Pyroptosis,and its Role in Central Nervous System Disease

Pyroptosis is an inflammatory form of cell death executed by transmembrane pore-forming proteins known as gasdermins and can be activated in an inflammasome-dependent or -independent manner. Inflammasome-dependent pyroptosis is triggered in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and has emerged as an important player in the pathogenesis of multiple inflammatory diseases, mainly by releasing inflammatory contents. More recently, numerous studies have revealed the intricate mechanisms of pyroptosis and its role in the development of neuroinflammation in central nervous system (CNS) diseases. In this review, we summarize current understandings of the molecular and regulatory mechanisms of pyroptosis. In addition, we discuss how pyroptosis can drive different forms of neurological diseases and new promising therapeutic strategies targeting pyroptosis that can be leveraged to treat neuroinflammation.     

Time perception,emotions and mood disorders

In this review, we describe recent internal clock models accounting for time perception and look at how they try to explain the time distortions produced by emotion. We then discuss the results of studies of patients suffering from affective disorders (depression) who experience the feeling of time slowing down. A distinction is thus made between time perception and explicit awareness of the passage of time. We conclude that the feeling that time is passing slowly is not systematically associated with a disruption in the basic mechanisms underlying time perception.     

Daily rest-activity patterns in the bipolar phenotype: A controlled actigraphy study

This study assessed daily rest-activity patterns in euthymic, medication-naïve bipolar phenotype individuals. The Mood Disorder Questionnaire was used to identify 19 bipolar phenotype individuals and 21 controls. Participants wore an Actiwatch-L for 2 weeks to assess their sleep behaviour and circadian rest-activity rhythmicity. Bipolar phenotype individuals had increased movement during sleep, as assessed by the fragmentation index, greater activity levels during their least active 5?h (2 am–7 am), and lower circadian relative amplitude compared to controls. Higher activity levels during sleep affecting circadian amplitude in young adults with the bipolar phenotype may be associated with vulnerability for developing mood disorder.     

Amyloids or prions? That is the question

ABSTRACT

Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.     

Developmental and temporal characteristics of clonal sperm mosaicism

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Modulatory role of the brain-derived neurotrophic factor Val66Met polymorphism on the effects of serious life events on impulsive aggression in borderline personality disorder

Impulsive aggression belongs to the key features of borderline personality disorder (BPD). In the development of BPD, serious life events are known to play a major role. Acute and chronic stress has been suggested to inhibit hippocampal brain-derived neurotrophic factor (BDNF) synthesis and to mediate neural plasticity in response to adverse social experiences. Recently it has been reported that the frequency of violent suicide attempts is higher in adult suicide attempters reporting severe childhood sexual abuse and carrying the Val⁶⁶Val genotype of the BDNF Val⁶⁶Met polymorphism. In this study we analysed modulating effects of BDNF Val⁶⁶Met polymorphism on the effects of physical maltreatment, rape and childhood sexual abuse on impulsive aggression. One hundred and fifty-nine BPD patients from Germany and of Caucasian descent were included. Impulsive aggression was assessed by the Buss-Durkee-Hostility Inventory (BDHI). Childhood sexual abuse accounted for 23.6% of the variance of BDHI sum score. Childhood sexual abuse decreased BDHI sum score in BDNF Val/Val carriers but not in Met carriers. In contrast to previous findings this study analysing a specific gene × environment interaction in BPD patients suggests a decreasing effect of childhood sexual abuse on impulsive aggression in BPD patients, particularly in BDNF Val/Val carriers. The interrelations between serious life events, impulsive aggression and the BDNF Val⁶⁶Met polymorphism as well as their implication for BPD are far from understood and require further investigations.     

Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder

Schizophrenia and bipolar disorder are associated with dopamine neurotransmission and show high comorbidity with tobacco dependence. Recent evidence indicates that the family of the NR4A orphan nuclear receptors, which are expressed in dopamine neurons and in dopaminoceptive brain areas, may play a role in dopamine‐mediated effects. We have, therefore, analysed the association of six single nucleotide polymorphisms (SNPs) within the three genes belonging to the NR4A orphan nuclear receptor family, NR4A1 (rs2603751, rs2701124), NR4A2 (rs12803, rs834835) and NR4A3 (rs1131339, rs1405209), with the degree of smoking in a sample of 204 unrelated schizophrenia patients, which included 126 smokers and 78 non‐smokers. SNPs within the NR4A3 gene (rs1131339 and rs1405209) were significantly associated with heavy smoking in this cohort, using a stepwise analysis of the escalated number of cigarettes smoked per day (P = 0.008 and 0.006, respectively; satisfying the Nyholt significance threshold of 0.009, an adjustment for multiple testing). We then repeated the association analysis of the NR4A3 markers (rs1131339 and rs1405209) in a larger cohort of 319 patients with bipolar disorder, which included 167 smokers and 152 non‐smokers. We have replicated the positive association with smoking of the NR4A3 SNP rs1131339 in this group (P = 0.04), providing an important confirmation of the involvement of the NR4A3 gene in nicotine addiction in patients with mental health disease, a population significantly at risk for nicotine addiction.