Tfg (Trk fused gene) is a Carma-1/IKKgamma interacting protein involved in CD40-induced canonical NF-KB signaling

Carma-1 is required for B cell receptor-/CD40- and T cell receptor-/CD28-induced B- and T-cell activation via JNK and NF-betaB. In B cells, Carma-1 becomes phosphorylated by PKCbeta, leading to its oligomerization. Subsequent Bcl10 binding induces IKKbeta-activation and, thereby, canonical NF-KB signalling. Despite these findings it is still unknown how exactly Carma-1 is connected to the plasma membrane and to the IKK-complex. Therefore, we purified Carma-1 complexes from mouse CH12 B cells using anti-Carma-1 affinity columns. Mass spectrometric analyses of the column eluates demonstrated the presence of Carma-1 as well as three previously uncharacterized adaptor proteins in B cells, one of which was the Trk-fused gene (Tfg), an adaptor protein containing PB1 and coiledcoil domains. Whereas Tfg was originally identified as fusion partner of oncogenic Trk tyrosine kinase mutants, the normal cellular homologue of Tfg has so far not been described in B cells. However, Tfg has been shown in other systems to interact with IKKgamma and to enhance TNFinduced NF-KB activation. Tfg and Carma-1 co-localized at the plasma membrane and perinuclear structures in B cells. We further corroborated the interactions of Tfg, IKKgamma and Carma-1 by Blue Native gel electrophoresis, where Carma-1 and Tfg formed a 0.7–1 MDa complex. Ectopic expression of Tfg increased the molecular mass of IKKgamma complexes, fused IKKgamma, Bcl10 and Carma-1 complexes to a ~2 MDa complex, and increased basal and CD40-induced canonical activity of NF-KB and IKKbeta. In contrast, shRNA-mediated silencing of Tfg decreased CD40-induced IKKbeta activity. Very interestingly, in primary B cells, highest expression of Tfg was detected in marginal zone and B1 B cells, and Carma-1 and Tfg formed complexes in these B cells. Since Carma-1 is required for marginal zone B cell and B1 B cell development, we suggest that a functional interaction between Carma-1 and Tfg contributes to development and maintenance of these cells by means of canonical NF-KB signals

COVID-19-Bürgertests im Sommer 2021: Demografie und Motivation der Testpersonen

Im Rahmen der Nationalen Teststrategie zur Pandemieeindämmung wurden Bürgerinnen und Bürgern ab März 2021 kostenfreie, von geschultem Personal durchgeführte Antigen-Schnelltests für den Nachweis von SARS-CoV-2 zur Verfügung gestellt. Diese sollten dazu beitragen, Infektionen möglichst frühzeitig aufzudecken und dienten in bestimmten Situationen als Zugangsvoraussetzungen. Der Erfolg dieser Strategie beruht u. a. auf der Inanspruchnahme und Frequenz der Testungen sowie den daraus resultierenden Verhaltensweisen der Testpersonen. Auf diese Parameter hin untersuchte das in Bamberg ansässige und mit dem Betrieb der lokalen Schnelltestzentren beauftragte Hygiene Technologie Kompetenzzentrum im Zeitraum von Kalenderwoche 25 bis 35/2021 diejenigen Personengruppen, die kostenfreie Schnelltests in Anspruch nahmen. In der vorliegenden Studie werden die ermittelten demografische Daten und Lebensumstände (Haushaltszusammensetzung, Erwerbsstatus) der Teilnehmenden sowie die je nach Altersgruppe variierenden Testhäufigkeiten und -motivationen dargestellt.Peer Reviewe

Cardiovascular Adverse Reactions During Antidepressant Treatment: A Drug Surveillance Report of German-Speaking Countries Between 1993 and 2010

Background: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. Methods: Of 169 278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. Results: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%),TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. Conclusions: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings

Survey in radiation oncology departments in Germany, Austria, and Switzerland: state of digitalization by 2023.

PURPOSE The aim of this work was to assess the current state of digitalization in radiation oncology departments in Germany, Austria, and Switzerland. METHODS A comprehensive survey was conducted in a digital format, consisting of 53 questions that covered various aspects of digitalization including patient workflow, departmental organization, radiotherapy planning, and employee-related aspects. RESULTS Overall, 120 forms were eligible for evaluation. Participants were mainly physicians or medical physicists responsible for digitalization aspects in their departments. Nearly 70% of the institutions used electronic patient records, with 50% being completely paperless. However, the use of smartphone apps for electronic patient reported outcomes (ePROMs) and digital health applications (DIGA) was limited (9% and 4.9%, respectively). In total, 70.8% of the radio-oncology departments had interfaces with diagnostic departments, and 36% had digital interchanges with other clinics. Communication with external partners was realized mainly through fax (72%), e‑mails (55%), postal letters (63%), or other digital exchange formats (28%). Almost half of the institutions (49%) had dedicated IT staff for their operations. CONCLUSION To the best of our knowledge, this survey is the first of its kind conducted in German-speaking radiation oncology departments within the medical field. The findings suggest that there is a varied level of digitalization implementation within these departments, with certain areas exhibiting lower rates of digitalization that could benefit from targeted improvement initiatives

How to move services from free to fee without jeopardizing the customer relationship : the role of pricing schemes, service level, and communication strategies

Over the past decades, manufacturing companies have been enriching their product portfolio through the addition of value-added service, which they often give away for free. In order to capture additional revenues and to stop services from being a pure cost driver, scholars and practitioners have recommended a transition of services “from free to fee”. However, customers have been conditioned to getting these services for free and thus it may pose a problem when free services are suddenly charged. Our online experiment with 347 customers of a large tool manufacturer shows that customers respond with negative perceptions and behavioral intentions when manufacturers start billing their services. Although we find that customers’ willingness-to-pay for individual services at a pay-per-use pricing scheme is 48 % higher than for a packaged version, the choice of this specific pricing scheme cannot fully mitigate customers’ disadvantageous reactions. We also investigate the effect of enhancing the presented service level on customers’ evaluations of the service offering and find that when moving services from free to fee, customers evaluate an enhanced service level not better than the one they are used to. Results also indicate that customers who are accustomed to paying a fee for productrelated services show similar evaluations of the service offering as in a condition where services are free. In this context, our next goal is to understand how to overcome the “from free to fee” hurdle to attenuate customers’ detrimental assessments of the service offering. Hence, we are currently working on a second online experiment to examine whether specific communication strategies exist that help shifting customers’ reference point away from a zero price and therefore facilitate a transition from free to fee. Results are expected to be available by the end of April and can thus be presented at this conference