• .

      Vasilogianni, Areti-Maria; orcid: 0000-0001-6665-6115; Achour, Brahim; orcid: 0000-0002-2595-5626; Scotcher, Daniel; orcid: 0000-0001-9144-3824; Peters, Sheila Annie; Al-Majdoub, Zubida M; orcid: 0000-0002-1497-3140; Barber, Jill; orcid: 0000-0002-5424-0291; Rostami-Hodjegan, Amin; orcid: 0000-0003-3917-844X; email: amin.rostami@manchester.ac.uk (2021-05-12)
      linked with physiologically based pharmacokinetic (PBPK) modelling is used to predict the fates of drugs in patients. Ideally, the IVIVE-PBPK models should incorporate "systems" information accounting for characteristics of the specific target population. There is a paucity of such scaling factors in cancer, particularly microsomal protein per gram of liver (MPPGL) and cytosolic protein per gram of liver (CPPGL). In this study, cancerous and histologically normal liver tissue from 16 patients with colorectal liver metastasis (CRLM) were fractionated to microsomes and cytosol. Protein content was measured in homogenates, microsomes and cytosol. The loss of microsomal protein during fractionation was accounted for using corrections based on NADPH cytochrome P450 reductase activity in different matrices. MPPGL was significantly lower in cancerous tissue (24.8 {plus minus} 9.8 mg/g) than histologically normal tissue (39.0 {plus minus} 13.8 mg/g). CPPGL in cancerous tissue was 42.1 {plus minus} 12.9 mg/g compared with 56.2 {plus minus} 16.9 mg/g in normal tissue. No correlations between demographics (sex, age and BMI) and MPPGL or CPPGL were apparent in the data. The generated scaling factors together with assumptions regarding the relative volumes of cancerous versus non-cancerous tissue were used to simulate plasma exposure of drugs with different extraction ratios. The PBPK simulations revealed a substantial difference in drug exposure (AUC), up to 3.3-fold, when using typical scaling factors (healthy population) instead of disease-related parameters in cancer population. These indicate the importance of using population-specific scalars in IVIVE-PBPK for different disease states. Accuracy in predicting the fate of drugs from in vitro data using IVIVE-PBPK depends on using correct scaling factors. The values for two of such scalars, namely microsomal and cytosolic protein per gram of liver, is not known in cancer patients. This study presents, for the first time, scaling factors from cancerous and matched histologically normal livers. PBPK simulations of various metabolically cleared drugs demonstrate the necessity of population-specific scaling for model-informed precision dosing in oncology. [Abstract copyright: Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics.]
    • .

      El-Khateeb, Eman; orcid: 0000-0002-8365-6528; email: eman.elkhateeb@manchester.ac.uk; Al-Majdoub, Zubida M; orcid: 0000-0002-1497-3140; Rostami-Hodjegan, Amin; orcid: 0000-0003-3917-844X; Barber, Jill; orcid: 0000-0002-5424-0291; Achour, Brahim; orcid: 0000-0002-2595-5626 (2021-05-27)
      Model-based assessment of the effects of liver disease on drug pharmacokinetics requires quantification of changes in enzymes and transporters responsible for drug metabolism and disposition. Different proteomic methods are currently used for protein quantification in tissues and systems, each with specific procedures and requirements. The outcome of quantitative proteomic assays from four different methods (one targeted and three label-free), applied to the same sample set, were compared in this study. Three pooled cirrhotic liver microsomal samples, corresponding to cirrhosis with non-alcoholic fatty liver disease, biliary disease or cancer, and a control microsomal pool, were analyzed using QconCAT-based targeted proteomics, the total protein approach (TPA), high three (Hi3) ion intensity approach, and intensity-based absolute quantification (iBAQ), to determine the absolute and relative abundance in disease compared with control. The relative abundance data provided a 'disease perturbation factor' (DPF) for each target protein. Absolute and relative abundances generated by standard-based label-free methods (iBAQ and Hi3) showed good agreement with targeted proteomics (limited bias and scatter) but TPA (standard-free method) over-estimated absolute abundances by approximately 2 fold. DPF was consistent between different proteomic methods but varied between enzymes and transporters, indicating discordance of effects of cirrhosis on various ADME proteins. DPF ranged from no change (e.g. for UGT1A6 in NAFLD group) to less than 0.3 (e.g. CES1 in cirrhosis of biliary origin). This study demonstrated that relative changes in enzymes and transporters (DPF) are independent of the quantitative proteomic methods used. Standard-based label-free methods such as high three ion intensity (Hi3) and intensity-based absolute quantification (iBAQ) methods, were less biased and more precise than the total protein approach (TPA), when compared with targeted data. The DPF reconciled differences across proteomic methods observed with absolute levels. Using this approach, differences were revealed in the expression of enzymes/transporters in cirrhosis associated with different etiologies. [Abstract copyright: Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics.]
    • A case of chain propagation: α-aminoalkyl radicals as initiators for aryl radical chemistry.

      Constantin, Timothée; orcid: 0000-0001-5376-1557; Juliá, Fabio; orcid: 0000-0001-8903-4482; Sheikh, Nadeem S; orcid: 0000-0002-0716-7562; Leonori, Daniele; orcid: 0000-0002-7692-4504 (2020-10-20)
      The generation of aryl radicals from the corresponding halides by redox chemistry is generally considered a difficult task due to their highly negative reduction potentials. Here we demonstrate that α-aminoalkyl radicals can be used as both initiators and chain-carriers for the radical coupling of aryl halides with pyrrole derivatives, a transformation often employed to evaluate new highly reducing photocatalysts. This mode of reactivity obviates for the use of strong reducing species and was also competent in the formation of sp C-P bonds. Mechanistic studies have delineated some of the key features operating that trigger aryl radical generation and also propagate the chain process. [Abstract copyright: This journal is © The Royal Society of Chemistry.]
    • A catalysis-driven artificial molecular pump.

      Amano, Shuntaro; orcid: 0000-0001-6017-6823; Fielden, Stephen D P; orcid: 0000-0001-7883-8135; Leigh, David A; orcid: 0000-0002-1202-4507; email: david.leigh@manchester.ac.uk (2021-06-23)
      All biological pumps are autonomous catalysts; they maintain the out-of-equilibrium conditions of the cell by harnessing the energy released from their catalytic decomposition of a chemical fuel . A number of artificial molecular pumps have been reported to date , but they are all either fuelled by light or require repetitive sequential additions of reagents or varying of an electric potential during each cycle to operate . Here we describe an autonomous chemically fuelled information ratchet that in the presence of fuel continuously pumps crown ether macrocycles from bulk solution onto a molecular axle without the need for further intervention. The mechanism uses the position of a crown ether on an axle both to promote barrier attachment behind it upon threading and to suppress subsequent barrier removal until the ring has migrated to a catchment region. Tuning the dynamics of both processes enables the molecular machine to pump macrocycles continuously from their lowest energy state in bulk solution to a higher energy state on the axle. The ratchet action is experimentally demonstrated by the progressive pumping of up to three macrocycles onto the axle from bulk solution under conditions where barrier formation and removal occur continuously. The out-of-equilibrium [n]rotaxanes (characterized with n up to 4) are maintained for as long as unreacted fuel is present, after which the rings slowly de-thread. The use of catalysis to drive artificial molecular pumps opens up new opportunities, insights and research directions at the interface of catalysis and molecular machinery.
    • A Crystalline Tri-thorium Cluster with σ-Aromatic Metal-Metal Bonding.

      Boronski, Josef T; orcid: 0000-0002-1435-6337; Seed, John A; orcid: 0000-0002-3751-0325; Hunger, David; orcid: 0000-0001-8653-9581; Woodward, Adam W; van Slageren, Joris; orcid: 0000-0002-0855-8960; Wooles, Ashley J; Natrajan, Louise S; orcid: 0000-0002-9451-3557; Kaltsoyannis, Nikolas; email: nikolas.kaltsoyannis@manchester.ac.uk; Liddle, Stephen T; orcid: 0000-0001-9911-8778; email: steve.liddle@manchester.ac.uk (2021-08-23)
      Metal-metal bonding is a widely studied area of chemistry , and has become a mature field spanning numerous d transition metal and main group complexes . In contrast, actinide-actinide bonding is predicted to be weak , being currently restricted to spectroscopically-detected gas-phase U and Th , U H and U H in frozen matrices at 6-7 Kelvin (K) , or fullerene-encapsulated U . Conversely, attempts to prepare thorium-thorium bonds in frozen matrices produced only ThH (n = 1-4) . Thus, there are no isolable actinide-actinide bonds under normal conditions. Computational investigations have explored the likely nature of actinide-actinide bonding , concentrating on localised σ-, π-, and δ-bonding models paralleling d transition metal analogues, but predictions in relativistic regimes are challenging and have remained experimentally unverified. Here, we report thorium-thorium bonding in a crystalline cluster, prepared and isolated under normal experimental conditions. The cluster exhibits a diamagnetic, closed-shell singlet ground-state with a valence-delocalised three-centre-two-electron σ-aromatic bond that is counter to the focus of previous theoretical predictions. The experimental discovery of actinide σ-aromatic bonding adds to main group and d transition metal analogues, extending delocalised σ-aromatic bonding to the heaviest elements in the periodic table and to principal quantum number six, and constitutes a new approach to elaborating actinide-actinide bonding. [Abstract copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.]
    • A focus group study of older Chinese people with CVD patients in the North West of the UK.

      Speed, Shaun; Sun, Zeyuan; Liu, Zhenmi (2021-06-03)
      Cardiovascular disease (CVD) is the leading cause of death for Chinese migrants around the world. Chinese CVD patients rely heavily on their native Chinese language, cultural values and beliefs, which adds challenges for the healthcare providers to offer primary healthcare services with standard protocol. The inappropriate treatment could lead to life loss, mistrust in doctor-patient relationship and heavy burden for healthcare funding. 28 participants were included for focus group study with the grounded theory methodology. There is considerable misunderstanding among the Chinese community about the role of primary care doctors in the treatment of cardiovascular disease resulting in the variable use of primary care services. Chinese CVD patients or identified risk factors for CVD arguably need closer management, culturally sensitive advice, support and robust follow-up compared to the general population. Doctors and nurses should enhance their practice and give them confidence in their interaction with Chinese patients on the basis of how they think and behave in relation to help seeking.
    • A fully automatic system to assess foot collapse on lateral weight-bearing foot radiographs: A pilot study.

      Lauder, J; Harris, J; Layton, B; Heire, P; Sorani, A; DeSancha, M; Davison, A K; Sammut-Powell, C; Lindner, C; email: claudia.lindner@manchester.ac.uk (2021-10-30)
      Foot collapse is primarily diagnosed and monitored using lateral weight-bearing foot x-ray images. There are several well-validated measurements which aid assessment. However, these are subject to inter- and intra-user variability. To develop and validate a software system for the fully automatic assessment of radiographic changes associated with foot collapse; automatically generating measurements for calcaneal tilt, cuboid height and Meary's angle. This retrospective study was approved by the Health Research Authority (IRAS 244852). The system was developed using lateral weight-bearing foot x-ray images, and evaluated against manual measurements from five clinical experts. The system has two main components: (i) a Random Forest-based point-finder to outline the bones of interest; and (ii) a geometry-calculator to generate the measurements based on the point positions from the point-finder. The performance of the point-finder was assessed using the point-to-point error (i.e. the mean absolute distance between each found point and the equivalent ground truth point, averaged over all points per image). For assessing the performance of the geometry-calculator, linear mixed models were fitted to estimate clinical inter-observer agreement and to compare the performance of the software system to that of the clinical experts. A total of 200 images were collected from 79 subjects (mean age: 56.4 years ±12.9 SD, 30/49 females/males). There was good agreement among all clinical experts with intraclass correlation estimates between 0.78 and 0.86. The point-finder achieved a median point-to-point error of 2.2 mm. There was no significant difference between the clinical and automatically generated measurements using the point-finder points, suggesting that the fully automatically obtained measurements are in agreement with the manually obtained measurements. The proposed system can be used to support and automate radiographic image assessment for diagnosing and managing foot collapse, saving clinician time, and improving patient outcomes. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • : a generic computer program for Monte Carlo modelling of crystal growth.

      Hill, Adam R; orcid: 0000-0002-1877-2231; Cubillas, Pablo; Gebbie-Rayet, James T; Trueman, Mollie; de Bruyn, Nathan; Harthi, Zulaikha Al; orcid: 0000-0002-1962-7490; Pooley, Rachel J S; Attfield, Martin P; orcid: 0000-0001-6508-1751; Blatov, Vladislav A; orcid: 0000-0002-4048-7218; Proserpio, Davide M; orcid: 0000-0001-6597-9406; et al. (2020-11-18)
      A Monte Carlo crystal growth simulation tool, , is described which is able to simultaneously model both the crystal habit and nanoscopic surface topography of any crystal structure under conditions of variable supersaturation or at equilibrium. This tool has been developed in order to permit the rapid simulation of crystal surface maps generated by scanning probe microscopies in combination with overall crystal habit. As the simulation is based upon a coarse graining at the nanoscopic level features such as crystal rounding at low supersaturation or undersaturation conditions are also faithfully reproduced. permits the incorporation of screw dislocations with arbitrary Burgers vectors and also the investigation of internal point defects in crystals. The effect of growth modifiers can be addressed by selective poisoning of specific growth sites. The tool is designed for those interested in understanding and controlling the outcome of crystal growth through a deeper comprehension of the key controlling experimental parameters. [Abstract copyright: This journal is © The Royal Society of Chemistry.]
    • A higher river sinuosity increased riparian soil structural stability on the downstream of a dammed river.

      Ran, Yiguo; email: ranyiguo@cigit.ac.cn; Liu, Yan; email: yan.liu-23@postgrad.manchester.ac.uk; Wu, Shengjun; email: wsj@cigit.ac.cn; Li, Wenjuan; email: liwenjuan@cigit.ac.cn; Zhu, Kai; email: zhukai@cigit.ac.cn; Ji, Yongyue; Mir, Yaseen; email: yaseenghp@mails.ucas.ac.cn; Ma, Maohua; email: mamaohua@cigit.ac.cn; Huang, Ping; email: huangping@cigit.ac.cn (2021-08-25)
      Hydropower dam constructions and operations have dramatically changed the original hydrological regime of natural rivers. Because of significantly slashed and suspended sediments blocked by damming, discharged "clear" water was found to play a strong undercutting effect on the riverbank and to exacerbate riparian soil erosion on the downstream near dams. Yet, it is still an unsettled issue whether the instability of riparian soil structure would be simply correlated negatively with the distance to a dam. In this study, soils along the downstream riparian zone of a huge dam on the River Yangtze, China, were sampled to examine the distance effect on the riparian soil structural stability. Water-stable aggregates were fractionated by the wet-sieving method. Mean weight diameter (MWD) and geometric mean diameter (GMD) were used to indicate riparian soil stability. Further, the fractal dimension (D) and soil erodibility parameter (K) were used to represent the likelihood of riparian erosion. Our results revealed that riparian soil structural stability demonstrated a high spatial heterogeneity along the River Yangtze, and was less affected by the spatial distance to the dam. Rather, the soil stability was primarily influenced by a river shape index (sinuosity) and local edaphic properties. The river sinuosity index demonstrated a positive relationship with soil structural stability. Additionally, soil organic matter was found as a major edaphic factor in stabilizing soil structure. The results indicated that river sinuosity plays a crucial role in stabilizing soil by accumulating soil organic matters. Our findings implied that the potential negative impact of damming effect on soil stability may be attenuated by maintaining a higher sinuosity of the river. Against the risk of riparian soil erosion along the dammed river, the configuration of river morphology shall be considered as one of the potential managements in offsetting the negative impacts of damming. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • A leftward bias for the arrangement of consumer items that differ in attractiveness

      Rodway, Paul; orcid: 0000-0002-7667-6782; Schepman, Astrid; orcid: 0000-0002-7407-362X (Informa UK Limited, 2020-06-24)
    • "A little bit more looking…listening and feeling" A qualitative interview study exploring advanced clinical practice in primary care and community pharmacy.

      Seston, Elizabeth Mary; orcid: 0000-0002-6672-8622; email: liz.seston@manchester.ac.uk; Schafheutle, Ellen Ingrid; Willis, Sarah Caroline (2021-11-22)
      Background Growing demands on healthcare globally, combined with workforce shortages, have led to greater skill mix in healthcare settings. Pharmacists are increasingly moving into complex areas of practice, a move supported by policy and education/training changes. Aim To understand the nature of extended roles for pharmacists practising at an advanced level in primary care and community pharmacy settings, to explore how clinical and physical examination was incorporated into practice and to understand the impact of providing such examination on practice and on patient relationships. Method Telephone interviews (N = 15) were conducted with a purposive sample of pharmacists using clinical and physical examination in their practice in Great Britain. The sample included primary care pharmacists (N = 5), community pharmacists (N = 4), pharmacists working across settings (N = 5) and one working in another primary care setting. Participants were recruited through professional networks, social media and snowballing. Results Primary care pharmacists and community pharmacists were utilising clinical and physical examination skills in their practice. Some community pharmacists were operating locally-commissioned services for low acuity conditions. Incorporating such examinations into practice enabled pharmacists to look at the patient holistically and enhanced pharmacist/patient relationships. Barriers to practise included lack of timely sharing of patient data and perceived reluctance on the part of some pharmacists for advanced practice. Conclusion With growing opportunities to provide patient-focussed care, it remains to be seen whether pharmacists, both in Great Britain and elsewhere, are able to overcome some of the organisational, structural and cultural barriers to advanced practice that currently exist in community pharmacy. [Abstract copyright: © 2021. The Author(s).]
    • A mathematical model which examines age-related stochastic fluctuations in DNA maintenance methylation.

      Zagkos, Loukas; email: l.zagkos@imperial.ac.uk; Roberts, Jason; Auley, Mark Mc (2021-11-11)
      Due to its complexity and its ubiquitous nature the ageing process remains an enduring biological puzzle. Many molecular mechanisms and biochemical process have become synonymous with ageing. However, recent findings have pinpointed epigenetics as having a key role in ageing and healthspan. In particular age related changes to DNA methylation offer the possibility of monitoring the trajectory of biological ageing and could even be used to predict the onset of diseases such as cancer, Alzheimer's disease and cardiovascular disease. At the molecular level emerging evidence strongly suggests the regulatory processes which govern DNA methylation are subject to intracellular stochasticity. It is challenging to fully understand the impact of stochasticity on DNA methylation levels at the molecular level experimentally. An ideal solution is to use mathematical models to capture the essence of the stochasticity and its outcomes. In this paper we present a novel stochastic model which accounts for specific methylation levels within a gene promoter. Uncertainty of the eventual site-specific methylation levels for different values of methylation age, depending on the initial methylation levels were analysed. Our model predicts the observed bistable levels in CpG islands. In addition, simulations with various levels of noise indicate that uncertainty predominantly spreads through the hypermethylated region of stability, especially for large values of input noise. A key outcome of the model is that CpG islands with high to intermediate methylation levels tend to be more susceptible to dramatic DNA methylation changes due to increasing methylation age. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]
    • A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

      Below, Christopher R; orcid: 0000-0003-1545-6281; Kelly, Joanna; Brown, Alexander; Humphries, Jonathan D; orcid: 0000-0002-8953-7079; Hutton, Colin; Xu, Jingshu; Lee, Brian Y; Cintas, Celia; orcid: 0000-0001-8730-9171; Zhang, Xiaohong; Hernandez-Gordillo, Victor; et al. (2021-09-13)
      Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α /α signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro. [Abstract copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.]
    • A microstructural model of tendon failure.

      Gregory, James; email: james.gregory@manchester.ac.uk; Hazel, Andrew L; Shearer, Tom (2021-06-30)
      Collagen fibrils are the most important structural component of tendons. Their crimped structure and parallel arrangement within the tendon lead to a distinctive non-linear stress-strain curve when a tendon is stretched. Microstructural models can be used to relate microscale collagen fibril mechanics to macroscale tendon mechanics, allowing us to identify the mechanisms behind each feature present in the stress-strain curve. Most models in the literature focus on the elastic behaviour of the tendon, and there are few which model beyond the elastic limit without introducing phenomenological parameters. We develop a model, built upon a collagen recruitment approach, that only contains microstructural parameters. We split the stress in the fibrils into elastic and plastic parts, and assume that the fibril yield stretch and rupture stretch are each described by a distribution function, rather than being single-valued. By changing the shapes of the distributions and their regions of overlap, we can produce macroscale tendon stress-strain curves that generate the full range of features observed experimentally, including those that could not be explained using existing models. These features include second linear regions occurring after the tendon has yielded, and step-like failure behaviour present after the stress has peaked. When we compare with an existing model, we find that our model reduces the average root mean squared error from 4.53MPa to 2.29MPa, and the resulting parameter values are closer to those found experimentally. Since our model contains only parameters that have a direct physical interpretation, it can be used to predict how processes such as ageing, disease, and injury affect the mechanical behaviour of tendons, provided we can quantify the effects of these processes on the microstructure. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.]
    • A mother’s hope in the midst of existential immobility from state and stigma

      Smith, Katherine; email: katherine.smith-3@manchester.ac.uk (Berghahn Books, 2021-06-01)
      The article is situated ethnographically in households on the main social housing estate in Harpurhey, North Manchester, England. It explores the affective dynamics of motherhood and imaginations of the future with a backdrop of prolonged government disinvestment. We follow the experiences of a mother and her son as they deal with moments of uncertainty and attempt to imagine and prepare for his future free from dependence on state welfare. Considering that parenting marks time in the most intimate of ways and it confronts parents with the passing of time in terms of biological “growth” that sequences time for us, this article addresses how and at what points dependence on the state, over time, reconfigures the affective dynamics of motherhood and imaginations of familial dependencies into the future.
    • A promiscuous glycosyltransferase generates poly-β-1,4-glucan derivatives that facilitate mass spectrometry-based detection of cellulolytic enzymes.

      Bulmer, Gregory S; orcid: 0000-0003-4794-2858; Mattey, Ashley P; orcid: 0000-0002-6564-7150; Parmeggiani, Fabio; Williams, Ryan; Ledru, Helene; Marchesi, Andrea; orcid: 0000-0002-1560-5921; Seibt, Lisa S; orcid: 0000-0002-8230-5371; Both, Peter; Huang, Kun; Galan, M Carmen; orcid: 0000-0001-7307-2871; et al. (2021-06-08)
      Promiscuous activity of a glycosyltransferase was exploited to polymerise glucose from UDP-glucose via the generation of β-1,4-glycosidic linkages. The biocatalyst was incorporated into biocatalytic cascades and chemo-enzymatic strategies to synthesise cello-oligosaccharides with tailored functionalities on a scale suitable for employment in mass spectrometry-based assays. The resulting glycan structures enabled reporting of the activity and selectivity of celluloltic enzymes.
    • A radical approach for the selective C-H borylation of azines.

      Kim, Ji Hye; Constantin, T; orcid: 0000-0001-5376-1557; Simonetti, M; Llaveria, J; orcid: 0000-0003-2260-3657; Sheikh, N S; Leonori, D; orcid: 0000-0002-7692-4504; email: daniele.leonori@manchester.ac.uk (2021-05-20)
      Boron functional groups are often introduced in place of aromatic carbon-hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments . Current approaches based on transition metal-catalysed C-H activation are effective for the borylation of many (hetero)aromatic derivatives but show narrow applicability to azines, N-containing aromatic heterocycles and key components of many pharmaceutical and agrochemical products. Here, we report an azine borylation strategy using stable and inexpensive amine-borane reagents. Photocatalysis converts these low molecular weight materials into highly reactive boryl radicals that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp carbon-boron bond assembly where the elementary steps of transition-metal mediated C-H activation and reductive elimination from azine-organometallic intermediates are replaced with a direct, Minisci -style, radical addition. The strong nucleophilic character of the amine-boryl radicals is the key feature enabling predictable and site-selective carbon-boron bond formation by targeting the azine's most activated position, including the challenging sites adjacent to the basic N-atom. This approach enables access to aromatic sites currently elusive to C-H activation strategies and has led to borylated materials that would otherwise be difficult to prepare. The process has been applied to the introduction of amine-borane functionalities onto complex and industrially-relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.
    • A re-examination of the origins of placental bed giant cells.

      Jones, Carolyn J P; email: carolyn.jones@manchester.ac.uk; Aplin, John D (2021-08-19)
      In view of controversy about the source of placental multinuclear giant cells, we have re-examined the literature which clearly shows they are derived from trophoblastic elements that have populated the decidua. Archival material for electron microscopy from 17 to 18 week placentae demonstrates they can be found connected via desmosomes to the outer extravillous cytotrophoblast cells of anchoring columns, thus identifying a primary source. We suggest their formation is a terminal differentiation step occurring at all stages of invasion from the cell column to the myometrium, progressively reducing the invasive population. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • A study of a nonlocal problem with Robin boundary conditions arising from technology

      Drosinou, Ourania; Kavallaris, Nikos I.; orcid: 0000-0002-9743-8636; Nikolopoulos, Christos V. (Wiley, 2021-05-04)