Hyperinsulinism-hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype-phenotype correlations

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion. Objectives: To study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods: Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed. Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 µmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified. Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations

How Wealth Accumulation Can Promote Cooperation

Explaining the emergence and stability of cooperation has been a central challenge in biology, economics and sociology. Unfortunately, the mechanisms known to promote it either require elaborate strategies or hold only under restrictive conditions. Here, we report the emergence, survival, and frequent domination of cooperation in a world characterized by selfishness and a strong temptation to defect, when individuals can accumulate wealth. In particular, we study games with local adaptation such as the prisoner's dilemma, to which we add heterogeneity in payoffs. In our model, agents accumulate wealth and invest some of it in their interactions. The larger the investment, the more can potentially be gained or lost, so that present gains affect future payoffs. We find that cooperation survives for a far wider range of parameters than without wealth accumulation and, even more strikingly, that it often dominates defection. This is in stark contrast to the traditional evolutionary prisoner's dilemma in particular, in which cooperation rarely survives and almost never thrives. With the inequality we introduce, on the contrary, cooperators do better than defectors, even without any strategic behavior or exogenously imposed strategies. These results have important consequences for our understanding of the type of social and economic arrangements that are optimal and efficient

Plasma amino acids and neopterin in healthy persons with Down’s syndrome

In persons with Down’s syndrome (DS) immunological abnormalities as well as hypothyroidism and Alzheimer type dementia are frequently observed. In addition, the activity of the enzyme cystathionine beta-synthase (CBS) is over-expressed which results in an altered homocysteine metabolism

The 2023/24 VIEWS Prediction challenge: Predicting the number of fatalities in armed conflict, with uncertainty

Governmental and nongovernmental organizations have increasingly relied on early-warning systems of conflict to support their decisionmaking. Predictions of war intensity as probability distributions prove closer to what policymakers need than point estimates, as they encompass useful representations of both the most likely outcome and the lower-probability risk that conflicts escalate catastrophically. Point-estimate predictions, by contrast, fail to represent the inherent uncertainty in the distribution of conflict fatalities. Yet, current early warning systems are preponderantly focused on providing point estimates, while efforts to forecast conflict fatalities as a probability distribution remain sparse. Building on the predecessor VIEWS competition, we organize a prediction challenge to encourage endeavours in this direction. We invite researchers across multiple disciplinary fields, from conflict studies to computer science, to forecast the number of fatalities in state-based armed conflicts, in the form of the UCDP ‘best’ estimates aggregated to two units of analysis (country-months and PRIO-GRID-months), with estimates of uncertainty. This article introduces the goal and motivation behind the prediction challenge, presents a set of evaluation metrics to assess the performance of the forecasting models, describes the benchmark models which the contributions are evaluated against, and summarizes the salient features of the submitted contributions

A low-cost high-precision measurement method of string motion

International audienceThe high-precision measurement of a string's motion requires either the use of an expensive apparatus or the development of a dedicated system. In this paper, a cheaper alternative based on opto-switch sensors combined with a suitable calibration is proposed. A sensitivity model requiring only two straightforward preliminary measurements to determine the parameters is presented. A comparison on a bench test between the opto-switch sensor and a high-speed camera has been performed. Results indicate that the calibrated opto-switch provides more accurate measurements of the string's motion in quasi-static as well as in dynamic states