Enhanced Immunomodulation in Inflammatory Environments Favors Human Cardiac Mesenchymal Stromal-Like Cells for Allogeneic Cell Therapies

Rising numbers of patients with cardiovascular diseases and limited availability of donor hearts require new and improved therapy strategies. Human atrial appendage-derived cells (hAACs) are promising candidates for an allogeneic cell-based treatment. In this study, we evaluated their inductive and modulatory capacity regarding immune responses and underlying key mechanisms in vitro. For this, cryopreserved hAACs were either cultured in the presence of interferon-gamma (IFNγ) or left unstimulated. The expression of characteristic mesenchymal stromal cell markers (CD29, CD44, CD73, CD105, CD166) was revealed by flow cytometry that also highlighted a predominant negativity for CD90. A low immunogeneic phenotype in an inflammatory milieu was shown by lacking expression of co-stimulatory molecules and upregulation of the inhibitory ligands PD-L1 and PD-L2, despite de novo expression of HLA-DR. Co-cultures of hAACs with allogeneic peripheral blood mononuclear cells, proved their low immunogeneic state by absence of induced T cell proliferation and activation. Additionally, elevated levels of IL-1β, IL-33, and IL-10 were detectable in those cell culture supernatants. Furthermore, the immunomodulatory potential of hAACs was assessed in co-cultures with αCD3/αCD28-activated peripheral blood mononuclear cells. Here, a strong inhibition of T cell proliferation and reduction of pro-inflammatory cytokines (IFNγ, TNFα, TNFβ, IL-17A, IL-2) were observable after pre-stimulation of hAACs with IFNγ. Transwell experiments confirmed that mostly soluble factors are responsible for these suppressive effects. We were able to identify indolamin-2,3-dioxygenase (IDO) as a potential key player through a genome-wide gene expression analysis and could demonstrate its involvement in the observed immunological responses. While the application of blocking antibodies against both PD-1 ligands did not affect the immunomodulation by hAACs, 1-methyl-L-tryptophan as specific inhibitor of IDO was able to restore proliferation and to lower apoptosis of T cells. In conclusion, hAACs represent a cardiac-derived mesenchymal stromal-like cell type with a high potential for the application in an allogeneic setting, since they do not trigger T cell responses and even increase their immunomodulatory potential in inflammatory environments

Early and Later Perceptions and Reactions to the COVID-19 Pandemic in Germany: On Predictors of Behavioral Responses and Guideline Adherence During the Restrictions

In March 2020, the German government enacted measures on movement restrictions and social distancing due to the COVID-19 pandemic. As this situation was previously unknown, it raised numerous questions about people’s perceptions of and behavioral responses to these new policies. In this context, we were specifically interested in people’s trust in official information, predictors for self-prepping behavior and health behavior to protect oneself and others, and determinants for adherence to social distancing guidelines. To explore these questions, we conducted three studies in which a total of 1,368 participants were surveyed (Study 1 N=377, March 2020; Study 2 N=461, April 2020; Study 3 N=530, April 2021) across Germany between March 2020 and April 2021. Results showed striking differences in the level of trust in official statistics (depending on the source). Furthermore, all three studies showed congruent findings regarding the influence of different factors on the respective behavioral responses. Trust in official statistics predicted behavioral responses in all three studies. However, it did not influence adherence to social distancing guidelines in 2020, but in 2021. Furthermore, adherence to social distancing guidelines was associated with higher acceptance rates of the measures and being older. Being female and less right-wing orientated were positively associated with guidelines adherence only in the studies from 2020. This year, political orientation moderated the association between acceptance of the measures and guideline adherence. This investigation is one of the first to examine perceptions and reactions during the COVID-19 pandemic in Germany across 1year and provides insights into important dimensions that need to be considered when communicating with the public

Monitoring des Programms Klinische Forschung (KLIF) für den Zeitraum 2011−2021

Seit 2014 fördert der FWF klinische Forschung mit einem eigenen Förderprogramm mit laufender Einreichung (Programm Klinische Forschung, KLIF). Der Etablierung des Programms im FWF-Förderportfolio ging eine dreijährige Pilotphase voraus: Zunächst wurden durch eine erste experimentelle Ausschreibung im Jahr 2010/11 die Förderlücken im Bereich der klinischen Forschung in Österreich identifiziert; zwei weitere Ausschreibungen in den Jahren 2011/12 und 2012/13 erweiterten die Pilotphase. Insgesamt wurden seit der ersten Ausschreibung 2010/11 bis Ende 2021 beim FWF 1.030 KLIF-Anträge eingereicht, von denen 144 bewilligt wurden. Mit diesen Antrags- und Bewilligungszahlen stellt KLIF im Programmportfolio des FWF ein kleines Förderprogramm dar: 3,6 % aller von 2011 bis 2021 eingereichten Anträge, 2,0 % aller bewilligten Projekte und 1,7 % der insgesamt vergebenen Projektmittel. Im Rahmen dieses Monitorings wird das KLIF-Programm inklusive Antrags- und Output-Kennzahlen analysiert. Der Evaluierungszeitraum umfasst die gesamte KLIF-Förderperiode von der ersten experimentellen Ausschreibung 2010/11 bis Ende 2021. Als Vergleichsgruppen werden Daten zu Einzelprojekten mit einem Mindestanteil von 51 % klinischer Medizin (in der Folge: KLIF-P) herangezogen sowie eine übergeordnete Gruppe aus den Einzelprojekten, die über einen Mindestanteil von 51 % in der Disziplinengruppe Humanmedizin und Gesundheitswissenschaften (in der Folge: Medizin-P) haben. Der Vergleich mit angrenzenden Forschungsgebieten hat zum Ziel, die spezifischen Strukturmerkmale von KLIF herauszuarbeiten, u. a. im Hinblick auf Bewilligungsquoten, Antrags- und Bewilligungssummen und Projektoutput

The SyBil-AA real-time fMRI neurofeedback study: protocol of a single-blind randomized controlled trial in alcohol use disorder

Background: Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study. Methods: N = 100 patients with Alcohol Use Disorder will be randomized to 5 parallel groups in a single-blind fashion and receive real-time functional magnetic resonance imaging neurofeedback while they are presented pictures of alcoholic beverages. The groups will either downregulate the ventral striatum, upregulate the right inferior frontal gyrus, negatively modulate the connectivity between these regions, upregulate, or downregulate the auditory cortex as a control region. After receiving 3 sessions of neurofeedback training within a maximum of 2 weeks, participants will be followed up monthly for a period of 3 months and relapse rates will be assessed as the primary outcome measure. Discussion: The results of this study will provide insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback training in the treatment of Alcohol Use Disorder as well as in the involved brain systems. This might help to identify predictors of successful neurofeedback treatment which could potentially be useful in developing personalized treatment approaches. Trial registration: The study was retrospectively registered in the German Clinical Trials Register (trial identifier: DRKS00010253 ; WHO Universal Trial Number (UTN): U1111–1181-4218) on May 10th, 2016

Effect of everolimus-based drug regimens on CMV-specific T-cell functionality after renal transplantation: 12-month ATHENA subcohort-study results

Post-transplant cytomegalovirus (CMV) infections and increased viral replication are associated with CMV-specific T-cell anergy. In the ATHENA-study, de-novo everolimus (EVR) with reduced-exposure tacrolimus (TAC) or cyclosporine (CyA) showed significant benefit in preventing CMV infections in renal transplant recipients as compared to standard TAC + mycophenolic acid (MPA). However, immunomodulatory mechanisms for this effect remain largely unknown. Ninety patients from the ATHENA-study completing the 12-month visit on-treatment (EVR + TAC n = 28; EVR + CyA n = 19; MPA + TAC n = 43) were included in a posthoc analysis. Total lymphocyte subpopulations were quantified. CMV-specific CD4 T cells were determined after stimulation with CMV-antigen, and cytokine-profiles and various T-cell anergy markers were analyzed using flow cytometry. While 25.6% of MPA + TAC-treated patients had CMV-infections, no such events were reported in EVR-treated patients. Absolute numbers of lymphocyte subpopulations were comparable between arms, whereas the percentage of regulatory T cells was significantly higher with EVR + CyA versus MPA + TAC (p = 0.019). Despite similar percentages of CMV-specific T cells, their median expression of CTLA-4 and PD-1 was lower with EVR + TAC (p < 0.05 for both) or EVR + CyA (p = 0.045 for CTLA-4) compared with MPA + TAC. Moreover, mean percentages of multifunctional CMV-specific T cells were higher with EVR + TAC (27.2%) and EVR + CyA (29.4%) than with MPA + TAC (19.0%). In conclusion, EVR-treated patients retained CMV-specific T-cell functionality, which may contribute to enhanced protection against CMV infections

Large-scale screening of HCMV-seropositive blood donors indicates that HCMV effectively escapes from antibodies by cell-associated spread

Immunoglobulins are only moderately effective for the treatment of human cytomegalovirus (HCMV) infections, possibly due to ineffectiveness against cell-associated virus spread. To overcome this limitation, we aimed to identify individuals with exceptional antibodies in their plasma that can efficiently block the cell-associated spread of HCMV. A Gaussia luciferase-secreting mutant of the cell-associated HCMV strain Merlin was generated, and luciferase activity evaluated as a readout for the extent of cell-associated focal spread. This reporter virus-based assay was then applied to screen plasma samples from 8400 HCMV-seropositive individuals for their inhibitory effect, including direct-acting antiviral drugs as positive controls. None of the plasmas reduced virus spread to the level of these controls. Even the top-scoring samples that partially reduced luciferase activity in the screening assay failed to inhibit focal growth when reevaluated with a more accurate, immunofluorescence-based assay. Selected sera with high neutralizing capacity against free viruses were analyzed separately, and none of them prevented the focal spread of three recent clinical HCMV isolates nor reduced the number of particles transmitted, as demonstrated with a fluorescent Merlin mutant. We concluded that donors with cell-to-cell-spread-inhibiting plasma are nonexistent or extremely rare, emphasizing cell-associated spread as a highly efficient immune escape mechanism of HCM

A Game-based Approach to Understand Human Factors in Supply Chains and Quality Management

Abstract Quality management is an important function for viable production networks. In order to qualify decision makers to understand the fundamental principles of quality management in production networks, a game-based simulation and learning environment is developed, which can furthermore be used to understand how human factors influence the quality of decisions in complex production networks. Previous studies have shown that underlying factors must exist, which predict the players&apos; performance. It is currently unexplored, which factors are contributing to high performance. To deeper investigate which human factors are critical for supply chain success and to further refine the quality management game a series of studies were examined. As expected, expertise had a great impact on performance, however contrary to the expectations cognitive skills had none. The refined decision dashboard, with seamlessly integrated self-adapting visualizations on key performance indicators, had a significant positive impact on game performance. The studies suggest that the developed game is a valuable contribution for the qualification of quality managers, as the quality of decision increased

MusA: Using Indoor Positioning and Navigation to Enhance Cultural Experiences in a museum

In recent years there has been a growing interest into the use of multimedia mobile guides in museum environments. Mobile devices have the capabilities to detect the user context and to provide pieces of information suitable to help visitors discovering and following the logical and emotional connections that develop during the visit. In this scenario, location based services (LBS) currently represent an asset, and the choice of the technology to determine users' position, combined with the definition of methods that can effectively convey information, become key issues in the design process. In this work, we present MusA (Museum Assistant), a general framework for the development of multimedia interactive guides for mobile devices. Its main feature is a vision-based indoor positioning system that allows the provision of several LBS, from way-finding to the contextualized communication of cultural contents, aimed at providing a meaningful exploration of exhibits according to visitors' personal interest and curiosity. Starting from the thorough description of the system architecture, the article presents the implementation of two mobile guides, developed to respectively address adults and children, and discusses the evaluation of the user experience and the visitors' appreciation of these application

Metabolic responses to high-fat diets rich in n-3 or n-6 long-chain polyunsaturated fatty acids in mice selected for either high body weight or leanness explain different health outcomes

<p>Abstract</p> <p>Background</p> <p>Increasing evidence suggests that diets high in polyunsaturated fatty acids (PUFA) confer health benefits by improving insulin sensitivity and lipid metabolism in liver, muscle and adipose tissue.</p> <p>Methods</p> <p>The present study investigates metabolic responses in two different lines of mice either selected for high body weight (DU6) leading to rapid obesity development, or selected for high treadmill performance (DUhTP) leading to a lean phenotype. At 29 days of age the mice were fed standard chow (7.2% fat, 25.7% protein), or a high-fat diet rich in <it>n</it>-3 PUFA (n-3 HFD, 27.7% fat, 19% protein) or a high-fat diet rich in <it>n</it>-6 PUFA (n-6 HFD, 27.7% fat, 18.6% protein) for 8 weeks. The aim of the study was to determine the effect of these PUFA-rich high-fat diets on the fatty acid profile and on the protein expression of key components of insulin signalling pathways.</p> <p>Results</p> <p>Plasma concentrations of leptin and insulin were higher in DU6 in comparison with DUhTP mice. The high-fat diets stimulated a strong increase in leptin levels and body fat only in DU6 mice. Muscle and liver fatty acid composition were clearly changed by dietary lipid composition. In both lines of mice n-3 HFD feeding significantly reduced the hepatic insulin receptor β protein concentration which may explain decreased insulin action in liver. In contrast, protein kinase C ζ expression increased strongly in abdominal fat of n-3 HFD fed DUhTP mice, indicating enhanced insulin sensitivity in adipose tissue.</p> <p>Conclusions</p> <p>A diet high in <it>n</it>-3 PUFA may facilitate a shift from fuel deposition in liver to fuel storage as fat in adipose tissue in mice. Tissue specific changes in insulin sensitivity may describe, at least in part, the health improving properties of dietary <it>n</it>-3 PUFA. However, important genotype-diet interactions may explain why such diets have little effect in some population groups.</p

Divergent responses of Atlantic cod to ocean acidification and food limitation

In order to understand the effect of global change on marine fishes, it is imperative to quantify the effects on fundamental parameters such as survival and growth. Larval survival and recruitment of the Atlantic cod (Gadus morhua) were found to be heavily impaired by end-of-century levels of ocean acidification. Here, we analysed larval growth among 35–36 days old surviving larvae, along with organ development and ossification of the skeleton. We combined CO2treatments (ambient: 503 µatm, elevated: 1,179 µatm) with food availability in order to evaluate the effect of energy limitation in addition to the ocean acidification stressor. As expected, larval size (as a proxy for growth) and skeletogenesis were positively affected by high food availability. We found significant interactions between acidification and food availability. Larvae fed ad libitum showed little difference in growth and skeletogenesis due to the CO2 treatment. Larvae under energy limitation were significantly larger and had further developed skeletal structures in the elevated CO2 treatment compared to the ambient CO2 treatment. However, the elevated CO2 group revealed impairments in critically important organs, such as the liver, and had comparatively smaller functional gills indicating a mismatch between size and function. It is therefore likely that individual larvae that had survived acidification treatments will suffer from impairments later during ontogeny. Our study highlights important allocation trade-off between growth and organ development, which is critically important to interpret acidification effects on early life stages of fish