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Mild cognitive impairment, dementia and osteoporosis are common diseases of ageing and, with the increasingly ageing global population, are increasing in prevalence. These conditions are closely associated, with shared risk factors, common underlying biological mechanisms and potential direct causal pathways. In this review, the epidemiological and mechanistic links between mild cognitive impairment, dementia and skeletal health are explored. Discussion will focus on how changes in brain and bone signalling can underly associations between these conditions, and will consider the molecular and cellular drivers in the context of inflammation and the gut microbiome. There is a complex interplay between nutritional changes, which may precede or follow the onset of mild cognitive impairment (MCI) or dementia, and bone health. Polypharmacy is common in patients with MCI or dementia, and there are difficult prescribing decisions to be made due to the elevated risk of falls associated with many drugs used for associated problems, which can consequently increase fracture risk. Some medications prescribed for cognitive impairment may directly impact bone health. In addition, patients may have difficulty remembering medication without assistance, meaning that osteoporosis drugs may be prescribed but not taken. Cognitive impairment may be improved or delayed by physical activity and exercise, and there is evidence for the additional benefits of physical activity on falls and fractures. Research gaps and priorities with the aim of reducing the burden of osteoporosis and fractures in people with MCI or dementia will also be discussed., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Consents and ethical approval: This narrative article contains no original data and thus issues of ethics, informed consent and patient confidentiality do not apply., (© 2024. The Author(s).)

The self-face advantage (SFA) is reflected through a faster recognition of a self-face compared with familiar and unfamiliar faces. Nevertheless, as Westerners and East Asians tend to present differences in self-concept styles, it is possible that the SFA is modulated by culture. The present study explored this possibility using a visual search task. British Caucasians and Malaysian Chinese participants were asked to search for frontal view images of self, friend, and unfamiliar faces among an array of unfamiliar faces. Regardless of race, participants were more accurate and faster in searching for the own face and friend's face compared with an unfamiliar face, with no differences in the search between the own and friend's face, and these findings could not be accounted by the cultural differences in self-concept (i.e., operationalised by scores from the Independent and Interdependent Self-Concept Scale and the Horizontal and Vertical Individualism and Collectivism Scale). Altogether our results suggest that culture does not modulate the SFA and that this effect is better explained by a familiar face advantage.

Electrical power sources used in outer planet missions are a key enabling technology for data acquisition and communications. State–of-the-art power sources generate electricity from alpha decay of 238Pu via thermoelectric conversion. However, production of 238Pu requires specialist facilities including a nuclear reactor, a source of 237Np for target irradiation and hotcells to chemically separate neptunium and plutonium within the irradiated targets. These specialist facilities are expensive to build and operate, so naturally, a more economical alternative is attractive to the industry. Within Europe 241Am is considered a promising alternative heat source for radioisotope thermoelectric generators (RTGs) and radioisotope heating units (RHUs). As a daughter product of 241Pu decay, 241Am exists in 1000 kgs quantities within the UK civil plutonium stockpile. A chemical separation process is required to extract the 241Am in a pure form and this paper describes the AMPPEX process (Americium and Plutonium Purification by Extraction), successfully developed over the past five years to isolate 241Am in high yield (> 99%) and to a high purity (> 99%). The process starts by dissolving plutonium dioxide in nitric acid with the aid of a silver(II) catalyst, which is generated electrochemically. The solution is then conditioned and fed to a PUREX type solvent extraction process, where the plutonium is separated from the americium and silver. The plutonium is converted back to plutonium dioxide and the americium is fed forward to a second solvent extraction step. Here the americium is selectively extracted leaving the silver in the aqueous phase. The americium is stripped from the solvent and recovered from solution as americium oxalate, which is calcined to give americium dioxide as the final product. This paper will describe the development of the separation process over a series of six solvent extraction separation trials using centrifugal contactors. The material produced (~ 4g 241Am) was used to make ceramic pellets to establish the behaviour of americium oxide material under high temperature (1450°C) sintering conditions. The chemical separation process is now demonstrated at concentrations expected on the full scale facility taking this process to TRL 4-5.

Matching the texture of fat in plant-based meat alternatives requires an in-depth understanding of the rheology of animal adipose tissue which, to-date, remains under-studied. Here, we characterised the small and large deformation behaviour of back fat from pork, beef, and lamb, with the underlying goal being the establishment of the temperature-dependent structure-function relationship governing the texture and rheology of adipose tissue. The dynamic rheological behaviour of the back fats was characterised via frequency and amplitude sweeps and large amplitude oscillatory strain (LAOS), as well as texture analysis via puncture tests. At 20 °C, prior to heating, the small and large deformation properties of adipose tissue were dominated by the solid fat phase within the adipose cells. Upon heating to 80 °C, with the fat phase molten, the protein network underpinning the structure of the back fats conferred elastic behaviour to the tissues, and the now-molten oil partly leaked from the adipocytes into the surrounding interstitial space. Upon re-cooling, a bicontinuous network of fat crystals and protein contributed to back fat rheology. Large deformation rheology revealed animal species-specific differences. Prior to heating, pork back fat was characterised by soft yielding behaviour while beef and lamb back fat showed abrupt yielding and intra-cycle strain stiffening. Post-heating, lamb showed the highest stiffness, compared to pork and beef, as well as non-linearities in its stress-strain relationship obtained via LAOS. Such fundamental understanding is essential to provide the required insights to replicate the functionality of adipose tissue using plant-based materials.

We investigated the temperature-dependent microstructure and thermal properties of back fat adipose tissue from pork, beef and lamb. Microstructural characterisation via electron, confocal and light microscopy showed that the back fats were structurally similar and consisted of fat dispersed as discrete units within a protein matrix akin to a closed cell foam. Differential scanning calorimetry showed distinct fat melting profiles for each of the tissues, which were ascribed to differences in fatty acid profile. Fat crystal organisation, melting and re-solidification signatures unique to each adipose tissue were found via X-ray diffraction and Raman spectroscopy. Overall, we found that the temperature-dependent microstructure of adipose fat was intricately linked to the fat phase melting behaviour, and importantly, to its protein matrix at elevated temperatures. Such understanding is necessary to provide the required insights to effectively replicate the functionality of adipose tissue using plant-based materials.

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: PRC2 is a histone methyltransferase complex associated with several cancer types. Tazemetostat was recently approved as the first inhibitor targeting the catalytic subunit EZH2 and several other EZH2 inhibitors are now under clinical evaluation. Beyond EZH2, researchers have also explored other approaches including PRC2 activators, dual agents inhibiting both EZH1 and EZH2, allosteric inhibitors binding to EED, and compounds which induce the degradation of PRC2 constituent proteins., Areas Covered: This review provides an overview of anticancer therapies targeting PRC2 during the period 2016-2020 including clinical trials, patents and the scientific literature., Expert Opinion: The approval of tazemetostat marks the clinical validation of EZH2 for the treatment of cancer. Despite this success many questions remain; for instance, tazemetostat was briefly placed on clinical hold for safety concerns, while another EZH2 inhibitor (GSK126) demonstrated insufficient efficacy during a Phase I/II trial. It is important to understand these risks as PRC2 therapies progress through clinic evaluation. Alternative approaches to target PRC2 may offer distinct advantages over the inhibition of EZH2, including the potential to overcome EZH2 resistance mutations. However, these emerging modalities may also incur new challenges as they progress toward the clinic. Nonetheless, the diversity of agents under development represents a wealth of therapeutic options for future patients.