SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10−9) and 10p11.21 (P = 3.6 × 10−8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10−3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10−3) and increased seizure-like events (P = 6.8 × 10−7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10−3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease

Damage assessment of threaded connections based on an advanced material model and local concepts

In the actual guidelines, for example the German VDI guideline 2230 [1] or the EUROCODE 3 [2], the fatigue assessment of bolted connections and bolts is based on the nominal stress approach. The FKM guideline for analytical strength assessment [3] does not include concepts for a threaded connection, it refers to the existing guidelines as [1]. At present there does not exist any guideline, which provides a damage assessment for general threaded connection by applying local concepts. In the present paper the basics of such a concept are outlined. The investigated metal is 34CrNiMo6, which is generally used for screw threads. The experimental determination of the local stress-strain behaviour in mechanically threaded connections is practically not feasible and needs a numerical approach. This numerical attempt consists of two main tasks, namely the description of the material properties and finite element (FE) analysis. The first one is concerned with the identification of material parameters, which are necessary for the FE analysis, especially for the advanced material model. The experimental work is given by determining the initial monotonic stressstrain curve, the initial unloading curve, the cyclic stress relaxation and cyclic creep. The parameter identification is accomplished using the software MATLAB, which includes the essential nonlinear optimization algorithms. The obtained parameters are entered in the FE software, which is used for the further FE analysis. The distinctive features of the FE analysis are the nonlinearity, especially nonlinear material behaviour, nonlinear contact algorithms and the consideration of large deformations, the high number of load steps and the various load ratio values (R = 0.06 and R = 0.71). The results of the FE analysis are used for the assessment of threaded connections. The damage assessment is realized with the local strain approach based on the damage parameters PSWT and PJ. Finally the result of the simplified method according to Schneider is applied on a high preloaded bolt connection (R = 0.71) and compared with the result achieved with the advanced material model. © 2014 The Authors. Published by Elsevier Ltd. Selection and peer-review under responsibility of the Politecnico di Milano, Dipartimento di Meccanica