Now showing items 1-20 of 2237

    • Pluronic F127 thermosensitive injectable smart hydrogels for controlled drug delivery system development

      Shriky, Banah; Kelly, Adrian L.; Isreb, Mohammad; Babenko, Maksims; Mahmoudi, N.; Rogers, S.; Shebanova, O.; Snow, T.; Gough, Timothy D. (2020-04-01)
      Understanding structure-property relationships is critical for the development of new drug delivery systems. This study investigates the properties of Pluronic smart hydrogel formulations for future use as injectable controlled drug carriers. The smart hydrogels promise to enhance patient compliance, decrease side effects and reduce dose and frequency. Pharmaceutically, these systems are attractive due to their unique sol-gel phase transition in the body, biocompatibility, safety and injectability as solutions before transforming into gel matrices at body temperature. We quantify the structural changes of F127 systems under controlled temperature after flow, as experienced during real bodily injection. Empirical formulae combining the coupled thermal and shear dependency are produced to aid future application of these systems. Induced structural transitions measured in-situ by small angle x-ray and neutron scattering reveal mixed oriented structures that can be exploited to tailor the drug release profile.
    • Synthesis by extrusion: continuous, large-scale preparation of MOFs using little or no solvent

      Crawford, Deborah E.; Casaban, J.; Haydon, R.; Giri, N.; McNally, T.; James, S.L. (2015-03)
      Grinding solid reagents under solvent-free or low-solvent conditions (mechanochemistry) is emerging as a general synthetic technique which is an alternative to conventional solvent-intensive methods. However, it is essential to find ways to scale-up this type of synthesis if its promise of cleaner manufacturing is to be realised. Here, we demonstrate the use of twin screw and single screw extruders for the continuous synthesis of various metal complexes, including Ni(salen), Ni(NCS)2(PPh3)2 as well as the commercially important metal organic frameworks (MOFs) Cu3(BTC)2 (HKUST-1), Zn(2-methylimidazolate)2 (ZIF-8, MAF-4) and Al(fumarate)(OH). Notably, Al(fumarate)(OH) has not previously been synthesised mechanochemically. Quantitative conversions occur to give products at kg h−1 rates which, after activation, exhibit surface areas and pore volumes equivalent to those of materials produced by conventional solvent-based methods. Some reactions can be performed either under completely solvent-free conditions whereas others require the addition of small amounts of solvent (typically 3–4 mol equivalents). Continuous neat melt phase synthesis is also successfully demonstrated by both twin screw and single screw extrusion for ZIF-8. The latter technique provided ZIF-8 at 4 kg h−1. The space time yields (STYs) for these methods of up to 144 × 103 kg per m3 per day are orders of magnitude greater than STYs for other methods of making MOFs. Extrusion methods clearly enable scaling of mechanochemical and melt phase synthesis under solvent-free or low-solvent conditions, and may also be applied in synthesis more generally.
    • Limits and possibilities in the geolocation of humans using multiple isotope ratios (H, O, N, C) of hair from east coast cities of the USA

      Reynard, L.M.; Burt, N.; Koon, Hannah E.C; Tuross, N. (2016-07)
      We examined multiple natural abundance isotope ratios of human hair to assess biological variability within and between geographic locations and, further, to determine how well these isotope values predict location of origin. Sampling locations feature differing seasonality and mobile populations as a robust test of the method. Serially-sampled hair from Cambridge, MA, USA, shows lower δ2 H and δ18 O variability over a one-year time course than model-predicted precipitation isotope ratios, but exhibits considerable differences between individuals. Along a ∼13° northsouth transect in the eastern USA (Brookline, MA, 42.3 ° N, College Park, MD, 39.0 ° N, and Gainesville, FL, 29.7 ° N) δ18 O in human hair shows relatively greater differences and tracks changes in drinking water isotope ratios more sensitively than δ2 H. Determining the domicile of humans using isotope ratios of hair can be confounded by differing variability in hair δ18 O and δ2 H between locations, differential incorporation of H and O into this protein and, in some cases, by tap water δ18 O and δ2 H that differ significantly from predicted precipitation values. With these caveats, randomly chosen people in Florida are separated from those in the two more northerly sites on the basis of the natural abundance isotopes of carbon, nitrogen, hydrogen, and oxygen.
    • Basilar portion porosity: A pathological lesion possibly associated with infantile scurvy

      Moore, Joanna; Koon, Hannah E.C. (2017-09)
      Recent analysis of the juvenile (≤12 years) human remains from a 19th century site in Wolverhampton, England revealed a relatively high level of nutritional deficiency diseases within the population. Indeed, 41.7% of the 48 juvenile skeletons analysed exhibited a combination of porous and proliferative bone lesions consistent with the pathological alterations associated with nutritional stress. This paper describes a pathological lesion on the inferior surface of the basilar portion of the occipital bone, not previously reported in association with infantile scurvy, but which was exhibited by 90% (N=9) of the 10 scorbutic individuals identified during this study.
    • A carbon and nitrogen isotopic investigation of a case of probable infantile scurvy (6th- 4th centuries BC, Slovenia)

      Nicholls, Rebecca A.; Buckberry, Jo; Beaumont, Julia; Črešnar, M.; Mason, P.; Koon, Hannah E.C. (2020-04)
      This paper presents a case study of a young infant, from a larger isotopic and osteological investigation of Bronze/Iron Age (14th-4th century BC) skeletal assemblages from Croatia and Slovenia. The osteological analysis of this infant identified pathological lesions including abnormal porosity and new bone formation consistent with malnutrition and phases of recovery. The distribution and appearance of these pathological lesions (i.e. diffuse micro-porosities and plaques of subperiosteal new bone formation on the skull and long bones) led to the conclusion that this infant probably suffered from scurvy (vitamin C deficiency). The diet and nitrogen balance of this individual were investigated by incremental dentine sampling and stable carbon and nitrogen isotope analysis. This sampling method provided a high resolution record of dietary and metabolic changes from pre-birth to around the time of death. The resulting isotope data exhibited unusually high δ13C values for this region and time period (between -11.3‰ and -12.6‰), while δ15N values were observed to be c. 3‰ above that of rib collagen sampled from contemporary adults recovered from the same site. The isotope profiles generated from the incremental dentine analysis show that δ13C and especially δ15N continue to increase until death. The evidence from the skeletal remains and high resolution isotopic data support the hypothesis that this infant suffered from severe malnutrition and an increasingly negative nitrogen balance. The paper discusses some scenarios which could have resulted in these unusual isotope ratios, whilst considering the diagnosis of possible metabolic disease. The paper also addresses the need for context when interpreting isotopic results. The isotope data should not be viewed in isolation, but rather as part of a multidisciplinary approach, considering the multiple causes of isotopic variability.
    • Curious Travellers: Repurposing imagery to manage and interpret threatened monuments, sites and landscapes

      Wilson, Andrew S.; Gaffney, Vincent L.; Gaffney, Christopher F.; Ch'ng, E.; Bates, R.; Sears, G.; Sparrow, T.; Murgatroyd, A.; Faber, E.; Coningham, R.A.E. (Oxbow, 2019-08)
      The AHRC-funded Curious Travellers project (www.visualisingheritage.org) is a data-mining and crowd sourced infrastructure to help record, manage and interpret archaeological sites, monuments and heritage at risk. It provides a priority response to the globally important challenge of sites that have been destroyed or are under immediate threat from natural disasters, neglect, conflict and cultural vandalism. The project uses two workflows to scrape web-based imagery and crowd-source imagery to recreate 3D models of sites and monuments at risk. Many threats to heritage are linked to issues of access – impacting conservation and site management as well as the safety of individuals. The project offers sustainable solutions – working with extant imagery that does not place individuals at additional safety risk, whilst helping to contextualise visible archaeology by linking to relevant site and landscape data and integrating this into local historic environment record frameworks that make this data freely accessible to all.
    • Optimising the glaucoma signal/noise ratio by mapping changes in spatial summation with area-modulated perimetric stimuli

      Rountree, Lindsay C.; Mulholland, P.J.; Anderson, R.S.; Garway-Heath, D.F.; Morgan, J.E.; Redmond, T. (2018-02)
      Identification of glaucomatous damage and progression by perimetry are limited by measurement and response variability. This study tested the hypothesis that the glaucoma damage signal/noise ratio is greater with stimuli varying in area, either solely, or simultaneously with contrast, than with conventional stimuli varying in contrast only (Goldmann III, GIII). Thirty glaucoma patients and 20 age-similar healthy controls were tested with the Method of Constant Stimuli (MOCS). One stimulus modulated in area (A), one modulated in contrast within Ricco’s area (CR), one modulated in both area and contrast simultaneously (AC), and the reference stimulus was a GIII, modulating in contrast. Stimuli were presented on a common platform with a common scale (energy). A three-stage protocol minimised artefactual MOCS slope bias that can occur due to differences in psychometric function sampling between conditions. Threshold difference from age-matched normal (total deviation), response variability, and signal/noise ratio were compared between stimuli. Total deviation was greater with, and response variability less dependent on defect depth with A, AC, and CR stimuli, compared with GIII. Both A and AC stimuli showed a significantly greater signal/noise ratio than the GIII, indicating that area-modulated stimuli offer benefits over the GIII for identifying early glaucoma and measuring progression.
    • Greener dye synthesis: continuous, solvent-free synthesis of commodity perylene diimides by twin-screw extrusion

      Cao, Q.; Crawford, Deborah E.; Shi, C.; James, S.L. (2020)
      A continuous, scalable, and solvent‐free method for the synthesis of various naphthalic imides and perylene diimides (PDIs) using twin‐screw extrusion (TSE) is reported. Using TSE, naphthalic imides were obtained quantitatively without the need for excess amine reactant or product purification. With good functional‐group tolerance, alkyl and benzyl amine derived PDIs (incl. commercial dyes) were obtained in 50–99 % yield. Use of K2CO3, enabled synthesis of more difficult aniline‐derived PDIs. Furthermore, an automated continuous TSE process for Pigments Black 31 and 32 is demonstrated, with a throughput rate of about 1500 g day−1, corresponding to a space time yield of about 30×103 kg m−3 day−1, which is 1–2 orders of magnitude greater than for solvent‐based batch methods. These methods provide substantial waste reductions and improved efficiency compared to conventional solvent‐based methods.
    • Comparative genomics shows differences in the electron transport and carbon metabolic pathways of Mycobacterium africanum relative to Mycobacterium tuberculosis and suggests an adaptation to low oxygen tension

      Ofori-Anyinam, B.; Riley, A.J.; Jobarteh, T.; Gitteh, E.; Sarr, B.; Faal-Jawara, T.I.; Rigouts, L.; Senghore, M.; Kehinde, A.; Onyejepu, N.; et al. (2020-01)
      The geographically restricted Mycobacterium africanum lineages (MAF) are primarily found in West Africa, where they account for a significant proportion of tuberculosis. Despite this phenomenon, little is known about the co-evolution of these ancient lineages with West Africans. MAF and M. tuberculosis sensu stricto lineages (MTB) differ in their clinical, in vitro and in vivo characteristics for reasons not fully understood. Therefore, we compared genomes of 289 MAF and 205 MTB clinical isolates from the 6 main human-adapted M. tuberculosis complex lineages, for mutations in their Electron Transport Chain and Central Carbon Metabolic pathway in order to explain these metabolic differences. Furthermore, we determined, in silico, whether each mutation could affect the function of genes encoding enzymes in these pathways. We found more mutations with the potential to affect enzymes in these pathways in MAF lineages compared to MTB lineages. We also found that similar mutations occurred in these pathways between MAF and some MTB lineages. Generally, our findings show further differences between MAF and MTB lineages that may have contributed to the MAF clinical and growth phenotype and indicate potential adaptation of MAF lineages to a distinct ecological niche, which we suggest includes areas characterized by low oxygen tension.
    • Time-resolved crystallography using the Hadamard transform

      Yorke, Briony A; Beddard, G.S.; Owen, R.L.; Pearson, A.R. (2014-11)
      We describe a method for performing time-resolved X-ray crystallographic experiments based on the Hadamard transform, in which time resolution is defined by the underlying periodicity of the probe pulse sequence, and signal/noise is greatly improved over that for the fastest pump-probe experiments depending on a single pulse. This approach should be applicable on standard synchrotron beamlines and will enable high-resolution measurements of protein and small-molecule structural dynamics. It is also applicable to other time-resolved measurements where a probe can be encoded, such as pump-probe spectroscopy.
    • Resilience strategies and the pharmaceutical supply chain: the role of agility in mitigating drug shortages

      Yaroson, Emilia V.; Breen, Liz; Hou, Jiachen; Sowter, Julie (2019)
      Supply chain resilience has been suggested to curb the impact of disruptions on supply chains. While this proposition seems coherent in theory, empirical evidence supporting this is limited, as existing literature has centred on exploring the impact of supply chain resilience on disruptions which are based on set time frames, non-supply chain specific as well as examining non-dynamic disruptive events. This study contends that resilience strategies are dynamic and as such their applications within supply chains differ. Therefore examining the impact of resilience will be appropriate on a dynamic disruption within a specific supply chain. In view of this, the paper examines through existing literature the applicability of agility within the pharmaceutical supply chain when dynamic disruptions like drug shortages occur. The study finds alertness, accessibility, connectivity and visibility as dimensions of supply chain agility that are capable of reducing the impact of drug shortages.
    • Whole genome sequence of Mycobacterium kansasii isolates of the genotype 1 from Brazilian patients with pulmonary disease demonstrates considerable heterogeneity

      Machado, E.; Vasconcellos, S.E.G.; Cerdeira, C.; Gomes, L.L.; Junqueira, R.; de Carvalho, L.D.; Ramos, J.P.; Redner, P.; Campos, C.E.D.; de Souza Caldas, P.C.; et al. (2018-06)
      Mycobacterium kansasii is an opportunistic pathogen and one of the most commonly encountered species in individuals with lung disease. We here report the complete genome sequence of 12 clinical isolates of M. kansasii from patients with pulmonary disease in Brazil.
    • Comparative genomics of Mycobacterium africanum Lineage 5 and Lineage 6 from Ghana suggests distinct ecological niches

      Otchere, I.D.; Coscollá, M.; Sánchez-Busó, L.; Asante-Poku, A.; Brites, D.; Loiseau, C.; Meehan, Conor J.; Osei-Wusu, S.; Forson, A.; Laryea, C.; et al. (2018-07)
      Mycobacterium africanum (Maf) causes a substantial proportion of human tuberculosis in some countries of West Africa, but little is known on this pathogen. We compared the genomes of 253 Maf clinical isolates from Ghana, including N = 175 Lineage 5 (L5) and N = 78 Lineage 6 (L6). We found that the genomic diversity of L6 was higher than in L5 despite the smaller sample size. Regulatory proteins appeared to evolve neutrally in L5 but under purifying selection in L6. Even though over 90% of the human T cell epitopes were conserved in both lineages, L6 showed a higher ratio of non-synonymous to synonymous single nucleotide variation in these epitopes overall compared to L5. Of the 10% human T cell epitopes that were variable, most carried mutations that were lineage-specific. Our findings indicate that Maf L5 and L6 differ in some of their population genomic characteristics, possibly reflecting different selection pressures linked to distinct ecological niches.
    • The relationship between transmission time and clustering methods in Mycobacterium tuberculosis epidemiology

      Meehan, Conor J.; Moris, P.; Kohl, T.A.; Pečerska, J.; Akter, S.; Merker, M.; Utpatel, C.; Beckert, P.; Gehre, F.; Lempens, P.; et al. (2018-11)
      Background: Tracking recent transmission is a vital part of controlling widespread pathogens such as Mycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult. Methods: This study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005–2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated. Findings: Our results suggest that clusters based on Spoligotyping could encompass transmission events that occurred almost 200 years prior to sampling while 24-loci-MIRU-VNTR often represented three decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events, e.g. in timespans of up to 10 years for a 5 SNP/allele cut-off. Interpretation: With the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting.
    • Significant under expression of the DosR regulon in M. tuberculosis complex lineage 6 in sputum

      Ofori-Anyinam, B.; Dolganov, G.; Van, T.; Davis, J.L.; Walter, N.D.; Garcia, B.J.; Voskuil, M.; Fissette, K.; Diels, M.; Driesen, M.; et al. (2017-05)
      Mycobacterium africanum lineage (L) 6 is an important pathogen in West Africa, causing up to 40% of pulmonary tuberculosis (TB). The biology underlying the clinical differences between M. africanum and M. tuberculosis sensu stricto remains poorly understood. We performed ex vivo expression of 2179 genes of the most geographically dispersed cause of human TB, M. tuberculosis L4 and the geographically restricted, M. africanum L6 directly from sputa of 11 HIV-negative TB patients from The Gambia who had not started treatment. The DosR regulon was the most significantly decreased category in L6 relative to L4. Further, we identified nonsynonymous mutations in major DosR regulon genes of 44 L6 genomes of TB patients from The Gambia and Ghana. Using Lebek's test, we assessed differences in oxygen requirements for growth. L4 grew only at the aerobic surface while L6 grew throughout the medium. In the host, the DosR regulon is critical for M. tuberculosis in adaptation to oxygen limitation. However, M. africanum L6 appears to have adapted to growth under hypoxic conditions or to different biological niches. The observed under expression of DosR in L6 fits with the genomic changes in DosR genes, microaerobic growth and the association with extrapulmonary disease.
    • Interplay of MicroRNA-21 and SATB1 in epidermal keratinocytes during skin aging

      Ahmed, M.I.; Pickup, M.E.; Rimmer, A.G.; Alam, M.; Mardaryev, Andrei N.; Poterlowicz, Krzysztof; Botchkareva, Natalia V.; Botchkarev, Vladimir A. (2019-12)
    • Stable Isotope Evidence for Dietary Contrast Between Pictish and Medieval Populations at Portmahomack, Scotland

      Curtis-Summers, Shirley; Montgomery, Janet; Carver, M. (2014-09)
      The Pictish and Medieval site at Portmahomack contained four skeletal populations belonging respectively to the late Iron-Age/early Pictish period (6th/7th century), to a monastery of the late Pictish/early medieval period (8th century), to a Norse and Scottish trading place (9th to 11th century) and to a late medieval parish (15th century). Carbon and nitrogen isotope analyses of bone and tooth root collagen from sample individuals from each period were measured for dietary reconstruction. Faunal bone collagen was also assessed to provide dietary comparisons. The results demonstrate a marked change in diet between the early and late medieval communities at Portmahomack. Faunal data also presented dietary differences between the early and later medieval periods, perhaps related to a change in husbandry practices. Due to the dearth of carbon and nitrogen isotope studies on medieval skeletal collections in many areas of Britain and Ireland, this study provides valuable data to enhance our knowledge of food consumption and subsistence in the medieval period.
    • A knight's tale: a rare case of inter-personal violence from medieval Norton Priory

      Curtis-Summers, Shirley; Boylston, Anthea; Ogden, Alan R. (2016-05)
      The opportunity to assess human skeletal remains from Norton Priory, near Runcorn (Cheshire), led to the discovery of peri-mortem blade trauma on an adult male skeleton. The burial evidence suggests that this individual was a wealthy knight and lay benefactor of the priory in the thirteenth century and skeletal evidence has revealed that he was the victim of inter-personal violence. Additionally, many skeletal elements were affected by advanced Paget’s disease, which may have resulted in a certain level of vulnerability due to restricted movement of his arms as a result of Pagetic thickening of the bones. This is the only evidence found of weaponrelated trauma on the Norton Priory skeletal assemblage, making it a rare case and contributing to our understanding of inter-personal violence associated with an ecclesiastical establishment in medieval Britain.
    • Comment on Charlier et al., 2019 "The Mandible of Saint-Louis (1270 AD): Retrospective diagnosis and circumstances of death"

      Snoddy, A.M.E.; Beaumont, Julia; Buckley, H.R.; Colombo, A.; Halcrow, S.E.; Kinaston, R.L.; Vlok, M. (2020)
      We read with interest the recent article by Charlier and colleagues entitled “The Mandible of Saint-Louis (1270 AD): Retrospective diagnosis and circumstances of death” [1]. This work, which consisted of macroscopic examination of a mandible purported to belong to the Crusader King of France and a review of historical accounts pertaining to his death, generated a good deal of press coverage and stimulated public interest in the fascinating field of palaeopathology. However, as researchers engaged in studying dental and nutritional disease in archaeological human remains we have some concerns with the methodology employed by the authors and the conclusions reached from the data they have collected. These include issues of provenance, lesion description, diagnostic methodology employed, and problems with historical references.
    • Back to the beginning: identifying lesions of diffuse idiopathic skeletal hyperostosis before vertebral ankylosis

      Castells Navarro, Laura; Buckberry, Jo (2020-03)
      Objective: To better understand the pathogenesis of DISH, identifying early or pre-DISH lesions in the spine and investigating the relationship between spinal and extra-spinal manifestations of DISH. Material: 44 skeletonized individuals with DISH from the WM Bass Donated Skeletal Collection. Methods: For each vertebra, location, extension, point of origin and appearance of vertebral outgrowths were recorded. The size of the enthesophytes at the olecranon process, patella and calcaneal tuberosity was measured with digital callipers. Results: At either end of the DISH-ankylosed segment, isolated vertical outgrowths arising from the central third of the anterior aspect of the vertebral body can usually be observed. These bone outgrowths show a well-organized external cortical layer, an internal structure of trabecular bone and usually are unaccompanied by or show minimal associated endplate degeneration. Analysis of the relationship between spinal and extra-spinal manifestations (ESM) suggests great inter-individual variability. No correlation between any ESM and the stage of spinal DISH was found. Conclusions: Small isolated outgrowths represent the earliest stages of the spinal manifestations of DISH. The use of ESM as an indicator of DISH should be undertaken with great caution until the relationship between these two features is understood. Significance: Improved accuracy of paleopathological diagnostic criteria of DISH. Limitations: Small sample comprised of only individuals with DISH. Future research: micro-CT analysis to investigate the internal structure of the spinal lesions. Analysis of extra-spinal enthesophytes in individuals with and without DISH to understand their pathogenesis and association with the spinal lesions in individuals with DISH.