Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

Extending the scope of biocatalysis to important non-natural reactions such as olefin cyclopropanation will open new opportunities for replacing multistep chemical syntheses of pharmaceutical intermediates with efficient, clean, and highly selective enzyme-catalyzed processes. In this work, we engineered the truncated globin of Bacillus subtilis for the synthesis of a cyclopropane precursor to the antithrombotic agent ticagrelor. The engineered enzyme catalyzes the cyclopropanation of 3,4-difluorostyrene with ethyl diazoacetate on a preparative scale to give ethyl-(1R, 2R)-2-(3,4-difluorophenyl)-cyclopropanecarboxylate in 79% yield, with very high diastereoselectivity (>99% dr) and enantioselectivity (98% ee), enabling a single-step biocatalytic route to this pharmaceutical intermediate

An Integrated Biorefinery Concept for Conversion of Sugar Beet Pulp into Value-added Chemicals and Pharmaceutical Intermediates

Over 8 million tonnes of sugar beet are grown annually in the UK. Sugar beet pulp (SBP) is the main by-product of sugar beet processing which is currently dried and sold as a low value animal feed. SBP is a rich source of carbohydrates, mainly in the form of cellulose and pectin, including D-glucose (Glu), L-arabinose (Ara) and D-galacturonic acid (GalAc). This work describes the technical feasibility of an integrated biorefinery concept for fractionation of SBP and conversion of these monosaccharides into value-added products. SBP fractionation is initially carried out by steam explosion under mild conditions to yield soluble pectin and insoluble cellulose fractions. The cellulose is readily hydrolysed by cellulases to release Glu that can then be fermented by a commercial Yeast strain to produce bioethanol with a high yield. The pectin fraction can be either fully hydrolysed, using physico-chemical methods, or selectively hydrolysed, using cloned arabinases and galacturonases, to yield Ara-rich and GalAc-rich streams. These monomers can be separated using either Centrifugal Partition Chromatography (CPC) or ultrafiltration into streams suitable for subsequent enzymatic upgrading. Building on our previous experience with transketolase (TK) and transaminase (TAm) enzymes, the conversion of Ara and GalAc into higher value products was explored. In particular the conversion of Ara into L-gluco-heptulose (GluHep), that has potential therapeutic applications in hypoglycaemia and cancer, using a mutant TK is described. Preliminary studies with TAm also suggest GluHep can be selectively aminated to the corresponding chiral aminopolyol. Current work is addressing upgrading of the remaining SBP monomer, GalAc, and modelling of the biorefinery concept to enable economic and Life Cycle Analysis (LCA)

Narcissism: a factor behind the selective sharing of news online

The current study examined the extent to which narcissism influences the social network users’ intention to share positive and negative life events with (close or unknown) online contacts. Using an online survey, small vignettes and a cross-sectional convenience sample of 119 participants, the results showed that narcissism positively predicted sharing intention of positive and negative life events with strangers. However, individuals rating higher in narcissism were less likely to share negative news with family. The research findings suggest that personality traits such as narcissism, the type of contacts online, and the nature of the news may shape what information is shared by online users. The type of news presented may therefore be a function of who is posting the content, their personality, and the kind of social network contacts they have online

Influence of Cofactor Regeneration Strategies on Preparative-Scale, Asymmetric Carbonyl Reductions by Engineered Escherichia coli

This study was designed to determine whether whole cells or crude enzyme extracts are more effective for preparative-scale ketone reductions by dehydrogenases as well as learning which cofactor regeneration scheme is most effective. Based on results from three representative ketone substrates (an α-fluoro-β-keto ester, a <i>bis</i>-trifluoromethylated acetophenone, and a symmetrical β-diketone), our results demonstrate that several nicotinamide cofactor regeneration strategies can be applied to preparative-scale dehydrogenase-catalyzed reactions successfully

Weight Stigma among Young Adults in Thailand: Reliability, Validation, and Measurement Invariance of the Thai-Translated Weight Self Stigma Questionnaire and Perceived Weight Stigma Scale

The previous studies found that the Weight Self Stigma Questionnaire (WSSQ) and Perceived Weight Stigma Scale (PWSS) have shown well-established psychometric properties for measuring weight stigma with strong reliability and validity from different languages. However, there is a lack of an appropriate instrument in assessing weight stigma in Thai samples. This study aimed to examine the Thai WSSQ and PWSS among Thai university students. Both instruments were also assessed for their measurement invariance across gender and weight status subgroups. A cross-sectional study was conducted on 801 university students in Thailand between January 2022 and July 2022. All participants completed a demographic questionnaire and a Thai version of the WSSQ, PWSS, and Depression Anxiety Stress Scale-21 (DASS-21) via an online survey. Reliability, validity, measurement invariance, and correlational analyses were performed to investigate whether the Thai versions of the WSSQ and PWSS psychometric properties were acceptable. Both translated questionnaires demonstrated overall acceptable psychometric properties and revealed a two-dimensional structure for the WSSQ, and unidimensional structure for the PWSS. Measurement invariance was obtained across gender and weight status subgroups. Additionally, both translated WSSQ and PWSS were significantly correlated with DASS-21. The Thai-translated WSSQ and PWSS showed strong validity, reliability, and factorial invariance across different subgroups for measuring weight stigma among Thai university students

Synthesis, structure and activity of artificial, rationally designed catalytic polypeptides

BIOLOGICAL macromolecules with catalytic activity can be created artificially using two approaches. The first exploits a system that selects a few catalytically active biomolecules from a large pool of randomly generated (and largely inactive) molecules. Catalytic antibodies1 and many catalytic RNA molecules2 are obtained in this way. The second involves rational design of a biomolecule that folds in solution to present to the substrate an array of catalytic functional groups3–8. Here we report the synthesis of rationally designed polypeptides that catalyse the decarboxylation of oxaloacetate via an imine intermediate. We determine the secondary structures of the polypeptides by two-dimensional NMR spectroscopy. We are able to trap and identify intermediates in the catalytic cycle, and to explore the kinetics in detail. The formation of the imine by our artificial oxaloacetate decarboxylases is three to four orders of magnitude faster than can be achieved with simple amine catalysts: this performance rivals that of typical catalytic antibodies

Patient perceptions of crisis pain management in sickle cell disease: a cross-cultural study

Sickle cell disease has a variety of signs and symptoms, the most common being painful vaso-occlusive crises. Due to the severity of the pain, narcotic analgesia is described in the literature as the drug of choice for pain relief. The UK, in line with many other countries, uses narcotic analgesia in crisis management. In Jamaica, however, mild analgesia is the usual drug of choice for the patient in crisis. This difference in management approaches between the two countries was seen as an area for exploration to determine the factors which may reflect the nursing strategies used. This paper describes a cross-cultural survey of patients' perceptions of the painful crises and their management within the home and healthcare settings in Jamaica (West Indies) and Birmingham (UK). The results of the study show many areas of similarities, particularly in relation to the causes of the crises, home management and in-patient admissions. However, there were significant differences in crisis length and the in-patient management of crises. The study highlighted areas of crisis management which must be improved in the UK if patients are to receive optimum care from primary care and hospital nurses, as well as from general practitioners