Bringing Light Into the Dark: Associations of Fire Interest and Fire Setting With the Dark Tetrad

Fire setting is a significant problem for society, costing many human lives and causing great property damage. One important risk factor of fire setting observed in forensic samples is fire interest. However, less is known about the relationship of fire interest and fire setting to other variables such as personality traits in subclinical samples. In this study, we observed the relationship of potentially important personality traits with fire interest and fire setting in a sample of N = 222 students. In addition to zero-order correlations, we calculated path models and a logistic regression including all predictor variables. From the Dark Tetrad, consisting of psychopathy, narcissism, Machiavellianism, and three facets of sadism, psychopathy, and physical sadism were found to be associated with fire interest and fire setting. Furthermore, vicarious sadism was associated with fire interest. The other Dark Tetrad traits and four sensation seeking facets did not substantially add to the predictions. This confirms the results of previous studies with clinical and forensic samples with psychopathy and sadism as relevant predictors for fire interest and fire setting. Our results also provide evidence for viewing sadism as the multidimensional construct discriminating between vicarious and other forms of sadism, for the distinction of psychopathy and Machiavellianism, and for the Dark Tetrad being linked to object related violence.Peer Reviewe

Phosphodiesterase 2 Protects against Catecholamine-induced Arrhythmias and Preserves Contractile Function after Myocardial Infarction

International audienceRationale: Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase 2 is upregulated in human heart failure, but its role in the heart is unknown.Objective: To explore the role of phosphodiesterase 2 in cardiac function, propensity to arrhythmia, and myocardial infarction.Methods and Results: Pharmacological inhibition of phosphodiesterase 2 (BAY 60–7550, BAY) led to a significant positive chronotropic effect on top of maximal β-adrenoceptor activation in healthy mice. Under pathological conditions induced by chronic catecholamine infusions, BAY reversed both the attenuated β-adrenoceptor–mediated inotropy and chronotropy. Conversely, ECG telemetry in heart-specific phosphodiesterase 2-transgenic (TG) mice showed a marked reduction in resting and in maximal heart rate, whereas cardiac output was completely preserved because of greater cardiac contraction. This well-tolerated phenotype persisted in elderly TG with no indications of cardiac pathology or premature death. During arrhythmia provocation induced by catecholamine injections, TG animals were resistant to triggered ventricular arrhythmias. Accordingly, Ca2+-spark analysis in isolated TG cardiomyocytes revealed remarkably reduced Ca2+ leakage and lower basal phosphorylation levels of Ca2+-cycling proteins including ryanodine receptor type 2. Moreover, TG demonstrated improved cardiac function after myocardial infarction.Conclusions: Endogenous phosphodiesterase 2 contributes to heart rate regulation. Greater phosphodiesterase 2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. Activating myocardial phosphodiesterase 2 may, thus, represent a novel intracellular antiadrenergic therapeutic strategy protecting the heart from arrhythmia and contractile dysfunction

CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2

Background: Ventricular arrhythmia and sudden cardiac death are the most common lethal complications after myocardial infarction. Antiarrhythmic pharmacotherapy remains a clinical challenge and novel concepts are highly desired. Here, we focus on the cardioprotective CNP (C-type natriuretic peptide) as a novel antiarrhythmic principle. We hypothesize that antiarrhythmic effects of CNP are mediated by PDE2 (phosphodiesterase 2), which has the unique property to be stimulated by cGMP to primarily hydrolyze cAMP. Thus, CNP might promote beneficial effects of PDE2-mediated negative crosstalk between cAMP and cGMP signaling pathways. Methods: To determine antiarrhythmic effects of cGMP-mediated PDE2 stimulation by CNP, we analyzed arrhythmic events and intracellular trigger mechanisms in mice in vivo, at organ level and in isolated cardiomyocytes as well as in human-induced pluripotent stem cell-derived cardiomyocytes. Results: In ex vivo perfused mouse hearts, CNP abrogated arrhythmia after ischemia/reperfusion injury. Upon high-dose catecholamine injections in mice, PDE2 inhibition prevented the antiarrhythmic effect of CNP. In mouse ventricular cardiomyocytes, CNP blunted the catecholamine-mediated increase in arrhythmogenic events as well as in ICaL, INaL, and Ca2+spark frequency. Mechanistically, this was driven by reduced cellular cAMP levels and decreased phosphorylation of Ca2+handling proteins. Key experiments were confirmed in human iPSC-derived cardiomyocytes. Accordingly, the protective CNP effects were reversed by either specific pharmacological PDE2 inhibition or cardiomyocyte-specific PDE2 deletion. Conclusions: CNP shows strong PDE2-dependent antiarrhythmic effects. Consequently, the CNP-PDE2 axis represents a novel and attractive target for future antiarrhythmic strategies

The great screen anomaly—a new frontier in product discovery through functional metagenomics

Functional metagenomics, the study of the collective genome of a microbial community by expressing it in a foreign host, is an emerging field in biotechnology. Over the past years, the possibility of novel product discovery through metagenomics has developed rapidly. Thus, metagenomics has been heralded as a promising mining strategy of resources for the biotechnological and pharmaceutical industry. However, in spite of innovative work in the field of functional genomics in recent years, yields from function-based metagenomics studies still fall short of producing significant amounts of new products that are valuable for biotechnological processes. Thus, a new set of strategies is required with respect to fostering gene expression in comparison to the traditional work. These new strategies should address a major issue, that is, how to successfully express a set of unknown genes of unknown origin in a foreign host in high throughput. This article is an opinionating review of functional metagenomic screening of natural microbial communities, with a focus on the optimization of new product discovery. It first summarizes current major bottlenecks in functional metagenomics and then provides an overview of the general metagenomic assessment strategies, with a focus on the challenges that are met in the screening for, and selection of, target genes in metagenomic libraries. To identify possible screening limitations, strategies to achieve optimal gene expression are reviewed, examining the molecular events all the way from the transcription level through to the secretion of the target gene product

The role of phosphodiesterase 2 in the heart

Herzinsuffizienz ist ein weltweites Gesundheitsproblem mit hoher Morbidität und Mortalität und immer noch schlechter Prognose. Ein charakteristisches Merkmal der molekularen und damit verbundenen strukturellen Veränderungen, die der terminalen Insuffizienz vorangehen ist die durch Desensitivierungsmechanismen vermittelte Abnahme des beta-adrenergen (β-AR) Signalmoleküls zyklisches Adenosinmonophosphat (cAMP) auf der einen Seite und der gleichzeitigen Zunahme des von natriuretischen Peptiden (NP) und Stickstoffmonoxid (NO) generierten zyklischen Guanosinmonophosphat (cGMP) auf der anderen Seite. Während hohe cAMP-Spiegel im Herzen als schädlich gelten, werden cGMP-abhängige Signalkaskaden vorwiegend als protektiv verstanden. Amplitude, Lokalisation und Halbwertszeit beider Signalmoleküle werden durch spezifische Enzyme, den Phosphodiesterasen (PDE) reguliert. Unter der PDE-Superfamilie wird die Isoform PDE2 als einzige von cGMP aktiviert, um dann verstärkt cAMP abzubauen und steht damit im Zentrum eines negativen Crosstalks dieser beiden Signalwege. PDE2 ist sowohl in der humanen als auch der experimentellen Herzinsuffizienz hochreguliert und scheint dort am β-AR Desensitivierungsprozess beteiligt zu sein. Im Rahmen dieser Arbeit wurde die pathophysiologische Rolle der PDE2 im Herzen näher charakterisiert. Es wird gezeigt, dass die PDE2 nicht nur in Kardiomyozyten, sondern auch in kardialen Fibroblasten exprimiert wird. In Fibroblasten inhibieren cAMP/cGMP-Signalwege die Transformation von kardialen Fibroblasten (CF) zu Myofibroblasten (MyoCF), einem zellulären Phänotyp, der unter anderem mit der persistenten Fibrotisierung des erkrankten Herzgewebes in Verbindung gebracht wird. In CF führte eine Überexpression von PDE2 zu eine starken Abnahme der basalen und β2-AR-vermittelten cAMP-Synthese und war ausreichend, um in Abwesenheit exogener, pro-fibrotischer Stimuli die Transformation zum MyoCF zu induzieren. In Übereinstimmung zeigten funktionale Analysen mit künstlich hergestelltem Bindegewebe aus PDE2-überexprimierenden CF eine deutliche Zunahme der Gewebssteifigkeit. PDE2 übte keinen Einfluss auf basale oder durch das atriale NP generiertes cGMP aus und reduzierte nur partiell die NO-induzierte cGMP-Akkumulation. Interessanterweise waren beide Stimuli in der Lage, trotz niedriger cAMP-Spiegel die PDE2-induzierte CF-Transformation zum MyoCF zu verhindern und lassen daher eine Redundanz dieser beiden sonst so gegensätzlichen Signalwege vermuten. Zur Untersuchung von PDE2 in Kardiomyozyten wurde ein transgenes (TG) Mausmodell mit spezifischer kardialer Überexpression herangezogen. Die Basalcharakterisierung zeigte eine erniedrigte Herzfrequenz (HR) mit kompensatorisch erhöhter, basaler Kontraktionskraft, sowie eine verminderte Maximalantwort bezüglich der HR nach akuter β-AR Stimulation. Auf molekularer Ebene war dieser Phänotyp mit einer verminderten Phosphorylierung verschiedener β-AR Zielstrukturen wie Troponin I, Phospholamban und Ryanodinrezeptor-2 assoziiert. Langzeitstudien belegten, dass eine Überexpression von PDE2 keine pathologischen Konsequenzen hat, sondern im Gegenteil die durchschnittliche Lebensspanne der Tiere eher verlängerte. Erste Studien im Herzinsuffizienzmodel der transversalen Aortenkonstriktion (TAC) zeigten bisher eine beständig erniedrigte HR und verminderte Wanddicken bei allerdings vergleichbarer Abnahme der kardialen Kontraktionskraft. Trotz der klaren Befunde und neuen Erkenntnisse über die vielfältige Rolle der PDE2 im Herzen lässt sich bisher noch nicht klar belegen, ob eine zusätzliche Aktivierung von myokardialen PDE2 tatsächlich im Sinne einer intrazellulären β-AR-Blockade die Progression zur Herzinsuffizienz verlangsamen oder verhindern könnte. Weitere darauf aufbauende Untersuchungen, wie z.B. eine akut induzierbare Aktivierung bzw. Deaktivierung in experimentellen Herzinsuffizienzmodellen könnten den Weg für die Entwicklung klinisch anwendbarer Ansätze zur therapeutischen Modulation dieser viel versprechenden Zielstruktur ebnen

In-depth epitope mapping of anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura patients using a large library of ADAMTS13 fragments

status: publishe

Aktuelle Herausforderungen für den Betrieb von dezentralen Energieverbundsystemen

Am 1. Juli 2022 trafen sich im Rahmen des Abschlusskolloquiums des Projekts ACA-Modes rund 60 Teilnehmende aus Forschung, Lehre und Industrie zu einer internationalen Konferenz an der Hochschule Offenburg. Hier wurden die Projektergebnisse rund um die erfolgreiche Implementierung modellprädiktiver Regelstrategien vorgestellt, aktuelle Fragestellungen diskutiert und Entwicklungspfade hin zu einem netzdienlichen Betrieb von Energieverbundsystemen skizziert

Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation

Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1 alpha, beta, and gamma in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of beta-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression. Using western blot analysis, we found greater abundance of PP1 isoforms alpha and gamma but unaltered PP1 beta levels in left ventricular myocardial tissues from HF patients as compared to non-failing controls. However, expression of all three PP1 isoforms was higher in atrial appendages from patients with AF compared to patients with sinus rhythm. Moreover, we found that in human failing ventricles, beta-blocker therapy was associated with lower PP1 alpha abundance and activity, as indicated by higher phosphorylation of the PP1 alpha-specific substrate eIF2 alpha. Greater eIF2 alpha phosphorylation is a known repressor of protein translation, and accordingly, we found lower levels of the endoplasmic reticulum (ER) stress marker Grp78 in the very same samples. We propose that isoform-specific targeting of PP1 alpha activity may be a novel and innovative therapeutic strategy for the treatment of human cardiac diseases by reducing ER stress conditions