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Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
Auswirkungen einer Mutation des Adhäsionrezeptors PSGL-1 bei humanen neutrophilen Granulozyten
(2009)
Der VNTR Polymorphismus des PSGL-1 ist schon seit längerer Zeit Gegenstand wissenschaftlicher Untersuchungen. Der Rezeptor weist je nach Genotyp eine unterschiedliche Länge auf. Dabei ist der Rezeptor mit dem Allel A der längste, das C-Allel weist phänotypisch den kürzesten Rezeptor auf. Der Rezeptor mit dem B-Allel liegt mit der Länge in der Mitte der drei Rezeptoren. In dieser Studie wurde das Roll- und das Adhäsionsverhalten von Leukozyten mit den Genotypen AA bzw. BB mit Hilfe eines Flusskammermodells untersucht. Dieses Verhalten kommt im Rahmen der Bindung zustande, welche P-Selektin und PSGL-1 miteinander eingehen. Das Blut von acht Probanden wurde untersucht, vier Probanden wiesen den Genotyp AA, die anderen vier den Genotyp BB auf. Die Leukozyten wurden aus dem Vollblut isoliert, verdünnt und in das Flusskammermodell eingespeist. Die verdünnte Zellsuspension wurde mittels einer Pumpe über ein Schlauchsystem durch eine Messkammer befördert, welche im Vorfeld mit P-Selektin beschichtet wurde. Dort konnten die Zellen mikroskopisch untersucht und videotechnisch dokumentiert werden. Anschließend konnte die Rollgeschwindigkeit der neutrophilen Granulozyten und die Anzahl der adhärenten Zellen an der Oberfläche durch Computerprogramme ermittelt werden. Als Resultat ergab sich ein signifikanter Unterschied zwischen der Rollgeschwindigkeit der Zellen des Genotyps AA und der Zellen des Genotyps BB. Dabei wiesen die Zellen mit dem B-Allel wegen der geringeren Länge des PSGL-1 eine höhere Rollgeschwindigkeit auf, als die Zellen mit dem AAllel, deren PSGL-1 länger ist. Zudem blieben signifikant weniger Leukozyten mit dem BAllel an der Oberfläche haften als die Leukozyten der anderen Gruppe. Daraus lässt sich schließen, dass die Bindungskraft zwischen PSGL-1 und PSelektin von der Länge des PSGL-1 abhängig ist. Der kürzere Rezeptor (B-Allel des PSGL-1) weist also eine geringere Bindungskraft auf als der längere Rezeptor (A-Allel des PSGL-1). Die Bindung zwischen PSGL-1 und PSelektin lässt sich wahrscheinlich pharmakologisch beeinflussen. Es wurden Antikörper entwickelt, die in klinischen Studien Erfolg versprechende Ansätze bei der Entzündungshemmung gezeigt haben. Die aktuelle Literatur zu klinisch pharmakologischen Behandlungsansätzen wurde in dieser Arbeit diskutiert.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019-2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019–2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
A Large Ion Collider Experiment (ALICE) has been conceived and constructed as a heavy-ion experiment at the LHC. During LHC Runs 1 and 2, it has produced a wide range of physics results using all collision systems available at the LHC. In order to best exploit new physics opportunities opening up with the upgraded LHC and new detector technologies, the experiment has undergone a major upgrade during the LHC Long Shutdown 2 (2019-2022). This comprises the move to continuous readout, the complete overhaul of core detectors, as well as a new online event processing farm with a redesigned online-offline software framework. These improvements will allow to record Pb-Pb collisions at rates up to 50 kHz, while ensuring sensitivity for signals without a triggerable signature.
The knowledge of baryonic resonance properties and production cross sections plays an important role for the extraction and understanding of medium modifications of mesons in hot and/or dense nuclear matter. We present and discuss systematics on dielectron and strangeness production obtained with HADES on p+p, p+A and A+A collisions in the few GeV energy regime with respect to these resonances.
