Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice.

Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. GLDC mutations cause a rare recessive disease non-ketotic hyperglycinemia (NKH). Mutations have also been identified in patients with neural tube defects (NTDs); however, the relationship between NKH and NTDs is unclear. We show that reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of NKH including glycine accumulation, early lethality and hydrocephalus. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates, as well as growth retardation and reduced cellular proliferation. Formate treatment normalizes the folate profile, restores embryonic growth and prevents NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism

Formate supplementation enhances folate-dependent nucleotide biosynthesis and prevents spina bifida in a mouse model of folic acid-resistant neural tube defects

The curly tail mouse provides a model for neural tube defects (spina bifida and exencephaly) that are resistant to prevention by folic acid. The major ct gene, responsible for spina bifida, corresponds to a hypomorphic allele of grainyhead-like 3 (Grhl3) but the frequency of NTDs is strongly influenced by modifiers in the genetic background. Moreover, exencephaly in the curly tail strain is not prevented by reinstatement of Grhl3 expression. In the current study we found that expression of Mthfd1L, encoding a key component of mitochondrial folate one-carbon metabolism (FOCM), is significantly reduced in ct/ct embryos compared to a partially congenic wild-type strain. This expression change is not attributable to regulation by Grhl3 or the genetic background at the Mthfd1L locus. Mitochondrial FOCM provides one-carbon units as formate for FOCM reactions in the cytosol. We found that maternal supplementation with formate prevented NTDs in curly tail embryos and also resulted in increased litter size. Analysis of the folate profile of neurulation-stage embryos showed that formate supplementation resulted in an increased proportion of formyl-THF and THF but a reduction in proportion of 5-methyl THF. In contrast, THF decreased and 5-methyl THF was relatively more abundant in the liver of supplemented dams than in controls. In embryos cultured through the period of spinal neurulation, incorporation of labelled thymidine and adenine into genomic DNA was suppressed by supplemental formate, suggesting that de novo folate-dependent biosynthesis of nucleotides (thymidylate and purines) was enhanced. We hypothesise that reduced Mthfd1L expression may contribute to susceptibility to NTDs in the curly tail strain and that formate acts as a one-carbon donor to prevent NTDs

Exploring how material cues drive sensorimotor prediction across different levels of autistic-like traits

This is the final version. Available from Springer (part of Springer Nature) via the DOI in this record.Recent research proposes that sensorimotor difficulties, such as those experienced by many autistic people, may arise from atypicalities in prediction. Accordingly, we examined the relationship between non-clinical autistic-like traits and sensorimotor prediction in the material-weight illusion, where prior expectations derived from material cues typically bias one’s perception and action. Specifically, prediction-related tendencies in perception of weight, gaze patterns, and lifting actions were probed using a combination of self-report, eye-tracking, motion-capture, and force-based measures. No prediction-related associations between autistic-like traits and sensorimotor control emerged for any of these variables. Follow-up analyses, however, revealed that greater autistic-like traits were correlated with reduced adaptation of gaze with changes in environmental uncertainty. These findings challenge proposals of gross predictive atypicalities in autistic people, but suggest that the dynamic integration of prior information and environmental statistics may be related to autistic-like traits. Further research into this relationship is warranted in autistic populations, to assist the development of future movement-based coaching methods.Economic and Social Research Counci

Predicting Variation in Endowment Effect Magnitudes

Hundreds of studies demonstrate human cognitive biases that are both inconsistent with “rational” decisionmaking and puzzlingly patterned. One such bias, the “endowment effect” (also known as “reluctance to trade”), occurs when people instantly value an item they have just acquired at a much higher price than the maximum they would have paid to acquire it. This bias impedes a vast range of real-world transactions, making it important to understand. Prior studies have documented items that do or do not generate endowment effects, and have noted that the effects vary in magnitude. But none has predicted any of the substantial between-item variation in those magnitudes across a large and novel set of items. Working from evolutionary theory, we derived six factors that predicted 52% of the between- item variation in magnitudes for a novel set of 24 items. These results deepen understanding of both the causes of and patterns in endowment effects. More broadly, they suggest that many other cognitive biases may be similarly approached, and potentially linked by a common theoretical framework

Comparative Approaches to Studying Strategy: Towards an Evolutionary Account of Primate Decision Making

How do primates, humans included, deal with novel problems that arise in interactions with other group members? Despite much research regarding how animals and humans solve social problems, few studies have utilized comparable procedures, outcomes, or measures across different species. Thus, it is difficult to piece together the evolution of decision making, including the roots from which human economic decision making emerged. Recently, a comparative body of decision making research has emerged, relying largely on the methodology of experimental economics in order to address these questions in a cross-species fashion. Experimental economics is an ideal method of inquiry for this approach. It is a well-developed method for distilling complex decision making involving multiple conspecifics whose decisions are contingent upon one another into a series of simple decision choices. This allows these decisions to be compared across species and contexts. In particular, our group has used this approach to investigate coordination in New World monkeys, Old World monkeys, and great apes (including humans), using identical methods. We find that in some cases there are remarkable continuities of outcome, as when some pairs in all species solved a coordination game, the Assurance game. On the other hand, we also find that these similarities in outcomes are likely driven by differences in underlying cognitive mechanisms. New World monkeys required exogenous information about their partners’ choices in order to solve the task, indicating that they were using a matching strategy. Old World monkeys, on the other hand, solved the task without exogenous cues, leading to investigations into what mechanisms may be underpinning their responses (e.g., reward maximization, strategy formation, etc.). Great apes showed a strong experience effect, with cognitively enriched apes following what appears to be a strategy. Finally, humans were able to solve the task with or without exogenous cues. However, when given the chance to do so, they incorporated an additional mechanism unavailable to the other primates - language - to coordinate outcomes with their partner. We discuss how these results inform not only comparative psychology, but also evolutionary psychology, as they provide an understanding of the evolution of human economic behavior, and the evolution of decision making more broadly

Evaluation of a Brazilian fuel alcohol yeast strain for Scotch whisky fermentations

Traditionally, distilling companies in Scotland have employed a very limited number of yeast strains in the production of alcohol for Scotch whiskies. Recent changes such as the decline in availability of brewers’ yeast as a secondary yeast strain and the availability of yeast in different formats (e.g., dried and cream yeast as alternatives to compressed yeast) have promoted interest in alternative Scotch whisky distilling yeasts. In previous work, we investigated different strains of yeasts, specifically Brazilian yeasts which had been isolated from and used in fuel alcohol distilleries. One of the Brazilian yeasts (CAT 1) showed a comparable fermentation performance and superior stress tolerance compared with a standard commercial Scotch whisky distilling yeast (M Type). The Brazilian CAT 1 yeast isolate was further assessed in laboratory scale fermentations and subsequent new make spirit was subjected to sensory analyses. The spirits produced using the Brazilian strain had acceptable flavour profiles and exhibited no sensory characteristics that were atypical of Scotch whisky new make spirit. This study highlights the potential of exploiting yeast biodiversity in traditional Scotch whisky distillery fermentation processes

Supporting metacognitive monitoring in mathematics learning for young people with autism spectrum disorder: A classroom-based study.

Previous research suggests impaired metacognitive monitoring and mathematics under-achievement in autism spectrum disorder. Within educational settings, metacognitive monitoring is supported through the provision of feedback (e.g. with goal reminders and by explicitly correcting errors). Given the strength of the relationship between metacognition, learning and educational attainment, this research tested new computer-based metacognitive support (the 'Maths Challenge') for mathematics learners with autism spectrum disorder within the context of their classroom. The Maths Challenge required learners to engage in metacognitive monitoring before and after answering each question (e.g. intentions and judgements of accuracy) and negotiate with the system the level of difficulty. Forty secondary school children with autism spectrum disorder and 95 typically developing learners completed the Maths Challenge in either a Feedback condition, with metacognitive monitoring support regarding the accuracy of their answers, goal reminders and strategy support, or with No Feedback. Contrary to previous findings, learners with autism showed an undiminished ability to detect errors. They did, however, demonstrate reduced cohesion between their pre- and post-test intentions. Crucially, support from the Feedback condition significantly improved task performance for both groups. Findings highlight important implications for educational interventions regarding the provision of metacognitive support for learners with autism to ameliorate under-performance in mathematics within the classroom

High-efficiency, high-power difference-frequency generation of 0.9–1.5 μm light in BBO

An efficient method for generation of high energy pulsed ir light between 0.9 and 1.5 μm is described. The technique uses difference frequency mixing of pulsed, visible dye and Nd:YAG laser light in a 10 mm long BBO crystal. Quantum efficiencies of up to 23% and ir pulse energies up to 4.5 mJ are demonstrated. The low shot-to-shot fluctuations of difference frequency generation in BBO make this technique an attractive alternative to the conventional optical parametric oscillator or Raman shifting methods that are currently used to access this spectral region

Homocysteine Metabolism in ZDF (Type 2) Diabetic Rats

Mild hyperhomocysteinemia is a risk factor for many diseases, including cardiovascular disease. We determined the effects of insulin resistance and of type 2 diabetes on homocysteine (Hcy) metabolism using Zucker diabetic fatty rats (ZDF/Gmi fa/fa and ZDF/Gmi fa/?). Plasma total Hcy was reduced in ZDF fa/fa rats by 24% in the pre-diabetic insulin-resistant stage, while in the frank diabetic stage there was a 59% reduction. Hepatic activities of several enzymes that play a role in the removal of Hcy: cystathionine β-synthase (CBS), cystathionine γ-lyase, and betaine:Hcy methyltransferase (BHMT) were increased as was methionine adenosyltransferase. CBS and BHMT mRNA levels and the hepatic level of S-adenosylmethionine were also increased in the ZDF fa/fa rats. Studies with primary hepatocytes showed that Hcy export and the transsulfuration flux in cells from ZDF fa/fa rats were particularly sensitive to betaine. Interestingly, liver betaine concentration was found to be significantly lower in the ZDf fa/fa rats at both 5 and 11 weeks. These results emphasize the importance of betaine metabolism in determining plasma Hcy levels in type 2 diabetes