New developments to Skalpel : a type error slicing method for explaining errors in type and effect systems

Type error reports provide programmers with a description of type errors which exist in their code. Such descriptions are frequently of poor quality, as they often present just one point in the program, rather than all locations in the code which contribute to that type error. Skalpel is a type error report system for the Standard ML language which tackles this problem, by presenting all and only the locations in the program which contribute to the type error. While the original Skalpel gives substantially better error reports than comparable systems, it has a number of limitations such as a lack of support for language features and poor efficiency. In this research we have made a number of contributions, including a full critique of both the Skalpel core theoretical system and its extensions, support for the remaining features of Standard ML, an analysis and improvements to the efficiency, and an investigation for the first time on Skalpel’s theoretical properties

Techniques for the Analysis of Organic Micro-Contaminants and Their Application to Environmental Monitoring

The rapid increase in the commercial use of organic chemicals since the mid twentieth century has led to a need for governments to monitor and regulate the levels of these chemicals introduced into the environment. This study was carried out to improve and expand the existing analytical methodology used in environmental organic contaminant monitoring, and to apply these methods to field investigations of two sites (Annick Water and Irvine Bay) where organic chemicals were suspected of having an adverse effect on the environment. Analytical organic contaminant monitoring methods were reviewed and the necessary component chemical and instrumental techniques required for the determination of both organochlorine and pyrethroid contaminants in an analytical method identified and investigated. A robust modular analytical method was developed, optimised and validated for river water, effluent, sediment and biota matrices. The optimised methods consisted of: 1. Duplicate liquid-liquid extractions of a 1 litre aqueous samples with 50mls of hexane, 2. Solid phase extractions of 1 litre aqueous samples using octadecyl bonded silica adsorbents, 3. Soxhlet extraction of solid matrices for 7 hours using MTBE as the extracting solvent, 4. Removal of coextracted sulphur using tert butyl ammonium sulphate or copper powder, 5. Cleanup of extracts using normal phase adsorption chromatography with either florisil, alumina or silver nitrate impregnated alumina as the adsorbent, 6. Separation of analyte classes using silica gel adsorption chromatography, 7. Separation and detection of the analytes by gas chromatography using a 60m medium polarity capillary column and electron capture detection. The suitability of the methods to field investigations and regulatory use was demonstrated by determining the fate and effects of a range of organic contaminants released by the textile and wool processing industry on a freshwater (Annick Water) and a marine (Irvine Bay) ecosystem. Permethrin, isomers of HCH, dieldrin, DDT and metabolites of DDT were detected in the effluent from Stewarton STW which discharges into the Annick Water. Permethrin and isomers of HCH were the compounds detected most frequently and at the highest concentrations. The concentrations of permethrin detected were likely to cause a breach of the freshwater environmental quality standard in the Annick Water immediately downstream of the STW. Permethrin, dieldrin, HCH isomers, DDT, metabolites of DDT and PCBs were detected in sediments from the Annick Water. Comparison of the concentrations of contaminants detected in the sediments with published sediment contaminant concentrations, derived sediment quality standards, and published sediment toxicity data indicated that permethrin was the most significant contaminant detected in the sediments. Comparison with invertebrate biotic index scores for the Annick water and fish population studies of the Annick water, indicated that the sediments between the STW and Chapeltoun were acutely toxic to invertebrates. Invertebrate biotic index scores from the lower reaches of the Annick Water were lower than could be explained by comparison with published sediment toxicity data. Faster degradation of trans permethrin in the environment to form a more toxic mixture of permethrin isomers, synergistic activity with organophosphorus pesticides and the negative insecticidal temperature coefficient of permethrin were suggested as a possible explanations of these low biotic index scores. Permethrin was not detected in eels caught from the Annick water or the Glazert Burn, suggesting that eels can metabolise permethrin. Dieldrin was the major contaminant detected in eels downstream of the STW. The concentrations of dieldrin detected in these eels were so high as to suggest that regular human consumption of these eels presented a significant hazard to human health and the viability of wild populations of fish-eating birds and aquatic mammals. Similar organochlorine contaminants were detected in effluents from Irvine and Garnock Valley sewers and in sediment from Irvine Bay. Contaminants found in the Irvine Bay sea outfall effluents include permethrin, HCH isomers, dieldrin, DDT and metabolites of DDT. Permethrin and isomers of HCH were the compounds most frequently detected and at the highest concentrations. The concentration of permethrin detected in the effluent from the valley sewers in typical conditions were likely to cause a slight breach of the EQS at the edge of the mixing zone. In adverse conditions the concentrations of permethrin in the effluent from both valley sewers were likely to result in permethrin concentrations at the edge of the mixing zone approximately 5 and 10 times higher than those permitted by the EQS. Permethrin, dieldrin, HCH isomers, DDT, DDT metabolites and PCBs were detected in sediments from Irvine Bay. Permethrin and G HCH were the major contaminants detected. The spatial distribution of organic carbon normalised contaminants indicated that the valley sewers are the major sources of these contaminants within Irvine Bay

Differential effects of nutritional folic acid deficiency and moderate hyperhomocysteinemia on aortic plaque formation and genome-wide DNA methylation in vascular tissue from ApoE-/- mice

Low folate intake is associated with vascular disease. Causality has been attributed to hyperhomocysteinemia. However, human intervention trials have failed to show the benefit of homocysteine-lowering therapies. Alternatively, low folate may promote vascular disease by deregulating DNA methylation. We investigated whether folate could alter DNA methylation and atherosclerosis in ApoE null mice. Mice were fed one of six diets (n = 20 per group) for 16 weeks. Basal diets were either control (C; 4% lard) or high fat (HF; 21% lard and cholesterol, 0.15%) with different B-vitamin compositions: (1) folic acid and B-vitamin replete, (2) folic acid deficient (−F), (3) folic acid, B6 and B12 deficient (−F−B). −F diets decreased plasma (up to 85%; P < 0.05), whole blood (up to 70%; P < 0.05), and liver folate (up to 65%; P < 0.05) and hepatic SAM/SAH (up to 80%; P < 0.05). −F−B diets reduced plasma (up to 76%; P < 0.05), whole blood (up to 72%; P < 0.05), and liver B12 (up to 39%; P < 0.05) and hepatic SAM/SAH (up to 90%; P < 0.05). −F increased homocysteine 2-fold, while −F−B increased homocysteine 3.6- and 6.8-fold in the C and HF groups (P < 0.05). Plaque formation was increased 2-fold (P < 0.0001) in mice fed a HF diet. Feeding a HF–F diet increased lesion formation by 17% (P < 0.05). There was no change in 5-methyldeoxycytidine in liver or vascular tissue (aorta, periadventitial tissue and heart). These data suggest that atherogenesis is not associated with genome-wide epigenetic changes in this animal model

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1ε (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration

Equine grass sickness (a multiple systems neuropathy) is associated with alterations in the gastrointestinal mycobiome

Background: Equine grass sickness (EGS) is a multiple systems neuropathy of grazing horses of unknown aetiology. An apparently identical disease occurs in cats, dogs, rabbits, hares, sheep, alpacas and llamas. Many of the risk factors for EGS are consistent with it being a pasture mycotoxicosis. To identify potential causal fungi, the gastrointestinal mycobiota of EGS horses were evaluated using targeted amplicon sequencing, and compared with those of two control groups. Samples were collected post mortem from up to 5 sites in the gastrointestinal tracts of EGS horses (EGS group; 150 samples from 54 horses) and from control horses that were not grazing EGS pastures and that had been euthanased for reasons other than neurologic and gastrointestinal diseases (CTRL group; 67 samples from 31 horses). Faecal samples were also collected from healthy control horses that were co-grazing pastures with EGS horses at disease onset (CoG group; 48 samples from 48 horses). Results: Mycobiota at all 5 gastrointestinal sites comprised large numbers of fungi exhibiting diverse taxonomy, growth morphology, trophic mode and ecological guild. FUNGuild analysis parsed most phylotypes as ingested environmental microfungi, agaricoids and yeasts, with only 1% as gastrointestinal adapted animal endosymbionts. Indices of alpha-diversity indicated that mycobiota richness and diversity varied throughout the gastrointestinal tract and were greater in EGS horses. There were significant inter-group and inter-site differences in mycobiota structure. A large number of phylotypes were differentially abundant among groups. Key phylotypes (n=56) associated with EGS were identified that had high abundance and high prevalence in EGS samples, significantly increased abundance in EGS samples, and were important determinants of the inter-group differences in mycobiota structure. Many key phylotypes were extremophiles and/or were predicted to produce cytotoxic and/or neurotoxic extrolites. Conclusions: This is the first reported molecular characterisation of the gastrointestinal mycobiota of grazing horses. Key phylotypes associated with EGS were identified. Further work is required to determine whether neurotoxic extrolites from key phylotypes contribute to EGS aetiology or whether the association of key phylotypes and EGS is a consequence of disease or is non-causal

Justifications-on-demand as a device to promote shifts of attention associated with relational thinking in elementary arithmetic

Student responses to arithmetical questions that can be solved by using arithmetical structure can serve to reveal the extent and nature of relational, as opposed to computational thinking. Here, student responses to probes which require them to justify-on-demand are analysed using a conceptual framework which highlights distinctions between different forms of attention. We analyse a number of actions observed in students in terms of forms of attention and shifts between them: in the short-term (in the moment), medium-term (over several tasks), and long-term (over a year). The main factors conditioning students´ attention and its movement are identified and some didactical consequences are proposed

Nutritional B vitamin deficiency alters the expression of key proteins associated with vascular smooth muscle cell proliferation and migration in the aorta of atherosclerotic apolipoprotein E null mice.

Low B vitamin status is linked with human vascular disease. We employed a proteomic and biochemical approach to determine whether nutritional folate deficiency and/or hyperhomocysteinemia altered metabolic processes linked with atherosclerosis in ApoE null mice. Animals were fed either a control fat (C; 4 % w/w lard) or a high-fat [HF; 21 % w/w lard and cholesterol (0/15 % w/w)] diet with different B vitamin compositions for 16 weeks. Aorta tissue was prepared and global protein expression, B vitamin, homocysteine and lipoprotein status measured. Changes in the expression of aorta proteins were detected in response to multiple B vitamin deficiency combined with a high-fat diet (P < 0.05) and were strongly linked with lipoprotein concentrations measured directly in the aorta adventitia (P < 0.001). Pathway analysis revealed treatment effects in the aorta-related primarily to cytoskeletal organisation, smooth muscle cell adhesion and invasiveness (e.g., fibrinogen, moesin, transgelin, vimentin). Combined B vitamin deficiency induced striking quantitative changes in the expression of aorta proteins in atherosclerotic ApoE null mice. Deregulated expression of these proteins is associated with human atherosclerosis. Cellular pathways altered by B vitamin status included cytoskeletal organisation, cell differentiation and migration, oxidative stress and chronic inflammation. These findings provide new insight into the molecular mechanisms through which B vitamin deficiency may accelerate atherosclerosis