Explosivity : an unusual challenge in drug development

There remains an urgent global need for new drugs to combat diseases such as malaria, tuberculosis and cancer, as well as overcoming increasing antibiotic resistance. Chemists are moving into ‘new chemical space’ for drug design (1,2) and with this comes the possibility of traditional (and stable) ‘carbon-carbon’ bond structures being replaced by more ‘exotic’ bonding arrangements. While the implication of this on pharmaceutical stability can often be mitigated by suitable formulation and storage strategies, we came across an unusual case of chemical stability: the possibility that the drug was an explosive! By pushing drug designing into uncharted chemical space it could be argued that the possibility of finding explosive molecules of pharmaceutical interest will increase

Developing sexual competence? Exploring strategies for the provision of effective sexualities and relationships education

School-based sexualities and relationships education (SRE) offers one of the most promising means of improving young people's sexual health through developing 'sexual competence'. In the absence of evidence on whether the term holds the same meanings for young people and adults (e.g. teachers, researchers, policy-makers), the paper explores 'adult' notions of sexual competence as construed in research data and alluded to in UK Government guidance on SRE, then draws on empirical research with young people on factors that affect the contexts, motivations and outcomes of sexual encounters, and therefore have implications for sexual competence. These data from young people also challenge more traditional approaches to sexualities education in highlighting disjunctions between the content of school-based input and their reported sexual experience. The paper concludes by considering the implications of these insights for developing a shared notion of what SRE is trying to achieve and suggestions for recognition in the content and approaches to SRE.</p

\u3ci\u3eMedicine Meets Virtual Reality 15\u3c/i\u3e

Chapter, Virtual Reality for Robotic Laparoscopic Surgical Training, co-authored by Nicholas Stergiou, UNO faculty member. Our culture is obsessed with design. Sometimes designers can fuse utility and fantasy to make the mundane appear fresh—a cosmetic repackaging of the same old thing. Because of this, medicine—grounded in the unforgiving realities of the scientific method and peer review, and of flesh, blood, and pain—can sometimes confuse “design” with mere “prettifying.” Design solves real problems, however. This collection of papers underwrites the importance of design for the MMVR community, within three different environments: in vivo, in vitro and in silico. in vivo: we design machines to explore our living bodies. Imaging devices, robots, and sensors move constantly inward, operating within smaller dimensions: system, organ, cell, DNA. in vitro: Using test tubes and Petri dishes, we isolate in vivo to better manipulate and measure biological conditions and reactions. in silico: We step out of the controlled in vitro environment and into a virtual reality. The silica mini-worlds of test tubes and Petri dishes are translated into mini-worlds contained within silicon chips. The future of medicine remains within all three environments: in vivo, in vitro, and in silico. Design is what makes these pieces fit together—the biological, the informational, the physical/material—into something new and more useful.https://digitalcommons.unomaha.edu/facultybooks/1235/thumbnail.jp

Indentation-based characterization of creep and hardness behavior of magnesium carbon nanotube nanocomposites at room temperature

The time-dependent plastic deformation response of magnesium/carbon nanotube (CNT) nanocomposites containing 0.25, 0.5, and 0.75 vol% of carbon nanotubes is investigated through depth nanoindentation tests against monolithic pure magnesium in the present study. The Mg-CNT nanocomposite materials were successfully synthesized via a powder metallurgy technique coupled with microwave sintering followed by hot extrusion to produce 8-mm diameter, long solid bars. All depth-sensing indentation creep tests were conducted at ambient (room) temperature employing a diamond Berkovich pyramidal indenter. These tests are dual-stage, i.e., loading to a prescribed peak load of 50 mN, holding the peak load constant for a dwell period of 500 s, and finally unloading. Various strain rates of 0.01, 0.1, 1, and 10 s−1were performed to assess the effects of strain rate and dwell time on the ambient temperature creep response of the Mg-CNT nanocomposites. The outcomes of these tests are explained through material hardness, microstructure, the extent of CNT content in each material, and strain rate sensitivity. Upon analyzing the nanoindentation creep tests, the dominant creep mechanism at room temperature was found to be a dislocation creep mechanism. It is also found that CNTs increase the creep resistance of magnesium. Findings of this study can be used as a starting point for a high-temperature creep study on Mg-CNT nanocomposites. This paper is a continued study from our group on time-dependent plastic deformation of Mg nanocomposites (i.e., see Haghshenas et al., Journal of Composite Materials, https://doi.org/10.1177/0021998318808358). The short-term goal is to provide a compressive picture of the controlling creep mechanisms and their dependency upon, time, temperature, strain rate, volume fraction of the nanoparticles, and the type of the nanoparticles. Mg, in general, is a notorious material for high-temperature application; therefore, the long-term objective is to propose Mg nanocomposite as reliable replacements for Mg when lightweight and creep resistance are needed. However, to be able to confidently suggest such a replacement detailed understanding on the controlling phenomena, mention as short-term goals, are required

Isothiourea-catalysed acylative kinetic resolution of aryl-alkenyl (sp2 vs. sp2) substituted secondary alcohols

We would like to thank the Engineering and Physical Sciences Research Council and CRITICAT Centre for Doctoral Training [Ph.D. studentship to S.F.M.; Grant code: EP/L016419/1 and EP/J018139/1] and The Leverhulme Trust [Early Career Fellowship to J.E.T.; ECF-2014-005] for financial support. A.D.S. thanks the Royal Society for a Wolfson Merit Award.The non-enzymatic acylative kinetic resolution of challenging aryl–alkenyl (sp2 vs. sp2) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl–alkenyl substituted alcohols has been evaluated, with either electron-rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2–1980). The use of this protocol for the gram-scale (2.5 g) kinetic resolution of a model aryl–vinyl (sp2 vs. sp2) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r.Publisher PDFPeer reviewe

Investigation of the chemocatalytic and biocatalytic valorization of a range of different lignin preparations: The importance of β-O-4 content

A set of seven different lignin preparations was generated from a range of organosolv (acidic, alkaline, ammonia-treated, and dioxane-based), ionic liquid, autohydrolysis, and Kraft pretreatments of lignocelluloses. Each lignin was characterized by 2D HSQC NMR spectroscopy, showing significant variability in the β-O-4 content of the different lignin samples. Each lignin was then valorised using three biocatalytic methods (microbial biotransformation with Rhodococcus jostii RHA045, treatment with Pseudomonas fluorescens Dyp1B or Sphingobacterium sp. T2 manganese superoxide dismutase) and two chemocatalytic methods (catalytic hydrogenation using Pt/alumina catalyst, DDQ benzylic oxidation/Zn reduction). Highest product yields for DDQ/Zn valorization were observed from poplar ammonia percolation-organosolv lignin, which had the highest β-O-4 content of the investigated lignins and also gave the highest yield of syringaldehyde (243 mg L -1 ) when using R. jostii RHA045 and the most enzymatic products using P. fluorescens Dyp1B. The highest product yield from the Pt/alumina hydrogenation was observed using oak dioxasolv lignin, which also had a high β-O-4 content. In general, highest product yields for both chemocatalytic and biocatalytic valorization methods were obtained from preparations that showed highest β-O-4 content, while variable yields were obtained with preparations containing intermediate β-O-4 content, and little or no product was obtained with preparations containing low β-O-4 content

Integrated processing of sugarcane bagasse : arabinoxylan extraction integrated with ethanol production.

The authors gratefully acknowledge the funding for “Project POC02_NOV 14 Campbell” from the Lignocellulosic Biorefinery Network (LBNet), funded by the Biotechnology and Biological Sciences Research Council (BBSRC).A proof-of-concept project compared extraction of arabinoxylans (AX) from sugarcane bagasse and wheat bran via alkaline hydrogen peroxide followed by enzyme-assisted extraction with combinations of feruloyl esterases and a xylanase. Bagasse contains comparable amounts of AX to wheat bran, but with a much lower arabinoxylan substitution on the xylan backbone (A:X ratio of around 0.2 compared with 0.6 for wheat bran), hence offering AX products with distinctive functionality and potential end uses. In the current work, bagasse released its AX more readily than wheat bran, and released a wider range of molecular weights. Use of feruloyl esterase and xylanase enzymes on their own or following alkaline peroxide extraction did not enhance AX release substantially; however, the xylanase appeared to be effective at reducing the size of AX molecules, and there is scope to optimise the effects of enzymes to produce specific AX product fractions. As bagasse frequently arises within the context of bioethanol production, integration of AX extraction with ethanol production could allow economic production of a portfolio of AX products, as has been demonstrated in principle for AX co-production in a wheat ethanol plant.PostprintPeer reviewe

Characterisation of Osteopontin in an In Vitro Model of Embryo Implantation

At the onset of pregnancy, embryo implantation is initiated by interactions between the endometrial epithelium and the outer trophectoderm cells of the blastocyst. Osteopontin (OPN) is expressed in the endometrium and is implicated in attachment and signalling roles at the embryo–epithelium interface. We have characterised OPN in the human endometrial epithelial Ishikawa cell line using three different monoclonal antibodies, revealing at least nine distinct molecular weight forms and a novel secretory pathway localisation in the apical domain induced by cell organisation into a confluent epithelial layer. Mouse blastocysts co-cultured with Ishikawa cell layers served to model embryo apposition, attachment and initial invasion at implantation. Exogenous OPN attenuated initial, weak embryo attachment to Ishikawa cells but did not affect the attainment of stable attachment. Notably, exogenous OPN inhibited embryonic invasion of the underlying cell layer, and this corresponded with altered expression of transcription factors associated with differentiation from trophectoderm (Gata2) to invasive trophoblast giant cells (Hand1). These data demonstrate the complexity of endometrial OPN forms and suggest that OPN regulates embryonic invasion at implantation by signalling to the trophectoder

Osmotic stress induces JNK-dependent embryo invasion in a model of implantation

In vitro culture during assisted reproduction technologies (ARTs) exposes pre-implantation embryos to environmental stressors, such as non-physiological nutritional, oxidative and osmotic conditions. The effects on subsequent implantation are not well understood but could contribute to poor ART efficiency and outcomes. We have used exposure to hyperosmolarity to investigate the effects of stress on the ability of embryos to interact with endometrial cells in an in vitro model. Culturing mouse blastocysts for 2 h in medium with osmolarity raised by 400 mosmol induced blastocoel collapse and re-expansion, but did not affect subsequent attachment to, or invasion of, the endometrial epithelial Ishikawa cell line. Inhibition of stress-responsive c-Jun N-terminal kinase (JNK) activity with SP600125 did not affect the intercellular interactions between these embryos and the epithelial cells. Four successive cycles of hyperosmotic stress at E5.5 had no effect on attachment, but promoted embryonic breaching of the epithelial cell layer by trophoblast giant cells in a JNK-dependent manner. These findings suggest that acute stress at the blastocyst stage may promote trophoblast breaching of the endometrial epithelium at implantation and implicates stress signalling through JNK in the process of trophectoderm differentiation into the invasive trophoblast necessary for the establishment of pregnancy. The data may lead to increased understanding of factors governing ART success rates and safety