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Molecular Mechanisms of Silicone Network Formation: Bridging Scales from Curing Reactions to Percolation and Entanglement Analyses
No full textThe curing of silicone networks from dimethylsilanediol and methylsilanetriol chainbuilder–crosslinker precursor mixtures is investigated from combined quantum/molecular mechanics simulations. Upon screening different crosslinker content from 5 to 15%, we provide a series of atomic-resolution bulk models all featuring 98–99% curing degree, albeit at rather different arrangement of the chains and nodes, respectively. To elucidate the nm scale alignment of the polymer networks, we bridge scales from atomic simulation cells to graph theory and demonstrate the analyses of 3-dimensional percolation of -O-Si-O- bonds, polydimethylsiloxane branching characteristics and the interpenetration of loops. Our findings are discussed in the context of the available experimental data to relate heat of formation, curing degree and elastic properties to the molecular scale structural details—thus promoting the in-depth understanding of silicone resins.This research was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—377472739/GRK 2423/2-2023.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation
Antimicrobial Photodynamic Inactivation of Pseudomonas aeruginosa Using Chlorophyllin
Get PDFAntimicrobial resistance (AMR) remains a global challenge. One of the leading pathogens contributing to the burden of AMR in 2019 and the priority target for the development of alternative antimicrobial agents is the opportunistic pathogen Pseudomonas aeruginosa. One of the promising antimicrobial strategies is antimicrobial photodynamic inactivation (aPDI). Yet, many photosensitizers are tested versus planktonic cells, which fails to mirror the real-life presence of biofilms. This study investigates the efficacy of chlorophyllin (CHL) exposed to red light alone and in combination with the cationic permeabilizer polyethylenimine (PEI) or the activator of mechanosensitive channels butylparaben (BP) against different physiological states of P. aeruginosa, including planktonic cells, persister cells and biofilms. Antimicrobial susceptibility tests were performed using the broth microdilution checkerboard method to determine the bactericidal concentrations. Serine hydroxamate was used for the induction of persister cells via amino acid starvation. Dark conditions were non-lethal to P. aeruginosa. However, under illumination, CHL effectively eradicated P. aeruginosa biofilm cells in colony biofilm. Persister cells exhibited more sensitivity to CHL/PEI combinations compared to growing cells; whereas they were less sensitive to CHL/BP combinations. Neither PEI, BP nor red light alone was lethal to P. aeruginosa under the tested conditions. Visual evidence from confocal and TEM images illustrates the influence of CHL and red light, which intensifies when combined with BP. These findings highlight the potential antimicrobial effect of CHL against P. aeruginosa biofilms and enhanced strategies for targeting persister cells. Further research is needed to optimize treatment parameters and evaluate its applicability
Determination of ligand-induced GPCR function by luminescence-based assays
Get PDFThe human genome encodes approximately 800 G protein-coupled receptors (GPCRs), which are involved in various physiological regulation processes. This makes them valuable targets for the treatment of pain, cardiovascular, pulmonary, neurodegenerative, neurological, and gastrointestinal diseases. Approximately 34 % of FDA-approved drugs target 108 different GPCRs highlighting the potential of addressing this class of receptors. In modern drug development, the design of ligands with highly specific signaling profiles including receptor subtype selectivity, functional selectivity between different signaling pathways, and location bias is a highly desirable but often challenging objective. The aim of this thesis was the biological investigation of novel ligands from our laboratory that target the β1/β2 adrenergic receptors, the μ opioid receptor, and the orexin-1 receptor. Suitable biological in vitro assay systems were successfully established and optimized for each of the specific questions addressed to identify promising new drug candidates with desired signaling profiles. In the functional studies conducted, pH-sensitive compounds that selectively target cellular compartments and tissues exposed to low pH levels were identified for the β1/β2 adrenergic receptors and the μ opioid receptor. Further, the β1/β2 adrenergic receptor signaling could be addressed specifically using recently designed negative allosteric modulators and conformationally restricted catecholamine analogs. Moreover, the functional selectivity of novel μ opioid receptor agonists was assessed, identifying promising candidates with G protein-biased signaling. Finally, insights into the kinetics of orexin receptor antagonism were obtained using a novel non-peptidic OX1R-selective antagonist. In summary, this work successfully characterized and identified promising new approaches for selective drug targeting
The role of C-terminal binding protein 1 (CTBP1) in cellular energetics
Get PDFKurzzusammenfassung/Abstract*:
C-terminal Binding Protein 1 (CTBP1) is a ubiquitously expressed dual-function protein that acts as a transcriptional co-repressor and membrane trafficking regulator. It controls a broad range of cellular processes including apoptosis, cellular proliferation, and metabolism. In neurons, it can shuttle between the nucleus and the presynapse in a (nicotinamide adenine dinucleotide) NAD+/NADH, and neuronal activity-dependent manner. In the nucleus, CTBP1 regulates synaptic plasticity- and neurodevelopment-associated genes. In the presynapse, it controls synaptic vesicle recycling and maintains synaptic transmission. A recently identified de novo
c.C991T mutation in the CTBP1 gene leads to the expression of p.R331W CTBP1 and causes hypotonia, ataxia, developmental delay, and tooth enamel defects syndrome (HADDTS). CTBP1 is a sensor of cellular metabolic state and was linked to cellular energetics in cancer. However, this aspect was not addressed for the function of CTBP1 in neurons and in connection to CTBP1R331W- linked HADDTS pathophysiology.
This work aimed to elucidate the role of CTBP1 in hippocampal metabolic homeostasis, and HADDTS pathophysiology using CTBP1 knock-out mice and human embryonic stem cells (hESC) with the HADDTS-linked CTBP1R331W mutation that were generated using CRISPR/Cas9 genome editing in the frame of this thesis. Using electrophysiological recordings in acute hippocampal slices under different metabolic stress conditions we demonstrated that CTBP1 promotes the resilience of hippocampal neurotransmission to metabolic stress and identified the presynaptic compartment as the putative locus of this dysfunction. The HADDTS hESC showed reduced pluripotency, proliferation rate and changes in their differentiation potential to 3 germ layers. To understand the underlying mechanisms, we performed Seahorse metabolic flux assay, transcriptional profiling and specific enzymatic activity assays. These experiments revealed that lower glycolytic capacity and mitochondrial dysfunction drive the increased effect of metabolic stress on hippocampal neurotransmission in Ctbp1 KO animals. In HADDTS hESCs we performed seahorse metabolic flux assay, BrdU staining-based proliferation rate assay, gene expression profiling of pluripotency state and 3-germ line differentiation, pluripotency analysis following 2-DG treatment, expressional analysis of TP53 and its downstream pathways analysis. These experiments revealed decreased resilience to metabolic stresses, decreased glycolytic capacity and proliferation rate, mitotic phase prolongation, decreased pluripotency, and decreased ectodermal and mesodermal marker expression during differentiation but increased endodermal markers and attenuated neuronal maturation. Therefore we identified TP53-mediated metabolic dysregulation as a molecular mediator of HADDTS pathology
These results provide new insight into the role of CTBP1 in the regulation of neuronal metabolism and reveal metabolic dysfunction as the key feature of cellular dysfunction in HADDTS. These results might contribute to the development of new therapeutic strategies in HADDTS and other CTBP1-linked pathological conditions
Functional Evaluation of Bivalent Ligands at Heterodimers of Dopamine D3 and Neurotensin 1 Receptors
No full textG protein-coupled receptors (GPCRs) comprise the largest family of cell surface receptors with over 800 proteins in humans. GPCRs are involved in and control numerous physiological processes, like neuronal transmission, sensory transduction, hormonal signaling, and cell-cell communication, and are activated by several stimuli, like peptide and non-peptide neurotransmitters, odorant molecules, hormones, small molecule metabolites, growth factors, and light. GPCRs are therefore ideal targets for drug development. More than 30% of the FDA-approved drugs on the market are targeting GPCRs, however, only 10% of the whole GPCR family is addressed.
The co-expression of NTSR1 and D2R and the allosteric modulation of NTSR1 on D2R within a D2R-NTSR1 heterodimer opened a new strategy to treat CNS disorders. Besides targeting D2R-NTSR1 heterodimers to potentially improve the therapy of Parkinson’s disease and schizophrenia, D3R-NTSR1 heterodimers could be addressed in addition for addiction and inflammatory diseases as well as pathological gambling.
Bivalent ligands present extremely powerful tools for the study of these GPCR heterodimers and may potentially serve as next generation therapeutics with reduced side effects.
In this thesis, the ability of bivalent ligands to bind to and foster heterodimerization of D3R with NTSR1 was analyzed using new potentially D3R-selective bivalent ligands. Functional analyses were carried out to characterize their pharmacological behavior and revealed an individual signaling profile of bivalently bound D3R-NTSR1 heterodimers.
First, the effects of the new potentially D3R-selective bivalent ligands on heterodimer formation were investigated using BRET saturation assays (chapter 3) and compared to the effects on D2R-NTSR1 heterodimer formation. Since bivalent ligands often possess a higher binding affinity to the dimer compared to the monomeric parent receptors, radioligand binding studies were employed to analyze the affinities of the new bivalent ligands and to investigate their ability to bivalently bind to the heterodimer (chapter 4). In addition, binding studies to D2R and D2R-NTSR1 demonstrated their binding selectivity for D3R and D3R-NTSR1. Further, heterodimerization can lead to altered signal transduction and receptor trafficking. Thus, the bivalent ligand-induced G protein activation, mini G protein and β-arrestin-2 recruitment to the heterodimer in comparison to the monomeric receptors, as well as the induced trafficking route of the receptors was investigated in the chapters 5 and 6. Therefore, enzyme complementation assays and several BRET-based approaches were utilized to investigate the bivalent ligand-induced potencies and efficacies, as well as kinetic studies, which were performed during my research stay in the laboratory of Prof. Davide Calebiro (University of Birmingham). In addition, D3R-NTSR1 heterodimerization were explored in CHO cells. These cells are well established for microscopic studies, especially using the high-resolution TIRF technology. The chapter 7 focuses on the evaluation of suitable conditions and receptor constructs for the microscopic investigation of D3R-NTSR1 on the plasma membrane of living cells. These experiments are also part of the research stay in the laboratory of Davide Calebiro at the University of Birmingham. Furthermore, a recently described allosteric modulator for NTSR1 (SBI-553) is considered as potential pharmacophore for novel hetero-bivalent ligands. An allosteric ligand could have the advantage to bypass the side effects of orthosteric NTSR1 ligands by modulating specific signaling pathways and inhibiting others. The focus of chapter 8 was the characterization of SBI-553 derivatives as allosteric NTSR1 pharmacophores, as well as the analysis of the most promising candidate incorporated into a bivalent ligand (synthesis by Patrick Shinkwin, Chair of Medicinal Chemistry, Gmeiner laboratory, FAU) for its effects on dopamine and neurotensin receptor heterodimer formation and ligand binding.
Overall, the results clearly demonstrate the D3R over D2R selectivity of the new potentially D3R-selective bivalent ligands in mono- and co-expression systems. The D3R-selective bivalent ligands with a spacer length of 44-atoms or more were able to bivalently bind to D3R-NTSR1 heterodimers and enhance the D3R-NTSR1 interaction. The pharmacological properties of D3R-NTSR1 are altered compared to monomeric D3 receptors: The bivalent ligands were able to induce mini Gq, mini Gs, mini Gi and ß-arrestin-2 recruitment to the heterodimer as well as the internalization of the heterodimer-bivalent ligand complex.
These results indicate the unique pharmacological properties of the bivalent ligands and demonstrate that the D3R-NTSR1 heterodimer serves as a novel functional entity. Treatment of these heterodimers with bivalent ligands may lead to an innovative tissue selective treatment option due to the high affinity of the bivalent ligands to the heterodimer over monomeric D3R
Modularer Oberflächenersatz bei Knorpeldefekten des Kniegelenks
Get PDFHintergrund und Ziele: Die Arthrose im Allgemeinen sowie jene des Kniegelenks im Speziellen stellt aufgrund der aktuellen demografischen Entwicklung und der damit einhergehenden alternden Gesellschaft - zusätzlich zum individuellen Leidensdruck der Patienten - eine wachsende sozioökonomische Belastung dar. Gegenwärtig führt die Erkrankung häufig zur Implantation eines künstlichen Gelenkersatzes. Die Entwicklung eines Gelenkimplantates, welches lediglich tatsächlich geschädigten Knorpel ersetzt und somit gesunder Knorpel sowie subchondraler Knochen erhalten werden können, könnte hierbei eine Alternativlösung bieten. In der vorliegenden Arbeit wurde ein solches Implantat in ex vivo Versuchen getestet.
Methoden: Das hier verwendete Implantat besteht aus einer resorbierbaren Polycaprolacton Membran, in die Bausteine aus Aluminium-Oxid zur Verankerung im Knochen eingeschmolzen wurden. Die Versuche wurden am porkinen Kniegelenk durchgeführt. Zunächst wurde ein künstlicher Knorpeldefekt an der medialen Femurkondyle gesetzt, welcher anschließend mittels des oben genannten Konstrukts aufgefüllt wurde. Nach einer festgelegten Anzahl an Belastungszyklen (1.000, 2.000 und 5.000 Bewegungen) in einer continous passive motion Schiene, erfolgte die Evaluation und der Vergleich mit einer Leerdefektgruppe ohne Knorpelersatz sowie einer Vergleichsgruppe mit einem bereits etablierten Knorpelersatz (Chondrogide®). Dies geschah einerseits durch eine makropskopische Beurteilung, welche durch eine Tuschefärbung gestützt wurde, und andererseits mittels Oberflächentopographie Messung inklusive Rauheitsmessung sowie einer histologischen Auswertung mit Hilfe eines semiquantitativen Scores nach durchgeführter Toluidinblau-Färbung.
Ergebnisse: Makroskopisch, topographisch und histologisch konnte kein signifikanter Unterschied zwischen Kontroll-, Leerdefekt- sowie Vergleichsgruppe beobachtet werden. Auch ein Vergleich der Rauheit erbrachte keinen signifikanten Unterschied. In allen Gruppen fiel eine Zunahme der Beschädigung der gegenüberliegenden Knorpelfläche bei steigender Lastwechselzahl auf. Das Implantat selbst wies nach Belastung keine Schäden auf und war fest im Knochen verankert.
Diskussion und Schlussfolgerung: Die Versorgung von Knorpelschäden mittels des hier untersuchten Konstrukts hat sich als eine vielversprechende Methode präsentiert, die in weiteren Versuchen noch genauer evaluiert werden muss. Um weitere Erkenntnisse zu erlangen, wäre der nächste Schritt, die Verträglichkeit in vivo im Tiermodell zu erproben.Background and Objectives: Osteoarthritis in general, and of the knee joint in particular, represents a growing socioeconomic burden due to current demographic trends and the associated aging society - in addition to the individual suffering of patients. Currently, the disease often leads to the implantation of an artificial joint replacement. The development of a joint implant, which only replaces actually damaged cartilage and thus healthy cartilage and subchondral bone can be preserved, could provide an alternative solution. In the present work, such an implant was tested in ex vivo experiments.
Design and Methods: The implant used here consists of a resorbable polycaprolactone membrane into which building blocks of aluminum oxide were fused for anchorage in bone. The experiments were performed on the porkine knee joint. First, an artificial cartilage defect was induced at the medial femoral condyle, which was subsequently filled using the above-mentioned construct. After a fixed number of load cycles (1.000, 2.000 and 5.000 movements) in a continuous-passive-motion splint, the evaluation and comparison to an empty defect group without cartilage replacement and a comparison group with an already established cartilage replacement (Chondrogide®) took place. On the one hand there was a macroscopic evaluation, which was supported by an ink stain, and on the other hand there was a surface topography measurement including roughness measurement as well as a histological evaluation with a semiquantitative score after toluidine blue staining.
Observation and Results: Macroscopically, topographically, and histologically, no significant difference was observed between control, empty defect, and comparison groups. In addition, a comparison of the roughness did not show a significant difference. In all groups, there was an increase in damage to the opposing cartilage surface with increasing number of load cycles. The implant itself showed no damage after loading and was firmly anchored in the bone.
Discussion and Conclusion: The treatment of cartilage damage investigated here has presented itself as a promising method, which requires additional evaluation in further trials. In order to gain further insights, the next step would be to test the compatibility in vivo in animal models
Die Handfunktion bei Psoriasispatienten und der Zusammenhang mit Knochendichte und gesundheitsbezogener Lebensqualität
No full textHintergrund und Ziele
Die Psoriasis ist eine chronisch entzündliche Erkrankung aus dem autoimmunen Formenkreis.
Sie manifestiert sich größtenteils an der Haut (Psoriasis vulgaris) und/oder
an den Gelenken (Psoriasis Arthritis). Neben einem erhöhten Risiko für kardiovaskuläre,
metabolische und renale Erkrankungen ist die Psoriasis häufig einhergehend mit
einer starken Beeinträchtigung der gesundheitsassoziierten Lebensqualität. Dies ist
unter anderem darauf zurückzuführen, dass sowohl beim Hautbefall als auch beim
Gelenkbefall die Hände häufig und früh betroffen sind. Ziel der Studie ist zum einen,
den Gelenkstatus zwischen Patienten mit Psoriasis Arthritis, mit reinem Hautbefall
und einer gesunden Kontrollgruppe zu vergleichen. Im nächsten Schritt wurde dann
ein Zusammenhang zwischen der Funktionalität der Hände und der subjektiven Lebenszufriedenheit
dargestellt.
Methoden
Die Probanden mit Psoriasis, Psoriasis Arthritis sowie eine gesunde Kontrollgruppe
wurden innerhalb des Universitätsklinikums Erlangen rekrutiert. Nach Aufklärung entsprechend
des Studienprotokolls (Ethikvotum #125_16B), in der der Studienablauf
sowie alle Risiken und Nebenwirkungen erläutert und die Fragen beantwortet wurden,
gaben die Probanden ihr schriftliches Einverständnis. Nachdem sie in Fragebögen ihr
subjektives Krankheitsempfinden (Health Assessment Questionnaire, Shortform-36)
beurteilt haben, erfolgte eine klinische Untersuchung der Gelenke. Anschließend wurden
die isometrische Handkraft mittels Handkraftdynamometer (in lbf) und die Handfunktion
mittels Moberg-Picking-Up Tests (in Sekunden) erhoben. Die Knochendichte
des distalen Radius und des Metacarpophalangealsgelenk II wurde mittels 3-dimensionaler
hochauflösender periphererer Computertomographie (XtremeCT, Scanco
Mediacl, Brüttisellen, Schweiz) erhoben. Die Scores der Fragebögen sowie die Messergebnisse
wurden mittels IBM SPSS erfasst und graphisch dargestellt. Für die
Analyse der Mittelwerte wurde der T-Test für unabhängige Stichproben verwendet.
Als Signifikanzniveau wurde p < 0,05 festgelegt.
Ergebnisse
In der Studie mit 194 Teilnehmern (48 Psoriasis, 92 Psoriasis Arthritis, 54 gesunde
Kontrollen) zeigten gesunde Kontrollen die besten Handkraft- (88,24 lbf ± 25,58) und
Funktionalitätsergebnisse (11,57 s ± 2,33). Psoriasispatienten lagen dazwischen
(83,65 lbf ± 34,79 und 14,95 s ± 4,95), während Psoriasis Arthritis-Patienten die
schlechtesten Werte aufwiesen (75,30 lbf ± 36,10 und 15,95 s ± 7,50). Anhand der
Ergebnisse des Health Assessment Questionnaire (HAQ), in dem ein hoher Score mit
einer schlechten Lebensqualität einhergeht, zeigten weibliche Psoriasis Arthritis Patientinnen
die schlechtesten Scores zur gesundheitsbezogenen Lebensqualität (Männer
0,50 ± 0,44; Frauen 0,76 ± 0,78), gefolgt von Psoriasispatienten (Männer 0,35 ±
0,63; Frauen 0,56 ± 0,55), am besten war die der gesunden Kontrollgruppe (Männer
0,08 ± 0,19; Frauen 0,35 ± 0,49). Bei den Endscores des Shortform-36 geht ein niedriger
Score mit einer höheren Lebensqualität einher. Auch hier zeigen weibliche Probandinnen
mit Psoriasis Arthritis die schlechtesten Scores (Männer 42,40 ± 12,15;
Frauen 40,23 ± 11,60), gefolgt von Psoriasispatienten (Männer 44,94 ± 12,31; Frauen
42,96 ± 11,20). Am besten waren die Scores der gesunden Kontrollgruppe (Männer
54,15 ± 5,12; Frauen 51,19 ± 7,24). Es zeigte sich gruppenübergreifend ein Zusammenhang
zwischen Handkraft/Handfunktion und der gesundheitsbezogenen Lebensqualität
(Health Assessment Questionnaire R²=0,370, Shortform-36 „psychisches
Wohlbefinden“ R²=0,059, Shortform-36 „körperliches Wohlbefinden“ R²=0,193). Bezüglich
der Knochendichtemessungen gab es keinen signifikanten Zusammenhang
zwischen der isometrischen Handkraft und der Handfunktionalität.
Schlussfolgerung
Psoriasis Arthritis hat einen Einfluss auf die Funktionalität der Hände und im speziellen
auf die Handkraft und -funktion. Darüber hinaus weisen die Patienten mit Psoriasis
Arthritis starke Einbußen hinsichtlich ihrer gesundheitsbezogenen Lebensqualität auf.
Psoriasis vulgaris gilt als größter Risikofaktor für die Entstehung einer Psoriasis Arthritis.
Dabei kann die Handkraft und -funktionalität bereits eingeschränkt sein, bevor
sich strukturelle Veränderungen darstellen lassen und ohne dabei die anderen
CASPAR-Kriterien zu erfüllen. Dies würde die Theorie der sogenannten subklinischen
Psoriasis Arthritis untermauern. Auch im vorliegenden Kollektiv gaben viele Psoriasispatienten
eine verminderte gesundheitsbezogene Lebensqualität an, allerdings
zeigte sich noch keine Gelenkentzündung und somit keine Arthritis. Die aktuelle Studienlage
ist sich einig, dass eine frühzeitige Detektion von Psoriasis Arthritis unter
Patienten mit Psoriasis vulgaris essenziell ist, um weitere Komorbiditäten zu verhüten.
Interessant ist nun die Frage, was genau zu dieser Funktionseinschränkung führt
und ob die Psoriasispatienten mit verminderter Handkraft im weiteren Verlauf eine
Psoriasis Arthritis entwickeln und strukturelle Schäden vorweisen. In diesem Fall
wäre die Handkraftmessung ein einfaches und schnelles Diagnosemittel, um einen
schweren Krankheitsverlauf zu prognostizieren. Bisher wurde die Handkraftmessung
als Diagnosemittel noch nicht ausreichend untersucht. Zum jetzigen Zeitpunkt bleibt
die Frage ungeklärt, sollte aber Gegenstand der weiteren Forschung sein und beispielsweise
eine längere Verlaufsstudie des Patientenkollektivs nach sich ziehen
Prognose schrittmacherabhängiger Patienten mit implantierbaren kardiovaskulären elektrischen Geräten
No full textBackground Data on the prognostic significance of pacing dependency in patients with cardiovascular implantable electronic devices (CIEDs) are sparse. Methods The prognostic significance of pacing dependency defined as absence of an intrinsic rhythm ≥ 30 bpm was determined in 786 patients with CIEDs at the authors’ institution using univariate and multivariate regression analysis to identify predictors of all-cause mortality. Results During 49 months median follow-up, death occurred in 63 of 130 patients with pacing dependency compared to 241 of 656 patients without pacing dependency (48% versus 37%, hazard ratio [HR] 1.34; 95% confidence interval [CI]: 1.02–1.78, P = 0.04). Using multivariate regression analysis, predictors of all-cause mortality included age (HR 1.07; 95% CI: 1.05–1.08, P < 0.01), history of atrial fibrillation (HR 1.32, 95% CI: 1.03–1.69, P < 0.01), chronic kidney disease (HR 1.28; 95% CI: 1.00–1.63, P = 0.048) and New York Heart Association (NYHA) class ≥ III (HR 2.00; 95% CI: 1.52–2.62, P < 0.01), but not pacing dependency (HR 1.15; 95% CI: 0.86–1.54, P = 0.35). Conclusions In contrast to age, atrial fibrillation, chronic kidney disease and heart failure severity as indexed by NYHA functional class III or IV, pacing dependency does not appear to be an independent predictor of all-cause mortality in patients with CIEDs.Zusammenfassung Hintergrund Daten zur prognostischen Relevanz der Schrittmacherabhängigkeit bei Patienten mit implantierbaren kardiovaskulären elektrischen Geräten („cardiovascular implantable electronic devices“ [CIED]) sind rar. Methoden Die prognostische Relevanz der Schrittmacherabhängigkeit, definiert als Fehlen eines intrinsischen Rhythmus von ≥ 30 Schlägen/min, wurde bei 786 Patienten mit CIED an der Einrichtung der Autoren ermittelt. Hierfür wurden univariate und multivariate Regressionsanalysen durchgeführt, um Prädiktoren der Gesamtmortalität zu identifizieren. Ergebnisse In einem medianen Follow-up von 49 Monaten verstarben 63 von 130 Patienten mit Schrittmacherabhängigkeit verglichen mit 241 von 656 Patienten ohne eine solche (48 % vs. 37 %, Hazard Ratio [HR] 1,34; 95 %-Konfidenzintervall [KI] 1,02–1,78, P = 0,04). In einer multivariaten Regressionsanalyse wurden als Prädiktoren der Gesamtmortalität identifiziert: Alter (HR 1,07; 95 %-KI 1,05–1,08, P < 0,01), Vorhofflimmern in der Vorgeschichte (HR 1,32, 95 %-KI 1,03–1,69, P < 0,01), chronische Nierenerkrankung (HR 1,28; 95 %-KI 1,00–1,63, P = 0,048) und New-York-Heart-Association(NYHA)-Klasse ≥ III (HR 2,00; 95 %-KI 1,52–2,62, P < 0,01), nicht aber die Schrittmacherabhängigkeit (HR 1,15; 95 %-KI 0,86–1,54, P = 0,35). Schlussfolgerungen Anders als Alter, Vorhofflimmern, chronische Nierenerkrankung und der Schweregrad der Herzinsuffizienz (ausgedrückt durch die NYHA-Funktionsklasse III oder IV) scheint die Schrittmacherabhängigkeit kein unabhängiger Prädiktor der Gesamtmortalität von Patienten mit CIED zu sein.Open Access funding enabled and organized by Projekt DEAL.Philipps-Universität Marburg (1009
Predicting plastron thermodynamic stability for underwater superhydrophobicity
Get PDFNon-wettable surfaces, especially those capable of passively trapping air in rough protrusions, can provide surface resilience to the detrimental effects of wetting-related phenomena. However, the development of such superhydrophobic surfaces with a long-lasting entrapped air layer, called plastron, is hampered by the lack of evaluation criteria and methods that can unambiguously distinguish between stable and metastable Cassie-Baxter wetting regimes. The information to evaluate the stability of the wetting regime is missing from the commonly used contact angle goniometry. Therefore, it is necessary to determine which surface features can be used as a signature to identify thermodynamically stable plastron. Here, we describe a methodology for evaluating the thermodynamic underwater stability of the Cassie-Baxter wetting regime of superhydrophobic surfaces by measuring the surface roughness, solid-liquid area fraction, and Young’s contact angle. The method allowed the prediction of passive plastron stability for over one year of continuous submersion, the impeding of mussel and barnacle adhesion, and inhibition of metal corrosion in seawater. Such submersion-stable superhydrophobicity, in which water is repelled by a stable passive air layer trapped between the solid substrate and the surrounding liquid for extended periods at ambient conditions, opens new avenues for science and technologies that require continuous contact of solids with aqueous media.Upon submersion, a superhydrophobic surface can trap a layer of air, termed “plastron”, that separates it from the surrounding liquid. Here, methodology is reported for predicting the thermodynamic stability of plastron by measuring surface roughness, solid-liquid area fraction, and Young’s contact angle.Deutsche Forschungsgemeinschaft (German Research Foundation)https://doi.org/10.13039/50110000165
Manifold‐Fused Porphyrin‐Nanographene Conjugates
Get PDFA library of novel π‐extended porphyrin‐hexabenzocoronene (HBC) architectures is presented. Two distinct synthetic pathways were utilized to obtain either phenyl‐ or HBC‐fused compounds. Absorption experiments reveal the species’ exciting photophysical and optoelectronic properties. Depending on the degree of π‐extension, the number of porphyrins, and their relative position, a decisive change in shape, panchromatic broadening, and red‐shifting of the absorption curves is observed. Theoretical studies give more profound insight into the molecule's electronic structures, showing vast decreases in HOMO‐LUMO energy gaps.The synthesis of a collection of phenyl‐ and hexabenzocoronene (HBC)‐fused porphyrin conjugates is presented. The architectures’ intriguing absorption properties were investigated, revealing the influence of the number of porphyrins, the degree of π‐extension, and their relative position in the molecule. imageDeutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/50110000165