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

Development of a two-dimensional dynamic model of the foot-ankle system exposed to vibration

Workers in mining, mills, construction and some types of manufacturing are exposed to vibration that enters the body through the feet. Exposure to foot-transmitted vibration (FTV) is associated with an increased risk of developing vibration-induced white foot (VIWFt). VIWFt is a vascular and neurological condition of the lower limb, leading to blanching in the toes and numbness and tingling in the feet, which can be disabling for the worker. This paper presents a two-dimensional dynamic model describing the response of the foot-ankle system to vibration using four segments and eight Kelvin-Voigt models. The parameters of the model have been obtained by minimizing the quadratic reconstruction error between the experimental and numerical curves of the transmissibility and the apparent mass of participants standing in a neutral position. The average transmissibility at five locations on the foot has been optimized by minimizing the difference between experimental data and the model prediction between 10 and 100 Hz. The same procedure has been repeated to fit the apparent mass measured at the driving point in a frequency range between 2 and 20 Hz. Monte Carlo simulations were used to assess how the variability of the mass, stiffness and damping matrices affect the overall data dispersion. Results showed that the 7 degree-of-freedom model correctly described the transmissibility: the average transmissibility modulus error was 0.1. The error increased when fitting the transmissibility and apparent mass curves: the average modulus error was 0.3. However, the obtained values were reasonable with respect to the average inter-participant variability experimentally estimated at 0.52 for the modulus. Study results can contribute to the development of materials and equipment to attenuate FTV and, consequently, lower the risk of developing VIWFt.INAI

The Rationality of Prejudices

We model an -player repeated prisoner's dilemma in which players are given traits (e.g., height, age, wealth) which, we assume, affect their behavior. The relationship between traits and behavior is unknown to other players. We then analyze the performance of “prejudiced” strategies—strategies that draw inferences based on the observation of some or all of these traits, and extrapolate the inferred behavior to other carriers of these traits. Such prejudiced strategies have the advantage of learning rapidly, and hence of being well adapted to rapidly changing conditions that might result, for example, from high migration or birth rates. We find that they perform remarkably well, and even systematically outperform both Tit-For-Tat and ALLD when the population changes rapidly

Correlations and forecast of death tolls in the Syrian conflict

The Syrian armed conflict has been ongoing since 2011 and has already caused thousands of deaths. The analysis of death tolls helps to understand the dynamics of the conflict and to better allocate resources and aid to the affected areas. In this article, we use information on the daily number of deaths to study temporal and spatial correlations in the data, and exploit this information to forecast events of deaths. We found that the number of violent deaths per day in Syria varies more widely than that in England in which non-violent deaths dominate. We have identified strong positive auto-correlations in Syrian cities and non-trivial cross-correlations across some of them. The results indicate synchronization in the number of deaths at different times and locations, suggesting respectively that local attacks are followed by more attacks at subsequent days and that coordinated attacks may also take place across different locations. Thus the analysis of high temporal resolution data across multiple cities makes it possible to infer attack strategies, warn potential occurrence of future events, and hopefully avoid further deaths

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

Saving Human Lives: What Complexity Science and Information Systems can Contribute

We discuss models and data of crowd disasters, crime, terrorism, war and disease spreading to show that conventional recipes, such as deterrence strategies, are often not effective and sufficient to contain them. Many common approaches do not provide a good picture of the actual system behavior, because they neglect feedback loops, instabilities and cascade effects. The complex and often counter-intuitive behavior of social systems and their macro-level collective dynamics can be better understood by means of complexity science. We highlight that a suitable system design and management can help to stop undesirable cascade effects and to enable favorable kinds of self-organization in the system. In such a way, complexity science can help to save human lives.Comment: 67 pages, 25 figures; accepted for publication in Journal of Statistical Physics [for related work see http://www.futurict.eu/