Barrett’s Oesophagus - studies of novel optical diagnostic tools and minimally invasive therapies

Dysplasia arising in Barrett’s oesophagus (BO) confers risk of progression to oesophageal adenocarcinoma (OAC), but it is variable and confounded by sampling error and diagnostic inter-observer variability. There is a need for biomarkers to accurately define risk and guide surveillance and treatment strategies. Oesophagectomy is the preferred treatment of high grade dysplasia (HGD), although this has been challenged by the emergence of endoscopic therapy. This thesis has shown image cytometric DNA ploidy analysis (ICDA) is accurate when compared to flow cytometry. In a multi centre biomarker validation study, ICDA predicted cancer risk in non dysplastic BO. ICDA also predicted relapse following photodynamic therapy (PDT). Nucleotyping (NT) is an imaging technique that evaluates textural changes of nuclei, which correlate with chromatin content and organisation. In this thesis NT was demonstrated to yield additional diagnostic information over ICDA alone, and the combination was highly accurate for dysplasia classification. In an experiment evaluating replication licensing factors in OAC, those representing the S-G2-M phases of the cell cycle correlated with aneuploidy. Polo like kinase 1 upregulation had the strongest correlation, the first time this has been shown in BO. Elastic scattering spectroscopy detected DNA ploidy abnormalities with equal accuracy using a standard or near infra-red enhanced spectrometer. In a prospective in vivo surveillance study, fewer biopsies were taken without a change in the diagnostic yield for dysplasia. A field carcinogenesis effect was also demonstrated, independent of both dysplasia and DNA ploidy abnormalities. Finally, in a randomised control trial of PDT for HGD, patients with BO less than 7cm had significantly higher efficacy and better tolerability with ALA than photofrin. Radiofrequency ablation was shown to be a safe and effective rescue therapy for patients that failed PDT. In summary these studies advance our understanding of biomedical optics for the risk stratification and treatment of Barrett’s oesophagus

Perceptual Pluralism

Perceptual systems respond to proximal stimuli by forming mental representations of distal stimuli. A central goal for the philosophy of perception is to characterize the representations delivered by perceptual systems. It may be that all perceptual representations are in some way proprietarily perceptual and differ from the representational format of thought (Dretske 1981; Carey 2009; Burge 2010; Block ms.). Or it may instead be that perception and cognition always trade in the same code (Prinz 2002; Pylyshyn 2003). This paper rejects both approaches in favor of perceptual pluralism, the thesis that perception delivers a multiplicity of representational formats, some proprietary and some shared with cognition. The argument for perceptual pluralism marshals a wide array of empirical evidence in favor of iconic (i.e., image-like, analog) representations in perception as well as discursive (i.e., language-like, digital) perceptual object representations

Widely-tunable mid-infrared ring cavity pump-enhanced OPO and application in photo-thermal interferometric trace ethane detection

Funding: Innovate UK (133076); Engineering and Physical Sciences Research Council (EP//L01596X/1, EP/M01326X/1, EP/M024385/1); European Research Council (ERC-2018-STG 803665).The development of a broadly and accurately tunable single-frequency mid-infrared laser source and its application to a sensitive laser absorption detection method are described. Photo-thermal interferometric spectroscopy is employed as a phase-sensitive method to detect the minute refractive index change caused by the heating of a gas under laser radiation. A separate probe beam allows for the spectrally-interesting mid-infrared region to be examined whilst utilizing low cost, high detectivity photodetectors in the visible/near-infrared region. We also describe the implementation of a Sagnac interferometer to minimize the effects of environmental perturbation and provide inherent passive stability. A continuous-wave ring-cavity pump-enhanced OPO has been developed to provide excitation light from 3–4 µm at 140 mW with the ability to mode-hop tune continuously over 90 cm−1 in 0.07 cm−1 steps. Complementary use of both detection apparatus and excitation source has allowed for presence of ethane to be detected down to 200 parts per billion.developed to provide excitation light from 3–4 µm at 140 mW with the ability to mode-hop tune continuously over 90 cm−1 in 0.07 cm−1 steps. Complementary use of both detection apparatus and excitation source has allowed for presence of ethane to be detected down to 200 parts per billion.Publisher PDFPeer reviewe

Biophysical characterization of DNA origami nanostructures reveals inaccessibility to intercalation binding sites

Intercalation of drug molecules into synthetic DNA nanostructures formed through self-assembled origami has been postulated as a valuable future method for targeted drug delivery. This is due to the excellent biocompatibility of synthetic DNA nanostructures, and high potential for flexible programmability including facile drug release into or near to target cells. Such favourable properties may enable high initial loading and efficient release for a predictable number of drug molecules per nanostructure carrier, important for efficient delivery of safe and effective drug doses to minimise non-specific release away from target cells. However, basic questions remain as to how intercalation-mediated loading depends on the DNA carrier structure. Here we use the interaction of dyes YOYO-1 and acridine orange with a tightly-packed 2D DNA origami tile as a simple model system to investigate intercalation-mediated loading. We employed multiple biophysical techniques including single-molecule fluorescence microscopy, atomic force microscopy, gel electrophoresis and controllable damage using low temperature plasma on synthetic DNA origami samples. Our results indicate that not all potential DNA binding sites are accessible for dye intercalation, which has implications for future DNA nanostructures designed for targeted drug delivery

A global map to aid the identification and screening of critical habitat for marine industries

Marine industries face a number of risks that necessitate careful analysis prior to making decisions on the siting of operations and facilities. An important emerging regulatory framework on environmental sustainability for business operations is the International Finance Corporation’s Performance Standard 6 (IFC PS6). Within PS6, identification of biodiversity significance is articulated through the concept of “Critical Habitat”, a definition developed by the IFC and detailed through criteria aligned with those that support internationally accepted biodiversity designations. No publicly available tools have been developed in either the marine or terrestrial realm to assess the likelihood of sites or operations being located within PS6-defined Critical Habitat. This paper presents a starting point towards filling this gap in the form of a preliminary global map that classifies more than 13 million km2 of marine and coastal areas of importance for biodiversity (protected areas, Key Biodiversity Areas [KBA], sea turtle nesting sites, cold- and warm-water corals, seamounts, seagrass beds, mangroves, saltmarshes, hydrothermal vents and cold seeps) based on their overlap with Critical Habitat criteria, as defined by IFC. In total, 5798×103 km2 (1.6%) of the analysis area (global ocean plus coastal land strip) were classed as Likely Critical Habitat, and 7526×103 km2 (2.1%) as Potential Critical Habitat; the remainder (96.3%) were Unclassified. The latter was primarily due to the paucity of biodiversity data in marine areas beyond national jurisdiction and/or in deep waters, and the comparatively fewer protected areas and KBAs in these regions. Globally, protected areas constituted 65.9% of the combined Likely and Potential Critical Habitat extent, and KBAs 29.3%, not accounting for the overlap between these two features. Relative Critical Habitat extent in Exclusive Economic Zones varied dramatically between countries. This work is likely to be of particular use for industries operating in the marine and coastal realms as an early screening aid prior to in situ Critical Habitat assessment; to financial institutions making investment decisions; and to those wishing to implement good practice policies relevant to biodiversity management. Supplementary material (available online) includes other global datasets considered, documentation and justification of biodiversity feature classification, detail of IFC PS6 criteria/scenarios, and coverage calculations

Spectroscopic Coronal Observations during the Total Solar Eclipse of 11 July 2010

The flash spectrum of the solar chromosphere and corona was measured with a slitless spectrograph before, after, and during the totality of the solar eclipse, of 11 July 2010, at Easter Island, Chile. This eclipse took place at the beginning of the Solar Cycle 24, after an extended minimum of solar activity. The spectra taken during the eclipse show a different intensity ratio of the red and green coronal lines compared with those taken during the total solar eclipse of 1 August 2008, which took place towards the end of the Solar Cycle 23. The characteristic coronal forbidden emission line of forbidden Fe XIV (5303 {\AA}) was observed on the east and west solar limbs in four areas relatively symmetrically located with respect to the solar rotation axis. Subtraction of the continuum flash-spectrum background led to the identification of several extremely weak emission lines, including forbidden Ca XV (5694 {\AA}), which is normally detected only in regions of very high excitation, e.g., during flares or above large sunspots. The height of the chromosphere was measured spectrophotometrically, using spectral lines from light elements and compared with the equivalent height of the lower chromosphere measured using spectral lines from heavy elements.Comment: 14 pages, 8 figures, 1 table; Solar Physics, 2012, Februar

Thermodynamics of non-local materials: extra fluxes and internal powers

The most usual formulation of the Laws of Thermodynamics turns out to be suitable for local or simple materials, while for non-local systems there are two different ways: either modify this usual formulation by introducing suitable extra fluxes or express the Laws of Thermodynamics in terms of internal powers directly, as we propose in this paper. The first choice is subject to the criticism that the vector fluxes must be introduced a posteriori in order to obtain the compatibility with the Laws of Thermodynamics. On the contrary, the formulation in terms of internal powers is more general, because it is a priori defined on the basis of the constitutive equations. Besides it allows to highlight, without ambiguity, the contribution of the internal powers in the variation of the thermodynamic potentials. Finally, in this paper, we consider some examples of non-local materials and derive the proper expressions of their internal powers from the power balance laws.Comment: 16 pages, in press on Continuum Mechanics and Thermodynamic

Creativity in savant artists with autism

Background: Individuals with autism spectrum disorder (ASD) often display impairments in creativity, yet savant artists with ASD can produce highly novel and original artistic outputs. To date, there have been no systematic attempts to explore creativity in savant artists with ASD. Methods: Nine savant artists with ASD were compared with nine talented artists, nine non-artistically talented individuals with ASD, and nine individuals with moderate learning difficulties (MLD), on tasks in and out of their domain of expertise. This was to ascertain whether the performance of the savant artists was related to their artistic ability, their diagnosis of ASD or their level of intellectual functioning. Results: On a drawing task (the Torrance Test of Creative Thinking; Torrance, 1974), the responses of the art students were more creative (scoring higher on measures of fluency, originality, elaboration and flexibility) than the savant, ASD and MLD groups. However, the savants did produce more elaborative responses than the ASD and MLD groups. On a non-drawing construction task (figural synthesis; Finke & Slayton, 1988), the savants produced more original outputs than the ASD and MLD groups (scoring similarly to the art students). No group differences were found regarding fluency on this task. Conclusions: On standardised creativity tasks, savant artists with ASD display high levels of elaboration (on drawing tasks) and originality (on non-drawing construction tasks), relative to groups with ASD or MLD. High elaboration and originality may result from a local processing bias, coupled with artistic talent, in this group

Electromagnetic field correlations near a surface with a nonlocal optical response

The coherence length of the thermal electromagnetic field near a planar surface has a minimum value related to the nonlocal dielectric response of the material. We perform two model calculations of the electric energy density and the field's degree of spatial coherence. Above a polar crystal, the lattice constant gives the minimum coherence length. It also gives the upper limit to the near field energy density, cutting off its $1/z^3$ divergence. Near an electron plasma described by the semiclassical Lindhard dielectric function, the corresponding length scale is fixed by plasma screening to the Thomas-Fermi length. The electron mean free path, however, sets a larger scale where significant deviations from the local description are visible.Comment: 15 pages, 7 figure files (.eps), \documentclass[global]{svjour}, accepted in special issue "Optics on the Nanoscale" (Applied Physics B, eds. V. Shalaev and F. Tr\"ager

A mutli-technique search for the most primitive CO chondrites

As part of a study to identify the most primitive COs and to look for weakly altered CMs amongst the COs, we have conducted a multi-technique study of 16 Antarctic meteorites that had been classified as primitive COs. For this study, we have determined: (1) the bulk H, C and N abundances and isotopes, (2) bulk O isotopic compositions, (3) bulk modal mineralogies, and (4) for some selected samples the abundances and compositions of their insoluble organic matter (IOM). Two of the 16 meteorites do appear to be CMs – BUC 10943 seems to be a fairly typical CM, while MIL 090073 has probably been heated. Of the COs, DOM 08006 appears to be the most primitive CO identified to date and is quite distinct from the other members of its pairing group. The other COs fall into two groups that are less primitive than DOM 08006 and ALH 77307, the previously most primitive CO. The first group is composed of members of the DOM 08004 pairing group, except DOM 08006. The second group is composed of meteorites belonging to the MIL 03377 and MIL 07099 pairing groups. These two pairing groups should probably be combined. There is a dichotomy in the bulk O isotopes between the primitive (all Antarctic finds) and the more metamorphosed COs (mostly falls). This dichotomy can only partly be explained by the terrestrial weathering experienced by the primitive Antarctic samples. It seems that the more equilibrated samples interacted to a greater extent with 16O-poor material, probably water, than the more primitive meteorites