Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8
T cell responses to the encoded transgene. ...Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8
T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL
We show now that induction of GagL
-specific CD8
T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL
and the two Ad-derived epitopes DNA-binding protein
(DBP
) and hexon
, we confirmed that Ad epitopes prevent induction of GagL
-specific CD8
T cells. Interestingly, while DBP
did not interfere with GagL
-specific CD8
T cell induction, the H-2D
-restricted hexon
suppressed the CD8
T cell response to the H-2D
-restricted GagL
strongly in H-2
mice but not in H-2
mice. This finding indicates that competition occurs at the level of responding CD8
T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL
-specific CD8
T cell responses to epitope strings in the presence of hexon
IL-2 codelivery did not restore GagL
responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses.
Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus,
, or
Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.
T cell responses are crucial for anti-tumor immunity. In chronic viral infections, anti-tumor T cell responses can be compromised due to various immunological mechanisms, including T cell exhaustion. ...To study mechanisms of anti-tumor immunity during a chronic viral infection, we made use of the well-established Friend virus (FV) mouse model. Chronically FV-infected mice are impaired in their ability to reject FBL-3 cells—a virus-induced tumor cell line of C57BL/6 origin. Here we aimed to explore therapeutic strategies to overcome the influence of T cell exhaustion during chronic viral infection, and reactivate effector CD8
+
and CD4
+
T cells to eliminate tumor cells. For T cell stimulation, agonistic antibodies against the tumor necrosis factor receptor (TNFR) superfamily members CD137 and CD134 were used, because they were reported to augment the cytotoxic program of T cells. αCD137 agonistic therapy, but not αCD134 agonistic therapy, resulted in FBL-3 tumor elimination in chronically FV-infected mice. CD137 stimulation significantly enhanced the cytotoxic activity of both CD4
+
and CD8
+
T cells, which were both required for efficient tumor control. Our study suggests that agonistic antibodies to CD137 can efficiently enhance anti-tumor immunity even in the setting of chronic viral infection, which might have promising therapeutic applications.
In the Friend retrovirus mouse model we developed potent adenovirus-based vaccines that were designed to induce either strong Friend virus GagL
-specific CD8
T cell or antibody responses, ...respectively. To optimize the immunization outcome we evaluated vaccination strategies using combinations of these vaccines.
While the vaccines on their own confer strong protection from a subsequent Friend virus challenge, the simple combination of the vaccines for the establishment of an optimized immunization protocol did not result in a further improvement of vaccine effectivity. We demonstrate that the co-immunization with GagL
/leader-gag encoding vectors together with envelope-encoding vectors abrogates the induction of GagL
-specific CD8
T cells, and in successive immunization protocols the immunization with the GagL
/leader-gag encoding vector had to precede the immunization with an envelope encoding vector for the efficient induction of GagL
-specific CD8
T cells. Importantly, the antibody response to envelope was in fact enhanced when the mice were adenovirus-experienced from a prior immunization, highlighting the expedience of this approach.
To circumvent the immunosuppressive effect of envelope on immune responses to simultaneously or subsequently administered immunogens, we developed a two immunizations-based vaccination protocol that induces strong immune responses and confers robust protection of highly Friend virus-susceptible mice from a lethal Friend virus challenge.
RRP22 (Ras‐related protein on chromosome 22) has been suggested as a candidate tumor suppressor in human cancers. Investigating a panel of 70 human gliomas, we found a frequent decrease in the RRP22 ...mRNA expression levels (67%), preferentially in high‐grade gliomas World Health Organization (WHO) grades III and IV as compared with low‐grade gliomas (WHO grade II). Moreover, reduced RRP22 mRNA expression was associated with shorter overall survival in 180 glioblastoma patients included in the National Institutes of Health Repository for Molecular Brain Neoplasia Data (NIH REMBRANDT) database. Decreased RRP22 expression levels were in part explained by 5'‐CpG island hypermethylation and increased by the treatment with the demethylating agent 5‐aza‐2'‐deoxycytidine in glioblastoma cell lines. In addition, the in vitro treatment with the histone deacetylase inhibitor trichostatin A alone resulted in RRP22 reexpression as well as a significant increase in the levels of RRP22 promoter DNA bound to pan‐acetylated histone H3 and H4. Moreover, in primary human glioblastomas, we observed an increase of H3K9me3‐bound and a decrease of pan‐Ac‐H3‐bound RRP22 in comparison with non‐neoplastic brain tissue, consistent with a heterochromatinization of the RRP22 promoter. Taken together, our findings demonstrate that both 5'‐CpG island hypermethylation and histone modifications contribute to the frequent and prognostically unfavorable transcriptional downregulation of RRP22 in malignant gliomas.
Interleukins (IL) are cytokines with stimulatory and modulatory functions in the immune system. In this study, we have chosen interleukins which are involved in the enhancement of TH2 responses and B ...cell functions to analyze their potential to improve a prophylactic adenovirus-based anti-retroviral vaccine with regard to antibody and virus-specific CD4+ T cell responses. Mice were vaccinated with an adenoviral vector which encodes and displays the Friend Virus (FV) surface envelope protein gp70 (Ad.pIXgp70) in combination with adenoviral vectors encoding the interleukins IL4, IL5, IL6, IL7 or IL23. Co-application of Ad.pIXgp70 with Ad.IL5, Ad.IL6 or Ad.IL23 resulted in improved protection with high control over FV-induced splenomegaly and reduced viral loads. Mice co-immunized with adenoviral vectors encoding IL5 or IL23 showed increased neutralizing antibody responses while mice co-immunized with Ad.IL6 or Ad.IL23 showed improved FV-specific CD4+ T cell responses compared to mice immunized with Ad.pIXgp70 alone. We show that the co-application of adenoviral vectors encoding specific interleukins is suitable to improve the vaccination efficacy of an anti-retroviral vaccine. Improved protection correlated with improved CD4+ T cell responses and especially with higher neutralizing antibody titers. The co-application of selected interleukin-encoding adenoviral vectors is a valuable tool for vaccination with regard to enhancement of antibody mediated immunity.
Der Digitale Zwilling Brücke leistet einen wichtigen Beitrag auf dem Weg zum prädiktiven Lebenszyklusmanagement. In der Lebenszyklusphase „Betrieb“ kann der Digitale Zwilling Brücke als effizientes ...Werkzeug in Bezug auf Analysieren, Vorhersagen, Steuern und Überwachen dienen. Ziel ist eine optimierte Erhaltung, deren Bedeutung angesichts der aktuellen Herausforderungen für Ingenieurbauwerke weiter steigt. Relevante Stakeholder mit ihren Bedarfen und Anforderungen müssen frühzeitig in die Konzeption des Digitalen Zwillings Brücke eingebunden werden. Dieser Weg wird durch die Bundesanstalt für Straßenwesen (BASt) in vielfältigen Forschungsprojekten verfolgt und auch in einem laufenden Projekt zur Entwicklung einer Gesamtkonzeption des Digitalen Zwillings Brücke fortgeführt. Mögliche Anwendungsfälle wurden gesammelt und den Themenbereichen „Betriebsprozesse“, „Erhaltungsplanung und ‐durchführung“ sowie „Strategisches Lebenszyklusmanagement“ zugeordnet. Im Rahmen eines Workshops dienten die Anwendungsfälle der Diskussion und zur initialen Priorisierung mit Stakeholdern. Die Ergebnisse bilden eine wichtige Grundlage für die Ausarbeitung des modularen Gesamtkonzepts Digitaler Zwilling Brücke und den Weg in die Praxis.
Use cases of a digital twin bridge in operation
The digital twin bridge makes an important contribution on the way to predictive life cycle management. The potentials are many, especially in the life cycle phase “operation”. There, the digital twin bridge can serve as an efficient tool in terms of analyses, predictions, control and monitoring. The goal is optimized maintenance, the importance of which continues to grow in view of the current challenges for civil engineering structures. It is therefore particularly important that relevant stakeholders with their needs and requirements are involved in the conception of the digital twin bridge at an early stage. This approach is being pursued by the German Federal Highway Research Institute (BASt) in various research projects that already cover partial aspects of the digital twin and is also being continued in an ongoing project to develop an overall concept for the digital twin bridge. Possible use cases were collected and assigned to the topics of “operational processes”, “maintenance planning and implementation” and “strategic life cycle management”. In a workshop, the use cases were discussed and initially ranked by and with stakeholders. The results form an important basis for the elaboration of the modular overall concept of the digital twin bridge and the way into practice.
Abstract
Der Digitale Zwilling Brücke leistet einen wichtigen Beitrag auf dem Weg zum prädiktiven Lebenszyklusmanagement. In der Lebenszyklusphase „Betrieb“ kann der Digitale Zwilling Brücke als ...effizientes Werkzeug in Bezug auf Analysieren, Vorhersagen, Steuern und Überwachen dienen. Ziel ist eine optimierte Erhaltung, deren Bedeutung angesichts der aktuellen Herausforderungen für Ingenieurbauwerke weiter steigt. Relevante Stakeholder mit ihren Bedarfen und Anforderungen müssen frühzeitig in die Konzeption des Digitalen Zwillings Brücke eingebunden werden. Dieser Weg wird durch die Bundesanstalt für Straßenwesen (BASt) in vielfältigen Forschungsprojekten verfolgt und auch in einem laufenden Projekt zur Entwicklung einer Gesamtkonzeption des Digitalen Zwillings Brücke fortgeführt. Mögliche Anwendungsfälle wurden gesammelt und den Themenbereichen „Betriebsprozesse“, „Erhaltungsplanung und ‐durchführung“ sowie „Strategisches Lebenszyklusmanagement“ zugeordnet. Im Rahmen eines Workshops dienten die Anwendungsfälle der Diskussion und zur initialen Priorisierung mit Stakeholdern. Die Ergebnisse bilden eine wichtige Grundlage für die Ausarbeitung des modularen Gesamtkonzepts Digitaler Zwilling Brücke und den Weg in die Praxis.
Abstract
Use cases of a digital twin bridge in operation
The digital twin bridge makes an important contribution on the way to predictive life cycle management. The potentials are many, especially in the life cycle phase “operation”. There, the digital twin bridge can serve as an efficient tool in terms of analyses, predictions, control and monitoring. The goal is optimized maintenance, the importance of which continues to grow in view of the current challenges for civil engineering structures. It is therefore particularly important that relevant stakeholders with their needs and requirements are involved in the conception of the digital twin bridge at an early stage. This approach is being pursued by the German Federal Highway Research Institute (BASt) in various research projects that already cover partial aspects of the digital twin and is also being continued in an ongoing project to develop an overall concept for the digital twin bridge. Possible use cases were collected and assigned to the topics of “operational processes”, “maintenance planning and implementation” and “strategic life cycle management”. In a workshop, the use cases were discussed and initially ranked by and with stakeholders. The results form an important basis for the elaboration of the modular overall concept of the digital twin bridge and the way into practice.
One of the challenges of the SARS-CoV-2 pandemic was a widespread skepticism about vaccination. To elucidate the underlying mental and emotional predispositions, we examined a sample of 1428 ...participants using latent profile analysis (LPA) on selected personality trait variables, mental health status, and measures of irrational beliefs. LPA revealed five distinct profiles: two classes of non-skeptics and three of skeptics. The smaller non-skeptic class reported the highest rates of mental health problems, along with high levels of neuroticism, hostility, interpersonal sensitivity, and external locus of control. The larger non-skeptic class was psychologically well-balanced. Conversely, the skeptic groups shared strong distrust of COVID-19 vaccination but differed in emotional and mental profiles, leading to graded differences in endorsing extreme conspiracy beliefs. This suggests that vaccine skepticism is not solely a result of mental illness or emotional instability; rather extreme skepticism manifests as a nuanced, graded phenomenon contingent on personality traits and conspirational beliefs.
Der Digitale Zwilling Brücke unterstützt den Übergang von einer bisher reaktiven Erhaltung zu einem prädiktiven Lebenszyklusmanagement von Brücken. Damit wird das
übergeordnete Ziel verfolgt, eine ...optimierte Unterstützung der Bauwerksbetreibenden bei der Gewährleistung der Sicherheit, Zuverlässigkeit und Verfügbarkeit zu leisten. Der
digitale Zwilling eines Ingenieurbauwerks kann als ein digitales Abbild eines realen Bauwerks verstanden werden und spiegelt sämtliche Eigenschaften und sein Verhalten
anhand verschiedener Modelle über dessen gesamten Lebenszyklus hinweg. Der digitale Zwilling aktualisiert sich kontinuierlich, um den aktuellen Status des realen Bauwerks sowie die daraus ableitbaren Prognosen möglichst zeitnah darzustellen. Zu diesem Zweck greift er auf große Datenmengen zurück, die u. a. am realen Bauwerk, dem Reallabor, gesammelt werden. Die Umsetzung des digitalen Zwillings für Brückenbauwerke ist aktuell Forschungsgegenstand, die Entwicklung einer Gesamtkonzeption
für den Digitalen Zwilling Brücke und einzelner Komponenten steht aktuell im Fokus der BASt-Forschung. Hierbei sind die Anwendung von virtueller und erweiterter Realität in
der Bauwerksprüfung, die KI-basierte (teil-)automatisierte Ableitung von Bestandsmodellen, und der Einsatz von KI-Verfahren zur Erkennung von Anomalien Beispiele für die Umsetzung einzelner Komponenten. Ein möglicher Einsatz des digitalen Zwillings kann über verschiedene Anwendungsfälle erfolgen, neben dem Themenbereich Erhaltungsplanung und -durchführung“ sind die Themenbereiche „Betriebsprozesse“ sowie „Strategisches Lebenszyklusmanagement“ von Relevanz. Für den Themenbereich „Erhaltungsplanung und -durchführung“ sind u. a. die Anwendungsfälle „Schadensanalyse“ und „Intervallbezogene Zustandserfassung“ von Bedeutung.
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