Identification of genetic modifiers of behavioral phenotypes in serotonin transporter knockout rats

BACKGROUND: Genetic variation in the regulatory region of the human serotonin transporter gene (SLC6A4) has been shown to affect brain functionality and personality. However, large heterogeneity in its biological effects is observed, which is at least partially due to genetic modifiers. To gain insight into serotonin transporter (SERT)-specific genetic modifiers, we studied an intercross between the Wistar SERT-/- rat and the behaviorally and genetically divergent Brown Norway rat, and performed a QTL analysis. RESULTS: In a cohort of >150 intercross SERT-/- and control (SERT+/+) rats we characterized 12 traits that were previously associated with SERT deficiency, including activity, exploratory pattern, cocaine-induced locomotor activity, and abdominal and subcutaneous fat. Using 325 genetic markers, 10 SERT-/--specific quantitative trait loci (QTLs) for parameters related to activity and exploratory pattern (Chr.1,9,11,14), and cocaine-induced anxiety and locomotor activity (Chr.5,8) were identified. No significant QTLs were found for fat parameters. Using in silico approaches we explored potential causal genes within modifier QTL regions and found interesting candidates, amongst others, the 5-HT1D receptor (Chr. 5), dopamine D2 receptor (Chr. 8), cannabinoid receptor 2 (Chr. 5), and genes involved in fetal development and plasticity (across chromosomes). CONCLUSIONS: We anticipate that the SERT-/--specific QTLs may lead to the identification of new modulators of serotonergic signaling, which may be targets for pharmacogenetic and therapeutic approaches.

What makes adults choose to learn:Factors that stimulate or prevent adults from learning

Adult learning policies need to be based on an understanding of the inequalities in the uptake and benefits of learning and why adults might not participate. This needs to go beyond a mere insight in barriers that, once removed, do no longer provide a reason for adults not to participate. This article aims to delph deeper in understanding what makes adults choose to learn. It starts by applying a capability approach perspective to adult learning to evaluate whether adults have freedom to value learning and, whether they can effectively turn this freedom into learning. This conceptual framing puts certain concepts in the spotlight, namely, ‘agency’, ‘conversion factors’ and ‘benefits of learning’, which were further explored through a narrative literature review analysing 109 articles. Thisresulted in an exploration of these concepts and their interplay feeding into a conceptual model, opening new perspectives for evaluating whether adults have equal opportunities to value adult learning and turn their willingness into actual learning. This model supports future empirical studies aimed to understand participation and non-participation of adults in learning that can in turn feed policy makers with better insights and tools to develop interventions actually provide the right encouragements for adults to learn

Minimally Invasive Sympathicotomy for Palmar Hyperhidrosis and Facial Blushing:Current Status and the Hyperhidrosis Expert Center Approach

Hyperhidrosis, the medical term for excessive sweating beyond physiological need, is a condition with serious emotional and social consequences for affected patients. Symptoms usually appear in focal areas such as the feet, hands, axillae and face. Non-surgical treatment options such as topical antiperspirants or systemic medications are usually offered as a first step of treatment, although these therapies are often ineffective, especially in severe and intolerable cases of hyperhidrosis. In the treatment algorithm for patients suffering from hyperhidrosis, surgical thoracoscopic sympathicotomy offers a permanent solution, which is particularly effective in the treatment of palmar hyperhidrosis and facial blushing. In this review, we describe the current status of thoracoscopic sympathicotomy for palmar hyperhidrosis and facial blushing. In addition, we share the specific treatment approach, technique and results of our Hyperhidrosis Expert Center. Last, we share recommendations to ensure an effective, reproducible and safe application of single-port thoracoscopic sympathicotomy for palmar hyperhidrosis and facial blushing, based on our extensive experience

Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques

Background: In most models of experimental thrombosis, healthy blood vessels are damaged. This results in the formation of a platelet thrombus that is stabilized by ADP signaling via P2Y(12) receptors. However, such models do not predict involvement of P2Y(12) in the clinically relevant situation of thrombosis upon rupture of atherosclerotic plaques. We investigated the role of P2Y(12) in thrombus formation on (collagen-containing) atherosclerotic plaques in vitro and in vivo, by using a novel mouse model of atherothrombosis. Methodology: Plaques in the carotid arteries from Apoe(-/-) mice were acutely ruptured by ultrasound treatment, and the thrombotic process was monitored via intravital fluorescence microscopy. Thrombus formation in vitro was assessed in mouse and human blood perfused over collagen or plaque material under variable conditions of shear rate and coagulation. Effects of two reversible P2Y(12) blockers, ticagrelor (AZD6140) and cangrelor (AR-C69931MX), were investigated. Principal Findings: Acute plaque rupture by ultrasound treatment provoked rapid formation of non-occlusive thrombi, which were smaller in size and unstable in the presence of P2Y(12) blockers. In vitro, when mouse or human blood was perfused over collagen or atherosclerotic plaque material, blockage or deficiency of P2Y(12) reduced the thrombi and increased embolization events. These P2Y(12) effects were present at shear rates >500 s(-1), and they persisted in the presence of coagulation. P2Y(12)-dependent thrombus stabilization was accompanied by increased fibrin(ogen) binding. Conclusions/Significance: Platelet P2Y(12) receptors play a crucial role in the stabilization of thrombi formed on atherosclerotic plaques. This P2Y(12) function is restricted to high shear flow conditions, and is preserved in the presence of coagulation

Polyadenylation of genomic RNA and initiation of antigenomic RNA in a positive-strand RNA virus are controlled by the same cis-element

Genomes and antigenomes of many positive-strand RNA viruses contain 3′-poly(A) and 5′-poly(U) tracts, respectively, serving as mutual templates. Mechanism(s) controlling the length of these homopolymeric stretches are not well understood. Here, we show that in coxsackievirus B3 (CVB3) and three other enteroviruses the poly(A) tract is ∼80–90 and the poly(U) tract is ∼20 nt-long. Mutagenesis analysis indicate that the length of the CVB3 3′-poly(A) is determined by the oriR, a cis-element in the 3′-noncoding region of viral RNA. In contrast, while mutations of the oriR inhibit initiation of (−) RNA synthesis, they do not affect the 5′-poly(U) length. Poly(A)-lacking genomes are able to acquire genetically unstable AU-rich poly(A)-terminated 3′-tails, which may be generated by a mechanism distinct from the cognate viral RNA polyadenylation. The aberrant tails ensure only inefficient replication. The possibility of RNA replication independent of oriR and poly(A) demonstrate that highly debilitated viruses are able to survive by utilizing ‘emergence’, perhaps atavistic, mechanisms

The prognostic value of IgA anti-citrullinated protein antibodies and rheumatoid factor in an early arthritis population with a treat-to-target approach

The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (&lt; 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in ‘quick-attained and persistent remission’ rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice.</p