increased the accessibility and high-throughput capabilities of the field. The improvement in assaying technologies will lead to both increased and faster screening of retinoids and related compounds, improving drug discovery workflows and implementation pipelines. This enabling technology will allow better understanding of the huge range of phenotypes closely linked to retinoid signaling, and through the development of improved treatments improve outlooks for diagnoses in these cases and those of closely related diseases. In this chapter we present an examination of historical and modern techniques for assaying the activity of retinoic acid derivatives against their binding proteins.

We have used a shortened construct form of the CYP26A1 gene promoter, in a promoter-less vector with either luciferase (known as E4) or a red fluorescent protein, RFP (known as E4.2) as the reporter gene and examined their responses to retinoids in transfected HepG2 and HEK293T cells. The promoter responded linearly to a wide concentration range of at-RA in cells cotransfected with retinoic acid receptors (RAR). The promoter also responded quantitatively to retinol and various other retinoids. An isolated clonal line of HEK293T cells that was permanently transfected with the promoter driving the expression of RFP responded to both at-RA and retinol, and the responses could be measured by fluorescence microscopy and flow cytometry. The promoter was also used to assess the retinoid activity of 3 novel synthetic retinoid analogues. Among them, EC23 was shown to be more potent than at-RA at lower concentrations and also more stable than at-RA. The promoter was also used to estimate the retinoid activities of intact rat serum samples as well as extracts of rat liver and lung, using retinol and at-RA as the reference standards. The retinoid activities could be measured in control rat serum samples and were increased in the serum of at-RA-treated rats. The total retinol and at-RA levels in the rat liver and lung samples determined by this promoter-based assay were compared with total retinol levels determined by the UPLC as the conventional methods. This system should offer a biologically-based alternative to mass-based retinoid analysis.

All-trans-retinoic acid (ATRA), the active metabolite of vitamin A, plays a pivotal role in cell differentiation, proliferation and embryonic development. It is an effective therapy for dermatological disorders and malignancies. ATRA is prone to isomerization and oxidation, which can affect its activity and selectivity. Novel diphenylacetylene-based ATRA analogues with increased stability can help to overcome these problems and may offer significant potential as therapeutics for a variety of cancers and neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we investigated the effects of these retinoids on cell viability and genotoxicity in the widely used model system of the rapidly proliferating Chinese hamster ovary cell line. DC360 is a fluorescent ATRA analogue and DC324 is a non-active derivative of DC360. EC23, DC525, DC540, DC645, and DC712 are promising analogues with increased bioactivity. The cytotoxic activity of the compounds was evaluated by ATP assay and DNA damage was tested by comet assay. No cytotoxicity was observed in the 10−6–10−5 M concentration range. All compounds induced DNA migration similar to ATRA, but DC324, DC360 and EC23 did so to a greater extent, particularly at higher concentrations. We believe that retinoid receptor-independent genotoxicity is a general characteristic of these compounds; however, further studies are needed to identify the molecular mechanisms and understand their complex biological functions.

We describe a one-pot synthesis method for carbon filament-supported mixed metal oxide nanoparticles. The thermal intracrystalline reaction of adamantanecarboxylate ions confined inside interlayer galleries of layered double hydroxide materials under a reducing atmosphere (H2) leads to carbon filaments forming in situ within the material. Raman spectroscopy and combined microscopy techniques show the formation of hybrid organic–inorganic carbon filaments with the mixed metal oxide particles interleaved.

The efficient synthesis of enantioenriched organoboron compounds has been recognized as an important topic in recent years. As an update review, this article aims to select key achievements in copper-catalyzed, electron-deficient alkene enantioselective hydroboration methodologies since the beginning of 2017. In addition, it covers relevant mechanistic investigations developed over the last six years, as well as total synthesis applications for preparing 1,3-diols as important medicinal intermediates.1 Introduction2 Methodologies for Copper-Catalyzed Hydroboration2.1 α,β-Unsaturated Ketones and Imines2.2 α,β-Unsaturated Esters and Cyanides2.3 Aryl Alkenes and Alkyl Alkenes3 Mechanistic Investigations on the Copper-Catalyzed Hydroboration3.1 A Cu–BX2 Intermediate3.1.1 Experimental Analysis3.1.2 Borylative Difunctionalization Methodologies3.1.3 Density Functional Theory3.2 A Cu–H Intermediate3.3 Other Mechanistic Proposals4 Synthetic Applications: Chiral 1,3-Diols5 Conclusions and Outlook

The direct selective halogenation of unactivated C(sp3)–H bonds into C-halogen bonds was achieved using a nano Ag/AgCl catalyst at RT under visible light or LED irradiation in the presence of an aqueous solution of NaX/HX as a halide source, in air. The halogenation of hydrocarbons provided mono-halide substituted products with 95% selectivity and yields higher than 90%, with the chlorination of toluene being 81%, far higher than the 40% conversion using dichlorine. Mechanistic studies demonstrated that the reaction is a free radical process using blue light (450–500 nm), with visible light being the most effective light source. Irradiation is proposed to cause AgCl bonding electrons to become excited and electron transfer from chloride ions induces chlorine radical formation which drives the substitution reaction. The reaction provides a potentially valuable method for the direct chlorination of saturated hydrocarbons.

The development of new imaging tools, molecules and modalities is crucial to understanding biological processes and the localised cellular impact of bioactive compounds. A small molecule photosensitiser, DC473, has been designed to be both highly fluorescent and to exhibit a strong Raman signal in the cell-silent region of the Raman spectrum due to a diphenylacetylene structure. DC473 has been utilised to perform a range of novel tandem fluorescence and Raman (fluoRaman) imaging probe experiments, enabling a thorough examination of the compound’s cellular localisation, exemplified in colorectal cancer cells (SW480). This multifunctional fluoRaman imaging modality has revealed the presence of the compound in lipid droplets and only weak signal in the cytosol, where both Raman and fluorescence results show the presence of the fluoRaman imaging probe. In addition, Raman microscopy detected the compound in a cell compartment we labelled as the nucleolus, where fluorescence microscopy did not detect the fluoRaman probe due to solvatochromatic effects in a local polar environment. This last finding was only possible with the use of tandem confocal Raman and fluorescence methods. By following the approach detailed herein, incorporation of strong Raman functional groups into fluorophores can enable a plethora of fluoRaman experiments, shedding further light on an imaging probe or potential drug compound’s cellular behaviour and biological activity.

The UK Counter Terrorism and Security Act (2015) (CTSA) calls for a partnership between the government, individuals, organisations and communities to prevent the radicalisation of individuals and to prevent their participation in terrorist and illegal activities. As part of this strategy, universities have a statutory duty placed upon them to remain vigilant to signs of extremism. Based upon 20 interviews with UK university lecturers, the paper examines reactions of the academic community to this governmental mandate. Key to our understanding is the deputisation of lecturers into a security regime and how they perform the duty of identifying and monitoring extremism. Equally, forms of resistance are evident in how lecturers understand their new roles and for universities themselves a conservative approach to risk may be gaining traction. We argue there is confusion around the CTSA based upon the ambiguous language in which it is presented and the conservative and defensive reactions that have subs...

The inability of neurites to grow and restore neural connections is common to many neurological disorders, including trauma to the central nervous system and neurodegenerative diseases. Therefore, there is need for a robust and reproducible model of neurite outgrowth, to provide a tool to study the molecular mechanisms that underpin the process of neurite inhibition and to screen molecules that may be able to overcome such inhibition. In this study a novel in vitro pluripotent stem cell based model of human neuritogenesis was developed. This was achieved by incorporating additional technologies, notably a stable synthetic inducer of neural differentiation, and the application of three-dimensional (3D) cell culture techniques. We have evaluated the use of photostable, synthetic retinoid molecules to promote neural differentiation and found that 0.01 μM EC23 was the optimal concentration to promote differentiation and neurite outgrowth from human pluripotent stem cells within our model. We have also developed a methodology to enable quick and accurate quantification of neurite outgrowth derived from such a model. Furthermore, we have obtained significant neurite outgrowth within a 3D culture system enhancing the level of neuritogenesis observed and providing a more physiological microenvironment to investigate the molecular mechanisms that underpin neurite outgrowth and inhibition within the nervous system. We have demonstrated a potential application of our model in co-culture with glioma cells, to recapitulate aspects of the process of neurite inhibition that may also occur in the injured spinal cord. We propose that such a system that can be utilised to investigate the molecular mechanisms that underpin neurite inhibition mediated via glial and neuron interactions., Graphical abstract Image 1, Highlights • Development of a robust, novel neurite outgrowth assay from human pluripotent stem cell derived neural cell aggregates. • Synthetic retinoids induce neural differentiation of pluripotent stem cells to a greater extent than natural ATRA. • Neurospheres cultured on a 3D scaffold provide a more physiologically relevant model of neurite outgrowth. • Suppression of neurite outgrowth by glioma cells in 3D enables the study of neurite inhibitory mechanisms in the glial scar.

This chapter considers Freedom of Information Act (FOIA) as a viable tool for academic research. To date, journalist, campaigners or concerned consumers have been to the forefront in using FOIs to gain information on issues as diverse as politician’s expenses, the cost of policing a royal event or the levels of food hygiene in restaurants. Yet this line of enquiry appears to be infrequently used by academic researchers. The chapter concentrates on the UK and will offer 5 areas for consideration. Firstly, we consider the value of FOIs as a research tool. Secondly, we reflect upon some of the limitations to using FOIs in research. Thirdly, we locate the FOIA within a broader process of modernising digital information and highlight some of the challenges that can present for researchers via this trend. Fourthly, we review effective use of FOI in research. Finally, we offer some observations from our own nascent research project that is using FOIs as a key methodological approach. The chapter concludes by stressing the usefulness of the FOIA for researchers to produce democratising and politically impactful research. The chapter’s aim is to highlight the practicalities of applying this method of enquiry and to further its contribution to academic research.

Retinoic acid (RA) regulates numerous aspects of central nervous system function through modulation of gene transcription via retinoic acid receptors (RARs). However, RA has important roles independent of gene transcription (non-genomic actions) and in the brain a crucial regulator of homeostatic plasticity is RAR control of glutamate receptor subunit 1 (GluR1) translation. An assay to quantify RAR regulation of GluR1 translation would be beneficial both to study the molecular components regulating this system and screen drugs that influence this critical mechanism for learning and memory in the brain. A bioluminescence reporter assay was developed that expresses firefly luciferase under the control of the GluR1 5′ untranslated region bound by RAR. This assay was introduced into SH-SY5Y cells and used to demonstrate the role of RARα in RA regulation of GluR1 translation. A screen of synthetic RAR and RXR ligands indicated that only a subset of these ligands activated GluR1 translation. The results demonstrate the practicality of this assay to explore the contribution of RARα to this pathway and that the capacity of RAR ligands to activate translation is a quality restricted to a limited number of compounds, with implications for their RAR selectivity and potentially their specificity in drug use.

An (4E,6E)-alkadienyl alcohol which is a solid compound which can be stored at rt, upon dissolving into a suitable solvent undergoes facile autoxidation (4E,6E)-alkadienyl alcohol 1 in air at room temperature. The result is complete decompose leading to a mixture of products, including benzaldehyde (24%) and cinnamaldehyde (29%). Possible mechanistic explanations for the autoxidation are discussed.

An efficient heterogeneous amidation catalyst has been prepared by co-polymerisation of styrene, DVB with 4-styreneboronic acid, which shows wide substrate applicability and higher reactivity than the equivalent homogeneous phenylboronic acid, suggesting potential cooperative catalytic effects. The catalyst can be easily recovered and reused; suitable for use in packed bed flow reactors.

The Foundation Spatial Data Framework (FSDF) is a framework of ten national authoritative geographic data themes that supports evidence-based social-economic decision making across multiple levels ...

Retinoids, such as all- trans-retinoic acid (ATRA), are endogenous signaling molecules derived from vitamin A that influence a variety of cellular processes through mediation of transcription events in the cell nucleus. Because of these wide-ranging and powerful biological activities, retinoids have emerged as therapeutic candidates of enormous potential. However, their use has been limited, to date, due to a lack of understanding of the complex and intricate signaling pathways that they control. We have designed and synthesized a family of synthetic retinoids that exhibit strong, intrinsic, solvatochromatic fluorescence as multifunctional tools to interrogate these important biological activities. We utilized the unique photophysical characteristics of these fluorescent retinoids to develop a novel in vitro fluorometric binding assay to characterize and quantify their binding to their cellular targets, including cellular retinoid binding protein II (CRABPII). The dihydroquinoline retinoid, DC360, exhibited particularly strong binding ( K

This book charts contemporary developments in counter-extremism within the UK education sector. Set against the background of the controversial Prevent strategy the book focuses on the expansion of counter‑extremism into education and draws on key legislation such as the Counter Terrorism and Security Act (2015) that imposed a statutory counter-extremism duty on public sector workers in the UK. The authors provide a wide-ranging critique that draws on theories of surveillance and power, an international review of counter‑extremism educational initiatives and a series of interviews with UK lecturers. Terrorism in the Classroom highlights the problems that occur when counter-extremism becomes an objective of education and a part of the curriculum, as well as the anxiety that is felt by educators who have been deputised into the role of counter-extremism practitioners. It will be of interest to students and scholars across a range of disciplines, including Criminology, International Relations, Politics and Education.

Drawing upon 157 responses to Freedom of Information Requests sent to Higher Education Institutions across England, Scotland and Wales, this article explores how the Prevent Duty has been enacted within UK higher education. The article shows how the duty has seen considerable repositioning and restructuring across the sector, conflated counterterrorism with safeguarding and introduced further bureaucracy. The article also explores the low number of Channel referrals, the justifications provided for these and the several instances in which institutions refused to disclose this information. We argue that these disproportionate developments have brought harmful depoliticising effects while also enhancing the mechanisms of surveillance and governance. Furthermore, we argue that our findings demonstrate the value in Freedom of Information Requests as a means of approach and suggest a continued need for critical researchers to explore the specific functioning of the duty to complement the broader critiques that are levelled at the policy as a whole.

The synthesis of novel tetrahydroquinolines (THQ) and dihydroquinolines (DHQ) are reported using three practical, scalable synthetic approaches to access highly lipophilic analogues bearing a 6-iodo substituent, each with a different means of cyclisation. A versatile and stable quinolin-2-one intermediate was identified, which could be reduced to the corresponding THQ with borane reagents, or to the DHQ with diisobutylaluminium hydride via a novel elimination that is more favourable at higher temperatures. Coupling these strongly electron-donating scaffolds to electron-accepting moieties caused the resulting structures to exhibit strong fluorescence.