• Construction of C-C bonds via photoreductive coupling of ketones and aldehydes in the metal-organic-framework MFM-300(Cr)

      Luo, Tian; Li, Lili; Chen, Yinlin; orcid: 0000-0001-7878-2063; An, Jie; email: jie_an@cau.edu.cn; Liu, Chengcheng; Yan, Zheng; Carter, Joseph H.; orcid: 0000-0001-5530-7390; Han, Xue; Sheveleva, Alena M.; Tuna, Floriana; orcid: 0000-0002-5541-1750; et al. (Nature Publishing Group UK, 2021-06-11)
      Abstract: Construction of C-C bonds via reductive coupling of aldehydes and ketones is hindered by the highly negative reduction potential of these carbonyl substrates, particularly ketones, and this renders the formation of ketyl radicals extremely endergonic. Here, we report the efficient activation of carbonyl compounds by the formation of specific host-guest interactions in a hydroxyl-decorated porous photocatalyst. MFM-300(Cr) exhibits a band gap of 1.75 eV and shows excellent catalytic activity and stability towards the photoreductive coupling of 30 different aldehydes and ketones to the corresponding 1,2-diols at room temperature. Synchrotron X-ray diffraction and electron paramagnetic resonance spectroscopy confirm the generation of ketyl radicals via confinement within MFM-300(Cr). This protocol removes simultaneously the need for a precious metal-based photocatalyst or for amine-based sacrificial agents for the photochemical synthesis.
    • Control of electron-electron interaction in graphene by proximity screening

      Kim, M.; orcid: 0000-0001-6304-6901; Xu, S. G.; orcid: 0000-0002-0589-5291; Berdyugin, A. I.; Principi, A.; Slizovskiy, S.; Xin, N.; Kumaravadivel, P.; orcid: 0000-0002-9817-1697; Kuang, W.; orcid: 0000-0003-4309-365X; Hamer, M.; Krishna Kumar, R.; et al. (Nature Publishing Group UK, 2020-05-11)
      Abstract: Electron-electron interactions play a critical role in many condensed matter phenomena, and it is tempting to find a way to control them by changing the interactions’ strength. One possible approach is to place a studied system in proximity of a metal, which induces additional screening and hence suppresses electron interactions. Here, using devices with atomically-thin gate dielectrics and atomically-flat metallic gates, we measure the electron-electron scattering length in graphene and report qualitative deviations from the standard behavior. The changes induced by screening become important only at gate dielectric thicknesses of a few nm, much smaller than a typical separation between electrons. Our theoretical analysis agrees well with the scattering rates extracted from measurements of electron viscosity in monolayer graphene and of umklapp electron-electron scattering in graphene superlattices. The results provide a guidance for future attempts to achieve proximity screening of many-body phenomena in two-dimensional systems.
    • 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. (Nature Publishing Group UK, 2021-04-12)
      A Correction to this paper has been published: https://doi.org/10.1038/s41416-021-01378-x
    • Correction: How do women experience a false-positive test result from breast screening? A systematic review and thematic synthesis of qualitative studies

      Long, Hannah; orcid: 0000-0001-7306-8987; email: hannah.long@manchester.ac.uk; Brooks, Joanna M.; Harvie, Michelle; orcid: 0000-0001-9761-3089; Maxwell, Anthony; orcid: 0000-0001-8344-4958; French, David P.; orcid: 0000-0002-7663-7804 (Nature Publishing Group UK, 2021-07-30)
    • Design and fabrication of recombinant reflectin-based multilayer reflectors: bio-design engineering and photoisomerism induced wavelength modulation

      Wolde-Michael, Emmanuel; Roberts, Aled D.; Heyes, Derren J.; Dumanli, Ahu G.; Blaker, Jonny J.; Takano, Eriko; Scrutton, Nigel S.; email: Nigel.Scrutton@manchester.ac.uk (Nature Publishing Group UK, 2021-07-16)
      Abstract: The remarkable camouflage capabilities of cephalopods have inspired many to develop dynamic optical materials which exploit certain design principles and/or material properties from cephalopod dermal cells. Here, the angle-dependent optical properties of various single-layer reflectin thin-films on Si wafers are characterized within the UV–Vis–NIR regions. Following this, initial efforts to design, fabricate, and optically characterize a bio-inspired reflectin-based multilayer reflector is described, which was found to conserve the optical properties of single layer films but exhibit reduced angle-dependent visible reflectivity. Finally, we report the integration of phytochrome visible light-induced isomerism into reflectin-based films, which was found to subtly modulate reflectin thin-film reflectivity.
    • Detection of early changes in the post-radiosurgery vestibular schwannoma microenvironment using multinuclear MRI

      Lewis, Daniel; email: daniel.lewis-3@postgrad.manchester.ac.uk; McHugh, Damien J.; Li, Ka-loh; Zhu, Xiaoping; Mcbain, Catherine; Lloyd, Simon K.; Jackson, Alan; Pathmanaban, Omar N.; King, Andrew T.; Coope, David J. (Nature Publishing Group UK, 2021-08-03)
      Abstract: Stereotactic radiosurgery (SRS) is an established, effective therapy against vestibular schwannoma (VS). The mechanisms of tumour response are, however, unknown and in this study we sought to evaluate changes in the irradiated VS tumour microenvironment through a multinuclear MRI approach. Five patients with growing sporadic VS underwent a multi-timepoint comprehensive MRI protocol, which included diffusion tensor imaging (DTI), dynamic contrast-enhanced (DCE) MRI and a spiral 23Na-MRI acquisition for total sodium concentration (TSC) quantification. Post-treatment voxelwise changes in TSC, DTI metrics and DCE-MRI derived microvascular biomarkers (Ktrans, ve and vp) were evaluated and compared against pre-treatment values. Changes in tumour TSC and microvascular parameters were observable as early as 2 weeks post-treatment, preceding changes in structural imaging. At 6 months post-treatment there were significant voxelwise increases in tumour TSC (p < 0.001) and mean diffusivity (p < 0.001, repeated-measures ANOVA) with marked decreases in tumour microvascular parameters (p < 0.001, repeated-measures ANOVA). This study presents the first in vivo evaluation of alterations in the VS tumour microenvironment following SRS, demonstrating that changes in tumour sodium homeostasis and microvascular parameters can be imaged as early as 2 weeks following treatment. Future studies should seek to investigate these clinically relevant MRI metrics as early biomarkers of SRS response.
    • Directed evolution of prenylated FMN-dependent Fdc supports efficient in vivo isobutene production

      Saaret, Annica; orcid: 0000-0001-6315-6537; Villiers, Benoît; email: benoit.villiers@global-bioenergies.com; Stricher, François; orcid: 0000-0003-0150-0878; Anissimova, Macha; orcid: 0000-0003-0552-8157; Cadillon, Mélodie; Spiess, Reynard; Hay, Sam; orcid: 0000-0003-3274-0938; Leys, David; orcid: 0000-0003-4845-8443; email: david.leys@manchester.ac.uk (Nature Publishing Group UK, 2021-09-06)
      Abstract: Isobutene is a high value gaseous alkene used as fuel additive and a chemical building block. As an alternative to fossil fuel derived isobutene, we here develop a modified mevalonate pathway for the production of isobutene from glucose in vivo. The final step in the pathway consists of the decarboxylation of 3-methylcrotonic acid, catalysed by an evolved ferulic acid decarboxylase (Fdc) enzyme. Fdc belongs to the prFMN-dependent UbiD enzyme family that catalyses reversible decarboxylation of (hetero)aromatic acids or acrylic acids with extended conjugation. Following a screen of an Fdc library for inherent 3-methylcrotonic acid decarboxylase activity, directed evolution yields variants with up to an 80-fold increase in activity. Crystal structures of the evolved variants reveal that changes in the substrate binding pocket are responsible for increased selectivity. Solution and computational studies suggest that isobutene cycloelimination is rate limiting and strictly dependent on presence of the 3-methyl group.
    • Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

      Gerrard, Dave T.; orcid: 0000-0001-6890-7213; Berry, Andrew A.; Jennings, Rachel E.; Birket, Matthew J.; orcid: 0000-0002-5985-6626; Zarrineh, Peyman; Garstang, Myles G.; Withey, Sarah L.; Short, Patrick; orcid: 0000-0002-7626-6177; Jiménez-Gancedo, Sandra; Firbas, Panos N.; et al. (Nature Publishing Group UK, 2020-08-06)
      Abstract: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.
    • Dynamical gene regulatory networks are tuned by transcriptional autoregulation with microRNA feedback

      Minchington, Thomas G.; Griffiths-Jones, Sam; email: sam.griffiths-jones@manchester.ac.uk; Papalopulu, Nancy; email: nancy.papalopulu@manchester.ac.uk (Nature Publishing Group UK, 2020-07-31)
      Abstract: Concepts from dynamical systems theory, including multi-stability, oscillations, robustness and stochasticity, are critical for understanding gene regulation during cell fate decisions, inflammation and stem cell heterogeneity. However, the prevalence of the structures within gene networks that drive these dynamical behaviours, such as autoregulation or feedback by microRNAs, is unknown. We integrate transcription factor binding site (TFBS) and microRNA target data to generate a gene interaction network across 28 human tissues. This network was analysed for motifs capable of driving dynamical gene expression, including oscillations. Identified autoregulatory motifs involve 56% of transcription factors (TFs) studied. TFs that autoregulate have more interactions with microRNAs than non-autoregulatory genes and 89% of autoregulatory TFs were found in dual feedback motifs with a microRNA. Both autoregulatory and dual feedback motifs were enriched in the network. TFs that autoregulate were highly conserved between tissues. Dual feedback motifs with microRNAs were also conserved between tissues, but less so, and TFs regulate different combinations of microRNAs in a tissue-dependent manner. The study of these motifs highlights ever more genes that have complex regulatory dynamics. These data provide a resource for the identification of TFs which regulate the dynamical properties of human gene expression.
    • Evidence for ligand- and solvent-induced disproportionation of uranium(IV)

      Du, Jingzhen; orcid: 0000-0003-4037-9281; Douair, Iskander; orcid: 0000-0002-7482-5510; Lu, Erli; orcid: 0000-0002-0619-5967; Seed, John A.; orcid: 0000-0002-3751-0325; Tuna, Floriana; orcid: 0000-0002-5541-1750; Wooles, Ashley J.; Maron, Laurent; orcid: 0000-0003-2653-8557; email: laurent.maron@irsamc.ups-tlse.fr; Liddle, Stephen T.; orcid: 0000-0001-9911-8778; email: steve.liddle@manchester.ac.uk (Nature Publishing Group UK, 2021-08-10)
      Abstract: Disproportionation, where a chemical element converts its oxidation state to two different ones, one higher and one lower, underpins the fundamental chemistry of metal ions. The overwhelming majority of uranium disproportionations involve uranium(III) and (V), with a singular example of uranium(IV) to uranium(V/III) disproportionation known, involving a nitride to imido/triflate transformation. Here, we report a conceptually opposite disproportionation of uranium(IV)-imido complexes to uranium(V)-nitride/uranium(III)-amide mixtures. This is facilitated by benzene, but not toluene, since benzene engages in a redox reaction with the uranium(III)-amide product to give uranium(IV)-amide and reduced arene. These disproportionations occur with potassium, rubidium, and cesium counter cations, but not lithium or sodium, reflecting the stability of the corresponding alkali metal-arene by-products. This reveals an exceptional level of ligand- and solvent-control over a key thermodynamic property of uranium, and is complementary to isolobal uranium(V)-oxo disproportionations, suggesting a potentially wider prevalence possibly with broad implications for the chemistry of uranium.
    • Exceptional uranium(VI)-nitride triple bond covalency from 15 N nuclear magnetic resonance spectroscopy and quantum chemical analysis

      Du, Jingzhen; orcid: 0000-0003-4037-9281; Seed, John A.; orcid: 0000-0002-3751-0325; Berryman, Victoria E. J.; Kaltsoyannis, Nikolas; Adams, Ralph W.; orcid: 0000-0001-8009-5334; email: ralph.adams@manchester.ac.uk; Lee, Daniel; orcid: 0000-0002-1015-0980; email: daniel.lee@manchester.ac.uk; Liddle, Stephen T.; orcid: 0000-0001-9911-8778; email: steve.liddle@manchester.ac.uk (Nature Publishing Group UK, 2021-09-24)
      Abstract: Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies.
    • Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder

      Hindi, Emad A.; Williams, Craig J.; Zeef, Leo A. H.; Lopes, Filipa M.; Newman, Katie; Davey, Martha M. M.; Hodson, Nigel W.; Hilton, Emma N.; Huang, Jennifer L.; Price, Karen L.; et al. (Nature Publishing Group UK, 2021-07-30)
      Abstract: Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy.
    • Experimental long-term diabetes mellitus alters the transcriptome and biomechanical properties of the rat urinary bladder

      Hindi, Emad A.; Williams, Craig J.; Zeef, Leo A. H.; Lopes, Filipa M.; Newman, Katie; Davey, Martha M. M.; Hodson, Nigel W.; Hilton, Emma N.; Huang, Jennifer L.; Price, Karen L.; et al. (Nature Publishing Group UK, 2021-07-30)
      Abstract: Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy.
    • FAK inhibition alone or in combination with adjuvant therapies reduces cancer stem cell activity

      Timbrell, Simon; Aglan, Hosam; Cramer, Angela; Foden, Phil; Weaver, David; Pachter, Jonathan; Kilgallon, Aoife; Clarke, Robert B.; Farnie, Gillian; email: gillian.farnie@ndorms.ox.ac.uk; Bundred, Nigel J.; orcid: 0000-0001-6007-056X; email: Bundredn@manchester.ac.uk (Nature Publishing Group UK, 2021-05-28)
      Abstract: Cancer stem-like cells (CSC) contribute to therapy resistance and recurrence. Focal adhesion kinase (FAK) has a role in CSC regulation. We determined the effect of FAK inhibition on breast CSC activity alone and in combination with adjuvant therapies. FAK inhibition reduced CSC activity and self-renewal across all molecular subtypes in primary human breast cancer samples. Combined FAK and paclitaxel reduced self-renewal in triple negative cell lines. An invasive breast cancer cohort confirmed high FAK expression correlated with increased risk of recurrence and reduced survival. Co-expression of FAK and CSC markers was associated with the poorest prognosis, identifying a high-risk patient population. Combined FAK and paclitaxel treatment reduced tumour size, Ki67, ex-vivo mammospheres and ALDH+ expression in two triple negative patient derived Xenograft (PDX) models. Combined treatment reduced tumour initiation in a limiting dilution re-implantation PDX model. Combined FAK inhibition with adjuvant therapy has the potential to improve breast cancer survival.
    • First-passage times and normal tissue complication probabilities in the limit of large populations

      Hufton, Peter G.; Buckingham-Jeffery, Elizabeth; email: e.buckingham-jeffery@manchester.ac.uk; Galla, Tobias (Nature Publishing Group UK, 2020-05-29)
      Abstract: The time of a stochastic process first passing through a boundary is important to many diverse applications. However, we can rarely compute the analytical distribution of these first-passage times. We develop an approximation to the first and second moments of a general first-passage time problem in the limit of large, but finite, populations using Kramers–Moyal expansion techniques. We demonstrate these results by application to a stochastic birth-death model for a population of cells in order to develop several approximations to the normal tissue complication probability (NTCP): a problem arising in the radiation treatment of cancers. We specifically allow for interaction between cells, via a nonlinear logistic growth model, and our approximations capture the effects of intrinsic noise on NTCP. We consider examples of NTCP in both a simple model of normal cells and in a model of normal and damaged cells. Our analytical approximation of NTCP could help optimise radiotherapy planning, for example by estimating the probability of complication-free tumour under different treatment protocols.
    • Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications

      Whitmore, L.; Mackay, R. I.; van Herk, M.; Jones, J. K.; Jones, R. M.; email: Roger.Jones@manchester.ac.uk (Nature Publishing Group UK, 2021-07-07)
      Abstract: This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.
    • Gene expression signatures predict response to therapy with growth hormone

      Stevens, Adam; orcid: 0000-0002-1950-7325; Murray, Philip; De Leonibus, Chiara; Garner, Terence; Koledova, Ekaterina; Ambler, Geoffrey; Kapelari, Klaus; Binder, Gerhard; Maghnie, Mohamad; Zucchini, Stefano; et al. (Nature Publishing Group UK, 2021-05-27)
      Abstract: Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.
    • Giant magneto-birefringence effect and tuneable colouration of 2D crystal suspensions

      Ding, Baofu; orcid: 0000-0001-6646-7285; Kuang, Wenjun; orcid: 0000-0003-4309-365X; Pan, Yikun; Grigorieva, I. V.; orcid: 0000-0001-5991-7778; Geim, A. K.; orcid: 0000-0003-2861-8331; email: geim@manchester.ac.uk; Liu, Bilu; orcid: 0000-0002-7274-5752; email: bilu.liu@sz.tsinghua.edu.cn; Cheng, Hui-Ming; orcid: 0000-0002-5387-4241; email: hmcheng@sz.tsinghua.edu.cn (Nature Publishing Group UK, 2020-07-24)
      Abstract: One of the long-sought-after goals in light manipulation is tuning of transmitted interference colours. Previous approaches toward this goal include material chirality, strain and electric-field controls. Alternatively, colour control by magnetic field offers contactless, non-invasive and energy-free advantages but has remained elusive due to feeble magneto-birefringence in conventional transparent media. Here we demonstrate an anomalously large magneto-birefringence effect in transparent suspensions of magnetic two-dimensional crystals, which arises from a combination of a large Cotton-Mouton coefficient and relatively high magnetic saturation birefringence. The effect is orders of magnitude stronger than those previously demonstrated for transparent materials. The transmitted colours of the suspension can be continuously tuned over two-wavelength cycles by moderate magnetic fields below 0.8 T. The work opens a new avenue to tune transmitted colours, and can be further extended to other systems with artificially engineered magnetic birefringence.
    • Graphene oxide integrated silicon photonics for detection of vapour phase volatile organic compounds

      Leo Tsui, H. C.; Alsalman, Osamah; Mao, Boyang; Alodhayb, Abdullah; Albrithen, Hamad; Knights, Andrew P.; Halsall, Matthew P.; Crowe, Iain F.; email: iain.crowe@manchester.ac.uk (Nature Publishing Group UK, 2020-06-12)
      Abstract: The optical response of a graphene oxide integrated silicon micro-ring resonator (GOMRR) to a range of vapour phase Volatile Organic Compounds (VOCs) is reported. The response of the GOMRR to all but one (hexane) of the VOCs tested is significantly higher than that of the uncoated (control) silicon MRR, for the same vapour flow rate. An iterative Finite Difference Eigenmode (FDE) simulation reveals that the sensitivity of the GO integrated device (in terms of RIU/nm) is enhanced by a factor of ~2, which is coupled with a lower limit of detection. Critically, the simulations reveal that the strength of the optical response is determined by molecular specific changes in the local refractive index probed by the evanescent field of the guided optical mode in the device. Analytical modelling of the experimental data, based on Hill-Langmuir adsorption characteristics, suggests that these changes in the local refractive index are determined by the degree of molecular cooperativity, which is enhanced for molecules with a polarity that is high, relative to their kinetic diameter. We believe this reflects a molecular dependent capillary condensation within the graphene oxide interlayers, which, when combined with highly sensitive optical detection, provides a potential route for discriminating between different vapour phase VOCs.
    • Heritability of haemodynamics in the ascending aorta

      McGurk, Kathryn A.; email: K.McGurk@imperial.ac.uk; Owen, Benjamin; Watson, William D.; Nethononda, Richard M.; Cordell, Heather J.; Farrall, Martin; Rider, Oliver J.; Watkins, Hugh; Revell, Alistair; Keavney, Bernard D.; email: Bernard.Keavney@manchester.ac.uk (Nature Publishing Group UK, 2020-09-01)
      Abstract: Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a ‘peak mean’ value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability (hPed2=41%[P=0.001], hSNP2=39%[P=0.002]), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12–13%; P>0.05). Heritability estimates of the geometric quantities alone; e.g. aortic diameter (hPed2=29%[P=0.009], hSNP2=30%[P=0.010]), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.