• Chemical Vapor Deposition of Graphene on Cu-Ni Alloys: The Impact of Carbon Solubility

      Al-Hilfi; email: 100119@uotechnology.edu.iq; Kinloch; email: Ian.Kinloch@manchester.ac.uk; Derby; email: Brian.Derby@manchester.ac.uk (MDPI, 2021-07-26)
      Chemical vapour deposition (CVD) is the most promising graphene synthesis route for film and electronic applications but the growth mechanism is still not fully understood. Herein, we investigate the role of the solubility of carbon in the underlying growth substrate on the CVD growth of graphene. A range of Cu-Ni alloys compositions that cover the carbon (C) solubility range between low C solubility (pure Cu) and high C solubility (pure Ni) were used as the catalytic growth substrates. The CVD of graphene on Cu-Ni alloys showed a transition from bilayer graphene (BLG) to few-layer graphene (FLG) at a substrate Ni concentration of 45 wt.%, which was attributed to an increase in the bulk diffusion of C. The Cu-rich alloys had a high graphene coverage (BLG) at a fast-cooling rate (367 °C/min), while the Ni-rich alloys had a low coverage (FLG) under the same cooling condition. In contrast, at slow cooling rates (27 °C/min), the Cu-rich alloys had a low coverage of graphene (BLG) and the Ni-rich alloys had a high coverage of graphene (FLG). Glow discharge optical emission spectroscopy (GDOES) was used to profile the subsurface composition, particularly the C concentration, as a function of depth.
    • Psychometric Validation of the Psoriasis Symptoms and Impacts Measure (P-SIM), a Novel Patient-Reported Outcome Instrument for Patients with Plaque Psoriasis, Using Data from the BE VIVID and BE READY Phase 3 Trials.

      Warren, Richard B; email: richard.warren@manchester.ac.uk; Gottlieb, Alice B; Merola, Joseph F; Garcia, Llenalia; Cioffi, Christopher; Peterson, Luke; Pelligra, Christopher; Ciaravino, Valerie (2021-07-14)
      Plaque psoriasis can significantly impact patients' quality of life. We assessed psychometric properties of the Psoriasis Symptoms and Impacts Measure (P-SIM), developed to capture patients' experiences of signs, symptoms and impacts of psoriasis. Pooled, blinded, 16-week data from 1002 patients in the BE VIVID and BE READY bimekizumab phase 3 trials were analysed. The suitability of the P-SIM missing score rule (weekly scores considered missing if ≥ 4 daily scores were missing) was assessed. Test-retest reliability was evaluated using intraclass correlation coefficients (ICCs). Convergent validity was assessed between P-SIM and relevant patient-reported outcome (PRO) (Dermatology Life Quality Index [DLQI], DLQI item 1 [skin symptoms], Patient Global Assessment of Psoriasis) and clinician-reported outcome (ClinRO) scores (Psoriasis Area and Severity Index [PASI], Investigator's Global Assessment [IGA]) at baseline and week 16. Known-groups validity was assessed, comparing P-SIM scores between patient subgroups predefined using PASI/IGA scores. Sensitivity to change over 16 weeks was evaluated; responder definition (RD) thresholds were explored. The missing score rule used did not impact P-SIM scores. Test-retest reliability analyses demonstrated excellent score reproducibility (ICC 0.91-0.98). Inter-item correlations at baseline and week 16 were strong (> 0.5), apart from "choice of clothing" with "skin pain" and "burning" at baseline (both 0.49). All P-SIM scores were moderately to strongly correlated with other outcomes, demonstrating convergent validity, apart from ClinROs (PASI, IGA) at baseline that had low variability. P-SIM scores discriminated known groups at week 16, confirming known-groups validity. Changes from baseline to week 16 in P-SIM and other clinically relevant outcomes were strongly correlated (> 0.5; weaker with ClinROs), establishing sensitivity to change. Anchor-based RD analyses determined a four-point P-SIM item score decrease as indicative of marked clinically meaningful improvement. P-SIM scores demonstrated good reliability, validity and sensitivity to change. A four-point RD threshold could be used to assess 16-week treatment effects. BE VIVID: NCT03370133; BE READY: NCT03410992. [Abstract copyright: © 2021. The Author(s).]
    • Asthma and COPD versus phenotypic traits: Toward precision medicine in chronic airway disease.

      Vedel-Krogh, Signe; Nielsen, Sune Fallgaard; Nordestgaard, Børge Grønne; Lange, Peter; Vestbo, Jørgen; email: jorgen.vestbo@manchester.ac.uk (2021-07-07)
      Asthma and COPD diagnoses are used to classify chronic airway diseases; however, both diseases are related to phenotypic traits like allergy, obesity, cough, sputum production, low-grade inflammation, smoking, elevated blood eosinophil count, comorbidities, and occupational exposures. Whether such traits can replace asthma and COPD diagnoses when assessing risk of exacerbation is unclear. We tested the hypothesis that individuals with either asthma or COPD diagnoses have similar risk of moderate and severe exacerbations when adjusted for differences in phenotypic traits. From the Copenhagen General Population Study, a cohort study of the general population, we included 7190 individuals with chronic airway disease. Phenotypic traits were recorded at baseline and risk of exacerbations was assessed during follow-up from 2003 to 2013. The incidence rate ratio (IRR) of moderate exacerbations in individuals with clinical COPD was 1.61 (95% Confidence Interval, 1.27-2.02) compared to individuals with asthma in a model only adjusted for age, sex, and education, but after the inclusion of phenotypic traits IRR was 1.05 (0.82-1.35). Corresponding IRRs of severe exacerbations in individuals with clinical COPD versus asthma were 3.82 (2.73-5.35) and 2.28 (1.63-3.20), respectively. When taking phenotypic traits into account, individuals with asthma and COPD had comparable risk of moderate exacerbations; however, corresponding risk of severe exacerbations was higher in individuals with COPD than in those with asthma. [Abstract copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.]
    • Reduced physiologically-based pharmacokinetic model of dabigatran etexilate-dabigatran and its application for prediction of intestinal P-gp-mediated drug-drug interactions.

      Lang, Jennifer; Vincent, Ludwig; Chenel, Marylore; Ogungbenro, Kayode; Galetin, Aleksandra; email: aleksandra.galetin@manchester.ac.uk (2021-07-11)
      Dabigatran etexilate (DABE) has been suggested as a clinical probe for intestinal P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) studies and, as an alternative to digoxin. Clinical DDI data with various P-gp inhibitors demonstrated a dose-dependent inhibition of P-gp with DABE. The aims of this study were to develop a joint DABE (prodrug)-dabigatran reduced physiologically-based-pharmacokinetic (PBPK) model and to evaluate its ability to predict differences in P-gp DDI magnitude between a microdose and a therapeutic dose of DABE. A joint DABE-dabigatran PBPK model was developed with a mechanistic intestinal model accounting for the regional P-gp distribution in the gastrointestinal tract. Model input parameters were estimated using DABE and dabigatran pharmacokinetic (PK) clinical data obtained after administration of DABE alone or with a strong P-gp inhibitor, itraconazole, and over a wide range of DABE doses (from 375 µg to 400 mg). Subsequently, the model was used to predict extent of DDI with additional P-gp inhibitors and with different DABE doses. The reduced DABE-dabigatran PBPK model successfully described plasma concentrations of both prodrug and metabolite following administration of DABE at different dose levels and when co-administered with itraconazole. The model was able to capture the dose dependency in P-gp mediated DDI. Predicted magnitude of itraconazole P-gp DDI was higher at the microdose (predicted vs. observed median fold-increase in AUC /AUC (min-max) = 5.88 (4.29-7.93) vs. 6.92 (4.96-9.66) ng.h/mL) compared to the therapeutic dose (predicted median fold-increase in AUC /AUC  = 3.48 (2.37-4.84) ng.h/mL). In addition, the reduced DABE-dabigatran PBPK model predicted successfully the extent of DDI with verapamil and clarithromycin as P-gp inhibitors. Model-based simulations of dose staggering predicted the maximum inhibition of P-gp when DABE microdose was concomitantly administered with itraconazole solution; simulations also highlighted dosing intervals required to minimise the DDI risk depending on the DABE dose administered (microdose vs. therapeutic). This study provides a modelling framework for the evaluation of P-gp inhibitory potential of new molecular entities using DABE as a clinical probe. Simulations of dose staggering and regional differences in the extent of intestinal P-gp inhibition for DABE microdose and therapeutic dose provide model-based guidance for design of prospective clinical P-gp DDI studies. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Proton-coupled electron transfer reactivities of electronically divergent heme superoxide intermediates: a kinetic, thermodynamic, and theoretical study.

      Mondal, Pritam; orcid: 0000-0002-7071-1970; Ishigami, Izumi; Gérard, Emilie F; Lim, Chaeeun; Yeh, Syun-Ru; de Visser, Sam P; orcid: 0000-0002-2620-8788; Wijeratne, Gayan B; orcid: 0000-0001-7609-6406 (2021-05-27)
      Heme superoxides are one of the most versatile metallo-intermediates in biology, and they mediate a vast variety of oxidation and oxygenation reactions involving O . Overall proton-coupled electron transfer (PCET) processes they facilitate may proceed several different mechanistic pathways, attributes of which are not yet fully understood. Herein we present a detailed investigation into concerted PCET events of a series of geometrically similar, but electronically disparate synthetic heme superoxide mimics, where unprecedented, PCET feasibility-determining electronic effects of the heme center have been identified. These electronic factors firmly modulate both thermodynamic and kinetic parameters that are central to PCET, as supported by our experimental and theoretical observations. Consistently, the most electron-deficient superoxide adduct shows the strongest driving force for PCET, whereas the most electron-rich system remains unreactive. The pivotal role of these findings in understanding significant heme systems in biology, as well as in alternative energy applications is also discussed. [Abstract copyright: This journal is © The Royal Society of Chemistry.]
    • Eradicating ethnic disadvantage in medical education and regulation.

      Esmail, Aneez; email: aneez.esmail@manchester.ac.uk; Everington, Sam (2021-07-13)
    • Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.

      Cipriani, Valentina; email: v.cipriani@qmul.ac.uk; Tierney, Anna; Griffiths, John R; Zuber, Verena; Sergouniotis, Panagiotis I; Yates, John R W; Moore, Anthony T; Bishop, Paul N; Clark, Simon J; Unwin, Richard D; email: r.unwin@manchester.ac.uk (2021-07-12)
      Age-related macular degeneration (AMD) is a leading cause of vision loss; there is strong genetic susceptibility at the complement factor H (CFH) locus. This locus encodes a series of complement regulators: factor H (FH), a splice variant factor-H-like 1 (FHL-1), and five factor-H-related proteins (FHR-1 to FHR-5), all involved in the regulation of complement factor C3b turnover. Little is known about how AMD-associated variants at this locus might influence FHL-1 and FHR protein concentrations. We have used a bespoke targeted mass-spectrometry assay to measure the circulating concentrations of all seven complement regulators and demonstrated elevated concentrations in 352 advanced AMD-affected individuals for all FHR proteins (FHR-1, p = 2.4 × 10 ; FHR-2, p = 6.0 × 10 ; FHR-3, p = 1.5 × 10 ; FHR-4, p = 1.3 × 10 ; FHR-5, p = 1.9 × 10 ) and FHL-1 (p = 4.9 × 10 ) when these individuals were compared to 252 controls, whereas no difference was seen for FH (p = 0.94). Genome-wide association analyses in controls revealed genome-wide-significant signals at the CFH locus for all five FHR proteins, and univariate Mendelian-randomization analyses strongly supported the association of FHR-1, FHR-2, FHR-4, and FHR-5 with AMD susceptibility. These findings provide a strong biochemical explanation for how genetically driven alterations in circulating FHR proteins could be major drivers of AMD and highlight the need for research into FHR protein modulation as a viable therapeutic avenue for AMD. [Abstract copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.]
    • The neural correlates of a central coherence task in young women with anorexia nervosa

      Leslie, Monica; orcid: 0000-0002-0216-7432; Halls, Daniel; Leppanen, Jenni; orcid: 0000-0003-2814-4375; Sedgewick, Felicity; Lang, Katie; Fonville, Leon; Simic, Mima; Mandy, William; Nicholls, Dasha; Williams, Steven; et al. (Wiley, 2021-07-18)
    • Canine Genetics and Epidemiology is now Canine Medicine and Genetics

      Ollier, William; email: Bill.Ollier@manchester.ac.uk; Gaschen, Frédéric; email: fgaschen@lsu.edu; Kennedy, Lorna (BioMed Central, 2020-07-27)
    • In-situ nanospectroscopic imaging of plasmon-induced two-dimensional [4+4]-cycloaddition polymerization on Au(111)

      Shao, Feng; orcid: 0000-0003-3879-5884; email: feng.shao@manchester.ac.uk; Wang, Wei; Yang, Weimin; Yang, Zhilin; Zhang, Yao; orcid: 0000-0002-6524-0289; Lan, Jinggang; email: jinggang.lan@chem.uzh.ch; Dieter Schlüter, A.; Zenobi, Renato; orcid: 0000-0001-5211-4358; email: zenobi@org.chem.ethz.ch (Nature Publishing Group UK, 2021-07-27)
      Abstract: Plasmon-induced chemical reactions (PICRs) have recently become promising approaches for highly efficient light-chemical energy conversion. However, an in-depth understanding of their mechanisms at the nanoscale still remains challenging. Here, we present an in-situ investigation by tip-enhanced Raman spectroscopy (TERS) imaging of the plasmon-induced [4+4]-cycloaddition polymerization within anthracene-based monomer monolayers physisorbed on Au(111), and complement the experimental results with density functional theory (DFT) calculations. This two-dimensional (2D) polymerization can be flexibly triggered and manipulated by the hot carriers, and be monitored simultaneously by TERS in real time and space. TERS imaging provides direct evidence for covalent bond formation with ca. 3.7 nm spatial resolution under ambient conditions. Combined with DFT calculations, the TERS results demonstrate that the lateral polymerization on Au(111) occurs by a hot electron tunneling mechanism, and crosslinks form via a self-stimulating growth mechanism. We show that TERS is promising to be plasmon-induced nanolithography for organic 2D materials.
    • “No Way Out Except From External Intervention”: First-Hand Accounts of Autistic Inertia

      Buckle, Karen Leneh; email: karenleneh.buckle@manchester.ac.uk; Leadbitter, Kathy; Poliakoff, Ellen; Gowen, Emma (Frontiers Media S.A., 2021-07-13)
      This study, called for by autistic people and led by an autistic researcher, is the first to explore ‘autistic inertia,’ a widespread and often debilitating difficulty acting on their intentions. Previous research has considered initiation only in the context of social interaction or experimental conditions. This study is unique in considering difficulty initiating tasks of any type in real life settings, and by gathering qualitative data directly from autistic people. Four face-to-face and 2 online (text) focus groups were conducted with 32 autistic adults (19 female, 8 male, and 5 other), aged 23–64 who were able to express their internal experiences in words. They articulate in detail the actions they have difficulty with, what makes it easier or harder to act, and the impact on their lives. Thematic analysis of the transcripts found four overarching themes: descriptions of inertia, scaffolding to support action, the influence of wellbeing, and the impact on day-to-day activities. Participants described difficulty starting, stopping and changing activities that was not within their conscious control. While difficulty with planning was common, a subset of participants described a profound impairment in initiating even simple actions more suggestive of a movement disorder. Prompting and compatible activity in the environment promoted action, while mental health difficulties and stress exacerbated difficulties. Inertia had pervasive effects on participants’ day-to-day activities and wellbeing. This overdue research opens the door to many areas of further investigation to better understand autistic inertia and effective support strategies.
    • Rapid compensatory evolution can rescue low fitness symbioses following partner switching.

      Sørensen, Megan E S; Wood, A Jamie; Cameron, Duncan D; Brockhurst, Michael A; email: michael.brockhurst@manchester.ac.uk (2021-07-01)
      Partner switching plays an important role in the evolution of symbiosis, enabling local adaptation and recovery from the breakdown of symbiosis. Because of intergenomic epistasis, partner-switched symbioses may possess novel combinations of phenotypes but may also exhibit low fitness due to their lack of recent coevolutionary history. Here, we examine the structure and mechanisms of intergenomic epistasis in the Paramecium-Chlorella symbiosis and test whether compensatory evolution can rescue initially low fitness partner-switched symbioses. Using partner-switch experiments coupled with metabolomics, we show evidence for intergenomic epistasis wherein low fitness is associated with elevated symbiont stress responses either in dark or high irradiance environments, potentially owing to mismatched light management traits between the host and symbiont genotypes. Experimental evolution under high light conditions revealed that an initially low fitness partner-switched non-native host-symbiont pairing rapidly adapted, gaining fitness equivalent to the native host-symbiont pairing in less than 50 host generations. Compensatory evolution took two alternative routes: either hosts evolved higher symbiont loads to mitigate for their new algal symbiont's poor performance, or the algal symbionts themselves evolved higher investment in photosynthesis and photoprotective traits to better mitigate light stress. These findings suggest that partner switching combined with rapid compensatory evolution can enable the recovery and local adaptation of symbioses in response to changing environments. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]
    • Calcium signaling in neuroglia.

      Lim, Dmitry; email: dmitry.lim@uniupo.it; Semyanov, Alexey; Genazzani, Armando; Verkhratsky, Alexei; email: alexej.verkhratsky@manchester.ac.uk (2021-04-10)
      Glial cells exploit calcium (Ca ) signals to perceive the information about the activity of the nervous tissue and the tissue environment to translate this information into an array of homeostatic, signaling and defensive reactions. Astrocytes, the best studied glial cells, use several Ca signaling generation pathways that include Ca entry through plasma membrane, release from endoplasmic reticulum (ER) and from mitochondria. Activation of metabotropic receptors on the plasma membrane of glial cells is coupled to an enzymatic cascade in which a second messenger, InsP is generated thus activating intracellular Ca release channels in the ER endomembrane. Astrocytes also possess store-operated Ca entry and express several ligand-gated Ca channels. In vivo astrocytes generate heterogeneous Ca signals, which are short and frequent in distal processes, but large and relatively rare in soma. In response to neuronal activity intracellular and inter-cellular astrocytic Ca waves can be produced. Astrocytic Ca signals are involved in secretion, they regulate ion transport across cell membranes, and are contributing to cell morphological plasticity. Therefore, astrocytic Ca signals are linked to fundamental functions of the central nervous system ranging from synaptic transmission to behavior. In oligodendrocytes, Ca signals are generated by plasmalemmal Ca influx, or by release from intracellular stores, or by combination of both. Microglial cells exploit Ca permeable ionotropic purinergic receptors and transient receptor potential channels as well as ER Ca release. In this contribution, basic morphology of glial cells, glial Ca signaling toolkit, intracellular Ca signals and Ca -regulated functions are discussed with focus on astrocytes. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]
    • Veteran help-seeking behaviour for mental health issues: a systematic review.

      Randles, Rebecca; orcid: 0000-0002-7401-5817; Finnegan, A; orcid: 0000-0002-2189-4926; email: a.finnegan@chester.ac.uk (2021-07-12)
      Serving military personnel and veterans have been identified to have a high prevalence of mental health disorders. Despite this, only a significantly small number seek mental healthcare. With the UK beginning to invest further support to the armed forces community, identification of barriers and facilitators of help-seeking behaviour is needed. Corresponding literature search was conducted in PsycINFO, PsycArticles, Medline, Web of Science and EBSCO. Articles which discussed barriers and facilitators of seeking help for mental health concerns in the veteran population were included. Those which discussed serving personnel or physical problems were not included within this review. A total of 26 papers were analysed. A number of barriers and facilitators of help-seeking for a mental health issue within the veteran population were identified. Barriers included stigma, military culture of stoicism and self-reliance, as well as deployment characteristics of combat exposure and different warzone deployments. Health service difficulties such as access and lack of understanding by civilian staff were also identified. Facilitators to help combat these barriers included a campaign to dispel the stigma, including involvement of veterans and training of military personnel, as well as more accessibility and understanding from healthcare staff. While some barriers and facilitators have been identified, much of this research has been conducted within the USA and on male veterans and lacks longitudinal evidence. Further research is needed within the context of other nations and female veterans and to further indicate the facilitators of help-seeking among veterans. [Abstract copyright: © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment

      Witkop, Michelle; Morgan, George; orcid: 0000-0003-2014-3415; email: george.morgan@hcdeconomics.com; O'Hara, Jamie; Recht, Michael; Buckner, Tyler W.; Nugent, Diane; Curtis, Randall; orcid: 0000-0002-6859-6432; O'Mahony, Brian; orcid: 0000-0001-9780-6972; Skinner, Mark W.; orcid: 0000-0002-0934-0680; Mulhern, Brendan; et al. (2021-07-26)
      Abstract: Introduction: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. Aim: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. Methods: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post‐treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. Results: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). Conclusion: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.
    • Chronic and rare disease patients' access to healthcare services during a health crisis: The example of the COVID‐19 pandemic in Turkey

      Aktas, Puren; orcid: 0000-0003-0783-8044; email: puren.aktas@postgrad.manchester.ac.uk (2021-07-26)
      Abstract: Objective: The restructuring of healthcare provision for the coronavirus disease 2019 (COVID‐19) pandemic caused disruptions in access for patients with chronic or rare diseases. This study explores the experiences of patients with chronic or rare diseases in access to healthcare services in Turkey during the COVID‐19 pandemic. Methods: Semi‐structured interviews were conducted with representatives (n = 10) of patient organisations (n = 9) based in Istanbul. Thematic analysis with an inductive approach was conducted to analyse the responses obtained through the interviews. Results: The lack of clinical information at the beginning of the pandemic caused fear among patients with chronic or rare diseases. Patients experienced obstacles in access to healthcare services because of the overcrowding of hospitals with COVID‐19 patients. Some treatment procedures were cancelled or postponed by physicians. Of these procedures, some were medically vital for those patients, leading to or exacerbating further health problems. The most positive measures that patients identified were where the Social Security Institution introduced regulations to facilitate access to prescribed medicine for chronic patients. Information exchange between the doctors and their patients was important to alleviate the uncertainty and reduce the anxiety among patients. Discussion: Access problems experienced by patients during the COVID‐19 pandemic were a complex mix of factors including shortages and physical barriers, but also perceptions of barriers. The findings of this study show that patient organisations can provide insights on disease‐specific experiences and problems that are very valuable to improve access to healthcare services to achieve the universal health coverage target. Hence, this study emphasises the inclusion of patient organisations in decision‐making processes during times of health crises. Public Contribution: Representatives of patient organisations participated in the interviews.
    • Effects of turn-structure on folding and entanglement in artificial molecular overhand knots.

      Song, Yiwei; orcid: 0000-0003-2471-6516; Schaufelberger, Fredrik; orcid: 0000-0001-5298-4310; Ashbridge, Zoe; orcid: 0000-0002-8647-712X; Pirvu, Lucian; orcid: 0000-0002-6395-0156; Vitorica-Yrezabal, Iñigo J; Leigh, David A; orcid: 0000-0002-1202-4507 (2020-12-08)
      The length and constitution of spacers linking three 2,6-pyridinedicarboxamide units in a molecular strand influence the tightness of the resulting overhand (open-trefoil) knot that the strand folds into in the presence of lanthanide(iii) ions. The use of β-hairpin forming motifs as linkers enables a metal-coordinated pseudopeptide with a knotted tertiary structure to be generated. The resulting pseudopeptide knot has one of the highest backbone-to-crossing ratios (BCR)-a measure of knot tightness (a high value corresponding to looseness)-for a synthetic molecular knot to date. Preorganization in the crossing-free turn section of the knot affects aromatic stacking interactions close to the crossing region. The metal-coordinated pseudopeptide knot is compared to overhand knots with other linkers of varying tightness and turn preorganization, and the entangled architectures characterized by NMR spectroscopy, ESI-MS, CD spectroscopy and, in one case, X-ray crystallography. The results show how it is possible to program specific conformational properties into different key regions of synthetic molecular knots, opening the way to systems where knotting can be systematically incorporated into peptide-like chains through design.
    • Can molecular flexibility control crystallization? The case of <i>para</i> substituted benzoic acids.

      Tang, Sin Kim; Davey, Roger J; orcid: 0000-0002-4690-1774; Sacchi, Pietro; orcid: 0000-0001-5066-4508; Cruz-Cabeza, Aurora J; orcid: 0000-0002-0957-4823 (2020-11-16)
      Despite the technological importance of crystallization from solutions almost nothing is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Nowhere is this more apparent than in our attempts to understand the behavior of increasingly large, flexible molecules developed as active components in the pharmaceutical arena. In our current contribution we develop a general protocol involving a combination of computation (conformation analysis, lattice energy), and experiment (measurement of nucleation rates), and show how significant advances can be made. We present the first systematic study aimed at quantifying the impact of molecular flexibility on nucleation kinetics. The nucleation rates of 4 <i>para</i> substituted benzoic acids are compared, two of which have substituents with flexible chains. In making this comparison, the importance of normalizing data to account for differing solubilities is highlighted. These data have allowed us to go beyond popular qualitative descriptors such 'crystallizability' or 'crystallization propensity' in favour of more precise nucleation rate data. Overall, this leads to definite conclusions as to the relative importance of solution chemistry, solid-state interactions and conformational flexibility in the crystallization of these molecules and confirms the key role of intermolecular stacking interactions in determining relative nucleation rates. In a more general sense, conclusions are drawn as to conditions under which conformational change may become rate determining during a crystallization process.
    • <i>CrystalGrower</i>: 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, <i>CrystalGrower</i>, 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. <i>CrystalGrower</i> 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.
    • Publisher Correction: Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study.

      Dave, Rajiv V; orcid: 0000-0001-6827-8090; email: rajiv.dave@nhs.net; Kim, Baek; Courtney, Alona; O'Connell, Rachel; Rattay, Tim; Taxiarchi, Vicky P; Kirkham, Jamie J; Camacho, Elizabeth M; Fairbrother, Patricia; Sharma, Nisha; et al. (2021-06-23)