Deregulierungspotentiale in der Bundesrepublik.

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Heterologous DNA-prime/protein-boost immunization with a monomeric SARS-CoV-2 spike antigen redundantizes the trimeric receptor-binding domain structure to induce neutralizing antibodies in old mice

A multitude of alterations in the old immune system impair its functional integrity. Closely related, older individuals show, for example, a reduced responsiveness to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. However, systematic strategies to specifically improve the efficacy of vaccines in the old are missing or limited to simple approaches like increasing the antigen concentration or injection frequencies. We here asked whether the intrinsic, trimeric structure of the SARS-CoV-2 spike (S) antigen and/or a DNA- or protein-based antigen delivery platform affects priming of functional antibody responses particularly in old mice. The used S-antigens were primarily defined by the presence/absence of the membrane-anchoring TM domain and the closely interlinked formation/non-formation of a trimeric structure of the receptor binding domain (S-RBD). Among others, we generated vectors expressing prefusion-stabilized, cell-associated (TM+) trimeric “S2-P” or secreted (TM−) monomeric “S6-PΔTM” antigens. These proteins were produced from vector-transfected HEK-293T cells under mild conditions by Strep-tag purification, revealing that cell-associated but not secreted S proteins tightly bound Hsp73 and Grp78 chaperones. We showed that both, TM-deficient S6-PΔTM and full-length S2-P antigens elicited very similar S-RBD-specific antibody titers and pseudovirus neutralization activities in young (2–3 months) mice through homologous DNA-prime/DNA-boost or protein-prime/protein-boost vaccination. The trimeric S2-P antigen induced high S-RBD-specific antibody responses in old (23-24 months) mice through DNA-prime/DNA-boost vaccination. Unexpectedly, the monomeric S6-PΔTM antigen induced very low S-RBD-specific antibody titers in old mice through homologous DNA-prime/DNA-boost or protein-prime/protein-boost vaccination. However, old mice efficiently elicited an S-RBD-specific antibody response after heterologous DNA-prime/protein-boost immunization with the S6-PΔTM antigen, and antibody titers even reached similar levels and neutralizing activities as in young mice and also cross-reacted with different S-variants of concern. The old immune system thus distinguished between trimeric and monomeric S protein conformations: it remained antigen responsive to the trimeric S2-P antigen, and a simple change in the vaccine delivery regimen was sufficient to unleash its reactivity to the monomeric S6-PΔTM antigen. This clearly shows that both the antigen structure and the delivery platform are crucial to efficiently prime humoral immune responses in old mice and might be relevant for designing “age-adapted” vaccine strategies

Serum neutralizing capacity and T-cell response against the omicron BA.1 variant in seropositive children and their parents one year after SARS-CoV-2 infection

IntroductionDurability of immune protection against reinfection with SARS-CoV-2 remains enigmatic, especially in the pediatric population and in the context of immune-evading variants of concern. Obviously, this knowledge is required for measures to contain the spread of infection and in selecting rational preventive measures.MethodsHere, we investigated the serum neutralization capacity of 36 seropositive adults and 34 children approximately one year after infection with the ancestral Wuhan strain of SARS-CoV-2 by using a pseudovirus neutralization assay.ResultsWe found that 88.9% of seropositive adult (32/36) and 94.1% of seropositive children (32/34) convalescents retained the neutralizing activity against the SARS-CoV-2 Wuhan strain (WT). Although, the neutralization effect against Omicron BA.1 (B.1.1.529.1) was significantly lower, 70.6% (24/34) of children and 41.7% (15/36) of adults possessed BA.1 cross-neutralizing antibodies. The spike 1 (S1)-specific T cell recall capacity using an activation-induced marker assay was analyzed in 18 adults and 16 children. All participants had detectable S1-specific CD4 T cells against WT, and 72.2% (13/18) adults and 81,3% (13/16) children had detectable S1 WT-specific CD8 T cells. CD4 cross-reactivity against BA.1 was demonstrated in all investigated adults (18/18), and 66.7% (12/18) adult participants had also detectable specific CD8 BA.1 T cells while we detected BA.1 S1 reactive CD4 and CD8 T cells in 81.3% (13/16) children.DiscussionTogether, our findings demonstrate that infection with the ancestral strain of SARS-CoV-2 in children as well as in adults induces robust serological as well as T cell memory responses that persist over at least 12 months. This suggests persistent immunological memory and partial cross-reactivity against Omicron BA.1

Phosphatidylserine-exposing extracellular vesicles in body fluids are an innate defence against apoptotic mimicry viral pathogens

Some viruses are rarely transmitted orally or sexually despite their presence in saliva, breast milk, or semen. We previously identified that extracellular vesicles (EVs) in semen and saliva inhibit Zika virus infection. However, the antiviral spectrum and underlying mechanism remained unclear. Here we applied lipidomics and flow cytometry to show that these EVs expose phosphatidylserine (PS). By blocking PS receptors, targeted by Zika virus in the process of apoptotic mimicry, they interfere with viral attachment and entry. Consequently, physiological concentrations of EVs applied in vitro efficiently inhibited infection by apoptotic mimicry dengue, West Nile, Chikungunya, Ebola and vesicular stomatitis viruses, but not severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus 1, hepatitis C virus and herpesviruses that use other entry receptors. Our results identify the role of PS-rich EVs in body fluids in innate defence against infection via viral apoptotic mimicries, explaining why these viruses are primarily transmitted via PS-EV-deficient blood or blood-ingesting arthropods rather than direct human-to-human contact

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

A General Purpose Detector Simulation for the EDDA Experiment : Application in Monte Carlo Studies of the Luminosity Detectors

T be EDDA experiment is an internal target experiment at t he Cooler Synchrotron COSY at t he Forschungszentrum Jülich. l t was designed to study proton-proton elastic scattering excitation fw1ctions ran ging from 500 MeV to 2500 MeV of laboratory kin etic energy with high relative accuracy. In the first phase of the experiment w1polarized differential cross sections were measured using CH2 fiber targets. To simulate the EDDA experiment, a simulation software named SIGI was developed. SIGI is based on the detector simulation toolkit Gismo. This t◊ol kit had to be extended by a hadronic shower code named MICRES, especially suitable for the energy range avai lab le. Several geometrical elements were added and the tracking in certain parts of the detector was optimized. Finally, a weil known simulation problem, the touching boundary problem, was solved. The problem occurs e.g., when two detector elements in a simulation setup touch. To normalize the data taken in the first pbase of the EDDA experiment, the luminosity was measured using two luminosity monitors, t he secondary electron monitor SEM and tbe PIN diodes. Tbe PIN diodes are siücon detectors, measuring the o-electrons emüted from the target. The efficiency of the PIN diodes depends on the beam momentum. To correctly interpret the data taken with the PIN diodes, their efficiency must be determined using the simulation software. An important aspect of this application are the systematic e1Tors, which are introduced by the simulation. Referring to t he employed combination of two PIN diodes the systematic e1Tor of the simulation is less than 1.0% for the major part of t he momentum range. Only for momenta below 1455 MeV/ c t he error increases to 3.1 %. For one particular PIN diode t he systematic error is even less tban 0.6% for tbe foll momentum range. These results permit tbe use of the PIN diodes to control the proper Operation of the secondary electron monitor SEM.Das EDDA Experiment findet an einem internen Targetplatz des Cooler Synchrotrons COSY am Forschungszentrum Jülich statt. Das Detektorkonzept erlaubt es, mit hoher relativer Genauigkeit Anregungsfunktionen der elastischen Proton-Proton-Streuung im Bereich kinetischer Laborenergien von 500 MeV bis 2500 MeV aufzunehmen. In der ersten Phase des Experiments wurden unpolari­sierte differentielle Wirkungsquerschnitte mit CH2-Fädchentargets gemessen. Zur Simulation des EDDA-Experiments wurde das Simulationsprogramm SIGI entwickelt. SIGI basiert auf dem Simula­tionspaket Gismo. Dieses Programmpaket wurde u.a. um einen Programmteil namens MICRES zur Simulation hadronischer Schauer erweitert, der für den zur Verfügung stehenden Energiebereich besonders geeignet ist. Darüber hinaus wurden diverse geometrische Elemente hinzugefügt und das Unterprogramm zur Spurverfolgung durch bestimmte Teile des Detektors optimiert. Schließlich wurden ein bekanntes Simulationsproblem, das "Touching-Boundary-Problem", gelöst. Es tritt z.B. bei Konfigurationen auf, bei denen sich zwei Detektorelemente berühren. Um die in der ersten Phase des Experimentes gemessenen Daten zu eichen, wurde die Luminosität mit Hilfe zweier Luminositätsmonitore, dem Sekundärelektronenmonitor SEM und den PIN-Dioden, aufgenommen. Bei den PIN-Dioden handelt es sich um Halbleiterdetektoren, die die vom Target emittierten d-Elektronen messen. Die Effizienz der PIN-Dioden hängt vom Strahlimpuls ab. Um mit den PIN-Dioden gemessene Daten korrekt interpretieren zu können, muss die Effizienz mit Hilfe der Simulation bestimmt werden. Ein wichtiger Aspekt dieser Anwendung ist eine Abschätzung der systematischen Fehler der Simulation. Bezogen auf die verwendete Kombination aus zwei PIN-Dioden beträgt der systematische Fehler im überwiegenden Teil des Impulsbereichs weniger als 1,0%. Lediglich für Impulse unter 1455 MeV/c steigt der Fehler auf 3,1% an. Für eine der PIN-Dioden liegt der systematische Fehler sogar unter 0,6% im gesamten Impulsbereich. Diese Ergebnisse erlauben die Nutzung der PIN-Dioden zur Kontrolle der Messungen mit dem Sekundärelektronenmonitor SEM

Recht auf Perspektive: Das Verhältnis von europäischen Minderheiten und den Sorben/Wenden zur Mehrheitsgesellschaft

In diesem Band sind drei Beiträge versammelt, die im Zusammenhang mit einer Tagung an der BTU Cottbus-Senftenberg zum Thema „Das Recht auf Perspektive – Regionalentwicklung bei indigenen Völkern, europäischen Minderheiten und den Sorben/Wenden“ im Dezember 2014 entstanden sind. Aus dieser Tagung ist ein weiterer Beitrag zum Thema des Guten Lebens hervorgegangen, der gesondert als einzelnes Heft in dieser Schriftenreihe erscheint (Waldmüller 2015). Diese Tagung schließt an eine Vorgängerveranstaltung an, deren Beiträge ebenfalls in dieser Schriftenreihe erschienen sind (Häfner/Laschewski 2013), in der das Verhältnis von (Minderheiten-)Kultur und Verfügungsmöglichkeiten an natürlichen Ressourcen thematisiert wurde. Als spezifischen Ausgangspunkt wurde damals die internationale Konvention der ILO 169 über die rechte indigener Völker gewählt. In dieser Tagung wurde deutlich, dass die Frage „nach der Selbst-Bestimmung von regionaler Entwicklung und Entwicklung der Kultur (...) komplex und kompliziert [wird], wenn eine Minderheiten-Kultur auch nicht exklusiv und eineindeutig einem bestimmten Territorium zugeordnet werden kann, wenn also Minderheiten auch in ihrem ‚angestammten Gebiet‘ selbst Minderheiten (geworden) sind. Und dies ist ja bei den Sorben/Wenden der Fall“ (Laschewski/Häfner 2013, 2). Die Beiträge in diesem Band schließen auf unterschiedliche Weise an diese Fragestellung an und thematisieren den europäischen und nationalen Kontext mit Blick auf die Frage des Verhältnisses zwischen Mehrheitsgesellschaft und Minderheiten