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We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS-CoV-2 virus., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Virtual fencing (VF) technology is gaining interest due to its potential to facilitate sustainable grazing management. It allows farmers to contain grazing livestock without physical fences, thereby reducing the time and labour associated with the implementation of conventional fences. From a conservation perspective, some sensitive areas within uplands should not be grazed during certain periods of the year, and VF provides an invisible and moveable fence line that can exclude livestock from these areas. However, there are also concerns associated with its use, including animal welfare impacts, cost-effectiveness, and public perception. The extent to which VF can contribute to make livestock systems more sustainable remains to be investigated. To address this gap, this study investigates the potential of VF to promote sustainable grazing management using the Efficiency, Substitution, and Redesign framework, which has been used for the first time in this context. The framework is particularly relevant in taking an active and normative approach to identify key aspects to focus on to help achieve sustainability. We consulted stakeholders including farmers, wildlife inspectors, veterinarians, policy officers, researchers, NGOs, farm advisors or certification managers, through focus groups (N = 4) and in-depth, semi-structured interviews (N = 5). Stakeholders have highlighted the potential of VF to provide new opportunities to increase the efficiency and sustainability of livestock grazing systems, enabling their redesign, and contributing to improved environmental and animal welfare outcomes, as well as higher financial and social performance. However, there are important aspects that remain to be addressed to achieve such redesign, including issues of reliability due to poor network signal, animals' ability to learn, biosecurity and safety issues related to the absence of physical fences, farm suitability and farmers' ability to use the systems effectively. This study highlights the need to ensure that the development and uptake of VF are mutually beneficial to farmers, animals, and the wider farming industry. This includes a highlight on the importance of participative approaches to involve key stakeholders to address concerns and maximise the potential of the technology., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sodium superionic conductors (NaSICONs) with general formula NaM 2 A 3 O 12 have attracted significant attention as solid electrolytes for all solid-state batteries owing to their remarkable room temperature ionic conductivity in the order of 10 -3 S cm -1 . Their flexible structural framework, which allows the incorporation of various aliovalent cations, affects the Na + ion transport. However, establishing a straightforward correlation between Na + mobility and NaSICON composition proves challenging due to competing influences such as framework alteration and stoichiometric changes of the cation substituents and thus the mobile Na + ions. Therefore, we systematically investigate the NaSICON system across various Na 1+ x M 2 Si x P 3- x O 12 compositions. We unravel and examine independently two key aspects impacting the Na + ion transport in NaSICONs: structural factors determined by introduced M 4+ framework cations and the substitution level ( x ). By employing DFT calculations, we explore the interstitial- and interstitialcy-like migration mechanisms, revealing that these mechanisms and the associated migration energies are primarily influenced by metastable transient states traversed during the Na + ion migration. The stability of these transient states, in turn, depends on the spatial arrangement of the Na + ions, the size of the M 4+ cations defining the structural framework, and x . This study enhances our fundamental understanding of Na + ion migration within NaSICONs across a wide range of compositions. The findings offer valuable insights into the microscopic aspects of NaSICON materials and provide essential guidance for prospective studies in this field.

Animal welfare standards are used within the food industry to demonstrate efforts in reaching higher welfare on farms. To verify compliance with those standards, inspectors conduct regular on-farm animal welfare assessments. Conducting these welfare assessments can, however, be time-consuming and prone to human bias. The emergence of Digital Livestock Technologies (DLTs) offers new ways of monitoring farm animal welfare and can alleviate some of the challenges related to animal welfare assessments by collecting data automatically and more frequently. Whilst automating welfare assessments with DLTs may be promising, little attention has been paid to farmers' perceptions of the challenges that could prevent successful implementation. This study aims to address this gap by focusing on the trial of a DLT (a 3D machinelearning camera) to automate mobility and body condition scoring on 11 dairy cattle farms. Semi-structured, in-depth interviews were conducted with farmers, technology developers and a stakeholder involved in a farm assurance scheme (N14). Findings suggest that stakeholders perceived important benefits to the use of the camera in this context, from building consumer trust by increasing transparency to improved management efficiency. There was also a potential for greater consistency in data collection and thus for enhanced fairness across the UK dairy sector, particularly on the issue of lameness prevalence. However, stakeholders also raised important concerns, such as a lack of clarity around data ownership, reliability, and use, and the possibility of some farmers being penalised (e.g., if the technology failed to work). More clarity should thus be given to farmers in relation to data governance and evidence provided in terms of technical performance and accuracy. The findings of this study highlighted the need for more inclusive approaches to ensure farmers' concerns are adequately identified and addressed. These approaches can help minimise negative consequences to farmers and animal welfare, whilst maximising the potential benefits of automating welfare-related data collection., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Digital Livestock Technologies (DLTs) can assist farmer decision-making and promise benefits to animal health and welfare. However, the extent to which they can help improve animal welfare is unclear. This study explores how DLTs may impact farm management and animal welfare by promoting learning, using the concept of boundary objects. Boundary objects may be interpreted differently by different social worlds but are robust enough to share a common identity across them. They facilitate communication around a common issue, allowing stakeholders to collaborate and co-learn. The type of learning generated may impact management and welfare differently. For example, it may help improve existing strategies (single-loop learning), or initiate reflection on how these strategies were framed initially (double-loop learning). This study focuses on two case studies, during which two DLTs were developed and tested on farms. In-depth, semi-structured interviews were conducted with stakeholders involved in the case studies (n = 31), and the results of a separate survey were used to complement our findings. Findings support the important potential of DLTs to help enhance animal welfare, although the impacts vary between technologies. In both case studies, DLTs facilitated discussions between stakeholders, and whilst both promoted improved management strategies, one also promoted deeper reflection on the importance of animal emotional well-being and on providing opportunities for positive animal welfare. If DLTs are to make significant improvements to animal welfare, greater priority should be given to DLTs that promote a greater understanding of the dimensions of animal welfare and a reframing of values and beliefs with respect to the importance of animals' well-being., Competing Interests: None., (© The Author(s) 2023.)

As a prerequisite for clinical treatments it was necessary to characterize the Elekta 1.5 T MRI-linac 7 MV FFF radiation beam. Following acceptance testing, beam characterization data were acquired with Semiflex 3D (PTW 31021), microDiamond (PTW 60019), and Farmer-type (PTW 30013 and IBA FC65-G) detectors in an Elekta 3D scanning water phantom and a PTW 1D water phantom. EBT3 Gafchromic film and ion chamber measurements in a buildup cap were also used. Special consideration was given to scan offsets, detector effective points of measurement and avoiding air gaps. Machine performance has been verified and the system satisfied the relevant beam requirements of IEC60976. Beam data were acquired for field sizes between 1  ×  1 and 57  ×  22 cm 2 . New techniques were developed to measure percentage depth dose (PDD) curves including the electron return effect at beam exit, which exhibits an electron-type practical range of 1.2 ± 0.1 cm. The Lorentz force acting on the secondary charged particles creates an asymmetry in the crossline profiles with an average shift of  +0.24 cm. For a 10  ×  10 cm 2 beam, scatter from the cryostat contributes 1% of the dose at isocentre. This affects the relative output factors, scatter factors and beam profiles, both in-field and out-of-field. The average 20%-80% penumbral width measured for small fields with a microDiamond detector at 10 cm depth is 0.50 cm. MRI-linac penumbral widths are very similar to that of the Elekta Agility linac MLC, as is the near-surface dose PDD(0.2 cm)  =  57%. The entrance surface dose is  ∼36% of Dmax. Cryostat transmission is quantified for inclusion within the treatment planning system. As a result, the 1.5 T MRI-linac 7 MV FFF beam has been characterised for the first time and is suitable for clinical use. This was a key step towards the first clinical treatments with the MRI-linac, which were delivered at University Medical Center Utrecht in May 2017 (Raaymakers et al 2017 Phys. Med. Biol. 62 L41-50).

Antiprotons (p[over]) remain confined in a Penning trap, in sufficient numbers to form antihydrogen (H[over ) atoms via charge exchange, when the radial field of a quadrupole Ioffe trap is added. This first demonstration with p[over] suggests that quadrupole Ioffe traps can be superimposed upon p[over] and e(+) traps to attempt the capture of H[over] atoms as they form, contrary to conclusions of previous analyses.