Control of feeding patterns in the barbary dove (streptopelia risoria)

This thesis reports a study of the temporal patterns of feeding behaviour in the Barbary dove or Blonde Ring dove, Streptopelia risoria. The normal diurnal distribution of feeding in the intact, freely feeding bird is described, as is the way in which this pattern may be altered by,a. surgical manipulation which removes much of the sensory inflow from the trigeminal nerve. On the basis of the observation of the effect of this sensory trigeminal nerve section in the doves, an alternative interpretion of the role of this nerve in the control' of feeding behaviour and food intake in birds to that presented in the literature, is offered. In line with this interpretation, it is shown that a manipulation of the physical nature of an offered food material will produce a change in the temporal patterning of food intake in a way similar to that brought about by trigeminal nerve section, and that the past feeding experience of a bird has an effect on the probability that nerve section will produce a noticeable disruption in gross food intake. The fine structure of feeding behaviour is described to demonstrate the principle that the feeding control system of these birds acts so that future needs are anticipated, and it is shown that environmental cues giving information about future deprivation are used by them to feed in advance of such deprivation. In addition, the feeding behaviour of the birds in a continiousy fixed ratio operant situation is described, to show how the means of observing a behaviour can alter the pattern of that behaviour, and also how this alteration can give information about the operation of the underlying control system

Gene editing for resistance to influenza A virus in swine

Influenza A Virus (IAV) presents a major threat to human health and animal welfare. As pigs are susceptible to infection from avian and mammalian origin IAVs, they can be an intermediate host for onwards transmission and act as a mixing vessel in which novel IAVs are generated. ANP32 family proteins have been identified in humans and chickens as host proteins critical to the efficiency of viral genome replication and host factors involved in IAVs adaptation. Host factors recruited by IAV present potential gene-editing targets for controlling IAV transmission and the editing of ANP32 genes in swine represents a potential method of IAV control. Using CRISPR/Cas technology, ANP32A and ANP32B were disrupted in a porcine tracheal cell line (NPTr) to determine whether they are recruited in the same manner as in humans and chickens by IAV polymerase to support viral genome replication. Our results show that human, avian and swine adapted IAVs can recruit ANP32 family proteins in NPTr, and that ANP32A and ANP32B are functionally redundant for IAV and must both be functionally knocked out to reduce the capacity for IAV to propagate. To consider industrial applicability, we have modelled the introgression of IAV resistance alleles into a commercial pig breeding herd by one-step zygote gene-editing. Our model results show that more efficient gene-editing methods will reach fixation quicker, even with greater rates of zygote death, and that the level of germline transmission for the gene-edited alleles will have the largest effect on the flow of alleles to commercial breeders. Together, these results have identified genes for further consideration regarding IAV resistance in swine and that gene-editing will need optimisation in porcine zygotes for implementation in the near-term

Price discovery and microstructure in ether spot and derivative markets

Ethereum is an important blockchain, being the first and most popular public platform for the smart contracts underpinning financial transactions, time-stamping of supply chains, decentralized applications and initial coin offerings. Ethereum's cryptocurrency, ether, is actively traded on centralized exchanges, second only to bitcoin. It has attracted investor's interest primarily because of its intrinsic value – small units of ether called ‘gas’ are used, essentially, as the fuel driving smart contract transactions on the Ethereum blockchain. We ask whether off-chain trading on ether derivatives plays a dominant role in ether spot price discovery, thereby driving ether's utility value for on-chain activity. Using minute-by-minute data we find that the ether perpetual swap on BitMEX, an unregulated cryptocurrency derivative exchange, has dominant trading volume and price discovery over the major spot exchanges. Furthermore, we identify interesting hour-of-day and day-of-week effects in trading volume on the spot exchanges, and these indicate that more informed institutional players are trading ether spot and derivatives

Martinoid : the peptoid martini force field

Many exciting innovations have been made in the development of assembling peptoid materials. Typically, these have utilised large oligomeric sequences, though elsewhere the study of peptide self-assembly has yielded numerous examples of assemblers below 6–8 residues in length, evidencing that minimal peptoid assemblers are not only feasible but expected. A productive means of discovering such materials is through the application of in silico screening methods, which often benefit from the use of coarse-grained molecular dynamics (CG-MD) simulations. At the current level of development, CG models for peptoids are insufficient and we have been motivated to develop a Martini forcefield compatible peptoid model. A dual bottom-up and top-down parameterisation approach has been adopted, in keeping with the Martini parameterisation methodology, targeting the reproduction of atomistic MD dynamics and trends in experimentally obtained log D7.4 partition coefficients, respectively. This work has yielded valuable insights into the practicalities of parameterising peptoid monomers. Additionally, we demonstrate that our model can reproduce the experimental observations of two very different peptoid assembly systems, namely peptoid nanosheets and minimal tripeptoid assembly. Further we can simulate the peptoid helix secondary structure relevant for antimicrobial sequences. To be of maximum usefulness to the peptoid research community, we have developed freely available code to generate all requisite simulation files for the application of this model with Gromacs MD software

Constant pH coarse-grained molecular dynamics with stochastic charge neutralization

pH dependence abounds in biochemical systems; however, many simulation methods used to investigate these systems do not consider this property. Using a modified version of the hybrid non-equilibrium molecular dynamics (MD)/Monte Carlo algorithm, we include a stochastic charge neutralization method, which is particularly suited to the MARTINI force field and enables artifact-free Ewald summation methods in electrostatic calculations. We demonstrate the efficacy of this method by reproducing pH-dependent self-assembly and self-organization behavior previously reported in experimental literature. In addition, we have carried out experimental oleic acid titrations where we report the results in a more relevant way for the comparison with computational methods than has previously been done

Fully automated delineation of the optic radiation for surgical planning using clinically feasible sequences

[EN] Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer's Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer's Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT: a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust pre-processing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 696 scans of predominantly healthy participants (539 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer's Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1¿mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer's Loop with clinically feasible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.Advance Queensland, Grant/Award Number: R-09964-01; Fundacion Merck Salud; Proyecto Societat Catalana Neurologia; Ministerio de Economia, Industria y Competitividad of Spain, Grant/Award Number: DPI2017-87743-R; Red Espanola de Esclerosis Multiple, Grant/Award Numbers: RD12/0032/0002, RD12/0060/01-02, RD16/0015/0002, RD16/0015/0003; Spanish Government; Instituto de Salud Carlos III, Grant/Award Numbers: FIS 2015 PI15/00061, FIS 2015 - PI15/00587, FIS 2018 - PI18/01030Reid, LB.; Martínez-Heras, E.; Manjón Herrera, JV.; Jeffree, RL.; Alexander, H.; Trinder, J.; Solana, E.... (2021). Fully automated delineation of the optic radiation for surgical planning using clinically feasible sequences. Human Brain Mapping. 42(18):5911-5926. https://doi.org/10.1002/hbm.25658S59115926421

On the nature of Globular and Open Clusters (GOC): a study of M16, M67, M3 & M71

A new study of two open clusters, M16 and M67, and two globular clusters, M3 and M71 is presented, exploring data taken with the WFC/INT and the Hubble Space Tele- scope (HST) in a variety of broad-band filters. A dedicated, fully functioning reduction pipeline was constructed to reduce the data used in this study. Employing SExtractor, photometry is conducted in both g and i band filters to obtain Hertzsprung-Russell (HR) diagrams which are fitted with isochrones to determine the average age, distance, metallicity and extinction of each cluster. We find that M16 is ≈ 2 kpc away, with a high dust extinction of E(B-V)≈ 0.5. For M67 the distance was found to be ≈ 0.7 kpc and the cluster is less affected by extinction, showing E(B-V)≈ 0.2. M3 is consistent with being 13 kpc away and it shows little to no extinction. For M71 the distance was found to be ∼ 3kpc and we estimate a moderate extinction of E(B-V)≈ 0.25. The re- sults of this study highlight the stark contrast between open and globular clusters. We find that M16 and M67 (open clusters) have average ages of < 10 Myrs and 3.5 Gyrs, respectively. Globular clusters are found to be much older with ages of 9.5Gyrs and 11 Gyrs for M3 and M71, respectively. It was found that open clusters contained stars that are on average more metal-poor, with lower metallicities of [Fe/H]≈ −0.8 to [Fe/H]≈ −0.5, compared to [Fe/H]≈ −0.5 and [Fe/H]≈ 0.05 for M16 and M67, re- spectively. Future work could be undertaken to correct for issues found in this study, and investigate/infer the metallicities of the birth clouds

Investigating the Potential Role of Genetic and Epigenetic Variation of DNA Methyltransferase Genes in Hyperplastic Polyposis Syndrome

BACKGROUND: Hyperplastic Polyposis Syndrome (HPS) is a condition associated with multiple serrated polyps, and an increased risk of colorectal cancer (CRC). At least half of CRCs arising in HPS show a CpG island methylator phenotype (CIMP), potentially linked to aberrant DNA methyltransferase (DNMT) activity. CIMP is associated with methylation of tumor suppressor genes including regulators of DNA mismatch repair (such as MLH1, MGMT), and negative regulators of Wnt signaling (such as WIF1). In this study, we investigated the potential for interaction of genetic and epigenetic variation in DNMT genes, in the aetiology of HPS. METHODS: We utilized high resolution melting (HRM) analysis to screen 45 cases with HPS for novel sequence variants in DNMT1, DNMT3A, DNMT3B, and DNMT3L. 21 polyps from 13 patients were screened for BRAF and KRAS mutations, with assessment of promoter methylation in the DNMT1, DNMT3A, DNMT3B, DNMT3L MLH1, MGMT, and WIF1 gene promoters. RESULTS: No pathologic germline mutations were observed in any DNA-methyltransferase gene. However, the T allele of rs62106244 (intron 10 of DNMT1 gene) was over-represented in cases with HPS (p<0.01) compared with population controls. The DNMT1, DNMT3A and DNMT3B promoters were unmethylated in all instances. Interestingly, the DNMT3L promoter showed low levels of methylation in polyps and normal colonic mucosa relative to matched disease free cells with methylation level negatively correlated to expression level in normal colonic tissue. DNMT3L promoter hypomethylation was more often found in polyps harbouring KRAS mutations (p = 0.0053). BRAF mutations were common (11 out of 21 polyps), whilst KRAS mutations were identified in 4 of 21 polyps. CONCLUSIONS: Genetic or epigenetic alterations in DNMT genes do not appear to be associated with HPS, but further investigation of genetic variation at rs62106244 is justified given the high frequency of the minor allele in this case series.Musa Drini, Nicholas C. Wong, Hamish S. Scott, Jeffrey M. Craig, Alexander Dobrovic, Chelsee A. Hewitt, Christofer Dow, Joanne P. Young, Mark A. Jenkins, Richard Saffery and Finlay A. Macra

Phospholemman Phosphorylation Regulates Vascular Tone, Blood Pressure, and Hypertension in Mice and Humans

Background: While it has long been recognized that smooth muscle Na/K ATPase (NKA) modulates vascular tone and blood pressure (BP), the role of its accessory protein phopholemman (PLM) has not been characterized. The aim of this study was to test the hypothesis that PLM phosphorylation regulates vascular tone in vitro and this mechanism plays an important role in modulation of vascular function and BP in experimental models in vivo and in man. Methods: Mouse studies: PLM knock-in mice (PLM3SA), in which PLM is rendered unphosphorylatable, were used to assess the role of PLM phosphorylation in vitro in aortic and mesenteric vessels using wire myography and membrane potential measurements. In vivo BP and regional blood flow were assessed using Doppler flow and telemetry in young (14-16 weeks) and old (57-60 weeks) wild-type (WT) and transgenic mice. Human studies: We searched human genomic databases for mutations in PLM in the region of the phosphorylation sites and performed analyses within two human data cohorts (UK Biobank and GoDARTS) to assess the impact of an identified SNP on BP. This SNP was expressed in HEK cells and its effect on PLM phosphorylation determined using Western Blotting. Results: PLM phosphorylation at Ser63 and Ser68 limited vascular constriction in response to phenylephrine. This effect was blocked by ouabain. Prevention of PLM phosphorylation in the PLM3SA mouse profoundly enhanced vascular responses to PE both in vitro and in vivo. In ageing WT mice PLM was hypophosphorylated and this correlated with the development of ageing-induced essential hypertension. In man we identified a non-synonymous coding variant, single nucleotide polymorphism rs61753924, which causes the substitution R70C in PLM. In HEK cells the R70C mutation prevented PLM phosphorylation at Ser68. This variant's rare allele is significantly associated with increased BP in middle-aged men. Conclusions: These studies demonstrate the importance of PLM phosphorylation in the regulation of vascular tone and BP and suggest a novel mechanism, and therapeutic target, for ageing-induced essential hypertension in man