The role of BDNF methylation and Val66Met in amygdala reactivity during emotion processing

Epigenetic alterations of the brain‐derived neurotrophic factor (BDNF) gene have been associated with psychiatric disorders in humans and with differences in amygdala BDNF mRNA levels in rodents. This human study aimed to investigate the relationship between the functional BDNF‐Val⁶⁶Met polymorphism, its surrounding DNA methylation in BDNF exon IX, amygdala reactivity to emotional faces, and personality traits. Healthy controls (HC, n = 189) underwent functional MRI during an emotional face‐matching task. Harm avoidance, novelty seeking and reward dependence were measured using the Tridimensional Personality Questionnaire (TPQ). Individual BDNF methylation profiles were ascertained and associated with several BDNF single nucleotide polymorphisms surrounding the BDNF‐Val⁶⁶Met, amygdala reactivity, novelty seeking and harm avoidance. Higher BDNF methylation was associated with higher amygdala reactivity (x = 34, y = 0, z = ?26, t₍₁₆₆₎ = 3.00, TFCE = 42.39, p_(FWE) = .045), whereby the BDNF‐Val⁶⁶Met genotype per se did not show any significant association with brain function. Furthermore, novelty seeking was negatively associated with BDNF methylation (r = ?.19, p = .015) and amygdala reactivity (r = ?.17, p = .028), while harm avoidance showed a trend for a positive association with BDNF methylation (r = .14, p = .066). The study provides first insights into the relationship among BDNF methylation, BDNF genotype, amygdala reactivity and personality traits in humans, highlighting the multidimensional relations among genetics, epigenetics, and neuronal functions. The present study suggests a possible involvement of epigenetic BDNF modifications in psychiatric disorders and related brain functions, whereby high BDNF methylation might reduce BDNF mRNA expression and upregulate amygdala reactivity.     

Sequence Conservation of Glycerophosphodiester Phosphodiesterase among Treponema pallidum Strains

Previous investigations have demonstrated that immunization with Treponema pallidum subsp. pallidum glycerophosphodiester phosphodiesterase significantly protects rabbits from subsequent treponeme challenge. In this report, we show that the glycerophosphodiester phosphodiesterase amino acid sequence is conserved among 12 strains from a total of five pathogenic treponemes. The invariant nature of this immunoprotective antigen makes it an attractive candidate for inclusion in a universal subunit vaccine against T. pallidum infection. In addition, these studies show a silent nucleotide substitution at position 579 of the gpd open reading frame which is consistently observed in the non-T. pallidum subsp. pallidum strains. This sequence alteration introduces a PleI restriction site in the nonsyphilis strains and thus allows genetic differentiation from T. pallidum subsp. pallidum strains.     

The internalization of the IgG2a antigen receptor does not require the association with Ig-α and Ig-β but the activation of protein tyrosine kinases does

The B cell antigen receptor of class IgM is a multimeric protein complex containing the membrane-bound immunoglobulin molecule and a heterodimer of the two B cell-specific transmembrane proteins Ig-α and Ig-β. The B cell antigen receptor fulfills a dual role on the surface of B cells. First, it is a signal transduction complex which can activate protein tyrosine kinases and induce the release of Ca²⁺ ions from intracellular stores. Second, its internalization mediates the specific uptake of bound antigens, which are processed intracellularly and presented as major histocompatibility complex-bound peptides on the cell surface. In case of the IgM antigen receptor, the association with the heterodimer is necessary for expression of large amounts of IgM on the surface. We show here that the IgG2a antigen receptor can be expressed on the surface of myeloma cells in two structurally different forms: either with or without the Ig-α/Ig-β heterodimer. A functional comparison of the two forms of antigen receptors demonstrates that the Ig-α and Ig-β molecules are required for the activation of protein tyrosine kinases after cross-linking of the B cell antigen receptor. In contrast, both forms of IgG2a are equally well internalized. This suggests that Ig-α and Ig-β are essential for signal transduction through the IgG2a antigen receptor, whereas internalization can occur independently of the heterodimer.     

Type I interferons have opposing effects during the emergence and recovery phases of colitis

The contribution of the innate immune system to inflammatory bowel disease (IBD) is under intensive investigation. Research in animal models has demonstrated that type I interferons (IFN‐Is) protect from IBD. In contrast, studies of patients with IBD have produced conflicting results concerning the therapeutic potential of IFN‐Is. Here, we present data suggesting that IFN‐Is play dual roles as regulators of intestinal inflammation in dextran sodium sulfate (DSS)‐treated C57BL/6 mice. Though IFN‐Is reduced acute intestinal damage and the abundance of colitis‐associated intestinal bacteria caused by treatment with a high dose of DSS, they also inhibited the resolution of inflammation after DSS treatment. IFN‐Is played an anti‐inflammatory role by suppressing the release of IL‐1β from the colon MHC class II⁺ cells. Consistently, IL‐1 receptor blockade reduced the severity of inflammation in IFN‐I receptor‐deficient mice and myeloid cell‐restricted ablation of the IFN‐I receptor was detrimental. The proinflammatory role of IFN‐Is during recovery from DSS treatment was caused by IFN‐I‐dependent cell apoptosis as well as an increase in chemokine production and infiltrating inflammatory monocytes and neutrophils. Thus, IFN‐Is play opposing roles in specific phases of intestinal injury and inflammation, which may be important for guiding treatment strategies in patients.     

Collaborative genetic mapping of 12 forensic short tandem repeat (STR) loci on the human X chromosome

A large number of short tandem repeat (STR) markers spanning the entire human X chromosome have been described and established for use in forensic genetic testing. Due to their particular mode of inheritance, X-STRs often allow easy and informative haplotyping in kinship analyses. Moreover, some X-STRs are known to be tightly linked so that, in combination, they constitute even more complex genetic markers than each STR taken individually. As a consequence, X-STRs have proven particularly powerful in solving complex cases of disputed blood relatedness. However, valid quantification of the evidence provided by X-STR genotypes in the form of likelihood ratios requires that the recombination rates between markers are exactly known. In a collaborative family study, we used X-STR genotype data from 401 two- and three-generation families to derive valid estimates of the recombination rates between 12 forensic markers widely used in forensic testing, namely DXS10148, DXS10135, DXS8378 (together constituting linkage group I), DXS7132, DXS10079, DXS10074 (linkage group II), DXS10103, HPRTB, DXS10101 (linkage group III), DXS10146, DXS10134 and DXS7423 (linkage group IV). Our study is the first to simultaneously allow for mutation and recombination in the underlying likelihood calculations, thereby obviating the bias-prone practice of excluding ambiguous transmission events from further consideration. The statistical analysis confirms that linkage groups I and II are transmitted independently from one another whereas linkage groups II, III and IV are characterised by inter-group recombination fractions that are notably smaller than 50%. Evidence was also found for recombination within all four linkage groups, with recombination fraction estimates ranging as high as 2% in the case of DXS10146 and DXS10134.     

Natural History of Mild and of Moderate Aortic Stenosis—New Insights From a Large Prospective European Study

Increased life expectancy has led to a higher prevalence of calcific aortic valve disease. Both ends of the disease spectrum—sclerosis of the aortic valve without hemodynamic obstruction and the late stage of aortic valve stenosis (AS)—have been associated with increased morbidity and mortality. This raises the question of the prognostic contribution of atherosclerotic diseases and other comorbidities as opposed to the hemodynamic effect of obstructive AS. Hence, the evaluation of asymptomatic patients with mild or moderate AS without comorbidities is of major interest. In the Simvastatin and Ezetimibe in Aortic Stenosis study, with the exception of hypertension, comorbidities were excluded, thus allowing an analysis of the effect of pure AS as well as the effect of hypertension on the progression and outcome of AS.     

Alcohol dependence and anxiety increase error‐related brain activity

Aims Detection of errors is crucial for efficient goal‐directed behaviour. The ability to monitor behaviour is found to be diminished in patients with substance dependence, as reflected in decreased error‐related brain activity, i.e. error‐related negativity (ERN). The ERN is also decreased in other psychiatric disorders with impaired response inhibition, such as attention‐deficit hyperactivity disorder and borderline personality disorder, but increased in anxiety disorders. The objective of the current study was to assess error monitoring in alcohol‐dependent patients in relation to psychiatric comorbidity. We expected decreased error monitoring in alcohol‐dependent patients with impulse control disorders and increased error monitoring in anxious alcohol‐dependent patients. Design In a case–control design alcohol‐dependent patients were compared with healthy controls. Setting and participants A consecutive series of 29 male alcohol‐dependent patients, between 18 and 55 years of age, applying for in‐patient detoxification were recruited at Novadic Kentron Center for Addiction Treatment. Fifteen age‐matched healthy controls were recruited through advertisements in regional newspapers. Measurements Event‐related potentials were recorded while performing a speeded choice‐reaction task, from which ERN amplitudes were calculated. Axis‐I and ‐II psychiatric comorbidity were assessed using the MINI International Neuropsychiatric Interview and the Structured Interview for DSM‐IV Personality disorders. All participants completed the Temperament and Character Inventory and Profile of Mood States. Findings ERN amplitudes were increased for alcohol‐dependent patients compared to healthy controls, particularly in patients with comorbid anxiety disorders. Conclusions Increased error monitoring in alcohol‐dependent patients, particularly those with comorbid anxiety disorders, is in contrast with previous studies that suggested decreased error monitoring to be a general feature in substance use disorders. Psychiatric disorders co‐occurring with alcohol dependence, such as anxiety disorders, may indicate subpopulations of alcohol‐dependent patients, with distinct neurobiological and genetic characteristics, possibly requiring different treatment strategies.