Gutenberg Open Science (Univ. Mainz)
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Der Einfluss von KSRP auf die IL-5, IL-10 und IL-13 Expression sowie der Expression des Transkriptionsfaktors c-MAF in T-Lymphozyten
Get PDFDas Immunsystem des Menschen besteht aus einer angeborenen und adaptiven Immunabwehr. Zytokine spielen im Rahmen einer Immunantwort eine entscheidende regulatorische Rolle. Sie werden von verschiedenen Zellen wie T-Lymphozyten freigesetzt und sind an der Regulation, Differenzierung und Aktivierung von Immunzellen beteiligt. Dabei ist eine strenge Kontrolle des Systems notwendig, um Gewebeschäden und Autoimmunität zu verhindern (1) .
Das RNA-bindende Protein KSRP greift über verschiedene Wege in die Genexpression regulatorisch ein (2). Seine Beteiligung an der Regulation der angeborenen Immunantwort ist bereits bekannt (3, 4). Käfer konnte 2019 (5) zum ersten Mal auch einen Nachweis über KSRP-vermittelte Effekte auf Zellen des adaptiven Immunsystems liefern. In murinen T-Lymphozyten, die aus der Milz von KSRP-defizienten Mäusen und Wildtyp Mäusen isoliert wurden, konnte Käfer in den KSRP-defizienten murinen Zellen im Vergleich zu den Wildtyp Zellen eine stärkere Proliferation von CD4+ T-Lymphozyten nachweisen. Des Weiteren detektierte er erhöhte Werte der Interleukine 5,10 und 13 in KSRP-defizienten murinen CD4+ T-Zellen. Die erhöhte Expression dieser Zytokine ist mit einer T-Helfer Zell (TH2) Immunantwort assoziiert. In dieser Arbeit sollten diese Versuche auf die immortalisierten murine T-Lymphozyten Linie EL4 mit und ohne reduzierte KSRP-Expression übertragen werden. Es sollte getestet werden, ob sich diese Zellen eignen, um KSRP-vermittelte Effekte auf die Expression TH2-assoziierter Zytokine zu untersuchen. Dabei zeigten sich abhängig vom Stimulationsmuster und der Stimulationszeit eine erhöhte mRNA-Expression in den EL4 siKSRP Zellen für IL-5 und IL-13 und erniedrigte Werte in der IL-10 mRNA-Expression im Vergleich zu den EL4 Kontrollzellen. In der Proteinanalyse zeigte sich ein erhöhtes IL-5 und IL-13 Expressionsmuster. Im Fall von IL-5 und IL-13 konnte eine KSRP-abhängige Zytokinexpression in immortalisierten EL4 Zellen nachgewiesen werden. Für IL-10 schienen die eingesetzten Zellen kein geeignetes Testsystem darzustellen.
Weiterhin offen war jedoch über welchen molekularen Mechanismus der Einfluss von KSRP auf die TH2-Immunantwort ausgeübt werden könnte. Daher wurde in dieser Arbeit der mir-155/MAF Signalweg als möglicher indirekter Regulationsmechanismus von KSRP auf die Expression der TH2-assoziierten Zytokine behandelt. Laut Literatur fördert KSRP die Reifung der mir-155, welche wiederum den Abbau des Transkriptionsfaktors MAF fördert (6, 7). Im Vergleich zu den Kontrollzellen, konnte in den siKSRP Zellen nach Stimulation überraschenderweise eine erhöhte mir-155-Expression sowie eine reduzierte c-MAF-Expression nachgewiesen werden. Folglich scheint KSRP die TH2-Zytokinexpression unabhängig von dem mir-155/MAF Signalweg zu beeinflussen. Der zugrundeliegende molekulare Mechanismus konnte nicht geklärt werden und bedarf weiteren Untersuchungen.VII, 74 Seiten ; Illustrationen, Diagramm
What are the most important quality of life domains for patients with aplastic anemia and paroxysmal nocturnal hemoglobinuria?
Get PDFÉtale motivic spectra and Voevodsky’s convergence conjecture
Get PDFWe prove a new convergence result for the slice spectral sequence, following work by Levine and Voevodsky. This verifies a derived variant of Voevodsky’s conjecture on convergence of the slice spectral sequence. This is, in turn, a necessary ingredient for our main theorem: a Thomason-style étale descent result for the Bott-inverted motivic sphere spectrum, which generalizes and extends previous étale descent results for special examples of motivic cohomology theories. Combined with first author’s étale rigidity results, we obtain a complete structural description of the étale motivic stable category
Interoception in individuals with autism spectrum disorder : a systematic literature review and meta-analysis
Get PDFThis systematic review and meta-analysis synthesize current research on interoception in individuals with autism spectrum disorder (ASD) across the lifespan. A total of 31 studies meeting stringent inclusion and quality criteria were identified, incorporating both descriptive and numerical analyses of cardiac interoceptive accuracy (cIA), interoceptive sensibility (IS), and interoceptive awareness (IAW) in children, adolescents, and adults with ASD. The meta-analysis of five adult studies using comparable assessment tools found no significant differences in cIA between adults with ASD and neurotypically developed (NTD) controls [N = 5; ˆμ = −.21 (SE = .11), p = .06]. Descriptive summaries of studies in children and adolescents, as well as those examining IS and IAW across age groups, revealed inconsistent findings—some studies reported reduced, increased, or similar interoceptive abilities in ASD compared to NTD. Methodological diversity, differences in measurement instruments, and variability in sample characteristics likely contribute to these inconsistencies. Moderator variables such as age, intelligence quotient (IQ), and comorbidities may influence interoceptive outcomes. Overall, the evidence indicates that ASD is not systematically associated with altered cIA, and the relationship between ASD and other interoceptive dimensions remains unclear. These findings underscore the need for more standardized methodologies and longitudinal research to clarify developmental trajectories and potential clinical implications of interoceptive processing in ASD. A deeper understanding of these mechanisms could lead interventions aimed at improving emotion regulation and social functioning in ASD
Synthesis, characterization, and exosomal corona formation of self-assembled dipeptide nanomaterials
Get PDFExosomes (Exos), also known as small extracellular vesicles, are naturally occurring nanoparticles (NPs), which are characterized by their nanometer size and negative charged in physiological environments. While it is widely accepted that proteins and biological compounds adhere to different nanomaterials (NMs), forming an outer layer known as the biomolecule corona (BC), the detailed understanding of factors contributing to BC formation as well as of its biological effects remains limited. Studies have shown that BC formation can affect the physicochemical properties of synthetic and natural NPs once contacting biological fluids. Here, we present a study investigating the novel concept of exosomal corona formation, which in contrast to the well-documented BC mainly consists of Exos/exosomal components. For this purpose, peptide-based Fmoc-Lysine (Fmoc-Lys) NMs were synthesized and characterized, and interaction studies with (cancer) cell-derived Exos were performed. Measurements of size, zeta potential, and colloidal stability indicate exosomal corona formation. Furthermore, cell viability experiments showed that the Exo-NM interaction resulted in reduced nanotoxicity profile indicating practical relevance for biological applications of these NMs. In summary, here we provide first evidence supporting the concept of exosomal corona formation around NMs that should become part of evaluating interactions at nano-bio-interfaces
CE-ICP-MS investigation of the carbonate complexation of Am(III), Th(IV), Np(V), and U(VI) and the influence of alkali cations
Get PDFCapillary electrophoresis inductively coupled plasma mass spectrometry (CE-ICP-MS) was used to investigate the carbonate complexation of Am(III), Th(IV), Np(V), and U(VI) at environmentally relevant concentrations. Experiments were conducted at an ionic strength of 0.33 M in different alkali chloride solutions (Li+, Na+, and K+). Formation constants for the three successive actinide carbonate complexes were determined for Am(III), Np(V), and U(VI). For Th(IV), the CE-ICP-MS measurements posed some challenges. The complexation of U(VI) with carbonate was determined to be stronger than previously assumed. A strong influence of alkali cations on the electrophoretic mobility μ of highly negatively charged actinide carbonate complexes was observed and attributed to the association of cations to those complexes. The electrophoretic mobility of negatively charged An-CO3 complexes was found to follow the trend |μLi| ≤ |μNa| < |μK|. Furthermore, the reaction of UO2(CO3)34– with different alkali cations (Me+ = Li+–Cs+) was studied. Complex formation constants for MeUO2(CO3)33– and Me2UO2(CO3)32– for all investigated cations were determined
Hydrogen bonding dynamics in liquids
Get PDFLiquids may appear disordered compared to the structured nature of crystals, but this is only true when considering long-range order. Unlike ideal gases, most liquids exhibit local order due to molecular interactions, ranging from dipole-dipole to electrostatic interactions. For example, water forms an extensive hydrogen bond network or molecular liquids such as alcohols can form aggregates. Understanding intermolecular forces, especially hydrogen bonding, is crucial for insights into phenomena like water’s density anomalies. This thesis addresses three topics within the framework of hydrogen bonding in liquids, with a particular focus on the dynamics of these bonds. We employ linear and two-dimensional infrared spectroscopy (2DIR) alongside ab initio molecular dynamics (AIMD) simulations to explore bonding in liquids.
In the first project, we employ linear and two dimensional infrared (2DIR) spectroscopy to investigate the correlation of the donating hydrogen bonds of water. Water has previously been proposed to form asymmetric hydrogen bonds based on X-ray absorption studies. This supposed asymmetry has been controversially discussed. Our results provide experimental evidence for dynamic anti correlations instead of static asymmetric hydrogen bonds. We use 2DIR spectroscopy to isolate the inhomogeneous contributions to the lineshape for pure and isotopically dilute (HOD in H2O) D2O in dimethylformamide (DMF). Through the dilution in DMF each water molecule only forms two donating hydrogen bonds to the solvent. This allows us to distinguish between symmetric and asymmetric stretching modes for D2O. Comparison with density functional theory calculations (DFT) show, that the about twice broader inhomogeneous lineshape of HOD can be explained by an anti correlated distribution of hydrogen bonds. Furthermore analysis of the crosspeaks for D2O give direct experimental evidence for the anti correlation. We find that this anti correlation quickly decays (< 500 fs). Furthermore similar experiments on urea also show this anti correlation, albeit less pronounced. This confirms that these short lived anti correlations are not special for water but rather expected for all XH2 containing molecules.[1]
In the second project we investigate the solvent properties of the fluorinated mono alcohol hexafluoroisopropanol (HFIP). HFIP is a solvent that is widely used in synthetic chemistry as well as chemical biology. It has been shown to open up novel reaction pathways and to increase the reaction speed of several reactions. This increase in reaction speed has been coined a "booster effect". We investigate the dynamic origins of the booster effect of HFIP, via vibrational and dielectric spectroscopy of HFIP and its non fluorinated counterpart isopropanol (IP). With polarization controlled time resolved IR spectroscopy (TRIR) we found that individual HFIP molecules show a slower reorientation than IP, even though linear IR spectroscopy suggests weaker hydrogen bonds between HFIP molecules compared to IP. 2DIR spectroscopy shows slower hydrogen bonding dynamics for HFIP. Using dielectric relaxation spectroscopy (DRS), we find faster collective reorientation of HFIP, suggesting a smaller average cluster size. Titration experiments with a hydrogen bond accepting substrate (diethylether) reveal that HFIP forms much stronger hydrogen bonds with the substrate than IP. Together our findings suggest that HFIP forms smaller clusters than IP, and thus has more terminal OH groups as potential hydrogen bond donors. The slower hydrogen bond dynamics and reorientation of
HFIP can stabilize the hydrogen bonded clusters, and thus make solvent substrate interactions more likely.[2]
The last projects is about specific ion effects on peptides. The strucure of peptides depends on the solvation environment. Ions can affect peptides directly through
electrostatic interactions as well as indirectly through disruption of the solvent environment. We investigate the effects of Ca2+ on the dipeptide L-alanyl-L-alanine (2Ala). Calcium is located on the protein denaturation side of the Hofmeister series. We in particular focus on the competition between the two potential binding sites with the carboxylate group and the amide carbonyl group. With linear and 2DIR spectroscopy we find a blueshifted shoulder for the carboxylate peak as well as a small redshift for the amide carbonyl. Experiments with 13C labeled 2ALa reveal that the shoulder is connected with Ca2+ interaction at the carboxylate group. Ab initio MD simulations show that Ca2+ binds to the carboxylate and to a lesser degree at the amide CO. This is consistent with an increasing lifetime of the amide CO peak found from 2DIR spectroscopy with increasing salt concentration. At the carboxylate we only find Ca2+ only monodentate bonded. Vibrational density of states (VDOS)
show that this is consistent with a spectral blueshift. Additionally we find configurations of two Ca2+ bound mono dentally to the two carboxylate oxygens. This configuration leads to an additional blueshift. Our results highlight the importance of taking competition between different binding sites into account, when designing model systems for peptide interactions.[3]xiv, 152 Seiten ; Illustrationen, Diagramm
mRNA-LNP vaccine strategies : effects of adjuvants on non-parenchymal liver cells and tolerance
Get PDFThe liver, which plays pivotal roles in metabolism and immunity, often confers tolerance, suppressing immune responses to pathogens. Adjuvanted, lipid nanoparticle-encapsulated mRNA vaccines (mRNA-LNPs) offer a promising approach to overcome immune tolerance. In this study, the immunostimulatory activity of well-documented adjuvants, i.e., 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), resiquimod (R848), and polyinosinic:polycytidylic acid (Poly I:C), on non-parenchymal liver cells was determined. When co-applied with mRNA-loaded LNPs, these adjuvants enhanced immune responses at variable extents. Moreover, the efficiency of mRNA translation in the presence of cGAMP was comparable with the non-adjuvanted control. Repetitive co-application of adjuvants with mRNA-LNPs showed improvement in cellular responses when R848 or R848/cGAMP treatments were used. These findings emphasize the need to delineate the delicate balance between immunomodulatory properties and the efficiency of mRNA translation when selecting adjuvants for mRNA-LNP vaccines and offer insights on how to enhance immunity to infectious diseases and cancers that affect the liver
A systematic review and meta-analysis of the effects of Entertainment-Education interventions on persuasive health outcomes
Get PDFEntertainment-Education (EE) refers to the integration of entertaining and educational components within popular media, with the objective of positively impacting social and health behaviors. This study aims to synthesize the effects of EE for health communication. In particular, the effects of EE on health knowledge, intentions, attitudes, behavior, and self-efficacy were analyzed. Further, a persuasion index was created based on the primary outcomes. Only controlled or randomized-controlled studies were considered, and after screening, K = 39 of N = 4183 studies were included. Pairwise meta-analyses were conducted to determine the effects of EE on persuasive health outcomes. Additionally, potential effects of the subgroups delivery mode, gender, healthcare, type of control group and type and taxonomy of health behavior on a weighted persuasion index were analyzed. Analyses revealed evidence for significant small to moderate effects on all outcomes, with the largest effect sizes on knowledge and self-efficacy. Subgroups seem to account for a significant amount of heterogeneity, as a significant effect could be observed for all analyzed subgroups except for healthcare and gender. The meta-analysis suggests that EE is suitable for the communication of health messages, particularly when targeting prevention topics. However, it is imperative to exercise caution when interpreting the results, and further research is needed
Polymere Trägersysteme für den Wirkstofftransport
Get PDFZiel dieser Arbeit war es polymerbasierte Trägersysteme herzustellen, die in der Lage
sind im Inneren unterschiedliche Substanzen einzuschließen und diese gezielt zu
transportieren. Dafür eignen sich besonders Polymersome mit einer dicken
hydrophoben Membran und einem wässrigen Kern, sowie kernvernetzte Mizellen mit
einem hydrophoben Kern.
Um Polymersome zu bilden wurden Polymere der drei Blockzusammensetzungen
P(DHPMA)-b-P(LMA), P(DHPMA)-b-P(LMA-stat-DDEMA) und P(DHPMA)-b-P(LMAstat-
DDEMA-stat-HHMA) hergestellt. Auf Basis von HPMA Polymeren der
Zusammensetzung P(HPMA)x-P(PDSM)y wurden kernvernetzte Mizellen gebildet. Die
Herstellung der Polymere erfolgte mittels RAFT -Polymerisation und einem
Reaktivester. Die Aggregation zu Partikeln erfolgte mittels dualer asymmetrischer
Zentrifuge. Die vesikulären Partikel wurden hinsichtlich ihres Potentials als
Wirkstoffträger hin untersucht, dafür wurden diese mit den Wirkstoffen Doxorubicin und
Rapamycin in der dualen asymmetrischen Zentrifuge beladen und die dazugehörigen
Beladungseffizienzen ermittelt. Die Aufreinigung erfolgte automatisiert mittels HPLC
um saubere Polymersome zu erhalten, die frei von nicht eingeschlossenem Wirkstoff
oder nicht assembliertem Polymer sind. Damit bietet die entwickelte
Aufreinigungsmethode die Möglichkeit, ein sehr sauberes Partikelsystem zu erhalten
welches gleichzeitig automatisierbar, skalierbar und reproduzierbar ist. Somit erfüllt
das System wichtige Voraussetzungen hinsichtlich eines späteren Einsatzes als
Transportsystem in der Pharmaindustrie. Die mit Doxorubicin beladenen Partikel
wurden in Zelltests hinsichtlich Zellaufnahme quantifiziert.
Über die Azid-Endgruppe war es möglich die äußere Hülle der assemblierten Partikel
mit Farbstoff oder Biotin zu funktionalisieren. Die Anreicherung solcher
farbstoffmarkierten Partikel konnte in Mäusen gezeigt werden.
Es wurde über den Reaktivester Block PFPMA ein Fluoreszenfarbstoff in das
Vorläuferpolymer eingebunden und für die HPMA basierten kernvernetzten Mizellen
verwendet. Der PDSM-Block des Polymers ermöglicht eine Kern-Vernetzung der
Partikel über Disulfidbrücken. Die Assemblierung der Mizellen erfolgte mittels solvent
switch Methode (Lösungsmittelaustausch) und über die duale asymmetrische
Zentrifuge. Beide Methoden wurden miteinander verglichen.IV, 190 Seiten ; Illustratione