Entanglement of Genetics and Epigenetics in Parkinson’s Disease

Parkinson disease (PD) is a common neurodegenerative disorder that progresses with age, with an increasing number of symptoms. Some of the efforts to understand PD progression have been focusing on the regulation of epigenetic mechanisms, that generally include small molecular modifications to the DNA and histones that are essential for regulating gene activity. Here, we have pointed out difficulties to untangle genetic and epigenetic mechanisms, and reviewed several studies that have aimed for untangling. Some of those have enabled more solid claims on independent roles for epigenetic mechanisms. Hereby, evidence that specific DNA hydroxymethylation, global hyperacetylation, and histone deacetylase (HDAC) dependent regulation of SNCA, one of the hallmark genes involved in PD, have become more prominent from the current perspective, than mechanisms that directly involve DNA methylation. In the absence of current epigenetic clinical targets to counteract PD progression, we also hypothesize how several mechanisms may affect local and global epigenetics in PD neurons, including inflammation, oxidative stress, autophagy and DNA repair mechanisms which may lead to future therapeutic targets

The effect of SSRIs on fear learning:A systematic review and meta-analysis

RationaleSelective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known.ObjectiveWe aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear.MethodsWe searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments.ResultsMeta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes.ConclusionsThis review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs

CO2 and non-CO2 balanced environmental scores module for flight performance evaluation and optimisation

The SESAR2020 exploratory research (ER4) programme CREATE (Grant 890898) developed a climate and weather aware Concept of Operations (ConOps) which encompasses a multi-aircraft 4D trajectory optimisation framework, which utilises a CO2 and non-CO2 balanced Environmental Scores Module (ESM) for the en-route flight phase. The ESM provides a computational method to evaluate the “greenness” of aircraft trajectories. Some components related to the internal ESM scoring are based on expert judgement, which is in line with the technology readiness level (TRL) 1 of the solution. Fast-time simulations were performed to demonstrate the proof-of-concept of the ESM in a multi-aircraft tactical optimisation scenario in the North-Atlantic region. The results show that, because of the simplicity of the metric, the ESM could be well used for trajectory optimisation and tactical replanning, and most likely as well as flight and ATC sector environmental performance evaluations.The work presented in this paper has received funding from the SESAR Joint Undertaking (JU) under grant agreement No 890898, corresponding to the project “Innovative Operations and Climate and Weather Models to Improve ATM Resilience and Reduce Impacts” (SESAR-H2020-ER4 CREATE) within the European Union's Horizon 2020 research and innovation program.Peer ReviewedPostprint (published version

The effect of selective serotonin reuptake inhibitors on fear learning:: a systematic review and meta-analysis

Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders such as panic disorder, generalized anxiety disorder and post-traumatic stress disorder. Fear learning plays an important role in the etiopathology of these disorders. However, it is unclear if and which fear learning processes are affected by SSRIs. This systematic review investigated the effect of six clinically effective SSRIs on the fear learning processes acquisition, expression and extinction. Since SSRIs have been shown to effectively treat anxiety-like disorders, the results of this systematic review could provide insight into which fear learning processes are important to include in future research regarding the development and treatment of anxiety-like disorders. A systematic search in the Medline and Embase databases yielded 128 articles that met the inclusion criteria. Of these articles 120 were eligible for the meta-analysis. Data regarding the study subjects, intervention, experimental design and size and direction of the effects were extracted. Meta-analysis was conducted in R, the R-package metafor [1] was used to estimate the overall effect size, using a random-effects model. Five categorical predefined moderators were coded to account for between-studies heterogeneity (type of SSRI, duration of treatment, disease induction, species, type of test). The effect of these moderators was analysed with a Bayesian penalized meta-regression (BRMA) which is a new method. This analysis was carried out with the pema R-package [2]. The meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian penalized meta-regression further suggested that chronic treatment with SSRIs is associated with stronger anxiolytics effects on cued fear expression than acute treatment. Other variables, including type of SSRI, species, disease induction and type of test, did not seem to moderate the effect of SSRIs This systematic review suggests that the clinical efficacy of SSRIs may be specifically related to their effects on fear expression and extinction, rather than fear acquisition. It could be that the effects of SSRIs on these fear processes are due to general inhibition of fear-related emotions. Therefore, it would be interesting to investigate how SSRIs affect other forms of anxiety, such as unconditioned fear responses. In addition, studies aimed at explaining the sources of the high levels of heterogeneity observed in our meta-analyses could help to optimise the experimental set-up to further investigate the mechanisms underlying fear learning. In order to gain more insight in how the effects of SSRIs on these processes contribute to the anxiolytic effects seen in the clinic, it would be valuable to conduct studies that use experimental designs that allow us to selectively evaluate the effects of SSRIs on fear extinction. This experimental data is interesting to obtain since various exposure therapies in patients are based on promoting extinction. Furthermore, we want to encourage fellow researchers to consider using BRMA when working with a dataset with small sample sizes containing high levels of multicollinearity to avoid overestimation of effects

The effect of SSRIs on fear learning: a systematic review and meta-analysis

RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. OBJECTIVE: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. METHODS: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. RESULTS: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. CONCLUSIONS: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs

Aurora A, MCAK, and Kif18b promote Eg5-independent spindle formation

Inhibition of the microtubule (MT) motor protein Eg5 results in a mitotic arrest due to the formation of monopolar spindles, making Eg5 an attractive target for anti-cancer therapies. However, Eg5-independent pathways for bipolar spindle formation exist, which might promote resistance to treatment with Eg5 inhibitors. To identify essential components for Eg5-independent bipolar spindle formation, we performed a genome-wide siRNA screen in Eg5-independent cells (EICs). We find that the kinase Aurora A and two kinesins, MCAK and Kif18b, are essential for bipolar spindle assembly in EICs and in cells with reduced Eg5 activity. Aurora A promotes bipolar spindle assembly by phosphorylating Kif15, hereby promoting Kif15 localization to the spindle. In turn, MCAK and Kif18b promote bipolar spindle assembly by destabilizing the astral MTs. One attractive way to interpret our data is that, in the absence of MCAK and Kif18b, excessive astral MTs generate inward pushing forces on centrosomes at the cortex that inhibit centrosome separation. Together, these data suggest a novel function for astral MTs in force generation on spindle poles and how proteins involved in regulating microtubule length can contribute to bipolar spindle assembly