Recent Submissions

  • Ultrasound-triggered therapeutic microbubbles enhance the efficacy of cytotoxic drugs by increasing circulation and tumour drug accumulation and limiting bioavailability and toxicity in normal tissues

    Ingram, N.; McVeigh, L.E.; Abou-Saleh, R.H.; Maynard, J.; Peyman, S.A.; McLaughlan, J.R.; Fairclough, M.; Marston, G.; Valleley, E.M.A.; Jimenez-Macias, J.L.; et al. (2020)
    Most cancer patients receive chemotherapy at some stage of their treatment which makes improving the efficacy of cytotoxic drugs an ongoing and important goal. Despite large numbers of potent anti-cancer agents being developed, a major obstacle to clinical translation remains the inability to deliver therapeutic doses to a tumor without causing intolerable side effects. To address this problem, there has been intense interest in nanoformulations and targeted delivery to improve cancer outcomes. The aim of this work was to demonstrate how vascular endothelial growth factor receptor 2 (VEGFR2)-targeted, ultrasound-triggered delivery with therapeutic microbubbles (thMBs) could improve the therapeutic range of cytotoxic drugs. Methods: Using a microfluidic microbubble production platform, we generated thMBs comprising VEGFR2-targeted microbubbles with attached liposomal payloads for localised ultrasound-triggered delivery of irinotecan and SN38 in mouse models of colorectal cancer. Intravenous injection into tumor-bearing mice was used to examine targeting efficiency and tumor pharmacodynamics. High-frequency ultrasound and bioluminescent imaging were used to visualise microbubbles in real-time. Tandem mass spectrometry (LC-MS/MS) was used to quantitate intratumoral drug delivery and tissue biodistribution. Finally, 89Zr PET radiotracing was used to compare biodistribution and tumor accumulation of ultrasound-triggered SN38 thMBs with VEGFR2 targeted SN38 liposomes alone. Results: ThMBs specifically bound VEGFR2 in vitro and significantly improved tumor responses to low dose irinotecan and SN38 in human colorectal cancer xenografts. An ultrasound trigger was essential to achieve the selective effects of thMBs as without it, thMBs failed to extend intratumoral drug delivery or demonstrate enhanced tumor responses. Sensitive LC-MS/MS quantification of drugs and their metabolites demonstrated that thMBs extended drug exposure in tumors but limited exposure in healthy tissues, not exposed to ultrasound, by persistent encapsulation of drug prior to elimination. 89Zr PET radiotracing showed that the percentage injected dose in tumors achieved with thMBs was twice that of VEGFR2-targeted SN38 liposomes alone. Conclusions: thMBs provide a generic platform for the targeted, ultrasound-triggered delivery of cytotoxic drugs by enhancing tumor responses to low dose drug delivery via combined effects on circulation, tumor drug accumulation and exposure and altered metabolism in normal tissues.
  • Dig! Arts Access Project: Finding Inspiration in the Park

    Giles, M.; Croucher, Karina T. (2019)
    Dig! Arts Access Project brought together excavation with artistic interpretations using collage, painting, drawing and poetry, to engage school learners in the legacy of the Whitworth Park Community Archaeology and History project. Through a series of workshops and site visits with local schools, participants expressed some of the ambiguities felt by urban children about parks. However, by the end of the sessions, they had increased their understanding of the history and heritage of their everyday places and were more confident about visiting parks.
  • Nucleosides Rescue Replication-Mediated Genome Instability of Human Pluripotent Stem Cells

    Ivana, Barbaric,; Peter W, Andrews,; Halliwell, J.A.; Frith, T.J.R.; Laing, O.; Price, C.J.; Bower, O.J.; Stavish, T.; Gokhale, P.J.; Hewitt, Z.; et al. (2020-06-09)
    Human pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death. However, we have found that the extent of DNA replication stress, DNA damage, and consequent aberrant mitoses can be substantially reduced by culturing PSCs in the presence of exogenous nucleosides, resulting in improved survival, clonogenicity, and population growth.
  • Resolution of coronavirus disease 2019 (COVID-19)

    Habas, Khaled S.A.; Nganwuchu, C.; Shahzad, F.; Gopalan, Rajendran C.; Haque, M.; Rahman, Sayeeda; Majumder, A.A.; Nasim, T. (2020)
    Introduction. Coronavirus disease 2019 (COVID-19) was first detected in China in December, 2019, and declared as a pandemic by the World Health Organization (WHO) on March 11, 2020. The current management of COVID-19 is based generally on supportive therapy and treatment to prevent respiratory failure. The effective option of antiviral therapy and vaccination are currently under evaluation and development. Areas covered. A literature search was performed using PubMed between December 1, 2019–June 23, 2020. This review highlights the current state of knowledge on the viral replication and pathogenicity, diagnostic and therapeutic strategies, and management of COVID-19. This review will be of interest to scientists and clinicians and make a significant contribution toward development of vaccines and targeted therapies to contain the pandemic. Expert Opinion. The exit strategy for a path back to normal life is required, which should involve a multi-prong effort toward development of new treatment and a successful vaccine to protect public health worldwide and prevent future COVID-19 outbreaks. Therefore, the bench to bedside translational research as well as reverse translational works focusing bedside to bench is very important and would provide the foundation for the development of targeted drugs and vaccines for COVID-19 infections.
  • A massive, Late Neolithic pit structure associated with Durrington Walls Henge

    Gaffney, Vincent L.; Baldwin, E.; Bates, M.; Bates, C.R.; Gaffney, Christopher F.; Hamilton, D.; Kinnaird, T.; Neubauer, W.; Yorston, R.; Allaby, R.; et al. (2020-06)
    A series of massive geophysical anomalies, located south of the Durrington Walls henge monument, were identified during fluxgate gradiometer survey undertaken by the Stonehenge Hidden Landscapes Project (SHLP). Initially interpreted as dewponds, these data have been re-evaluated, along with information on similar features revealed by archaeological contractors undertaking survey and excavation to the north of the Durrington Walls henge. Analysis of the available data identified a total of 20 comparable features, which align within a series of arcs adjacent to Durrington Walls. Further geophysical survey, supported by mechanical coring, was undertaken on several geophysical anomalies to assess their nature, and to provide dating and environmental evidence. The results of fieldwork demonstrate that some of these features, at least, were massive, circular pits with a surface diameter of 20m or more and a depth of at least 5m. Struck flint and bone were recovered from primary silts and radiocarbon dating indicates a Late Neolithic date for the lower silts of one pit. The degree of similarity across the 20 features identified suggests that they could have formed part of a circuit of large pits around Durrington Walls, and this may also have incorporated the recently discovered Larkhill causewayed enclosure. The diameter of the circuit of pits exceeds 2km and there is some evidence that an intermittent, inner post alignment may have existed within the circuit of pits. One pit may provide evidence for a recut; suggesting that some of these features could have been maintained through to the Middle Bronze Age. Together, these features represent a unique group of features related to the henge at Durrington Walls, executed at a scale not previously recorded.
  • Additive Manufacturing of a Point-of-Care “Polypill:” Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease

    Pereira, B.C.; Isreb, Abdullah; Isreb, Mohammad; Forbes, R.T.; Oga, E.F.; Alhnan, M.A. (2020-07)
    Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed “polypill” capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.
  • The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR method

    Abraham, M.H.; Abraham, R.J.; Aghamohammadi, Amin; Afarinkia, Kamyar; Liu, Xiangli (2020-10-01)
    We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations. The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
  • (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent

    Hjorth, S.; Waters, S.; Waters, N.; Tedroff, J.; Svensson, P.; Fagerberg, A.; Edling, M.; Svanberg, B.; Ljung, E.; Gunnergren, J.; et al. (2020-09)
    Here we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data, coupled to drug exposure support the hypothesis that 5‑HT7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease.
  • Multi-Proxy Characterisation of the Storegga Tsunami and Its Impact on the Early Holocene Landscapes of the Southern North Sea

    Gaffney, Vincent L.; Fitch, Simon; Bates, M.; Ware, R.L.; Kinnaird, T.; Gearey, B.; Hill, T.; Telford, Richard; Batt, Catherine M.; Stern, Ben; et al. (2020-07-15)
    Doggerland was a landmass occupying an area currently covered by the North Sea until marine inundation took place during the mid-Holocene, ultimately separating the British landmass from the rest of Europe. The Storegga Event, which triggered a tsunami reflected in sediment deposits in the northern North Sea, northeast coastlines of the British Isles and across the North Atlantic, was a major event during this transgressive phase. The spatial extent of the Storegga tsunami however remains unconfirmed as, to date, no direct evidence for the event has been recovered from the southern North Sea. We present evidence of a tsunami deposit in the southern North Sea at the head of a palaeo-river system that has been identified using seismic survey. The evidence, based on lithostratigraphy, geochemical signatures, macro and microfossils and sedimentary ancient DNA (sedaDNA), supported by optical stimulated luminescence (OSL) and radiocarbon dating, suggests that these deposits were a result of the tsunami. Seismic identification of this stratum and analysis of adjacent cores showed diminished traces of the tsunami which was largely removed by subsequent erosional processes. Our results confirm previous modelling of the impact of the tsunami within this area of the southern North Sea, and also indicate that these effects were temporary, localized, and mitigated by the dense woodland and topography of the area. We conclude that clear physical remnants of the wave in these areas are likely to be restricted to now buried, palaeo-inland basins and incised river valley systems.
  • Synthesis and Characterization of Novel Nopyl-Derived Phosphonium Ionic Liquids

    Yu, Jiangou; Wheelhouse, Richard T.; Honey, M.A.; Karodia, N. (2020-10-10)
    A series of novel nopyl-derived chiral phosphonium ionic liquids have been successfully synthesised and characterised. Analysis of each novel ionic liquid was conducted in order to confirm structure, purity and thermal stability.
  • Intriguing High Z'' Cocrystals of Emtricitabine

    Palanisamy, V.; Sanphui, P.; Bolla, G.; Narayan, Aditya; Seaton, Colin C.; Vangala, Venu R. (Crystal Growth & Design, 2020-08)
    Emtricitabine (ECB) afforded dimorphic cocrystals (Forms I, II) of benzoic acid (BA), whereas with p-hydroxybenzoic acid (PHBA), p-aminobenzoic acid (PABA) are resulted in as high Z'' cocrystals. Intriguingly, the Z'' of cocrystals are trends from two to fourteen based on the manipulation of functional groups on the para position of BA (where H atom is replaced with that of OH or NH2 group). ECB‒PABA cocrystal consists of six molecules each and two water molecules in the asymmetric unit (Z''=14) with 2D planar sheets represents the rare pharmaceutical cocrystal. The findings suggest that the increment of H bond donor(s) systematically via a suitable coformer are in correspondence with attaining high Z'' cocrystals. Further, solid state NMR spectroscopy in conjunction with single crystal X-ray diffraction are demonstrated as significant tools to enhance the understanding of the number of symmetry independent molecules in the crystalline lattice and provide insights to the mechanistic pathways of crystallization.
  • Technological, Refitting and Microwear of the Stone Artefact Assemblage

    Pope, M.; Davis, R.; Evans, Adrian A. (SpoilHeap, 2020-08)
  • Ex vivo and in vitro evaluation of the influence of the inhaler device and formulation on lung deposition of budesonide

    Aloum, Fatima; Al Ayoub, Yuosef; Mohammad, Mohammad A.; Obeed, Muthana; Paluch, Krzysztof J.; Assi, Khaled H. (2020-07-15)
    Two different types of dry powder inhalers (Easyhaler® and RS01®) were used in this work to evaluate the ex vivo and in vitro performance of a budesonide inhaled formulation with recrystallised mannitol, commercial DPI-grade mannitol, or lactose. The aerodynamic performance of the budesonide formulation with recrystallised mannitol was superior when RS01® was used (FPF = 45.8%) compared to Easyhaler® (FPF = 14%). However, the aerodynamic profile was very poor in both devices when commercial mannitol was used. Interestingly, the aerosol performance of the marketed budesonide formulation significantly improved when RS01® was used compared to Easyhaler® (the original device for the formulation). Due to the significant increases in the surface energy of the commercial mannitol formulation, the aerodynamic performance of the formulation was very poor. This work demonstrates the impact of inhaler devices on the performance of inhaled formulations and considers the particle surface energy during formulation development.
  • Ambiguity in high definition: Gaze determines physical interpretation of ambiguous rotation even in the absence of a visual context

    Souto, D.; Smith, L.; Sudkamp, J.; Bloj, Marina (2020)
    Physical interactions between objects, or between an object and the ground, are amongst the most biologically relevant for live beings. Prior knowledge of Newtonian physics may play a role in disambiguating an object’s movement as well as foveation by increasing the spatial resolution of the visual input. Observers were shown a virtual 3D scene, representing an ambiguously rotating ball translating on the ground. The ball was perceived as rotating congruently with friction, but only when gaze was located at the point of contact. Inverting or even removing the visual context had little influence on congruent judgements compared with the effect of gaze. Counterintuitively, gaze at the point of contact determines the solution of perceptual ambiguity, but independently of visual context. We suggest this constitutes a frugal strategy, by which the brain infers dynamics locally when faced with a foveated input that is ambiguous.
  • Unaltered perception of suprathreshold contrast in early glaucoma despite sensitivity loss

    Bham, H.A.; Dewsbery, S.D.; Denniss, Jonathan (2020-07)
    PURPOSE. Glaucoma raises contrast detection thresholds, but our natural visual environment is dominated by high contrast that may remain suprathreshold in early to moderate glaucoma. This study investigates the effect of glaucoma on the apparent contrast of visible stimuli. METHODS. Twenty participants with glaucoma with partial visual field defects (mean age, 72 ± 7 years) and 20 age-similar healthy controls (mean age, 70 ± 7 years) took part. Contrast detection thresholds for Gabor stimuli (SD, 0.75°) of four spatial frequencies (0.5, 1.0, 2.0, and 4.0 c/deg) were first measured at 10° eccentricity, both within and outside of visual field defects for participants with glaucoma. Subsequently, the contrast of a central Gabor was matched to that of a peripheral Gabor with contrast fixed at two times or four times the detection threshold. Data were analyzed by linear mixed modelling. RESULTS. Compared with controls, detection thresholds for participants with glaucoma were raised by 0.05 ± 0.025 (Michelson units, ± SE; P = 0.12) and by 0.141 ± 0.026 (P < 0.001) outside and within visual field defects, respectively. For reference stimuli at two times the detection contrast, matched contrast ratios (matched/reference contrast) were 0.16 ± 0.039 (P < 0.001) higher outside compared with within visual field defects in participants with glaucoma. Matched contrast ratios within visual field defects were similar to controls (mean 0.033 ± 0.066 lower; P = 0.87). For reference stimuli at four times the detection contrast, matched contrast ratios were similar across all three groups (P = 0.58). Spatial frequency had a minimal effect on matched contrast ratios. CONCLUSIONS. Despite decreased contrast sensitivity, people with glaucoma perceive the contrast of visible suprathreshold stimuli similarly to healthy controls. These results suggest possible compensation for sensitivity loss in the visual system.
  • The assessment of intramolecular hydrogen bonding in ortho-substituted anilines by an NMR method

    Abraham, M.H.; Abraham, R.J.; Aghamohammadi, Amin; Afarinkia, Kamyar; Liu, Xiangli (2020-10)
    We describe the Δlog P method for the assessment of intramolecular hydrogen bonds (IMHBs), and show that it is not a very general method of distinguishing between molecules in which there is an IMHB and molecules in which there is no IMHB. The ‘double’ Δlog P method of Shalaeva et al. is a much more reliable method for the assessment of IMHB but requires the synthesis of a model compound and the determination of no less than four water-solvent partition coefficients. In addition, it is difficult to apply to compounds that contain more than one hydrogen bond acidic group capable of IMHB. We then describe our NMR method of assessing IMHB, based on 1H NMR chemical shifts in solvents DMSO and CDCl3. We have determined 1H NMR chemical shifts for a number of ortho-substituted anilines and show that the only compound we have studied that forms an IMHB is methyl 2-methylaminobenzoate though there is no IMHB present in methyl 2-aminobenzoate. This apparently anomalous result is supported by both MM and ab initio calculations. The NMR method is much simpler and less time consuming than other methods for the assessment of IMHB. It provides a quantitative assessment of IMHB and can be applied to molecules with more than one hydrogen bond acidic group.
  • 5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells

    Poterlowicz, Krzysztof; Yarker, Joanne L.; Malashchuk, Igor; Lajoie, B.R.; Mardaryev, Andrei N.; Gdula, M.R.; Sharov, A.A.; Kohwi-Shigematsu, T.; Botchkarev, Vladimir A.; Fessing, Michael Y. (2017)
    Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription.
  • Assembling Archaeology: Teaching, practice and research

    Cobb, H.; Croucher, Karina T. (Oxford University Press, 2020-07-01)
    Assembling Archaeology provides a radical rethinking of the relationships between teaching, researching, and practicing as an archaeologist in the twenty-first century. At its heart, this book addresses the marketization of higher education, demonstrating how this fundamentally impacts contemporary archaeological practice. The book proposes a solution which is grounded in a theoretical rethinking of archaeological teaching, training, and practice. Archaeology is currently undergoing a material turn which sees the revaluing of artefacts, objects, and the non-human in understanding the world. Drawing upon this, Cobb and Croucher approach the discipline as a subject of investigation and offer a new perspective founded upon the notion of learning assemblages. The holistic approach they propose challenges traditional power structures and the global marketization of the higher education system. The issues addressed here are global and applicable wherever archaeology is taught, practiced, and researched. This book is therefore valuable to all archaeologists, from academics to those in Cultural Resource Management, from heritage professionals to undergraduate students, and provides significant insights for educators throughout higher education.
  • Association of anthropometric measures across the life-course with refractive error and ocular biometry at age 15 years

    Bruce, A.; Ghorbani Mojarrad, Neema; Santorelli, G. (2020-07-08)
    Background A recent Genome-wide association meta-analysis (GWAS) of refractive error reported shared genetics with anthropometric traits such as height, BMI and obesity. To explore a potential relationship with refractive error and ocular structure we performed a life-course analysis including both maternal and child characteristics using data from the Avon Longitudinal Study of Parents and Children cohort. Methods Measures collected across the life-course were analysed to explore the association of height, weight, and BMI with refractive error and ocular biometric measures at age 15 years from 1613children. The outcome measures were the mean spherical equivalent (MSE) of refractive error (dioptres), axial length (AXL; mm), and radius of corneal curvature (RCC; mm). Potential confounding variables; maternal age at conception, maternal education level, parental socio-economic status, gestational age, breast-feeding, and gender were adjusted for within each multi-variable model. Results Maternal height was positively associated with teenage AXL (0.010 mm; 95% CI: 0.003, 0.017) and RCC (0.005 mm; 95% CI: 0.003, 0.007), increased maternal weight was positively associated with AXL (0.004 mm; 95% CI: 0.0001, 0.008). Birth length was associated with an increase in teenage AXL (0.067 mm; 95% CI: 0.032, 0.10) and flatter RCC (0.023 mm; 95% CI: 0.013, 0.034) and increasing birth weight was associated with flatter RCC (0.005 mm; 95% CI: 0.0003, 0.009). An increase in teenage height was associated with a lower MSE (− 0.007 D; 95% CI: − 0.013, − 0.001), an increase in AXL (0.021 mm; 95% CI: 0.015, 0.028) and flatter RCC (0.008 mm; 95% CI: 0.006, 0.010). Weight at 15 years was associated with an increase in AXL (0.005 mm; 95% CI: 0.001, 0.009). Conclusions At each life stage (pre-natal, birth, and teenage) height and weight, but not BMI, demonstrate an association with AXL and RCC measured at age 15 years. However, the negative association between refractive error and an increase in height was only present at the teenage life stage. Further research into the growth pattern of ocular structures and the development of refractive error over the life-course is required, particularly at the time of puberty.
  • The WAVE Regulatory Complex Is Required to Balance Protrusion and Adhesion in Migration

    Whitelaw, J.A.; Swaminathan, Karthic; Kage, F.; Machesky, L.M. (2020-07-07)
    Cells migrating over 2D substrates are required to polymerise actin at the leading edge to form lamellipodia protrusions and nascent adhesions to anchor the protrusion to the substrate. The major actin nucleator in lamellipodia formation is the Arp2/3 complex, which is activated by the WAVE regulatory complex (WRC). Using inducible Nckap1 floxed mouse embryonic fibroblasts (MEFs), we confirm that the WRC is required for lamellipodia formation, and importantly, for generating the retrograde flow of actin from the leading cell edge. The loss of NCKAP1 also affects cell spreading and focal adhesion dynamics. In the absence of lamellipodium, cells can become elongated and move with a single thin pseudopod, which appears devoid of N-WASP. This phenotype was more prevalent on collagen than fibronectin, where we observed an increase in migratory speed. Thus, 2D cell migration on collagen is less dependent on branched actin.

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