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Das Glioblastom ist ein hochmaligner und aggressiver Hirntumor, der von der WHO als Grad IV eingestuft wird. Die Betroffenen haben eine mittlere Überlebenszeit von 12 bis 15 Monaten, was auf dem invasiven Wachstum und der Chemo- und Radioresistenz des Tumors beruht. Dadurch existiert keine kurative Behandlung und es kommt in nahezu allen Fällen zu Rezidiven. Zunehmend wird deutlich, dass das Glioblastom einen stark veränderten Energiestoffwechsel aufweist, wobei das sogenannte lipidomic remodelling (Koundouros und Poulogiannis, 2020), welches für maßgebliche Alterationen im Fettsäuremetabolismus sorgt, besonders interessant erscheint. Die Fettsäureoxidation sowie damit assoziierte Prozesse und Proteine sind als eine bedeutende Energiequelle in den Fokus der Forschung getreten. So auch der hoch-affine Carnitintransporter OCTN2 (SLC22A5), welcher essentiell für den Carnitinhaushalt und damit die β-Oxidation der Zelle ist. In der vorgelegten Arbeit wurde daher das komplexe OCTN2/L-Carnitin System in seiner Funktion als potenzielle pharmakologische Zielstruktur zur therapeutischen Intervention beim Glioblastom tiefergehend untersucht und vorhandenes Wissen weiter ausgebaut. Hierzu diente eine Vielzahl experimenteller Bedingungen und Methoden, um Teilcharakteristiken des Glioblastoms darzustellen und die Bedeutung des OCTN2/L-Carnitin System zu überprüfen.
Da in vorausgegangenen Studien eine erhöhte Expression von OCTN2 mit einem signifikant schlechteren Überleben von Patienten mit Glioblastom nachgewiesen werden konnte, wurden als weitere potentiell interessante Zielstrukturen der niedrig-affine Carnitintransporter OCTN1 (SLC22A4) sowie Komponenten der β-Oxidation (CPT1C, CRAT) in die Patientenanalysen eingeschlossen. Zwar konnte für OCTN1 eine signifikant erhöhte mRNA-Expression in den humanen Glioblastomproben festgestellt werden, diese war jedoch nicht mit dem Überleben der Patienten assoziiert. Auch CPT1C und CRAT zeigten sich nicht als relevante Zielstrukturen beim Glioblastom.
In den durchgeführten Zellkulturexperimenten mit humanen LN-18 und murinen GL261 Glioblastomzellen zeigten sich partiell signifikante Effekte auf die wachstumsfördernden Kinasen AKT1 und ERK1/2, deren Phosphorylierungsgrad durch L-Carnitin moduliert wurde und die damit möglicherweise an carnitinvermittelten Wirkungen beteiligt sein könnten. Auf die Zellviabilität und Zellvitalität ließen sich hemmende Wirkungen des OCTN2-Inhibitors Meldonium sowie des CPT1-Hemmstoffes Etomoxir nachweisen, welche teilweise durch die zusätzliche Gabe von L-Carnitin revertiert wurden. Hinsichtlich der durch Zytostatika (Doxorubicin, Carmustin, Vincristin und Temozolomid) induzierten Apoptose konnte L-Carnitin nur die durch Carmustin in niedriger Dosierung ausgelöste Caspase-3 Aktivierung verhindern. Ein durch L-Carnitin ausgelöster Effekt auf die Migration der Glioblastomzellen konnte nicht nachgewiesen werden, jedoch wurde die migratorische Aktivität durch die Zytostatika Temozolomid und Carmustin, sowie interessanterweise auch durch den CPT1-Inhibitor Etomoxir, beeinträchtigt.
Um die Möglichkeit einer zielgerichteten Therapie gegen das OCTN2/L-Carnitin System präklinisch zu evaluieren, wurden tierexperimentelle Studien durchgeführt. Unter Verwendung eines orthotopen Glioblastommodelles der Maus konnte gezeigt werden, dass Etomoxir und Meldonium einen hemmenden Einfluss auf das in vivo Tumorwachstum besitzen, wobei dieser Effekt nur für den OCTN2-Inhibitor Meldonium signifikant ausfiel. In den OCTN2-defizienten jvs(-/-)-Mäusen konnte keine ausreichende Anzahl von Versuchstieren erreicht werden, um zuverlässige und finale Aussagen zu tätigen. In den heterozygoten jvs(+/-)-Mäusen, die zwar phänotypisch unauffällig sind, aber durch die geringere OCTN2 Ausstattung verminderte Carnitin-Gewebespiegel aufweisen, zeigte sich eine leichte, nicht signifikante Reduktion des intrazerebralen Tumorwachstums im Vergleich zu den C57BL/6-Wildtyp Mäusen.
Zusammenfassend wurde in der vorliegenden Arbeit das OCTN2/L-Carnitin System und seine Bedeutung für das Glioblastom umfassend dargelegt und experimentell überprüft. Als Endresultat dieser Studie können Etomoxir und Meldonium als Substanzen zur zielgerichteten Beeinflussung des Glioblastomwachstums angesehen werden und sollten in weiteren Versuchsreihen detailliert auf ihre Eignung für die Entwicklung neuer Therapieformen überprüft werden.
Zink-Transporter 8-Autoantikörper sind auch in Kindern ohne hereditäres Diabetes-Risiko in der Lage, das Erkrankungsrisiko zu stratifizieren, was auf eine ähnliche Pathophysiologie hinweist, und insbesondere in anderweitig als niedrig-risikobehaftet eingestuften und in IA-2A-negativen Individuen diejenigen identifiziert, die manifestieren werden.
ZnT8A sind zudem hilfreich in der Identifizierung eines autoimmun-vermittelten Diabetes mellitus im Erwachsenenalter, insbesondere bei phänotypisch als T2D eingestuften Patient*innen, sodass eine entsprechende Therapie und damit die Prognose sowie das Langzeit-Outcome in diesem Patientenkollektiv positiv beeinflusst werden kann.
Das entsprechend des SNP im kodierenden SLC30A8-Gen getriggerte Reaktionsmuster ist in T1D-Patient*innen und hoch-risikobehafteten Kindern mit überwiegend davon unabhängiger Autoantikörperantwort gegenüber der ZnT8WA-dominierenden Antwort in LADA-Patient*innen deutlich different, was die Hypothese unterschiedlicher Pathomechanismen dieser beiden Diabetesformen unterstützt.
Die zusätzliche Testung von ZnT8QA trägt nicht zu einer zusätzlichen Risikostratifizierung bei, sodass ein kombiniertes ZnT8A-Screening mit einem ZnT8-Arg325-Trp325-Hybridkonstrukt eine deutliche Zeit- und Kostenersparnis ohne Sensitivitätsverlust darstellt.
Bei spezifischen klinischen Konstellationen ist eine Lumbalpunktion zur Liquoranalytik
wichtig, um die Ätiologie der epileptischen Anfälle bzw. eines Status epilepticus zu klären und
alternative Erkrankungen auszuschließen. Die im Rahmen der vorliegenden Studie entwickelte
IDEAL-Checkliste stellt vor diesem Hintergrund einen einfach umzusetzenden und in den
klinischen Alltag leicht zu implementierenden Algorithmus dar, der behandelnde Ärztinnen
und Ärzte bei der Entscheidung für oder gegen die Durchführung einer Liquoruntersuchung
unterstützt. Gleichzeitig bewahrt die Anwendung der Checkliste Patientinnen und Patienten vor
einer nicht notwendigen Liquorpunktion mit entsprechenden Risiken. In den hier vorliegenden
Studien hätte bei etwa der Hälfte der Fälle (43 % in der prospektiven bzw. 49 % in der
retrospektiven Kohorte) auf eine Lumbalpunktion verzichtet werden können. Damit hätten die
periprozedurale Belastung der Patientinnen und Patienten sowie potentielle Komplikationen
einer Lumbalpunktion vermieden werden können.
Gleichzeitig besteht aufgrund des hohen negativen prädiktiven Wertes von 99-100 % eine hohe
Wahrscheinlichkeit eine liquorrelevante Ätiologie auch nicht zu übersehen, wenn kein Item der
kombinierten IDEAL-Checkliste zutrifft und damit auf eine Lumbalpunktion zur Liquoranalyse
verzichtet wird.
Eine multizentrische, prospektive Beobachtungsstudie sollte unter Anwendung der nationalen
und demographischen MoCA-Werte und auch im Hinblick auf unterschiedliche
Diagnostikstrategien bzw. Indikationskriterien, die breite klinische Anwendung, aber auch die
Erfassung seltener Ätiologien (z. B. immunsupprimierte Patientinnen und Patienten,
systemische Autoimmunerkrankungen) zur weiteren Validierung der IDEAL-Checkliste
erfolgen.
Modulation der Immunantwort durch Vagotomie im Mausmodell der postoperativen Immundysfunktion
(2024)
Die postoperative Immunsuppression ist ein häufiges Problem nach großen abdominalchirurgischen Eingriffen und geht mit einer erhöhten Mortalität insbesondere durch septische Komplikationen einher. Eine wichtige Rolle bei der Entstehung der Immunsuppression spielt der Nervus vagus, dies ist schon lange als cholinerger antiinflammatorischer Signalweg (engl. CAP) bekannt, wobei weder die Signalkaskaden auf zellulärer Ebene noch die Effekte des Nervus vagus hinreichend verstanden sind und kontrovers diskutiert werden.
Anhand der vorliegenden Ergebnisse dieser Arbeit lässt sich feststellen, dass das Traumamodell der surgically-induced immune dysfunction (SID) weitreichende Auswirkungen auf das Immunsystem hat. So konnten in-vivo signifikant veränderte Serumspiegel von IFN-γ, IL-2 und IL-6 gemessen und somit vorherige Ergebnisse anderer Arbeiten unserer Forschungsabteilung bestätigt werden. Außerdem führte die SID zu deutlichen Veränderungen hinsichtlich der Abwehrlage des angeborenen Immunsystems: wir fanden erniedrigte CD4+/CD8+-Relationen innerhalb der T-Zell-Population sowie insbesondere in der Spätphase ein erhöhtes Ly6Chigh/Ly6Clow-Verhältnis als Ausdruck einer gestörten angeborenen Immunabwehr durch patrolling macrophages, welche sich zusätzlich durch eine Abnahme der MHCII-Expression auf den Makrophagen unter Vagotomie äußerte.
Bei der ex-vivo-Betrachtung des Immunsystems unter Hinzunahme von Funktionstests mit Lipopolysaccharid (LPS) konnten wir beobachten, dass der Ablauf der Immunreaktion anhand der TNF-α-Ausschüttung von Makrophagen interessante Ähnlichkeiten mit dem bekannten SIRS-CARS-Modell der Sepsis aufweist. Wir konnten zeigen, dass die Vagotomie insbesondere in der Frühphase nach SID die hyperinflammatorische Reaktion der Milzmakrophagen noch weiter verstärkt. In der Spätphase 72 Stunden nach Trauma hat die Vagotomie einen geringeren Einfluss auf die Immunantwort und führt zu einer verstärkten Suppression, die allerdings nicht so stark ausgeprägt ist wie die Hyperinflammation in der Frühphase. Die Ausschaltung des N. vagus führt also in beiden Phasen zu einer Abweichung zu den Extremen hin und bedingt eine nachhaltige Störung des immunologischen Gleichgewichts.
Mit der vorliegenden Arbeit konnte ein wichtiger Beitrag zur Grundlagenforschung dieses klinisch so bedeutsamen Problems geleistet werden. Weitere Untersuchungen auf diesem Gebiet sind notwendig, um in Zukunft nach operativem Trauma z.B. in Form von spezifischen Agonisten am alpha7-Rezeptor eine wirksame Therapie oder besser eine Prophylaxe zur Vermeidung anbieten zu können.
Copper tungsten oxide films are deposited with the help of reactive high power impulse magnetron sputtering (HiPIMS) in an argon/oxygen gas mixture. Two magnetrons, one equipped with a tungsten target and the other with a copper target, are employed. The HiPIMS discharge is operated with a repetition frequency of f=100 Hz. Pulse widths of 100 and 20 µs separated by 25 µs are chosen for the tungsten and copper target, respectively. Films deposited on two different glass substrates [soda lime glass and fluorine doped tin oxide (FTO) coated glass] are characterized by energy dispersive x-ray spectroscopy, x-ray photoelectron spectroscopy, x-ray diffraction, Raman spectroscopy, and ellipsometry. Photoelectrochemical activity was investigated by linear voltammetry. The composition and crystal structure of as-deposited and annealed films are found to depend on the deposition conditions. Annealed films deposited on FTO glass are composed of WO3 and CuWO4 or Cu2WO4 crystal phases. Films deposited on soda lime glass are subject to sodium diffusion into the films during annealing and the formation of Na2W2O7 and Na2W4O13 phases.
This article sheds light on the obstacles that women face as members of the government by answering the questions: How does the sex of ministers shape the way MPs’ assess the quality of their work? And, how does this relationship differ depending on the political ideology of MPs? We argue that legislators assess the competencies of women ministers differently after the activation of gender stereotypes, but that the way they react depends on the ideological orientation of their party. We investigate this topic in a real-word context using a unique survey experiment with German and Austrian MPs. The evidence reveals that, while MPs belonging to right-wing parties perceive women in the executive as less competent than men ministers, their colleagues from left-wing parties actually assess them more favorably. These findings highlight the persistence of old myths about women’s lacking political skills and the emergence of new ones about women’s superior ability to govern.
Introduction: Adiposity and excessive weight are on the rise in western industrialized countries. In cases where conservative measures fail and surgical interventions are not (yet) desired, gastric balloon therapy has proven to be a safe and reversible endoscopic method. Methods: Aside from weight progression under gastric balloon therapy and by using MRI, our research paper describes the behavior of different abdominal body fat compartments at the beginning and at the end of the gastric balloon therapy. Additionally, the volume of the left liver lobe as well as the fill volume and performance of the gastric balloon were analyzed over the duration of treatment. For assessing potential impacts of weight reduction on the muscle mass, we determined the area of the m. psoas on a comparable cross-sectional area at the beginning and at the end of the therapy. Results: We were able to verify a significant reduction of the layer of subcutaneous fat, adipose capsule of the kidney, and intra-abdominal fatty tissue during the therapy. The volume of the left liver lobe was shrinking in addition to a muscle loss during the balloon therapy. The volume of the gastric balloon remained stable (not hyperinflation). There were variable gas bubbles in the gastric balloon. Conclusion: The gastric balloon is a temporary and successful option for weight reduction by reducing body fat, liver volume, but also muscle mass.
Thioredoxine (Trxs) bilden eine Familie ubiquitärer Oxidoreduktasen, welche durch posttranslationale Redox-Modifikationen von Cysteinyl-Thiolgruppen sowie die Regulation der intrazellulären Wasserstoffperoxidgehaltes die zelluläre Redoxantwort steuern. Es ist bekannt, dass Thioredoxine, Glutaredoxine (Grxs) und Peroxiredoxine (Prxs) wesentliche Signalwege von Inflammation, Proliferation und Apoptose beeinflussen und somit in vielen Pathologien, insbesondere bei entzündlichen Erkrankungen wie dem allergischen Asthma, eine entscheidende Rolle spielen. Derzeit sind vorwiegend die intrazellulären Funktionen der Proteine der Trx-Familie in Gesundheit und Krankheit umfassend untersucht, doch die extrazellulären Funktionen bei der Redox-Signalübertragung bleiben bis zum heutigen Tage weitestgehend im Dunkeln. In dieser Arbeit haben wir uns daher zum Ziel gesetzt, Verteilung und Funktion von Proteinen der Trx-Familie in der Regulation der Immunantwort zu untersuchen, wobei der Schwerpunkt auf dem extrazellulären Vorkommen und den damit verbundenen Eigenschaften liegt.
Allergische Atemwegsentzündungen sind durch bronchiale Obstruktion und chronischen Umbau sowie Hyperreagibilität der Atemwege gekennzeichnet. Die Anhäufung reaktiver Sauerstoffspezies in der bronchialen Flüssigkeit der Lunge und die sich daraus ergebenden Veränderungen des Redoxzustands in den bronchialen Epithelzellen sind in den letzten Jahren in den Fokus der Asthmaforschung gerückt. Mehrere Studien beschrieben eine positive Wirkung von Trx1 und Grx1 in Atemwegsinfektionen, so würde eine Th2-typische Immunmodulation reduziert und verringere in der Folge den Umbau der Atemwegsstruktur – eine zentrale Pathologie des Asthmas.
In dieser Studie untersuchten wir die Expressionsniveaus von Proteinen der Trx-Familie in Lungengewebe und bronchoalveolärer Lavageflüssigkeit in einem Mausmodell der Ovalbumin (OVA) induzierten allergischen Atemwegsentzündung. Wir konnten eine Zunahme von Grx2 und Prx4 in intrazellulären Proben aus der Mäuselunge nach einsetzen der induzierten Atemwegsinfektion zeigen. Ausschließlich unter OVA-induzierter Inflammation wurde in diesen Proben eine zweite Isoform von Grx2, zytosolisches Grx2c, nachgewiesen. Die Behandlung von Mäusen mit intraperitoneal appliziertem, rekombinantem Grx2 parallel zur Induktion der Entzündung mit OVA, hatte eine entzündungshemmende Wirkung, die zu einer Verringerung des asthmatischen Phänotyps in der Immunhistochemie und einer signifikanten Reduktion der Gesamtzahl der Entzündungszellen, besonders der eosinophilen Granulozyten führte. Die Verabreichung der rekombinanten Grx2C40S-Mutante, der die Fähigkeit zur Katalyse des Dithiol-Reaktionsmechanismus fehlt, hatte nicht die gleiche entzündungshemmende Wirkung. Eine zusätzlich durchgeführte His-Tag-Färbung zeigte eine Aufnahme von rekombinantem Grx2 in die Epithelzellen und Makrophagen der entzündeten Lunge. Die Färbung von Lungenabschnitten für HIF1- und Pro-Caspase3 nahm nach Beginn der allergischen Atemwegsentzündung zu und ging bei den mit dem wildtyp Grx2 behandelten Mäusen deutlich zurück.
In den extrazellulären Fraktionen war die Konzentration von Trx1, Grx1, Prx2 und Prx4 unter Entzündungsbedingungen erhöht, zudem konnte Prx4 in dieser Studie erstmals nur in der Entzündung, nicht aber bei gesunden Mäusen nachgewiesen werden. In-vitro-Experimente, bei denen Makrophagen aus Balb/c-Mäusen stimuliert wurden, sollten Aufschluss über die Funktionen von Trxs und Grxs in der Immunantwort geben. Grx2 und Trx1 wurden als potenzielle Stimulatoren von Makrophagen identifiziert, die die Sekretion von RANTES, IL-6, IL-10 und TNF-α induzieren, während die Zytokinspiegel von IL-4 und INF-γ nicht verändert wurden. Bei kombinierter Verabreichung von Redoxinen mit LPS/IFN-γ, die einen Entzündungszustand nachahmt, wurde gezeigt, dass Trx1 die Zytokinspiegel von TNF-α und INF-γ im Vergleich zu LPS/IFN-γ allein senkt. Die Behandlung mit Trx1/LPS/IFN-γ induzierte die Produktion von IL-6 und RANTES auf ein Niveau vergleichbar mit der alleinigen Stimulation durch LPS/IFN-γ.
Diese Arbeit beleuchtet Proteinveränderungen von Thioredoxinen, Glutaredoxinen und Peroxiredoxinen in einem Mausmodell für allergische Atemwegsentzündungen mit besonderem Schwerpunkt auf der extrazellulären Verteilung und Funktion der Proteine. Wir zeigen, dass die Veränderungen der Proteinspiegel selektiv reguliert werden und zu einem fein abgestimmten Netzwerk von Partnern in der Redox-Signalgebung beitragen und somit Potenzial für mögliche Therapieansätze bieten.
Purpose
The German Retina.net ROP registry and its Europe-wide successor, the EU-ROP registry, collect data from patients treated for ROP. This analysis compares input parameters of these two registries to establish a procedure for joint analyses of different registry data using exemplary datasets from the two registries.
Methods
Exemplary datasets from the two databases over a 1-year period each (German Retina.net ROP Registry, 2011, 22 infants; EU-ROP Registry, 2021, 44 infants) were compared. The parameters documented in the two databases were aligned and analysed regarding demographic parameters, treatment modalities, complications within first 24 h and retreatments.
Results
The current analysis showed that data can be aligned for joint analyses with some adjustments within the data structure. The registry with more detailed data collection (EU-ROP) needs to be reduced regarding granularity in order to align the different registries, as the registry with lower granularity determines the level of analyses that can be performed in a comparative approach. In the exemplary datasets, we observed that the overall most common ROP severity in both registries was zone II, 3+ (2011: 70.5%; 2021: 65%), with decreasing numbers of clock hours showing preretinal neovascularisations (2011: 10–12 clock hours in 29% of cases, 2021: 4–6 clock hours in 38%). The most prevalent treatment method was laser coagulation in 2011 (75%) and anti-VEGF therapy in 2021 (86.1%). Within the anti-VEGF group, all patients were treated with bevacizumab in 2011 and with ranibizumab in 2021. Retreatment rates were comparable in 2011 and 2021.
Conclusion
Data from two different ROP registries can be aligned and jointly analysed. The analysis reveals a paradigm shift in treatment modalities, from predominantly laser to anti-VEGF, and within the anti-VEGF group from bevacizumab to ranibizumab in Germany. In addition, there was a trend towards earlier treatment in 2021.
Hibernation is a widespread adaptation in animals to seasonally changing environmental conditions. In the face of global anthropogenic change, information about plastic adjustments to environmental conditions and associated mortality costs are urgently needed to assess population persistence of hibernating species. Here, we used a five-year data set of 1047 RFID-tagged individuals from two bat species, Myotis nattereri and Myotis daubentonii that were automatically recorded each time they entered or left a hibernaculum. Because the two species differ in foraging strategy and activity pattern during winter, we expected species–specific responses in the timing of hibernation relative to environmental conditions, as well as different mortality costs of early departure from the hibernaculum in spring. Applying mixed-effects modelling, we disentangled population-level and individual-level plasticity in the timing of departure. To estimate mortality costs of early departure, we used both a capture mark recapture analysis and a novel approach that takes into account individual exposure times to mortality outside the hibernaculum. We found that the timing of departure varied between species as well as among and within individuals, and was plastically adjusted to large-scale weather conditions as measured by the NAO (North Atlantic Oscillation) index. Individuals of M. nattereri, which can exploit milder temperatures for foraging during winter, tuned departure more closely to the NAO index than individuals of M. daubentonii, which do not hunt during winter. Both analytical approaches used to estimate mortality costs showed that early departing individuals were less likely to survive until the subsequent hibernation period than individuals that departed later. Overall, our study demonstrates that individuals of long-lived hibernating bat species have the potential to plastically adjust to changing climatic conditions, although the potential for adjustment differs between species.
We apply the charge simulation method (CSM) in order to compute the logarithmic capacity of compact sets consisting of (infinitely) many “small” components. This application allows to use just a single charge point for each component. The resulting method therefore is significantly more efficient than methods based on discretizations of the boundaries (for example, our own method presented in Liesen et al. (Comput. Methods Funct. Theory 17, 689–713, 2017)), while maintaining a very high level of accuracy. We study properties of the linear algebraic systems that arise in the CSM, and show how these systems can be solved efficiently using preconditioned iterative methods, where the matrix-vector products are computed using the fast multipole method. We illustrate the use of the method on generalized Cantor sets and the Cantor dust.
Hintergrund
Migräne ist eine hochprävalente Erkrankung, die bei betroffenen Patient*innen eine hohe Belastung sowohl durch die Kopfschmerzen an sich als auch durch die Einschränkung ihres Sozial- und Berufslebens hervorruft. Die Therapie besteht aus einer Akuttherapie der Kopfschmerzattacken sowie einer prophylaktischen Therapie zur Reduktion der Kopfschmerzfrequenz und -schwere. In der Prophylaxe stehen mit Antikörpern gegen das Calcitonin-gene-related-peptide (CGRP) und dessen Rezeptor erstmalig für die Migräne entwickelte gezielte prophylaktische Therapien zur Verfügung. Es stellt sich jedoch hierbei die Frage, ob CGRP-Antikörper lediglich symptomatisch in der Peripherie des trigemino-vaskulären-Systems wirken oder auch im zentralen Nervensystem die zugrundeliegenden pathophysiologischen Mechanismen beeinflussen, was einer krankheitsmodifizierenden Wirkung entspräche. Ziel unserer Studie war es, die Nullhypothese einer rein symptomatischen Wirkung gegen die Alternativhypothese einer Krankheitsmodifikation und somit zentralnervösen Wirkung, zu prüfen, indem bei Patient*innen mit episodischer Migräne der nozizeptive Blinkreflex vor und nach der Behandlung mit CGRP-Antikörpern untersucht wurde.
Methoden
22 Patient*innen mit episodischer Migräne (21 Frauen, 46,2 ± 13,8 Jahre alt) und 22 alters- und geschlechts-gematchte Kontrollen wurden im Rahmen dieser prospektiven Beobachtungsstudie eingeschlossen. Sie erhielten einen umfassenden Fragebogen zur Erhebung demografischer Charakteristika sowie der Kopfschmerzanamnese. Es erfolgte eine Messung des Blinkreflexes (10 Durchgänge à 6 Stimuli) vor (V0) und 3 Monate (V3) nach der Behandlung mit CGRP-Antikörpern (Kontrollen wurden einmalig gemessen). Im Rahmen der Messung wurden wiederholt schmerzhafte Stimuli supraorbital appliziert, die direkte Rückschlüsse auf die zentralnervöse Erregbarkeit des Hirnstamms als pathophysiologisch zentralen Mechanismus im Rahmen der Migräneentstehung zulassen. Die Area-under-the-curve (AUC) der R2-Komponente der Muskelsummenaktionspotentiale des Blinkreflexes sowie das Habituationsverhalten (Regressionskoeffizient über mehrere Blöcke) der stimulierten sowie nicht-stimulierten Seite wurden über 10 Blöcke hinweg evaluiert (primärer Endpunkt). Es wurde jeweils zuerst ein Test auf globale Veränderungen durchgeführt, der dann durch post-hoc-Analysen weiter spezifiziert wurde.
Ergebnisse
Alle Patient*innen zeigten eine signifikante Reduktion der Kopfschmerztage/Monat (V0: 12,4±3,3, V3: 6,6 ± 4,9) nach Beginn der Behandlung mit einem CGRP-/Rezeptorantikörper. Auf der stimulierten Seite reduzierte sich die AUC signifikant in den Blöcken eins, zwei sowie acht (Fglobal=5,86, p<0,001; block 1: R2a_s: -28%, p<0,001). Auf der nicht-stimulierten Seite zeigten sich Block eins, zwei, drei, acht sowie zehn als signifikant reduziert (Fglobal=8,22, p<0,001, block 1: R2a_ns: -22%, p=0,003). Die Veränderung der Habituation erwies sich in den Blöcken sechs, sieben, acht und zehn auf der nicht-stimulierten Seite als signifikant (Fglobal=3,07, p<0,001; block 6: R2h_ns: r=-1,36, p=0,007). Weder die AUC noch die Habituation des ersten Messtermins (V0) korrelierte mit dem späteren klinischen Ansprechen, sodass kein Prädiktor für das Therapieansprechen detektiert werden konnte (binär logistische Regression; alle Prädiktoren p>0,05).
Diskussion & Zusammenfassung
Die Ergebnisse dieser Studie zeigen, dass die dreimonatige Therapie mit CGRP-Antikörpern die Erregbarkeit des Hirnstamms als Antwort auf wiederholte schmerzhafte Stimuli bei Patient*innen mit Migräne normalisiert und liefert somit Hinweise für ein krankheitsmodifizierendes Potenzial. Veränderungen der Habituation korrelierten signifikant mit der Verringerung der Kopfschmerz-Frequenz, weitere Studien sind jedoch nötig, um zu eruieren, ob Parameter als Prädiktor geeignet sind um eine Voraussage über das Therapieansprechen und das Risiko einer Verschlechterung nach Beendigung der Therapie zu ermöglichen.
Representative epidemiologic data on the average volume of the parotid gland in a large population-based MRI survey is non-existent. Within the Study of Health in Pomerania (SHIP), we examined the parotid gland in 1725 non-contrast MRI-scans in T1 weighted sequence of axial layers. Thus, a reliable standard operating procedure (Intraclass Correlation Coefficient > 0.8) could be established. In this study, we found an average, single sided parotid gland volume of 27.82 cm3 (95% confidence interval (CI) 27.15 to 28.50) in male and 21.60 cm3 (95% CI 21.16 to 22.05) in female subjects. We observed positive associations for age, body mass index (BMI), as well as male sex with parotid gland size in a multivariate model. The prevalence of incidental tumors within the parotid gland regardless of dignity was 3.94% in the Northeast German population, slightly higher than assumed. Further epidemiologic investigations regarding primary salivary gland diseases are necessary.
Kognitive Beeinträchtigungen treten bei 43-70 % der Patient*innen mit Multipler Sklerose (MS) auf [1]. Der Symbol Digit Modalities Test (SDMT) ist ein kognitiver Test, der ein empfindliches Maß für die Informationsverarbeitungsgeschwindigkeit ist, und bei MS-Patient*innen häufig beeinträchtigt ist [2, 3]. In bildgebenden Studien wurden bereits die Bedeutung von Läsionen in der weißen Substanz, aber auch der grauen Substanz im Bereich des beidseitigen superioren Parietallappens (Brodman Areal [BA] 7A) für die Durchführung des SDMT hervorgehoben [4–6]. Bislang liegen jedoch nur wenige Daten speziell zur Integrität der von BA 7A absteigenden Bahnen der weißen Substanz vor. Ein Zusammenhang zwischen der Integrität des BA 7A Traktes der weißen Substanz und der Informationsverarbeitungsgeschwindigkeit bei Patient*innen mit Multipler Sklerose ist bisher noch unbekannt.
In dieser Studie untersuchten wir die Assoziation zwischen der Integrität des von BA 7A ausgehenden Traktes der weißen Substanz und der Leistung im SDMT in einer Gruppe von 101 MS-Erkrankten. Dazu verwendeten wir die Diffusionstensor Bildgebung (DTI), um diesen Trakt mit der probabilistischen Traktographie zu rekonstruieren. Anhand der quantifizierten mittleren fraktionalen Anisotropie (FA), ein Maß für die Abweichung von isotroper Diffusivität in allen Richtungen und der SDMT Leistung konnten wir mit und ohne Maskierung der zuvor festgestellten Läsionen der weißen Substanz mögliche Korrelationen berechnen. Dabei zeigte sich, dass die Werte der fraktionalen Anisotropie positiv mit den verminderten Ergebnissen des SDMT assoziiert waren. Für den kortikospinalen Trakt als Kontrolltrakt ergab sich diese Assoziation erwartungsgemäß nicht, da er mit motorischen und nicht mit kognitiven Beeinträchtigungen in Verbindung gebracht wird [7]. Der positive Zusammenhang blieb auch nach Maskierung der Läsionen innerhalb des BA 7A Traktes bestehen, was auf eine zusätzliche Schädigung der normal erscheinenden weißen Substanz schließen lässt.
Die Beziehung zwischen der Geschwindigkeit der Informationsverarbeitung bei Patient*innen mit Multipler Sklerose und der Integrität des BA 7A-Traktes der weißen Substanz wurde festgestellt. Durch diese Studie können weitere Erkenntnisse über die strukturelle Korrelation der weißen Substanz des Gehirns mit der kognitiven Leistung von MS-Erkrankten gewonnen werden. In der Zukunft ist eine Kombination aus strukturellen mit funktionellen Messungen sinnvoll.
Hematophagous leeches express a broad variety of secretory factors in their salivary glands; among them are hirudins, inhibitors of blood coagulation, and decorsins/ornatins, inhibitors of platelet aggregation. Here, we describe the identification and molecular and functional characterization of putative hirudins and decorsins/ornatins in two leech species of American origin, Limnobdella mexicana and Haementeria vizottoi. The leech species represent two orders of leeches, the proboscis-bearing Rhynchobdellida and the non-proboscis-bearing Arhynchobdellida. Members of the hirudin superfamily, such as hirudins or decorsins/ornatins, are described for the first time in the genus Haementeria. Both species expressed very potent inhibitors of platelet aggregation, but only the putative hirudins of L. mexicana displayed high thrombin-inhibitory potency, whereas the putative hirudin of H. vizottoi turned out to be a hirudin-like factor. The results of our study provide new insights into the evolutionary background of the blood-sucking lifestyle in leeches.
Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.
The predominantly vegetative propagating duckweeds are of growing commercial interest. Since clonal accessions within a respective species can vary considerably with respect to their physiological as well as biochemical traits, it is critical to be able to track the clones of species of interest after their characterization. Here, we compared the efficacy of five different genotyping methods for Spirodela polyrhiza, a species with very low intraspecific sequence variations, including polymorphic NB-ARC-related loci, tubulin-gene-based polymorphism (TBP), simple sequence repeat variations (SSR), multiplexed ISSR genotyping by sequencing (MIG-seq), and low-coverage, reduced-representation genome sequencing (GBS). Four of the five approaches could distinguish 20 to 22 genotypes out of the 23 investigated clones, while TBP resolved just seven genotypes. The choice for a particular method for intraspecific genotyping can depend on the research question and the project budget, while the combination of orthogonal methods may increase the confidence and resolution for the results obtained.
Target Mechanisms of the Cyanotoxin Cylindrospermopsin in Immortalized Human Airway Epithelial Cells
(2022)
Cylindrospermopsin (CYN) is a cyanobacterial toxin that occurs in aquatic environments worldwide. It is known for its delayed effects in animals and humans such as inhibition of protein synthesis or genotoxicity. The molecular targets and the cell physiological mechanisms of CYN, however, are not well studied. As inhalation of CYN-containing aerosols has been identified as a relevant route of CYN uptake, we analyzed the effects of CYN on protein expression in cultures of immortalized human bronchial epithelial cells (16HBE14o−) using a proteomic approach. Proteins whose expression levels were affected by CYN belonged to several functional clusters, mainly regulation of protein stability, cellular adhesion and integration in the extracellular matrix, cell proliferation, cell cycle regulation, and completion of cytokinesis. With a few exceptions of upregulated proteins (e.g., ITI inhibitor of serine endopeptidases and mRNA stabilizer PABPC1), CYN mediated the downregulation of many proteins. Among these, centrosomal protein 55 (CEP55) and osteonectin (SPARC) were significantly reduced in their abundance. Results of the detailed semi-quantitative Western blot analyses of SPARC, claudin-6, and CEP55 supported the findings from the proteomic study that epithelial cell adhesion, attenuation of cell proliferation, delayed completion of mitosis, as well as induction of genomic instability are major effects of CYN in eukaryotic cells.
Background: Little is known about how substance use affects health-related quality of life (HRQOL) in depressed individuals. Here, associations between alcohol consumption and HRQOL in hospital and ambulatory care patients with past-year depressive symptoms are analyzed. Method: The sample consisted of 590 participants (26.8% non-drinkers) recruited via consecutive screenings. Individuals with alcohol use disorders were excluded. HRQOL was assessed with the Veterans Rand 12-item health survey (VR-12). Multivariable fractional polynomials (MFP) regression analyses were conducted (1) to test for non-linear associations between average daily consumption and HRQOL and (2) to analyze associations between alcohol consumption and the physical and mental health component summaries of the VR-12 and their subdomains. Results: Alcohol consumption was positively associated with the physical health component summary of the VR-12 (p = 0.001) and its subdomains general health (p = 0.006), physical functioning (p < 0.001), and bodily pain (p = 0.017), but not with the mental health component summary (p = 0.941) or any of its subdomains. Average daily alcohol consumption was not associated with HRQOL. Conclusion: Alcohol consumption was associated with better physical HRQOL. Findings do not justify ascribing alcohol positive effects on HRQOL. Data indicate that non-drinkers may suffer from serious health disorders. The results of this study can inform the development of future alcohol- and depression-related interventions.
Simple Summary
The treatment of high-risk neuroblastoma patients with anti-GD2 antibodies has improved survival, and it is an established treatment strategy; however, many patients still experience a late relapse. One disadvantage of passive immunotherapy is the absence of a memory response. Therefore, developing an active immunotherapy leading to a sustained immune response may provide a solution and prevent the occurrence of late relapses following anti-GD2 antibody therapy. Here, we describe the first-in-man compassionate use of the ganglidiomab vaccine following passive immunotherapy with an anti-GD2 antibody (dinutuximab beta) in seven neuroblastoma patients. The vaccine was well-tolerated, and all patients not pre-treated by haploidentical transplantation developed vaccine-specific immune responses.
Abstract
(1) Background: High-risk neuroblastoma (HR-NB) is associated with a poor prognosis despite a multimodal high-intensity treatment regimen, including immunotherapy with anti-GD2 monoclonal antibodies (mAb). Here, we investigated the effects of an anti-idiotypic vaccine based on the mAb ganglidiomab that structurally mimics GD2. (2) Methods: Patients with HR-NB treated with anti-GD2 mAb dinutuximab beta and who achieved complete remission after frontline or salvage therapy were offered the vaccine (0.5 mg ganglidiomab adsorbed to Alhydrogel®). Side effects (CTCAE v4.03) and immune responses were determined on each visit. We also evaluated the time to relapse or progression until the last follow-up. (3) Results: Seven HR-NB patients (five frontlines, two relapsed) received 6–22 subcutaneous injections every two weeks. Six of the seven patients showed an immune response. The non-responding patient had a haploidentical stem cell transplantation as part of the previous treatment. No fever, pain, neuropathy, or toxicities ≥ grade 3 occurred during or post-treatment. All immunized patients did not experience relapses or progressions of their neuroblastoma. (4) Conclusions: This is the first-in-man use of the ganglidiomab vaccine, which was well-tolerated, and all patients not pre-treated by haploidentical transplantation developed vaccine-specific immune responses. These findings provide an important basis for the design of prospective clinical trials.
Eicosanoids are lipid mediators generated from arachidonic acid with pro- and anti-inflammatory properties. Despite these lipid mediators being known for decades, quantitative determination in biological samples is still challenging due to low abundance, instability, the existence of regio- and stereoisomers, and a wide polarity range that hampers chromatographic separation. In this study, we developed a supercritical fluid chromatography mass spectrometry (SFC-MS) platform for the quantification of relevant eicosanoids. Application of a chiral amylose-based column and modifier combination of 2-propanol/acetonitrile offered separation and sufficient resolution of 11 eicosanoids (5-, 12-, 15-HETE, PGB1, LTB4, t-LTB4, 20-OH-LTB4, PGE2, PGD2, PGF2α, TxB2) with baseline separation of isobaric analytes within 12 min. The method was validated in terms of range (78–2500 ng/mL), linearity, accuracy, precision, and recovery according to EMA guidelines. Finally, we confirmed the method’s applicability by quantifying eicosanoid levels in human primary blood cells. In conclusion, we present a validated SFC-MS method for the determination of relevant eicosanoids in biological samples with a wide range of polarity while maintaining baseline separation of isobars, which allows coupling to a single quadrupole mass detector.
A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis
(2022)
We performed this cohort study to test whether further analysis of intrathecal inflammation can be omitted if the free light chain kappa (FLCκ) quotient is within the reference range in the corresponding quotient diagram. FLCκ concentrations were measured in serum and cerebrospinal fluid (CSF) samples. The intrathecal fraction (IF) of FLCκ was calculated in relation to the hyperbolic reference range. 679 patient samples were used as a discovery cohort (DC). The sensitivity and negative predictive value (NPV) of the FLCκ-IF for the detection of an intrathecal humoral immune response (CSF-specific OCB and/or IF IgG/A/M > 0%) was determined. Based on these data, a diagnostic algorithm was developed and prospectively validated in an independent validation cohort (VC, n = 278). The sensitivity of the FLCκ-IF was 98% in the DC and 97% in the VC with a corresponding NPV of 99%. The use of the FLCκ-IF as a first line analysis would have reduced the Ig and OCB analysis by 62% in the DC and 74% in the VC. The absence of a FLCκ-IF predicts the absence of a humoral intrathecal immune response with a very high NPV of 99%. Thus, integration of our proposed algorithm into routine CSF laboratory analysis could help to reduce analytical efforts.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme.
Background: Colorectal carcinoma (CRC) is a heterogeneous disease, and differences in outcomes have been reported among patients diagnosed with the same disease stage. Prognostic and predictive biomarkers provide information for patient risk stratification and guide treatment selection. Although numerous studies have analyzed the effects of systemic inflammatory factors on CRC outcomes, clinical significance remains to be elucidated. In particular, the treatment strategy of colon cancer patients is different from that of rectal cancer due to outcome and recurrence differences. The identification of patients with a poor prognosis who might benefit from intensive treatment approaches is clinically necessary. Methods: This study aimed to evaluate the value of different blood-based markers and assess the significance of our newly developed inflammatory-nutrition-related biomarker (NCR = BMI × albumin/CRP) in patients with colon cancer. A two-stage design was used with 212 patients with colon cancer (CC) in the discovery cohort (n = 159) and in an external validation cohort (n = 53). Results: A lower preoperative NCR level was significantly correlated with a worse prognosis, sidedness, undifferentiated histology, nodal involvement, and advanced UICC stage. We compared the NCR with other established prognostic indices and showed that the NCR is a more reliable indicator of a poor prognosis for patients with CC. Patients with low NCR levels experienced a significantly shorter Overall Survival (OS) than patients with high levels. Multivariate analysis confirmed preoperative NCR levels as an independent predictor for overall survival with a hazard ratio of 3.3 (95% confidence interval 1.628–6.709, p < 0.001). Finally, we confirmed the predictive value of the NCR in an independent validation cohort and confirmed NCR as an independent prognostic factor for OS. Conclusion: Taken together, we discovered a new prognostic index (NCR) based on BMI, albumin, and CRP levels as an independent prognostic predictor of OS in patients with colon cancer. In all UICC stages, our newly developed NCR marker is able to distinguish patients with better and worse prognoses. We, therefore, propose that NCR may serve as a supplement to the TNM staging system to optimize the risk stratification in CC patients towards personalized oncology. In particular, NCR can be used in clinical trials to stratify patients with UICC II and III tumors and help better select patients who might benefit from adjuvant treatment.
An already existing shortage of nurses was exacerbated by the COVID-19 pandemic. Inactive (former) nurses were regarded as a so-called silent reserve and were called upon by various agencies to volunteer for nursing. The question arose as to what factors might encourage or hinder such volunteering and facilitate deployment.
First, inactive nurses were asked via an online survey whether they had registered for deployment or not and what the reasons were for this decision. Further information on professional background was collected, including the reason for having left the profession in the first place. Based on the results of the online survey, focus group discussions were conducted with registered and unregistered inactive nurses, with nurses who had returned to the profession permanently, and with care home managers.
Only one third of the participants in the online survey said they had registered for a temporary assignment during the pandemic. The main reasons for registering were that inactive nurses ‘wanted to do their bit’ to manage the crisis, felt it was their duty and/or felt a sense of belonging to the nursing profession. The main reasons given for not having registered was that respondents ‘could not see a reason at the moment’, had health concerns, and ‘other relevant job commitments’. The majority of respondents still had jobs related to health, care or nursing.
The topics covered in the focus group discussions included the following: perception of the pandemic as a crisis, identity as a nurse and sense of professional commitment, role of current occupation in the decision to register, winning over inactive nurses with a very negative attitude towards returning to care during a crisis situation, support measures and offers regarding a deployment in nursing.
Both in the online survey and in the focus group discussions, a sense of belonging to the nursing profession was evident among many participants. However, this identity does not necessarily lead to a willingness to return to nursing during a crisis situation. Weighing up the risk of deployment against the positive or negative experiences gained during the active period can influence willingness. However, the possibility of taking a break from current work and returning to nursing at short notice is not always given. Many inactive nurses continue to work in the health sector and fulfil equally important tasks during a crisis situation which render them unavailable for deployment.
Different kinds of support for those willing to return to nursing during a crisis situation and communication on conditions of deployments need to be implemented and continuously improved to offer the inactive nurses the greatest possible security and to enable a largely unbureaucratic deployment.
Materials and Methods:
Literature search was conducted using electronic MEDLINE/ Cochrane databases, relevant references, citations and hand search was conducted. Academic Colleges were contacted to identify relevant studies and full texts. Inclusion Criteria were Randomized clinical trials, human cohort and case series reporting increasing vertical dimension and restoring worn dentition in adults suffering from tooth wear using fixed, minimal invasive and adhesive techniques.
The search period spanned from 2000 up to January 2023. Of the 550 articles identified, 111 went throw full text screening for eligibility and 12 studies were included in our study.
Failure, follow-up period for all the studies were assessed. Attrition , Bruxism, increase of vertical dimension rates and mean time of failure were calculated using random effect models.
Results:
Tooth wear was reported equally in anterior and posterior region, and restorations were done in direct and indirect manners, mostly with pre-evaluation of the needed increase of vertical dimension. The mean of increased vertical dimension was 2.3 mm. The mean observation time of the restorations was 41.3 months with a minimum observation period of 12 months and a maximum of 84 months. Failure rate of all the included studies was 9.9% (95% CI: 91.00 % to 95.80%) high heterogeneity was detected in Failure rate with I2 of (93.85). Time to fail was calculated to be 37.5 months for 2458 cases (95% CI:32.32 to 91.13%). A fixed effect model was performed to calculate the event of increasing vertical dimension , the event rate was 81.72% (95% CI: 0.00 to 88.10%).
Conclusion:
The performance of direct and indirect restorations is satisfactory, and the failure rate is low, which leads us to conclude that these non-invasive restorations are a reliable and cost-effective middle-term treatment method to restore vertical dimension in moderate to severe worn dentition.
Conflict of interest: None
Pentathiepine sind siebengliedrige, heterocyclische Polysulfane. Sie gehören damit zur Gruppe organischer Polysulfide und somit zu einer Stoffklasse, die in den letzten Jahren wachsendes Interesse hinsichtlich pharmazeutisch/medizinisch nutzbarer Eigenschaften geweckt hat. Sie besitzen unterschiedliche biologische Wirkungen, die möglicherweise auf die Aktivierung durch Thiole, wie zum Beispiel Glutathion (GSH), zurückzuführen sind. Dazu gehören die Erzeugung von reaktiven Sauerstoffspezies und die oxidative Fragmentierung von DNA.
Pentathiepine zeigen sich als gelbe, schwer lösliche Feststoffe und sind in sauren Lösungen sehr stabil. In Lösungen, die Basen oder Nukleophile enthielten, nahm der Gehalt an Pentathiepinen jedoch sehr schnell ab. In dieser Arbeit sollte hauptsächlich untersucht werden, inwieweit sich die Stabilität der Pentathiepine auf die biologischen Eigenschaften auswirkt. Neben der Ermittlung der Verteilungskoeffizienten 23 verschiedener Pentathiepine, wurden auch enzymbasierte Assays durchgeführt.
Dazu gehörte die Bestimmung der Reversibilität der Hemmung an boviner Glutathionperoxidase-1 (GPx-1) sowie der Einfluss unterschiedlicher Inkubationsbedingungen auf die inhibitorische Wirkung. Dabei wurde für das untersuchte Pentathiepin mittels jump dilution keine irreversible Hemmung an boviner GPx-1 gefunden. Eine irreversible Inhibierung konnte jedoch für Mercaptobernsteinsäure gezeigt werden. Die Ergebnisse der unterschiedlichen Inkubationsbedingungen erlauben die Schlussfolgerung, dass der intakte Pentathiepinring wahrscheinlich nicht an der Hemmung der GPx-1 beteiligt ist, sondern die aus der Reaktion mit GSH gebildeten Abbauprodukte. Es konnte jedoch auch gezeigt werden, dass der Pentathiepinring mindestens als „Schwefeltransporter“ benötigt wird. Ein Übertrag des GPx-Assays auf die HPLC konnte als prinzipiell möglich, für die Pentathiepine jedoch als nicht geeignet gezeigt werden.
Im zweiten Teil der Arbeit wurden sechs Pentathiepine mit vier unterschiedlichen Grundgerüsten hinsichtlich ihrer Stabilität in Gegenwart von GSH untersucht. Dabei gab es hinsichtlich der Reaktivität der Pentathiepine sehr starke Unterschiede. Trotz dieser großen Unterschiede konnten keine Unterschiede hinsichtlich der GPx-Hemmung und der antiproliferativen Eigenschaften beobachtet werden. Auch eine Absenkung der intrazellulären GSH-Konzentration durch Inkubation mit DL-Buthioninsulfoximin in drei humanen Krebszelllinien mit unterschiedlichem Glutathiongehalt ergab keine Unterschiede zwischen den getesteten Substanzen. Sie waren nach Vorinkubation der Zellen durchgehend aktiver.
Aufgrund der vergleichsweise hohen Reaktivität in Gegenwart von GSH sollte ein Pentathiepin in einem proof of concept in Liposomen formuliert werden. Diese Formulierung sollte einerseits das Pentathiepin vor Reaktionen mit Thiolen wie GSH schützen, andererseits die Wasserlöslichkeit erhöhen. Dabei ergab sich, dass die Wasserlöslichkeit der Pentathiepine durch Formulierung in DOPC-Liposomen von unter 3 μM auf über 400 μM erhöht werden konnte. In Hinsicht auf die Stabilität ergab sich eine erhöhte Stabilität des untersuchten Pentathiepins in Anwesenheit von 10 mM GSH um den Faktor 4 in der Zeit bis zum vollständigen Abbau. Hinsichtlich der antiproliferativen Eigenschaften ergab sich keine Abnahme der Wirkung des Pentathiepins durch Formulierung in Liposomen.
Background
Neuroinflammation and maladaptive neuroplasticity play pivotal roles in migraine (MIG), trigeminal autonomic cephalalgias (TAC), and complex regional pain syndrome (CRPS). Notably, CRPS shares connections with calcitonin gene-related peptide (CGRP) in its pathophysiology. This study aims to assess if the documented links between CRPS and MIG/TAC in literature align with clinical phenotypes and disease progressions. This assessment may bolster the hypothesis of shared pathophysiological mechanisms.
Methods
Patients with CRPS (n = 184) and an age-/gender-matched control group with trauma but without CRPS (n = 148) participated in this case–control study. Participant answered well-established questionnaires for the definition of CRPS symptoms, any headache complaints, headache entity, and clinical management.
Results
Patients with CRPS were significantly more likely to suffer from migraine (OR: 3.23, 95% CI 1.82–5.85), TAC (OR: 8.07, 95% CI 1.33–154.79), or non-classified headaches (OR: 3.68, 95% CI 1.88–7.49) compared to the control group. Patients with MIG/TAC developed CRPS earlier in life (37.2 ± 11.1 vs 46.8 ± 13.5 years), had more often a central CRPS phenotype (60.6% vs. 37.0% overall) and were three times more likely to report allodynia compared to CRPS patients with other types of headaches. Additionally, these patients experienced higher pain levels and more severe CRPS, which intensified with an increasing number of headache days. Patients receiving monoclonal antibody treatment targeting the CGRP pathway for headaches reported positive effects on CRPS symptoms.
Conclusion
This study identified clinically relevant associations of MIG/TAC and CRPS not explained by chance. Further longitudinal investigations exploring potentially mutual pathomechanisms may improve the clinical management of both CRPS and primary headache disorders.
Trial registration
German Clinical Trials Register (DRKS00022961).
Einleitung/Hintergrund
DC_TRAIN_APHASIA ist eine multizentrische, randomisiert-kontrollierte Studie, die seit November 2019 unter Federführung der Universitätsmedizin Greifswald durchgeführt wird (ClinicalTrials.gov Identifier: NCT03930121). Die Studie untersucht, ob adjuvante transkranielle Gleichstromstimulation („transcranial direct current stimulation“, tDCS) den Erfolg einer 3‑wöchigen intensiven Sprachtherapie bei chronischer Aphasie steigern kann.
Material und Methode
Bis Ende 2024 sollen bundesweit 130 Patient:innen eingeschlossen werden. Die Entwicklung innovativer Rekrutierungsstrategien stellt seit Beginn der Studie eine Herausforderung dar. Neben gängigen Rekrutierungsmethoden wie der direkten Ansprache von Menschen mit Aphasie in Kliniken, Logopädiepraxen, Rehabilitationseinrichtungen und Selbsthilfegruppen wurden Radiowerbespots, Fernsehbeiträge und Auftritte in sozialen Medien erprobt.
Zwischenergebnisse
Bis zum aktuellen Zeitpunkt konnten 110 Patient:innen in die Studie eingeschlossen werden. Zum größten kurzzeitigen Rücklauf führte die Rekrutierung über einen Fernseh- bzw. Radiobeitrag. Den größten langfristigen Rücklauf ergab die Rekrutierung über Logopädie- und Neurologiepraxen, Selbsthilfegruppen und soziale Medien. Teilnehmer:innen berichteten als „Testimonials“ positiv von der Sprachtherapie und der Anwendung von tDCS, die sich als gut verträglich erwies.
Diskussion
Die multizentrische Studie DC_TRAIN_APHASIA prüft die Wirksamkeit von tDCS als adjuvante Applikation für intensive Sprachtherapie bei chronischer Aphasie. Die vorliegende Übersicht soll künftigen Studien als Leitfaden zur Rekrutierung von Stichproben dienen, die Menschen mit eingeschränkten kommunikativen Fähigkeiten umfassen.
Perception of climate change-related forest dieback in mountain forests among the local population
(2023)
Mountain forests provide multiple benefits but are threatened by climate change-induced forest dieback. Although many studies summarize perceptions of forest ecosystem services, relatively few deal with mountain forests. The local population’s perception of forest dieback in mountain forests in relation to climate change has rarely been investigated so far. Their perspective is relevant as local people are often deeply attached to “their” forests, they actively use forest ecosystems and—as voters and taxpayers—they need to support the state’s adaptation and funding measures. Therefore, this study investigates the climate change and forest dieback perception of local inhabitants in two mountain areas of Southern Germany (the German Alps and the Bavarian Forest) with a quantitative survey based on representative online samples (n = 709). Relying conceptually on van der Linden’s (J Environ Psychol 41:112–124, 2015. https://doi.org/10.1016/j.jenvp.2014.11.012) climate change risk perception model, the results show that experiential processing, cognitive and socio-cultural factors are related to locals’ forest dieback and climate change perception, while socio-demographics show no or few connections. Nearly two-thirds (64.7%) of the respondents perceive moderate to strong forest dieback, while more than half (55.0%) of the respondents already observe consequences of climate change. The perceptions of climate change and forest dieback are positively correlated with medium to high strength. This shows that forest dieback could be interpreted as an indicator of climate change, which is difficult to observe due to its long-term nature. We identify three groups of respondents regarding preferred forest adaptation strategies to climate change. In general, respondents support nature-based forest adaptation strategies over intense measures.
Toarciconiopteryx dipterosimilis gen. et sp. nov. is described from the Lower Toarcian of Grimmen (Western Pomerania, Germany) based on a hind wing. This enigmatic wing superficially resembles a dipteran forewing, but analysis in detail establishes that it belongs to the Neuroptera. We assign it to the Coniopterygidae with great confidence by its great concordance with the hind wings of that family, but a small possibility remains that it might belong to the Dipteromantispidae, although the very derived haltere-like hind wings of all its known members are entirely unlike it. We, therefore, consider it to be the oldest record of Coniopterygidae. We create the new subfamily Toarciconiopteryginae subfam. nov. for it, which is distinguished from other Coniopterygidae by its hind wings possessing two branches of RP and a proximal forking of M. These conditions are also known in some Sialidae (Megaloptera), supporting the hypothesis that Coniopterygidae is the sister group of all other Neuroptera, as Megaloptera is considered by most authors to be sister to Neuroptera. New interpretations of some aspects of the Coniopterygidae venation are proposed.
This anthology is about the representations and uses of medieval saints, heroes, and heroic events as elements of popular, local, and national culture during the 19th and 20th centuries in the Baltic Sea region: Scandinavia, Finland, Baltic countries, Northern Germany and North-Western Russia. Authors examine the processes of how medieval saints and heroes have been remembered, commemorated, interpreted, used, and reflected during modernity, and by whom. The focus of the anthology is on "doing" memory as a practice that commemorated the past and shaped spaces and identities in the present. It approaches the memory of saints and heroes, for example, Swedish Saints Birgitta and Eric, Danish Saint Knud, Kyivan Princess Olga, Swedish military leader in Finland Tyrgils Knutsson, Liv/Latvian warrior Imanta and Holsatian count Gerhard III as a shared heritage and as part of national, local and popular culture. The anthology contributes to the understanding of the Baltic Sea region through the study of saints, cults and heroic representations in the longue durée between the Middle Ages and modernity. It also adds nuance to the use of popular concepts of memory studies, particularly an update of Pierre Nora’s lieux de mémoire.
Clear cell renal cell carcinoma is the most frequent malignant kidney tumor in adults. It is often associated with biallelic VHL mutations. We characterized our cell lines according to their HIF expression pattern. Cell lines RCC4, UOK-220 and CaKi-2 were assigned to subtype H1H2, cell lines 786-O and A-498 were assigned to subtype H2 and cell lines CaKi-1 and Rc-124 were assigned to subtype VHLwt.
Previous work of our group had shown, that p53 can be activated in ccRCC following irradiation but is not able to induce apoptosis. An important link to p53 activity with strong antiapoptotic qualities is the NFB pathway, which can be activated e. g. by irradiation.
We irradiated the three subtypes previously established as well as two control cell lines, SAOS-2 (p53 negative cell line) and HEK 293 (contains functioning p53) with 2 Gy and 10 Gy and analyzed several proteins of the pathway by using western blots. Several target genes with antiapoptotic qualities were analyzed by using rt-PCR.
We found, that out of the cell lines analyzed, both control cell lines (SAOS-2, HEK 293) showed the strongest response (activation of the NFB pathway) following irradiation. Among the three ccRCC subtypes the VHLwt cell lines showed the strongest response. H2 cell lines showed almost no response at all.
A connection between the missing ability of p53 to induce apoptosis and an induction of transcription factors by the NFB pathway could not be determined. We also could not determine biological differences between the subtypes.
We analyzed, whether any NFB proteins were present in the nucleus following irradiation and found, that only p50 homodimers were present in the nucleus. This might point towards p50 homodimers, which have been described to have different characteristics than heterodimers. More research is needed to analyze this important finding.
Seventeen bacterial strains able to suppress plant pathogens have been isolated from healthy Vietnamese crop plants and taxonomically assigned as members of the Bacillus cereus group. In order to prove their potential as biocontrol agents, we perform a comprehensive analysis that included the whole-genome sequencing of selected strains and the mining for genes and gene clusters involved in the synthesis of endo- and exotoxins and secondary metabolites, such as antimicrobial peptides (AMPs). Kurstakin, thumolycin, and other AMPs were detected and characterized by different mass spectrometric methods, such as MALDI-TOF-MS and LIFT-MALDI-TOF/TOF fragment analysis. Based on their whole-genome sequences, the plant-associated isolates were assigned to the following species and subspecies: B. cereus subsp. cereus (6), B. cereus subsp. bombysepticus (5), Bacillus tropicus (2), and Bacillus pacificus. These three isolates represent novel genomospecies. Genes encoding entomopathogenic crystal and vegetative proteins were detected in B. cereus subsp. bombysepticus TK1. The in vitro assays revealed that many plant-associated isolates enhanced plant growth and suppressed plant pathogens. Our findings indicate that the plant-associated representatives of the B. cereus group are a rich source of putative antimicrobial compounds with potential in sustainable agriculture. However, the presence of virulence genes might restrict their application as biologicals in agriculture.
Peatlands contribute to a wide range of ecosystem services. They play an important role as carbon sinks in their natural state, but when they are drained, they cause carbon emissions. Rewetting drained peatlands is required to reduce carbon emissions and create new carbon sinks. However, drained peatlands are commonly used as grassland or croplands; therefore, alternative agriculture schemes are required following rewetting. Paludiculture, i.e., agriculture on wet and rewetted peatlands, is an option in these areas after rewetting to produce biomass sustainably. Monitoring of peatland management is challenging, yet needed to ensure a successful rewetting and plantation of, e.g., Phragmites australis and Typha spp., two plants which are commonly used in paludiculture. Remote sensing is an excellent tool for monitoring the vegetation composition of vast rewetted peatland regions. However, because many peatland species have similar spectral characteristics, such monitoring is ideally based on high-spatial, high-temporal hyperspectral images. Data that complies with all these requirements does not exist on a regular basis. Therefore, we assessed the potential for mapping peatland vegetation communities in the Peene and Trebel river basins of the federal state of Mecklenburg-Western Pomerania, Germany, using multi-date hyperspectral (PRISMA) data. We used regression-based unmixing to map fractions of different peatland vegetation classes. Results were analyzed with regard to the contribution of multi-date observations and, in comparison, to multispectral datasets (Landsat-8/Sentinel-2). Our results showed that different classes are best mapped at different observation dates. The multi-date hyperspectral datasets produced less Mean Absolute Error (MAE = 16.4%) than the single-date hyperspectral images (ΔMAE + 1%), with high accuracies for all classes of interest. Compared to the results obtained with multispectral data from similar acquisition dates and annual spectral-temporal metrics (STM), the results from hyperspectral data were always clearly superior (ΔMAE + 4%). Besides the superior performance during comparisons, our results also indicate that information that can be derived from the hyperspectral data with the regression-based unmixing goes clearly beyond that of discrete classification. With more hyperspectral sensors coming up and an expected higher availability of multi-data hyperspectral imagery, these data can be expected to play a bigger role in the future monitoring of peatlands.
The male genitalia of pholcid spiders, which is one of the most species-rich spider families, are characterized by a procursus, which is a morphologically diverse projection of the copulatory organ. It has been shown that the procursus interacts with the female genitalia during copulation. Here, we investigate the function of the procursus in Gertschiola neuquena, a species belonging to the early branched and understudied subfamily Ninetinae, using behavioural and morphological data. Although many aspects of the copulatory behaviour of G. neuquena follow the general pattern described for the family, males use only one pedipalp during each copulation. Based on our micro-CT analysis of cryofixed mating pairs using virgin females, we can show that the long and filiform procursus is inserted deeply into the unpaired convoluted female spermatheca, and the intromittent sclerite, the embolus, is rather short and stout only reaching the most distal part of the female sperm storage organ. Histological data revealed that sperm are present in the most proximal part of the spermatheca, suggesting that the procursus is used to allocate sperm deeply into the female sperm storage organ. This represents the first case of a replacement of the sperm allocation function of the intromittent sclerite in spiders.
Background
The alignment of large numbers of protein sequences is a challenging task and its importance grows rapidly along with the size of biological datasets. State-of-the-art algorithms have a tendency to produce less accurate alignments with an increasing number of sequences. This is a fundamental problem since many downstream tasks rely on accurate alignments.
Results
We present learnMSA, a novel statistical learning approach of profile hidden Markov models (pHMMs) based on batch gradient descent. Fundamentally different from popular aligners, we fit a custom recurrent neural network architecture for (p)HMMs to potentially millions of sequences with respect to a maximum a posteriori objective and decode an alignment. We rely on automatic differentiation of the log-likelihood, and thus, our approach is different from existing HMM training algorithms like Baum–Welch. Our method does not involve progressive, regressive, or divide-and-conquer heuristics. We use uniform batch sampling to adapt to large datasets in linear time without the requirement of a tree. When tested on ultra-large protein families with up to 3.5 million sequences, learnMSA is both more accurate and faster than state-of-the-art tools. On the established benchmarks HomFam and BaliFam with smaller sequence sets, it matches state-of-the-art performance. All experiments were done on a standard workstation with a GPU.
Conclusions
Our results show that learnMSA does not share the counterintuitive drawback of many popular heuristic aligners, which can substantially lose accuracy when many additional homologs are input. LearnMSA is a future-proof framework for large alignments with many opportunities for further improvements.
Fortbildungen sind zentrale Lerngelegenheiten für die Professionalisierung pädagogischen Personals in Kindertageseinrichtungen. Inwiefern Inhalte von Fortbildungen in der alltäglichen Praxis Anwendung finden, stellt ein zentrales Qualitätskriterium von Fortbildungen dar. Daher existieren vielfältige Vorstellungen und Konzepte darüber, wie diese Anwendung – der Transfer – unterstützt werden kann. Der vorliegende Beitrag greift theoretische und empirische Erkenntnisse aus der Bildungs- und Lehr-Lernforschung auf und stellt ein Modell der Wissenstransformation von der Theorie in Handlungen und von Handlungen in die Theorie vor. Zentral an diesem Modell ist die Vorstellung, dass Wissen durch verschiedene Akteure (Fortbildner_innen sowie pädagogische Fachkräfte) transformiert wird und kontextuelle sowie individuelle Merkmale diesen Transformationsprozess beeinflussen. Implikationen für Forschung und -praxis werden diskutiert.
The multi-cell Penning–Malmberg trap concept has been proposed as a way to accumulate and confine unprecedented numbers of antiparticles, an attractive but challenging goal. We report on the commissioning and first results (using electron plasmas) of the World's second prototype of such a trap, which builds and improves on the findings of its predecessor. Reliable alignment of both ‘master’ and ‘storage’ cells with the axial magnetic field has enabled confinement of plasmas, without use of the ‘rotating wall’ (RW) compression technique, for over an hour in the master cell and tens of seconds in the storage cells. In the master cell, attachment to background neutrals is found to be the main source of charge loss, with an overall charge-confinement time of 8.6 h. Transfer to on-axis and off-axis storage cells has been demonstrated, with an off-axis transfer rate of 50% of the initial particles, and confinement times in the storage cells in the tens of seconds (again, without RW compression). This, in turn, has enabled the first simultaneous plasma confinement in two off-axis cells, a milestone for the multi-cell trap concept.
Das Zurücktreten der Erzählstimme in der Literatur der Hebräischen Bibel wurde oft benannt. Dies wurde allerdings nur selten mit der erzähltheoretischen Analysekategorie des Modus fundiert. Letzteres gilt besonders für die Darstellung von Figurenrede. Dabei ist umstritten, ob sich neben direkter und indirekter Rede auch erlebte Rede in der Hebräischen Bibel nachweisen lässt. Diese vor allem von Meir Sternberg vertretene Möglichkeit hat Cynthia L. Miller abgelehnt. Millers Einwände lassen sich aber mit einer linguistisch fundierten Erzählanalyse hinterfragen, was die grundsätzliche Möglichkeit erlebter Rede bei wᵉhinne-Phrasen begründet.
The controlled formation and adjustment of size and density of magnetic skyrmions in Ta/CoFeB/MgO trilayers with low Dzyaloshinskii–Moriya interaction is demonstrated. Close to the out-of-plane to in-plane magnetic spin reorientation transition, we find that small energy contributions enable skyrmion formation in a narrow window of 20 pm in CoFeB thickness. Zero-field stable skyrmions are established with proper magnetic field initialization within a 10 pm CoFeB thickness range. Using magneto-optical imaging with quantitative image processing, variations in skyrmion distribution and diameter are analyzed quantitatively, the latter for sizes well below the optical resolution limit. We demonstrate the controlled merging of individual skyrmions. The overall demonstrated degree of comprehension of skyrmion control aids to the development of envisioned skyrmion based magnetic memory devices.
Recent experimental campaigns in the Wendelstein 7-X stellarator, a
plasma-confining device designed to investigate the Magnetic Confinement Fusion
(MCF) approach to generating electrical power, have shown that the injection of
fuelling pellets had an unexpected and considerable impact on the performance of
the plasma. Rather than simply refuelling the device and `diluting' the plasma
energy, pellet injection is followed by a significant increase in the ratio of
the ion temperature to the electron temperature. It has been suggested that this
is not merely due to the improved confinement following the reduction of
turbulent transport after the pellet material has homogenised with the bulk
plasma, but also due to a direct transfer of energy from electrons to ions. The
proposed mechanism for this energy transfer is the ambipolar expansion of the
pellet plasmoid, the localised plasma structure produced by the
ionisation of ablated pellet material, along magnetic field lines.
Early work on pellet plasmoid expansion predicted that half the heating power
deposited in plasmoid electrons by collisions with hot ambient electrons is
transferred to plasmoid ions in the form of flow velocity as the plasmoid
expands. The complicated nature of the system of the pellet plasmoid embedded in
the ambient plasma, particularly the behaviour of electrons, which experience
many collisional and collisionless phenomena on multiple disparate timescales,
means that early models of the expansion were not wholly self-consistent, but
rather made use of strong approximations that apply in some regions of the
plasmoid but not in others. For example, only electrons and ions associated with
the plasmoid were rigorously treated, meaning that the framework was one of
`expansion into vacuum'. Combined with the assumption of Maxwellian electrons,
this led to an electric potential that was unbounded at infinity. Naturally, the
validity of the conclusions of such a model are called into question because the
approximations lose their validity far from the plasmoid and as time advances,
yet predictions about the final state of the plasma are desired. A deeper
investigation is required: careful consideration of the phenomena in question
and the timescales (and lengthscales) on which they act must be made in order to
rigorously construct a model that is valid throughout the entire expansion.
The first two papers presented in this thesis iterate on the model established
in the paper that first predicted the electron-to-ion energy transfer; their aim
was to find out how the character of the expansion changes with a more
sophisticated and accurate description of various phenomena, while remaining
within the existing framework of expansion into vacuum. Ultimately, we find that
the qualitative character is unchanged, and that approximately half the heating
power deposited in plasmoid electrons is transferred to ions.
Two other papers in this thesis address the limitations of the original model.
This is achieved by properly considering the electron kinetic problem in a
plasmoid. One paper considers the electron kinetic problem when electrons are
highly isotropised. In this case the kinetic equation can be integrated to
remove all but two independent variables, which is the maximum possible
reduction considering it is a time-dependent problem. The full nonlinear
integro-differential Landau self-collision operator is integrated exactly and
few approximations are made, leading to a rather general kinetic equation.
However, for fuelling pellets some anisotropy in the electron distribution is
expected. Another paper considers the electron kinetic problem (and the entire
plasmoid expansion) allowing for electron anisotropy. Careful consideration of
the ordering of timescales of electron phenomena in a pellet plasmoid leads to a
steady-state kinetic problem that we call collisional quasi-equilibrium (QE). QE
appears in many ways similar to the collisional steady-state characterising a
true thermal equilibrium. It was found that the time-dependent kinetic problem
of the earlier paper, with isotropic electrons, produces the QE distribution
function, corroborating the existence of the QE state. We then take moments of
the electron kinetic equation that is valid on the expansion timescale, assuming
that the electron distribution is that given as the solution to the QE kinetic
problem. This is completely analogous to what is done to obtain the Braginskii
equations or any Chapman-Enskog theory. The result is a set of equations for the
long-term evolution of the macroscopic quantities that describe the distribution
function existing in a quasi-steady-state at each point in time. It is from this
point that one may feasibly describe the plasmoid expansion with an accurate
picture of the electron kinetics and finally obtain the electron-to-ion energy
transfer so desired in a rigorous model of the expansion.
From a broader point of view, the two frameworks provided by these rigorous
investigations of the electron kinetic problem serve as a basis for the future
study of plasmoids. Such a `first-principles' approach to plasmoid dynamics is
novel and interesting in its own right, but it will be demonstrated that such an
approach is essential for pellet plasmoids owing to the fact that they are
poorly described by the `standard tools' of plasma physics.
Using the QE framework it was found that, once more, about half the heating
power experienced by plasmoid electrons is transferred to plasmoid ions. The
incredible robustness of the prediction of such an energy transfer is, in the
author's opinion, the result of the self-similar nature of the expansion found
as a solution to the original model. As a rule, the profiles of self-similar
solutions tend to be attractors for the `real', more complicated, system, and
the qualitative predictions involving no parameters, of which the
electron-to-ion energy transfer is one, tend to be very sturdy.
Aside from fuelling pellets, composed of hydrogen or deuterium, one paper in
this thesis investigates the physics of high-Z pellets that are designed to
terminate the plasma safely in the event of a `disruption', where much of the
magnetic field energy is channelled into a runaway electron beam with
potentially disastrous consequences if the beam encounters a plasma-facing
component. The paper draws on the work carried out in the paper concerning the
kinetic problem of isotropised electrons in a plasmoid.
This thesis is `cumulative'; the vast majority of the work carried out is
described within a set of Papers, labelled A-E, placed at the back of the text.
There is a preceding `wrapper text' (given in numbered Sections) tasked with
introducing the reader to the topic, guiding the reader through the papers, and
expounding some of their main results. Some amount of material not present in
the papers is also provided in the wrapper text. Naturally, the wrapper text
mainly focusses on the results of the papers which are under my first
authorship. In the course of publishing papers over an extended period of time
the nomenclature is bound to vary. Although it is mostly consistent between the
papers, a few difference do arise, and the section `Common symbols and
subscripts' is provided in the frontmatter to alleviate confusion. Particular
care should be taken with the symbols x and z; both can refer to the
coordinate parallel to the magnetic field line, but in papers where z is used
for this purpose x tends to have another definition. In the wrapper text the
choice of symbols is generally chosen to reflect those in the corresponding
paper.
Minced Cartilage Implantation in Acetabular Cartilage Defects: Case Series with 2-Year Results
(2023)
Objective
The objective was to evaluate clinical outcome and safety of arthroscopic, autologous minced cartilage implantation for acetabular cartilage lesions observed during hip arthroscopy to treat femoroacetabular impingement syndrome (FAIS).
Design
Eleven male patients, average age: 29.4 ± 5.4 years, average body mass index (BMI): 24.2 ± 2.2 kg/m2, scheduled for hip arthroscopy due to FAIS accompanied by an acetabular cartilage lesion were included in the case series. Cartilage tissue was harvested and minced from the loose cartilage flap at the chondrolabral lesion by arthroscopic shaver, augmented with autologous conditioned plasma, implanted into the defect, and fixated by autologous thrombin. Concomitant interventions were performed as indicated. The patients were evaluated preoperatively and at 24-month follow-up, using the International Hip Outcome Tool-12 (iHOT-12) and Visual Analog Scale (VAS) pain score and by magnetic resonance imaging (MRI) using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) grading scale at the 2-year follow-up.
Results
The defect size was on average 3.5 cm2 (1.5-4.5 cm2). From preoperatively to 2 years postoperatively, the iHOT-12 significantly improved from 50.2 ± 18 to 86.5 ± 19 (P < 0.0001), and pain score decreased from 5.6 ± 1.8 to 1.0 ± 1.5 (P < 0.0001) on the Visual Analog Scale pain score. Regarding functional outcome and pain, 10 of the 11 patients and all patients reached the minimal clinically important difference (MCID), respectively. The postoperative average MOCART score was 87.2 (± 9.2). No adverse events or reoperations were observed.
Conclusions
Arthroscopic, autologous minced cartilage implantation for treating full-thickness acetabular cartilage lesions in FAIS shows statistically and clinically significant improvement at short-term follow-up.
Background:
Minced cartilage implantation (MCI) has seen a renaissance in recent years. In this evolved technique, human articular cartilage is harvested with an arthroscopic shaver, augmented with platelet-rich plasma (PRP), and implanted with autologous thrombin. This modified technique combines the possibility of cell-based surgical cartilage repair with a minimally invasive autologous 1-step procedure. However, evidence on cell survival and preserved function after shaver-based mincing and PRP supplementation is limited.
Purpose:
To evaluate the effects of arthroscopic shaver mincing and augmentation with PRP on human cartilage tissue.
Study Design:
Controlled laboratory study.
Methods:
Standardized samples were taken from 12 donors during autologous MCI. A comparison of cell outgrowth, cell viability, proliferation capacity, and ability to produce extracellular matrix–specific proteoglycans after chondrogenic redifferentiation was made between cartilage taken by curettage from the border of the cartilage defect, cartilage tissue minced by an arthroscopic shaver, and cartilage tissue minced by an arthroscopic shaver that was additionally augmented with autologous PRP.
Results:
There was no difference between all 3 groups in terms of cell outgrowth or proliferation capacity. Metabolic activity relative to the cell number of chondrocytes isolated from shaver-minced cartilage was higher compared with chondrocytes isolated from cartilage that was derived by curettage or shaver-minced cartilage that was augmented with PRP. After chondrogenic stimulation, the normalized proteoglycan content was higher in spheroids of cells derived from shaver-minced cartilage augmented with PRP than in spheroids of cells derived from curettage. A high correlation of cell outgrowth, proliferation capacity, and viability between isolated cells from all 3 groups taken from an individual donor was observed.
Conclusion:
Chondrocytes isolated from human cartilage tissue that was harvested and minced with an arthroscopic shaver remained viable and proliferative. The augmentation of shaver-minced cartilage with PRP led to the enhanced proteoglycan production of chondrogenic spheroids in vitro, pointing toward the development of a cartilage-specific extracellular matrix. This in vitro study yields promising results regarding the use of an arthroscopic shaver and augmentation with PRP in the context of MCI.
Clinical Relevance:
Knowledge that shaver mincing and augmentation with PRP are feasible for processing articular cartilage during MCI is highly relevant for surgical cartilage repair.
Introduction: Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. Methods: Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. Results: In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. Conclusion: The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.
In future fusion reactors disruptions must be avoided at all costs. Disruptions due to the density limit (DL) are typically described by the power-independent Greenwald scaling. Recently, a power dependence of the disruptive DL was predicted by several authors (Zanca et al 2019 Nucl. Fusion 59 126011; Giacomin et al 2022 Phys. Rev. Lett. 128 185003; Singh and Diamond 2022 Plasma Phys. Control. Fusion 64 084004; Stroth et al 2022 Nucl. Fusion 62 076008; Brown and Goldston 2021 Nucl. Mater. Energy 27 101002). It is investigated whether this increases the operational range of the tokamak. Increasing the heating power in the L-mode can induce an L-H transition, and therefore a power-dependent DL and the L-H transition cannot be considered independently. The different models are tested on a data base for separatrix parameters at the separatrix of ASDEX Upgrade and compared with the concept (SepOS) presented in Eich and Manz (2021 Nucl. Fusion 61 086017). The disruptive separatrix density scales with the power ne ∝ P0.38±0.08 in good agreement to all models. Also the back transition from high to low (H-L) confinement shows an approximately Greenwald scaling with an additional power dependence ne ∝ P0.4 according to the SepOS concept. For future devices operating at much higher heating power such a power scaling may allow operation at much higher separatrix densities than are common in H-mode operation. Preconditions to extrapolation for future devices are discussed.
The pulse length dependence of a reactive high power impulse magnetron sputtering (HiPIMS) discharge with a tungsten cathode in an argon+oxygen gas mixture gas was investigated. The HiPIMS discharge is operated with a variable pulse length of 20–500 µs. Discharge current measurements, optical emission spectroscopy of neutral Ar, O, and W lines, and energy-resolved ion mass spectrometry are employed. A pronounced dependence of the discharge current on pulse length is noted while the initial discharge voltage is maintained constant. Energy-resolved mass spectrometry shows that the oxygen-to-tungsten (O+/W+) and the tungsten oxide-to-tungsten (WO+/W+) ion ratio decreases with pulse length due to target cleaning. Simulation results employing the SDTrimSP program show the formation of a non-stoichiometric sub-surface compound layer of oxygen which depends on the impinging ion composition and thus on the pulse length.
Semiosis is the process in which a sign unfolds its effect—the meaning that humans ‘suddenly’ see in acts, objects or facts. The semiotic tenet is applied to the event and the question of why we narrate it. The graphics are dedicated to the author’s contribution: ‘The event and its consequences: a semiotic analysis.’
Ein wichtiges Nachsorgekonzept nach erfolgter Parodontitistherapie besteht im Angebot einer Unterstützdenden Parodontitis Therapie (UPT). Hierfür stehen herkömmliche Methoden wie Hand-, Schall- und Ultraschallinstrumente einerseits sowie Luft-Pulver-Wasserstrahlgeräte andererseits zur Verfügung.
Die vorliegende Arbeit untersucht in diesem Kontext einen spezifischen Aspekt der Luft-Pulver-Wasserstrahltechnik. Es soll betrachtet werden, welche Wirkung niedrig-abrasive Prophylaxepulver auf die Farbstabilität von Zahnschmelz haben und wie dieser Effekt sich im Vergleich zu herkömmlicher Zahnpolitur mit Polierpaste darstellt. Ein weiterer Beitrag der Studie besteht in der eigenständigen Entwicklung eines in-vitro Modells, in dem das Färbeverhalten von Zahnoberflächen reproduzierbar erfasst werden kann.
Insgesamt liegen aus dieser Untersuchung Daten von 152 extrahierten Zähnen vor, welche durch verschiedene Verfahren oberflächlich behandelt und anschließend in eine Färbelösung aus Kaffee gegeben wurden. Die Zahnfarben wurden zu verschiedenen Zeitpunkten mittels digitaler Bildanalyse bestimmt.
Im gewählten Versuchsaufbau (Durchlauf 1 und 2) ließ sich zunächst kein signifikanter Unterschied im Färbeverhalten nach Behandlung mit den Prophylaxepulvern Airflow Plus, Airflow Perio (EMS, Nyon, Schweiz) oder der Polierpaste Cleanic Prophy Paste flouride (Kerr Hawe, Bioggio, Schweiz) feststellen. Die Anwendung der verglichenen drei Produkte nach Herstellerangaben in der Studiensimulation erbrachte demnach keine signifikanten Verfärbungsunterschiede. Erst eine Modifikation des Versuchsablaufs im 3. Durchlauf, bei welchem die Zahnproben zusätzlich mit einer gesättigten Lösung aus Prophylaxemittel und Aqua Dest exponiert wurden, konnte einen signifikanten Einfluss des Prophylaxepulvers Airflow Plus auf das Färbeverhalten zeigen. Es ist von einem chemischen Einfluss des Inhaltsstoffes Chlorhexidin im Pulver Airflow Plus auszugehen, welcher in einer Konzentration von ≤0,3% im Pulver enthalten ist.
Diese Nebenwirkung ist aus der Praxis und aus der Literatur bekannt und wurde bereits in zahlreichen Untersuchungen bestätigt.
Gegenstand zukünftiger Arbeiten könnte die Untersuchung des Einflusses des Hauptbestandteils Erythritol auf das Färbeverhalten von Zahnoberflächen sein, oder der Einfluss höherer Druck- und Wassereinstellungen des Prophylaxegerätes. Des weiteren könnte ein Einfluss speziell auf das Färbeverhalten von Dentin oder Kompositrestaurationen durch das Prophylaxepulver EMS Airflow Plus und seine einzelnen Bestandteile untersucht werden.
Der Vergleich der Ernährungsgewohnheiten zweier populationsbasierter Kohorten
zeigt signifikante regionale Unterschiede in Deutschland. Anhand der in Vorpommern
ansässigen SHIP-Kohorte und der KORA-Kohorte der Region Augsburg lassen sich
sowohl Aussagen zu einem möglichen Nord-Süd-Gefälle als auch zu persistierenden
Unterschiede zwischen neuen und alten Bundesländern nach der deutschen
Wiedervereinigung treffen. In Vorpommern wird der Verzehr von Fleisch, Fisch, Obst
und Softdrinks häufiger angegeben. In der Region Augsburg dagegen ist die
Verzehrhäufigkeit von Gemüse und Cerealien höher. Mit dem ebenfalls erhobenen
Food Frequency Score lässt sich die Qualität der Ernährung messen und anhand einer
Bewertungsmatrix der einzelnen Nahrungsmittelkategorien in Beziehung zu deren
Wert gemäß den Ernährungsempfehlungen der Deutschen Gesellschaft für Ernährung
vergleichen. Die südwestdeutsche KORA-Kohorte weist einen höheren Score und
damit eine ausgewogenere Ernährung auf als die nordostdeutsche SHIP-Kohorte. Die
regionalen Unterschiede in den Ernährungsgewohnheiten bieten eine mögliche
Erklärung für die regionalen Unterschiede in der Lebenserwartung sowie in der
Prävalenz der Wohlstandserkrankungen. Die Ernährungsweisen in beiden Regionen
werden von bestimmten soziodemographischen Faktoren beeinflusst. Alter,
Geschlecht, Bildungs- und Einkommensstatus sind die Faktoren, deren Einfluss
untersucht wurden. Im Wesentlichen zeigen sich die Differenzen zwischen den
Kohorten in gleicher Ausprägung, auch unabhängig vom Geschlecht. Nur für einzelne
Lebensmittelgruppen besteht ein stärkerer Effekt. Bei Vergleich dreier Altersgruppen
ließ sich feststellen, dass die regionalen Unterschiede am deutlichsten in der Gruppe
der 60-80-jährigen sind. Das Einkommen hat in einzelnen Nahrungsmittelgruppen
keinen signifikanten Einfluss auf den Unterschied zwischen den Kohorten. Eine höhere
Schulbildung dagegen verringert die Differenz zwischen SHIP und KORA bezogen auf
den Verzehr von Sättigungsbeilagen, Fisch und Eiern. Diese Assoziation kann jedoch
nicht auf andere Lebensmittelkategorien übertragen werden. Der Food Frequency
Score liegt bei der KORA Kohorte für alle untersuchten soziodemographischen
Faktoren höher als bei der SHIP Kohorte. Für männliche Teilnehmer und Teilnehmer
mit einer Bildungsdauer über 10 Jahren ist der Effekt signifikant größer. Die Faktoren,
die mit einer ungesünderen Ernährungsweise assoziiert sind, bieten also
Angriffspunkte für Präventionsmaßnahmen für einzelne Bevölkerungsgruppen.
Der vorliegende Aufsatz untersucht aus systematisch-theologischer Sicht den von dem Heidelberger und Marburger Praktischen Theologen Friedrich Niebergall (1866–1932) zwischen ca. 1900 bis 1925 ausgeabeiteten Ansatz einer „Praktischen Dogmatik“. Niebergall wollte damit primär eine pastoraltheologisch orientierte Dogmatik entwickeln, die dem christlichen Prediger Handwerkszeug für seine „Erziehungsarbeit“ an der Gemeinde bereitstellt, mit deren Hilfe er die Gemeindeglieder zur Integration christlicher Ideale in die Pluralität ihres sozialen Alltags anleiten soll. Der Aufsatz unternimmt eine kritische Sichtung von theologischen Voraussetzungen, Inhalt, Aufbau und Folgen von Niebergalls Ansatz und stellt auch die Frage nach der Möglichkeit einer heutigen Adaption.
The current study analyzes the trajectory of the goose vowel in Received Pronunciation (RP) over ten decades (1920s-2010s). Recordings of eighty-seven RP speakers were transcribed in ELAN, and vowel tokens were extracted by FAVE, measuring F1 and F2 values at the midpoint. Showing the life-cycle of a sound change from start to (almost) completion, the results confirm that goose-fronting has been an active sound change for many decades in RP, with F2 starting to increase in the middle of the twentieth century and accelerated changes in the 1970s and the 2010s. We observe similar predictor strengths of linguistic factors as in previous studies. The results are interpreted in light of the social changes in the social composition of the RP group in the second part of the twentieth century, involving increased dialect contact.
Properties of self-excited dust acoustic waves under the influence of active compression of the dust particle system were experimentally studied in the laboratory and under microgravity conditions (parabolic flight). Ground based laboratory experiments clearly show that wave properties can be manipulated by changing the discharge volume, its aspect ratio, and thus the dust particle density. Complementary experiments under microgravity conditions, performed to exclude the effects of gravity inflicted sedimentation and anisotropic behavior, were less conclusive due to residual fluctuations in the planes acceleration indicating the need for a better microgravity environment. A theoretical model, using plasma parameters obtained from particle-in-cell simulations as input, supports the experimental findings. It shows that the waves can be described as a new observation of the dust acoustic mode, which demonstrates their generic character.
This article is the first to show that gender shapes the degree to which legislators use formal mechanisms to oversee government activities. Extensive scholarly work has analysed the use of oversight instruments, especially regarding who monitors whom. Whether, how, and why the conformity of men and women with institutional roles differs, has not yet received scholarly attention. We hypothesise that women become more active than men in overseeing the executive when in opposition while reducing their monitoring activities even more strongly than men when in government because of different social roles ascribed to men and women as well as differences in risk aversity between sexes. We analyse panel data for three oversight tools from the German Bundestag between 1949 and 2013 to test this proposition. Our findings imply that characteristics of political actors influence even a strongly institutionalised process as oversight and further clarify the gender bias in political representation.
Objective: In acute pancreatitis (AP), bacterial translocation and subsequent infection of pancreatic necrosis are the main risk factors for severe disease and late death. Understanding how immunological host defence mechanisms fail to protect the intestinal barrier is of great importance in reducing the mortality risk of the disease. Here, we studied the role of the Treg/Th17 balance for maintaining the intestinal barrier function in a mouse model of severe AP.
Design: AP was induced by partial duct ligation in C57Bl/6 or DEREG mice, in which regulatory T-cells (Treg) were depleted by intraperitoneal injection of diphtheria toxin. By flow cytometry, functional suppression assays and transcriptional profiling we analysed Treg activation and characterised T-cells of the lamina propria as well as intraepithelial lymphocytes (IELs) regarding their activation and differentiation. Microbiota composition was examined in intestinal samples as well as in murine and human pancreatic necrosis by 16S rRNA gene sequencing.
Results: The prophylactic Treg-depletion enhanced the proinflammatory response in an experimental mouse model of AP but stabilised the intestinal immunological barrier function of Th17 cells and CD8+/γδTCR+ IELs. Treg depleted animals developed less bacterial translocation to the pancreas. Duodenal overgrowth of the facultative pathogenic taxa Escherichia/Shigella which associates with severe disease and infected necrosis was diminished in Treg depleted animals.
Conclusion: Tregs play a crucial role in the counterbalance against systemic inflammatory response syndrome. In AP, Treg-activation disturbs the duodenal barrier function and permits translocation of commensal bacteria into pancreatic necrosis. Targeting Tregs in AP may help to ameliorate the disease course.
Zusammenfassung
Die Verordnung einer Stressulkusprophylaxe im Rahmen stationärer Aufenthalte ist im medizinischen Alltag weit verbreitet. Die Verschreibungspraxis einer SUP wurde bisher vor allem im Bereich der Intensivmedizin und der Inneren Medizin untersucht [33, 40, 42, 45, 46]. Allerdings konnte gezeigt werden, dass eine stressulkusbedingte gastrointestinale Blutung unter stationären Bedingungen ein sehr seltenes Ereignis darstellt [12,17]. Im Bereich chirurgischer, nicht kritisch erkrankter Patienten gibt es bislang nur wenige Studien zur aktuellen Praxis der Verschreibung einer SUP [16, 46].
Um die aktuelle Verschreibungspraxis einer SUP in einem chirurgischen Patientenkollektiv beschreiben und bezüglich des Vorliegens einer Indikation nach aktuellen Leitlinien charakterisieren zu können, wurden retrospektiv von Januar bis Juni 2016 Patientendaten an der Universitätsmedizin Greifswald erhoben und ausgewertet [49]. Des Weiteren erfolgte eine Untersuchung der landesweiten Verschreibungspraxis einer SUP auf der Basis einer Befragung der Abteilungsleiter und Mitarbeiter chirurgischer Abteilungen der Akutkliniken in Mecklenburg-Vorpommern [50].
Die Auswertung der retrospektiv erhobenen Patientendaten zeigte eindeutig, dass im weit überwiegenden Anteil der Patienten mit neu verordneter SUP keine Risikofaktoren für die Ausbildung von Stressulzera und stressulkusbedingten Blutungen vorlagen [49]. In 85.7-99.6 % der Patienten mit SUP konnte die Indikation für die Gabe nicht nachvollzogen werden [49].
Die Befragung chirurgisch tätiger Ärzte in Mecklenburg-Vorpommern zeigte, dass die Verschreibung der SUP nur in einer Minderzahl der Kliniken durch eine SOP geregelt war [50]. In den Kliniken mit vorhandener SUP war deren Inhalt nur einer Minderheit der klinisch tätigen Ärzte inhaltlich bekannt [50]. Eine kritische Reevaluation der Indikation einer SUP erfolgte nicht regelhaft bei Verlegung von Intensiv- auf die Normalstation oder bei Entlassung [50].
Die vorliegende Untersuchung zeigt, dass bei chirurgischen Patienten auch heute noch eine massive Überverschreibung einer medikamentösen Stressulkusprophylaxe zur medizinischen Routine gehört [49, 50]. Dabei scheint von den behandelnden Ärzten das Risiko eines Auftretens stressulkusbedingter Blutungen massiv überschätzt beziehungsweise den Patientengruppen nicht regelrecht zugeordnet werden zu können [49, 50]. Angesichts der Tatsache, dass den zur SUP verwendeten Medikamente eine zunehmend größere Zahl unerwünschter Nebenwirkungen (bakterielle Gastroenteritis, akute interstitielle Nephritis, Vitamin-B12-Mangel, ein erhöhtes Risiko für eine Covid-19-Infektion, ambulant und nosokomial erworbene Pneumonien, Demenzerkrankungen, Osteoporose sowie Elektrolytstörungen) zugeordnet werden kann, sollte die Verschreibung der SUP nach einem festen Indikationsschemas erfolgen und im Laufe des stationären Aufenthaltes wiederholt kritisch hinterfragt werden [23-27].
Die Entwicklung einheitlicher Empfehlungen und Richtlinien zur Handhabung von SUP und die Sensibilisierung chirurgisch tätiger Ärzte im Rahmen von Fort- und Weiterbildungen erscheint somit, angesichts der erarbeiteten Daten, dringend notwendig zu sein.
Hass im Netz findet in Deutschland zunehmend Verbreitung und ist besonders für junge Menschen mittlerweile Teil des Alltags geworden, wobei Hass ausgeübt, erlebt oder beobachtet wird. Unter Hass im Netz lassen sich Phänomene wie Cyberbullying, Hassrede und digitale Gewalt beschreiben. Dieses Gutachten betrachtet zunächst die theoretischen und empirischen Grundlagen dieser Phänomene und benennt zentrale Gemeinsamkeiten und Unterschiede, um davon ausgehend Maßnahmen zu erörtern und deren Evidenzbasierung kritisch zu reflektieren, die zur Prävention sowie zur Intervention und Reaktion bei Hass im Netz zur Verfügung stehen. Aus der Zusammenschau werden dann weiterführende Impulse für Forschung und Praxis abgeleitet. Ein besonderer Fokus der Betrachtung liegt dabei auf der Situation in Niedersachsen.
Diese Arbeit beschreibt die Konstruktion einer 3D-gedruckten modularen
Messapparatur (M3DOMA), die eine simultane Messung von Kraft und Drehmoment in allen drei Raumachsen (X, Y und Z) an drei beliebigen Zähnen des Zahnbogens erlaubt und in weiteren Ausbaustufen auf alle Zähne eines Zahnbogens erweitert werden kann. Die Messapparatur wird in Hinblick auf den Aufbau und dessen Eigenschaften, wie der Ruherausch, die Wiederholbarkeit, sowie die Verlässlichkeit der Messungen, beschrieben.
With high prevalence and mortality, myocardial infarction constitutes a social and economic burden in Germany and worldwide. Current guidelines for MI treatment require prompt reperfusion to salvage heart tissue and minimize short- and long-term complications. However, there are currently no treatments available to attenuate reperfusion injury. Ischemic as well as pharmacological post-conditioning have been identified as important clinical strategies to improve outcome. Membrane stabilizers, like Poloxamer 188 (P188), have been shown to improve myocardial ischemia reperfusion (IR) injury and mitochondrial function but have not yet been proven to directly offer mitochondrial protection. Mitochondrial function is crucial for cardiomyocyte function, and mitochondrial dysfunction plays an important role in myocardial injury.
In this study, hearts from 79 Sprague Dawley rats were isolated and perfused ex-vivo with oxygenated Krebs Buffer for 20 min before 30 min of no-flow ischemia. Hearts were reperfused for 10 min with Krebs buffer or 1 mM P188. Cardiac mitochondria were isolated with 1 mM P188 vs 1 mM polyethylene glycol (PEG) vs vehicle by differential centrifugation. Mitochondrial function was assessed as adenosine triphosphate (ATP) synthesis, oxygen consumption and calcium retention for complex I and II substrates of the respiratory chain.
An improvement of myocardial function with 10 min P188 post-conditioning could not be shown. Direct mitochondrial protection of P188 or PEG could not be observed in this model either. Further research is needed to ascertain whether P188 has a direct protective effect on mitochondria and, if so, on what pathways of IR injury it acts.
Die Migration von Endothelzellen unter hämodynamischen Flussbedingungen ist ein komplex regulierter Vorgang. In dieser Arbeit konnten die Aktivierung des Apelin-Rezeptors und die Zugabe von Statinen als Einflussfaktoren auf die Migration der Endothelzellen unter verschiedener Schubspannung identifiziert werden. Dabei wurden folgende Kernaussagen herausgearbeitet:
1. Der Apelin-Rezeptor reguliert die Endothelzellen-Migration in Abhängigkeit von der Schubspannung und dem Gefäßbett. In HUVEC wirkt der APLNR migrationsfördernd unter physiologischen Schubspannungen und migrationshemmend unter höheren Schubspannungen. Keinen Einfluss zeigt der APLNR auf die Migration von HCAEC.
2. Physiologische Statinkonzentrationen reduzieren die EC-Migration in HCAEC. Dies steht im Gegensatz zu der beschriebenen migrationsfördernden Wirkung von statinbehandelten HUVEC. In supraphysiologischen Konzentrationen zeigten sich Unterschiede zwischen dem lipophilen Atorvastatin und dem hydrophilen Pravastatin.
3. Die Wirkung der Statine auf die EC-Migration scheint teilweise über den APLNR zu erfolgen. Dies könnte möglicherweise abhängig von ihrer Lipophilie geschehen.
Hinsichtlich der klinischen Relevanz scheint insbesondere der Einfluss des APLNR auf die endotheliale Migration, sowie sein Zusammenspiel mit Atorvastatin von Bedeutung zu sein. In diesem experimentellen Setting konnte bei Betrachtung von arteriellen EC kein Vorteil eines der Statine bezüglich ihrer Migration herausgearbeitet werden. Inwieweit sich diese jedoch klinisch unterscheiden, müsste in in vivo Studien untersucht werden.
In Zusammenschau mit den Studien der aktuellen Literatur zeigte die hier vorliegende Arbeit besonders, wie stark zum Beispiel die Auswahl des Zellmodells die Ergebnisse beeinflusst. So lassen sich Arbeiten mit dem für Arteriosklerose oft gewählten HUVEC-Zellmodell kaum mit Experimenten an HCAEC vergleichen, obgleich es sich bei beiden um vaskuläre Endothelzellen handelt. Außerdem zeigte sich, dass die Wirkung der Statine oder der APLNR-Blockierung unter physiologischen Schubspannungen teilweise gegenteilig zu ihrer Wirkung unter höheren Schubspannungen ist.
In der individualisierten Medizin wird angestrebt für jeden einzelnen Patienten entsprechend seiner Erkrankungen, die optimalste Therapie zu finden. Wo Atorvastatin für den einen Patienten von Vorteil ist, sorgt bei einer anderen Patientin Pravastatin für mehr Sicherheit. Dass diese Wirkstoffgruppe nicht so homogen ist, zeigen die hier erhobenen Ergebnisse. Um den modernen Therapieansatz zu verfolgen, sollten auch die wissenschaftlichen Fragestellungen bezüglich der Wirkstoffgruppe der Statine konkreter abgestimmt beantworten.
In den Weltmeeren findet rund die Hälfte der jährlichen globalen Kohlenstofffixierung statt, davon ein großer Anteil in küstennahen Regionen. Hier kommt es zu wiederkehrenden saisonalen Algenblüten, die durch eine zeitlich begrenzte explosionsartige Vermehrung von Mikroalgen (hauptsächlich Diatomeen und Coccolithophoren) charakterisiert sind. Vor allem Frühjahrsblüten (März-Mai) haben aufgrund ihrer zeitlichen und räumlichen Vorhersagbarkeit einen hohen Stellenwert als Modellsysteme, anhand deren sich der Kohlenstoffkreislauf der Meere untersuchen lässt.
Mikroalgen produzieren eine große Vielfalt an Makromolekülen, die für die mit ihnen vergesellschafteten Bakterien als Nahrungsgrundlage dienen. Besonders im Fokus stehen hier die für den Kohlenstoffkreislauf relevanten Polysaccharide. Im Gegensatz zu anderen natürlichen Makromolekülen wie DNA oder Proteinen können Polysaccharide aus vielen verschiedenen Monomeren mit unterschiedlichsten Bindungen bestehen. Zusätzlich finden sich an diesen Zuckermonomeren viele Modifikationen wie Acetylierungen, Methylierungen oder Sulfatierungen, die die Komplexität weiter erhöhen. Diese Variabilität bedingt eine hohe strukturelle und funktionale Diversität. So können Polysaccharide Speicherstoffe, Zellwandbestandteile oder Teile der extrazellulären Matrix darstellen.
Komplementär hierzu besitzen Polysaccharid-verwertende Bakterien entsprechend komplexe, enzymatische Abbaumechanismen. Besonders hervorzuheben sind hier die Bakterien des Phylums Bacteroidota, die sich in verschiedensten Nischen auf den Abbau von Polysacchariden spezialisiert haben. Sie finden sich in Bodenproben, als Teil der menschlichen Darmflora, oder eben auch als bedeutende Begleiter von Algenblüten.
Bacteroidota (und in marinen Systemen hauptsächlich die zu ihnen gehörenden Flavobakterien) besitzen zum Abbau diverser Polysaccharide sogenannte Polysaccharide utilization loci (PULs), genomische Inseln, die alle notwendigen Proteine zur Aufnahme und Abbau eines bestimmten Polysaccharids codieren. Hierzu gehören hochspezifische Enzyme (Carbohydrate-active enzymes, CAZymes), transkriptionelle Regulatoren sowie Transportersysteme, die initial gespaltene Oligosaccharide über die Membran in das Bakterium transportieren, wo sie von weiteren Enzymen vollständig abgebaut werden. Diese Co-Lokalisation der benötigten Gene und deren gemeinsame Regulation stellt einen enormen Selektionsvorteil der Bacteroidota dar und ist der Grund, warum sie, ähnlich wie Algen, einer jährlich wiederkehrenden Sukzession folgen, die sich gut untersuchen lässt.Die Forschungsartikel, die Teil dieser Doktorarbeit sind, untersuchen das Zusammenspiel von Polysaccharid-produzierenden Algen mit den Bakterien, die sie abbauen, aber auch darauf basierende Beziehungen der Bakterien untereinander. Die erste Publikation beschäftigt sich mit dem weit verbreiteten Speicherpolysaccharid α-Glucan, für das der Großteil der blütenbegleitenden Bakterien einen spezifischen aktiven PUL besitzt. Eine Untersuchung der in der Blüte vorhandenen Algenarten bestätigte, dass die Blüte von β-Glucan-produzierenden Algen dominiert wird. Da Bakterien aber selbst α-Glucane als Speicherpolysaccharide verwenden, konnte gezeigt werden, dass nicht die Algen selbst, sondern die Bakterien Hauptproduzent dieser Polysaccharide während einer Phytoplanktonblüte sind. Bakterielle Proteine, die dem Abbau von Algen-β-Glucan und dem daraus folgenden Aufbau von bakteriellem α-Glucan dienen, waren in Umweltproben und in Laborkulturen unter ähnlichen Bedingungen abundant. Die Untersuchung von extrahiertem bakteriellem Polysaccharid bewies, dass dieses nicht nur α-Glucan enthält, sondern dass dieses Polysaccharid auch in der Lage war, α-Glucan PULs mariner Bakterien zu induzieren. Hier zeigte sich ein innerhalb des marinen Kohlenstoffkreislaufs bisher wenig berücksichtigter Kreislauf, indem Bakterien Polysaccharide anderer Bakterien nutzen, die z.B. durch Viren lysiert wurden.
Die anderen zwei Artikel dieser Arbeit befassen sich mit dem Abbau von Zellwandpolysacchariden durch blütenassoziierte Modellbakterien. In einer der Studien wird detailliert der Abbau eines β-Mannans (ein Polysaccharid das hauptsächlich aus dem Monosaccharid Mannose besteht) durch ein Bakterium des Genus Muricauda beschrieben. Die PUL-Struktur dieses Bakteriums kam in mehreren anderen Phytoplanktonblüten-assoziierten Bakterien vor. Diese Beobachtung wies darauf hin, dass es sich hier um ein Mannan mit zusätzlichen Galactose- und Glucose-Substitutionen handelte. Proteom-Untersuchungen bestätigten, dass das Bakterium derartige Substrate unter Induktion des β-Mannan-PULs nutzen können. β-Mannan konnte durch Antikörpermarkierung in Blütenproben sowie spezifischen Mikroalgenarten (Chaetoceros, Coscinodiscus) nachgewiesen werden. Die in dieser Publikation charakterisieren β-Mannan-PUL-codierten Enzyme waren in der Lage, dieses Signal zu löschen, was bewies, dass Muricauda sp. Mannan-basierte Zellwandpolysaccharide bestimmter Arten von Mikroalgen abbauen kann.
Die dritte Studie geht näher auf den Abbau von Xylanen (bestehend aus Xylose) durch ein blütenassoziiertes Bakterium des Genus Flavimarina ein. In diesem Bakterium wurden anhand der enthaltenen Xylanasen zwei putative Xylan-PULs annotiert. Wachstumsexperimente und Proteom-Untersuchungen zeigten, dass einer dieser PULs hauptsächlich bei Wachstum auf Glucoronoxylan induziert wird, während der andere PUL aufArabinoxylane stärker reagierte. Untersuchung der PUL-CAZymes bestätigte diese Ergebnisse durch Charakterisierung mehrerer Xylanasen sowie Glucoronidasen und Arabinofuranosidasen. Zusätzlich codierten beide PULs für Esterasen, die eine Modifikation der natürlichen Substrate durch Acetylierungen oder Methylierungen nahelegen. Da all diese Merkmale von terrestrischen Xylanen geteilt werden und in Blütenproben aus Küstennahen Regionen Xylane nachgewiesen wurden, ist es möglich, dass Bakterien aus solchen Regionen sowohl Xylane terrestrischen Ursprungs (z.B. durch Flusseinspeisung) sowie marinen Ursprungs abbauen können.
Für frühgeborene Kinder ist Muttermilch die empfohlene enterale Ernährung mit vielen bereits gut untersuchten positiven Effekten. Jedoch ist der Gehalt an Makronährstoffen zu niedrig, um die Bedürfnisse von Frühgeborenen zu decken. Zusätzlich zeigt native Muttermilch eine hohe inter- und intraindividuelle Variabilität der Makronährstoffe. Die Effizienz der allgemein verbreiteten Standardfortifizierung mit kommerziell erhältlichen Fortifiern ist durch diese Variabilität beeinträchtigt und kann so in einem Großteil der Muttermilchproben zu einer inadäquaten Nährstoffzufuhr führen, die zu niedrig, jedoch auch zu hoch ausfallen kann. Unzureichende Ernährung kann einen negativen Einfluss auf das Wachstum und die Körperzusammensetzung sowie Folgeerkrankungen im Erwachsenenalter haben.
Diese Studie zeigt anhand eines Datensatzes mit realen Messwerten zur Zusammensetzung der Muttermilch in über 3300 Proben, dass die Messung der Makronährstoffe in nativer Muttermilch und die anschließende, darauf basierende Targetfortifizierung mit der individuellen Ergänzung der fehlenden Makronährstoffen zu adäquaten Nährstoffeinträgen führt. Mit diesem Ansatz kann auf die Variabilität der nativen Muttermilch reagiert und die Variation der Makronährstoffeinfuhr signifikant verringert werden. In dieser Arbeit wurden drei verschiedene optimierte Standardfortifier entwickelt. Deren Zusammensetzung erhöht den Makronährstoffeintrag bereits unter Standardfortifizierung, aber noch mehr bei ein oder zwei Muttermilchanalysen pro Woche.
Weiterhin wurde in dieser Arbeit der Einfluss der durch die verschiedenen Fortifizierungsstrategien erzeugten Nährstoffzufuhren auf die Wachstumsraten berechnet, die für Standardfortifizierung ungenügende und für Targetfortifizierung hauptsächlich zufriedenstelle Ergebnisse zeigt.
Verschiedene Kombinationen von Pooling mit bis zu drei Proben oder von Pooling einer größeren Anzahl wie in einer Milchbank zu Verfügung stehenden Proben verringerten nicht die Variabilität der Nährstoffzufuhr. Ebenso zeigte die Gefriertrocknung keine zufriedenstellenden Ergebnisse für alle Makronährstoffkonzentrationen.
Die Ergebnisse dieser Arbeit verdeutlichen, dass standardfortifizierte Muttermilch trotz verschiedener Poolingstrategien keine adäquate Makronährstoffzufuhr für frühgeborene Kinder sicherstellt. Für den klinischen Alltag wird die Bedeutung der Targetfortifizierung deutlich, die mit regelmäßiger Muttermilchanalyse und unter Anwendung optimierter Standardfortifier zufriedenstellend gelingen kann und so zu physiologischen Wachstumsraten führen kann.
Our study examined whether potentially critical indications from depression questionnaires, interviews, and single items on suicidal ideation among partici-pants in a large prospective population-based study are related to short-term sui-cides within one year. For this purpose, we studied the association between (a) the severity of depressive symptoms according to the M-CIDI and the PHQ-9, BDI-II, and CID-S depression screening and (b) elevated scores on single sui-cidal ideation items and mortality according to claims databases.
In the baseline cohort, the frequency of depressive symptoms measured by CID-S was 12.90% (SHIP-START-0). The frequency for “Moderate” to “Severe de-pression” measured by the PHQ-9 (≥ 10 points) and BDI-II (≥ 20 points) ques-tionnaires ranged from 5.40% (SHIP-LEGENDE) to 8.80% (SHIP-TREND Morbid-ity follow-up). The 1-month prevalence of unipolar depression, measured by the M-CIDI in SHIP LEGENDE, was 2.31%.
Between 5.90% (SHIP-TREND Morbidity follow-up) and 6.60% (SHIP-LEGENDE) of respondents showed a certain degree of suicidal ideation in the two weeks preceding the assessment, according to BDI-II and PHQ-9.
Our results show the high frequency of depressive symptoms in the study region, with women being affected more frequently than men, especially in the higher categories. Furthermore, women were more frequently affected by suicidal idea-tion, although this difference was not evident in the highest categories.
There was one potential suicide in the year after a SHIP examination.
From our results, we cannot conclude that severe self-reported symptoms from depression questionnaires should be reported back to participants of an obser-vational population-based study to prevent suicide deaths within one year.
Decreased inflammatory profile in oral leukoplakia tissue exposed to cold physical plasma ex vivo
(2023)
Background
Oral leukoplakia (OL) is an unfavorable oral disease often resistant to therapy. To this end, cold physical plasma technology was explored as a novel therapeutic agent in an experimental setup.
Methods
Biopsies with a diameter of 3 mm were obtained from non-diseased and OL tissues. Subsequently, cold atmospheric pressure plasma (CAP) exposure was performed ex vivo in the laboratory. After 20 h of incubation, biopsies were cryo-conserved, and tissue sections were quantified for lymphocyte infiltrates, discriminating between naïve and memory cytotoxic and T-helper cells. In addition, the secretion pattern related to inflammation was investigated in the tissue culture supernatants by quantifying 10 chemokines and cytokines.
Results
In CAP-treated OL tissue, significantly decreased overall lymphocyte numbers were observed. In addition, reduced levels were observed when discriminating for the T-cell subpopulations but did not reach statistical significance. Moreover, CAP treatment significantly reduced levels of C-X-C motif chemokine 10 (CXCL10) and granulocyte-macrophage colony-stimulating factor in the OL biopsies' supernatants. In idiopathically inflamed tissues, ex vivo CAP exposure reduced T-cells and CXCL10 as well but also led to markedly increased interleukin-1β secretion.
Conclusion
Our findings suggest CAP to have immuno-modulatory properties, which could be of therapeutic significance in the therapy of OL. Future studies should investigate the efficacy of CAP therapy in vivo in a larger cohort.
Purpose
The significance of the underlying literature in clinical guidelines can be weakened by the risk of bias, which could negatively affect the recommendations. Especially in controversial matters, such as fluoride use for caries prevention in children, biased results may be not reliable and lead to incorrect conclusions. This study was performed to detect bias in underlying literature of the German guideline for caries prevention using fluoride in children, where no consensus was reached between paediatricians and paediatric dentists.
Methods
Three tools used for risk of bias assessments of different study designs were RoB 2 for RCTs, ROBINS-I for non-randomized studies, and ROBIS for systematic reviews. For each study cited in the guideline two independent risk of bias assessments were performed. Disagreements were resolved by consensus.
Results
Out of 58 papers, 48.3% (n = 28) showed high risk of bias, with the majority in sections regarding fluoride tablets, fluoridated toothpaste, and paediatricians’ recommendations. 9 out of 20 recommendations and statements were based on studies with high risk of bias, all of which were in these three controversial sections. 13 out of 29 RCTs showed high risk of bias (44.8%), as all 13 non-randomized trials did, while only 2 of 16 (12.5%) systematic reviews had high risk of bias.
Conclusion
Considering risk of bias of cited studies in clinical guidelines may result in substantial changes in its recommendations and aid in reaching consensus. Efforts should be made to assess risk of bias of underlying literature in future clinical guidelines.
Urbanization, industrialization, and intensification of agriculture have led to considerable heavy metal pollution across the globe, harming our ecosystems. Concentrations of arsenic (As), cadmium (Cd), copper (Cu), and lead (Pb) have been analysed in 249 eggshells collected between 2006 and 2021 from 83 female Common Cranes (Grus grus) nesting within north-eastern Germany. Information on the presence of trace elements in cranes from Europe and their potential adverse effects on the reproduction are largely missing. Only Cu and Pb were found to be present in eggshell samples. Levels of both metals did not exceed concentrations considered potentially toxic in birds and unhatched eggs did not contain higher metal concentrations compared to eggshell residues from hatched eggs. Statistical analysis revealed that trace element concentrations decreased significantly over the course of the study period. The ban of leaded gasoline in the early twenty-first century and strict limitations of heavy metal-based biocontrol products are likely responsible for this decrease over the years. However, as Cu levels gradually increase with increasing proportions of agricultural areas within the cranes’ home ranges, we suggest that considerable amounts of Cu originating from agricultural practises are still being released into the environment. We found no increase in metal concentrations in eggshells with increasing female age, suggesting that heavy metals do not accumulate in the circulatory systems of the adults over time. This study is the first to assess heavy metal contamination in Common Cranes and indicates the suitability of crane’s eggshells as bioindicator for monitoring environmental pollution.
Hintergrund:
Kardiovaskuläre Präventionsleitlinien empfehlen unterschiedliche Instrumente zur kardiovaskulären 10-Jahres-Risikobestimmung. In der hausärztlichen Praxis wird dafür häufig das arriba-Instrument verwendet und durch die Leitlinie „Hausärztliche Risikoberatung zur kardiovaskulären Prävention“ empfohlen. Ziel der Studie ist die Validierung der arriba-Risikoprädiktion auf Basis von Morbiditäts- und Mortalitätsdaten der bevölkerungsbasierten Study of Health in Pomerania.
Methoden:
In einer retrospektiven Längsschnittanalyse wurde für Probanden ohne vorheriges kardiovaskuläres Ereignis das kardiovaskuläre 10-Jahres-Gesamtrisiko (Myokardinfarkt oder Schlaganfall) zur Basisuntersuchung mit dem arriba-, SCORE-Deutschland- und PROCAM-Algorithmus (Myokardinfarkt) berechnet. Aus Daten der Folgeuntersuchungen wurden kardiovaskuläre Ereignisraten ermittelt und Diskriminierungs- und Kalibrierungsmaße für die Risikobestimmungsinstrumente berechnet.
Ergebnisse:
In die Analyse wurden 2277 Proband:innen (Durchschnittsalter 53 ± 13 Jahre, 50% Männer) eingeschlossen. Nach durchschnittlich 10,2 Jahren betrug die kardiovaskuläre Ereignisrate 8,6% (196/2277). Das Verhältnis aus prädizierter und beobachteter Ereignisrate betrug für Proband:innen mit niedrigem, mittlerem und hohem kardiovaskulären Risiko 0,8, 1,5 und 1,3. Arriba unterschätzte bei Frauen und überschätzte in den Altersgruppen 30-44 und 45-59 Jahren die kardiovaskulären Ereignisraten.
Schlussfolgerung:
Diskriminierungswerte für das arriba-Instrument sind mit SCORE-Deutschland und PROCAM vergleichbar, eine individuelle Anpassung an die Zielpopulation ist jedoch nötig.
The maintenance of protein homeostasis in muscle by degradation systems, e.g. the autophagy lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS), is of great importance. It prevents the accumulation of nonfunctioning and not properly folded proteins, which can lead to protein aggregate myopathies (PAMs) and several other protein storage diseases. Degradation by the UPS depends on the transfer of ubiquitin to a target protein. This happens in a cascade of E1-E2-E3 proteins. This process is also involved in protein location and regulation of protein activity. E3 ligases are often tissue specific. Muscle RING-finger proteins (MuRFs) are a family of really interesting new gene (RING)-Finger E3 ubiquitin ligases, that are almost exclusively expressed in the striated muscle. They play a role in muscle wasting, but are also important for the maintenance of the structure of striated muscle. MuRF proteins are also involved in the regulation of the striated muscle energy metabolism. Previous work has demonstrated that MuRF1/MuRF3 DKO mice show a protein surplus myopathy characterized by an accumulation of myosin heavy chain proteins in striated muscles and a reduction in function of both heart and skeletal muscle. The aim of this study was to test the hypothesis that the myopathic phenotype of MuRF1/MuRF3 DKO mice is mediated by a disturbed energy homeostasis in the heart and skeletal muscle, with focus on mitochondrial function. Because sex-specific differences have not been investigated in these mice so far, a further aim was to investigate any differences between male and female mice.
To test these hypotheses, we measured the weight of the heart and the hindlimb muscles tibialis anterior and soleus to detect a possible hypertrophy in the DKO mice. Hematoxylin and eosin staining of histological cross sections of the tibialis anterior were performed to investigate protein accumulations. Muscle function was quantitated via grip strength and specific force measurements. Possible changes in protein amounts were detected via mass spectrometry analyses and western blot analyses. Changes in gene expression were investigated by qRT-PCR. Coimmunoprecipitation was used to determine direct interactions between proteins. Protein stability and ubiquitination were investigated by cycloheximide (CHX) and ubiquitination assays, respectively.
DKO mice showed an increase in heart and skeletal muscle weights. Grip strength assays revealed limb weakness of DKO mice. H&E staining of histological cross sections of the tibialis anterior muscle (TA) showed protein aggregates within myofibers. Mass spectrometry analyses of proteins isolated from TA and heart muscle revealed an increase of muscle stress markers and structural proteins in DKO mice, while proteins involved in the energy metabolism were reduced. Especially interesting here were the proteins of the mitochondrial electron transport chain (ETC), which play a major role in the energy production of the mitochondria by catalyzing the phosphorylation of ADP to ATP, the universal energy carrier in all living organisms. These changes were more pronounced in TA compared to heart. Western blot and qRT-PCR results of ETC subunits supported our proteome data. They also revealed a sex-specific difference, in which the reduction ETC subunits was more pronounced in females than males. In female
TA NDUFB8, SDHB, UQCRC2, MTCO1 and ATP5 were significantly reduced compared to controls, while only UQCRC2 and ATP5 were decreased in male TA compared to controls. A significant reduction in gene expression of Ndufb8, Sdhb, Mtco1 and Atp5 was detected in TA of female mice compared to controls, while only Ndufb8, Sdhb and Atp5 were decreased in male TA compared to controls. We observed the same pattern in Heart of male (protein: NDUFB8; mRNA: Mtco1) and female (protein: UQCRC2, MTCO1, ATP5; mRNA: Sdhb, Mtco1) DKO mice compared to their controls. The reduction in ETC subunits was paralleled by a reduction in complex I and complex III activity in the TA of DKO mice, but not in heart. However, this was only significant in the TA of female but not male mice. Mechanistical analyses using coimmunoprecipitation, cycloheximide chase and ubiquitination assays showed that MuRF1 physically interacted with the transcriptional repressor histone deacetylase 5 (HDAC5), mediated its ubiquitination as well as its UPS-dependent degradation. The absence of MuRF1 and MuRF3 in DKO mice let to an increase in the amounts of HDAC5 in TA. Because HDAC5 binds to PGC-1α, the master regulator of mitochondrial biogenesis (encoded by Ppargc1a), we investigated its gene expression in DKO muscle and found it to be reduced.
These data connect MuRF1 and MuRF3 directly to the striated muscle energy metabolism, by regulating mitochondrial function. The results provide insights into the development of PAMs and possibly other protein storage diseases, where a decrease of mitochondrial function has already been described.
Medieval texts reveal the normalised presence of Saami peoples in medieval Fennoscandia, suggesting close interactions involving trade, relationships, rituals, and magic. Despite growing recognition of these relations, the Saami remain overlooked in general studies of the Middle Ages, often relegated to symbolic roles or footnotes. As a result, Saami characters are typically depicted as the exotic Other within Norse society, often being stripped of agency and humanity in historical narratives. To counter these biases and distorted narratives, an essential step is analysing exclusionary structures in medieval literature and critically reviewing existing research on Saami representation. This process challenges dehumanising portrayals and confronts present-day stereotypes. The present study aims to ‘re-humanize’ (as Paulette F. C. Steeves puts it) the medieval Saami past by using decolonising frameworks and perspectives offered by the so-called ‘Indigenous turn’ of medieval studies, bridging medieval studies and Indigenous studies within a Norse context.
Comparative neuroanatomy of the central nervous system in web-building and cursorial hunting spiders
(2023)
Spiders (Araneae) include cursorial species that stalk their prey and more stationary species that use webs for prey capture. While many cursorial hunting spiders rely on visual cues, web-building spiders use vibratory cues (mechanosensation) for prey capture. We predicted that the differences in primary sensory input between the species are mirrored by differences in the morphology/architecture of the central nervous system (CNS). Here, we investigated the CNS anatomy of four spider species, two cursorial hunters Pardosa amentata (Lycosidae) and Marpissa muscosa (Salticidae), and two web-building hunters Argiope bruennichi (Araneidae) and Parasteatoda tepidariorum (Theridiidae). Their CNS was analyzed using Bodian silver impregnations, immunohistochemistry, and microCT analysis. We found that there are major differences between species in the secondary eye pathway of the brain that pertain to first-order, second-order, and higher order brain centers (mushroom bodies [MB]). While P. amentata and M. muscosa have prominent visual neuropils and MB, these are much reduced in the two web-building species. Argiope bruennichi lacks second-order visual neuropils but has specialized photoreceptors that project into two distinct visual neuropils, and P. tepidariorum lacks MB, suggesting that motion vision might be absent in this species. Interestingly, the differences in the ventral nerve cord are much less pronounced, but the web-building spiders have proportionally larger leg neuropils than the cursorial spiders. Our findings suggest that the importance of visual information is much reduced in web-building spiders, compared to cursorial spiders, while processing of mechanosensory information requires the same major circuits in both web-building and cursorial hunting spiders.
o-Hydroxyarylphosphanes are fascinating compounds by their multiple-reactivity features, attributed to the ambident hard and soft Lewis- and also Brønstedt acid-base properties, wide tuning opportunities via backbone substituents with ±mesomeric and inductive, at P and in o-position to P and O also steric effects, and in addition, the configurational stability at three-valent phosphorus. Air sensitivity may be overcome by reversible protection with BH3, but the easy oxidation to P(V)-compounds may also be used. Since the first reports on the title compounds ca. 50 years ago the multiple reactivity has led to versatile applications. This includes various P−E−O and P=C−O heterocycles, a multitude of O-substituted derivatives including acyl derivatives for traceless Staudinger couplings of biomolecules with labels or functional substituents, phosphane-phosphite ligands, which like the o-phosphanylphenols itself form a range of transition metal complexes and catalysts. Also main group metal complexes and (bi)arylphosphonium-organocatalysts are derived. Within this review the various strategies for the access of the starting materials are illuminated, including few hints to selected applications.
Aim
To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1H-NMR) spectroscopy with periodontitis and tooth loss.
Materials and Methods
A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing.
Results
While only spurious associations between lipoprotein levels from conventional blood tests were found—that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity.
Conclusions
Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.
Aim
Climate change challenges temperate forest trees by increasingly irregular precipitation and rising temperatures. Due to long generation cycles, trees cannot quickly adapt genetically. Hence, the persistence of tree populations in the face of ongoing climate change depends largely on phenotypic variation, that is the capability of a genotype to express variable phenotypes under different environmental conditions, known as plasticity. We aimed to quantify phenotypic variation of central Europe's naturally dominant forest tree across various intraspecific scales (individuals, mother trees (families), populations) to evaluate its potential to respond to changing climatic conditions.
Location
Europe.
Time Period
2016–2019.
Major Taxa Studied
European beech (Fagus sylvatica L.).
Methods
We conducted a fully reciprocal transplantation experiment with more than 9000 beech seeds from seven populations across a Europe-wide gradient. We compared morphological (Specific Leaf Area), phenological (leaf unfolding) and fitness-related (growth, survival) traits across various biological scales: within single mother trees, within populations and across different populations under the contrasting climates of the translocation sites.
Results
The experiment revealed significant phenotypic variation within the offspring of each mother tree, regardless of geographic origin. Initially, seedling height growth varied among mother trees and populations, likely due to maternal effects. However, the growth performance successively aligned after the first year. In summary, we observed a consistent growth response in different beech populations to diverse environments after initial maternal effects.
Main Conclusions
The study strikingly demonstrates the importance of considering intraspecific variation. Given the surprisingly broad spectrum of phenotypes each mother tree holds within its juvenile offspring, we conclude that Fagus sylvatica might have the potential for medium-term population persistence in face of climate change, provided that this pattern persists into later life stages. Hence, we also suggest further investigating the inclusion of passive adaptation and natural dynamics in the adaptive management of forests.
Die Untersuchung widmet sich der Analyse von Darstellungen von Erde und Kosmos in ausgewählten Drucken der Inkunabelzeit zwischen 1450 und 1500. Das Forschungskorpus umfasst verschiedene Werke, darunter das „Buch der Natur“ von Konrad von Megenberg, den „Lucidarius“, den „Schatzbehalter“ von Stephan Fridolin und die „Weltchronik“ Hartmann Schedels. Im Fokus steht die Untersuchung des Verhältnisses von Text und Bild sowie der Funktionen der Holzschnitte bei der Vermittlung von Wissen über die Welt. Bei der Analyse werden Aspekte wie Layout, Bildformeln, Kolorierung und das Zusammenspiel von Text und Bild bei der Rezeption berücksichtigt. Die Werke repräsentieren unterschiedliche Textgattungen und ermöglichen Einblicke in die sich wandelnde Rezeption von Wissen über Erde und Kosmos im Übergang von der Handschrift zum Druckmedium.
Protein engineering is essential for altering the substrate scope, catalytic activity and selectivity of enzymes for applications in biocatalysis. However, traditional approaches, such as directed evolution and rational design, encounter the challenge in dealing with the experimental screening process of a large protein mutation space. Machine learning methods allow the approximation of protein fitness landscapes and the identification of catalytic patterns using limited experimental data, thus providing a new avenue to guide protein engineering campaigns. In this concept article, we review machine learning models that have been developed to assess enzyme-substrate-catalysis performance relationships aiming to improve enzymes through data-driven protein engineering. Furthermore, we prospect the future development of this field to provide additional strategies and tools for achieving desired activities and selectivities.
Boronate esters, formed by the reaction of an oligonucleotide bearing a 5′-boronic acid moiety with the 3′-terminal cis-diol of another oligonucleotide, support the assembly of functional nucleic acid architectures. Reversible formation of boronate esters occurs in templated fashion and has been shown to restore the activity of split DNA and RNA enzymes as well as a split fluorescent light-up aptamer. Apart from their suitability for the design and application of split nucleic acid enzymes and aptamers in the field of biosensing, boronate esters may have played an important role in early life as surrogates of the natural phosphodiester bond. Their formation is reversible and thus fulfills an important requirement for biological self-assembly. Here we discuss the general concept of stimuli-dependent boronate formation and its application in biomolecules with implications for future research.
Aim
To estimate association between the use of interdental cleaning aids (IDAs) and type on 7-year follow-up levels of interdental plaque, interdental gingival inflammation, interdental periodontitis severity, the number of interdental sound surfaces and the number of missing teeth in a population-based cohort study.
Materials and Methods
We used 7-year follow-up data of 2224 participants from the Study of Health in Pomerania (SHIP-TREND). We applied generalized linear and ordinal logistic models, adjusting for confounding and selection bias using inverse probability treatment weighting and multiple imputation.
Results
Flossers were 32% less likely to have higher interdental plaque (iPlaque) levels than non-users of IDAs (odds ratio [OR] = 0.68; 95% confidence interval [CI]: 0.50–0.94); flossing resulted in 5% lower means of iPlaque. Effects on interdental bleeding on probing (iBOP), mean interdental probing depths and mean interdental clinical attachment levels were direction-consistent but statistically non-significant. Interdental brushing was associated with lower follow-up levels for interdental plaque (OR = 0.73; 95% CI: 0.57–0.93) and iBOP (OR = 0.69; 95% CI: 0.53–0.89). IDAs were more effective in reducing iPlaque in participants with periodontitis, whereas iBOP reduction was more pronounced in participants with no or mild periodontitis. The analyses did not suggest that the use of IDAs affected caries. Finally, applying change score analyses, flossing reduced tooth loss incidence (incidence rate ratio [IRR] = 0.71) compared with non-users of IDAs.
Conclusions
Recommending flossing and interdental brushing in dental practices represents an approach to the prevention of gingivitis and consequently periodontitis.
Animals face strong environmental variability even on short time scales particularly in shallow coastal habitats, forcing them to permanently adjust their metabolism. Respiration rates of aquatic ectotherms are directly influenced by water temperature, whereas ingestion rates might additionally be influenced by behavior. We aim to understand how respiration and ingestion rates of an aquatic invertebrate respond to changing temperature during a diurnal thermal fluctuation cycle and how both processes are related. We studied the benthopelagic mysid Neomysis integer as an important food web component of coastal ecosystems. Mysids were collected at the southern Baltic Sea coast and exposed in the laboratory to either constant temperature of 15°C or daily temperature fluctuation of 15 ± 5°C. Short-term (1–2 h) respiration and ingestion rates were measured at four equidistant time points within 24 h and did not differ among time points at constant temperature, but differed among time points in the fluctuating treatment. Respiration was highest at the thermal maximum and lowest at the thermal minimum. Ingestion rates showed the opposite pattern under fluctuation, likely due to differences in underlying thermal performance curves. When temperature transited the average, the direction of temperature change influenced the animals' response in respiration and ingestion rates differently. Our results suggest that respiration is not only instantaneously affected by temperature, but also influenced by the previously experienced direction of thermal change. Our experiment, using an important non-model organism, delivered new insights on the relationship between the crucial organismal processes ingestion and respiration under thermal variability.
Introduction
The number of mentally altered patients a dentist meets in practice is increasing and interaction with them can be very challenging. As a baseline for an interventional study, we want to assess the attitude of dental students and identify areas of improvement in patient communication. This work compares the attitude of dental students towards people suffering from dementia to the attitudes of trained medical caregivers and the general population. Our aim is to use the results to assess the need for training in communicating with mentally altered patients.
Materials and Methods
Fourth-year dental students attended two lectures on dementia given by a psychiatrist as part of the geriatric dentistry lecture and were questioned afterwards using the Dementia Attitude Scale. In 2016 and 2017, 73 students at the University of Greifswald were interviewed. The response rate was 84%. Using a factor analysis, the Dementia Attitude Scale's validated questions were interpreted and compared with data from nursing staff from Switzerland and the USA.
Results
The factor analysis of the data showed the same two-factor loadings as the comparative groups, and that dental students' attitude is more comparable to the general population than to medically trained nursing staff.
Conclusion
Given the results, we conclude that the implementation of a communication module can serve in improving the attitude of dental students towards patients with dementia.
Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea–hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.
In der vorliegenden Arbeit wurde ein Routine-TDM auf einer Intensivstation über 3 Jahre bei Patient:innen mit Sepsis während einer kontinuierlichen Meropenemtherapie durchgeführt und auf die Umsetzung und den praktischen Nutzen hin untersucht. Da Meropenem ein Antibiotikum mit zeitabhängiger Wirkung ist, war das Ziel Konzentrationen unterhalb der 4-fachen MHK und ein dadurch bedingtes mögliches Therapieversagen zu vermeiden.
Die Patient:innen erhielten zu Beginn eine Tagesdosierung von 6 g/d mit einem initialen Bolus von 0,5 g Meropenem. Die Dosierung wurde entsprechend der erhobenen Meropenemkonzentrationen durch das Routine-TDM nach Einschätzung des ärztlichen Personals angepasst. Es wurden keine Vorgaben bzgl. eines oberen Grenzwertes oder Umsetzung der Dosisanpassungen gemacht. Das TDM ergab gerade zu Beginn erhöhte Meropenemkonzentrationen, sodass Dosissteigerungen fast ausschließlich erst nach vorheriger Dosisreduktion durchgeführt werden mussten. Konzentrationen, bei denen eine Steigerung oder eine Reduktion der Dosis beschlossen wurde, wiesen eine hohe Variabilität auf. Das Anpassungsverhalten des ärztlichen Personals kann als sehr konservativ beschrieben werden. Die Dosissteigerungen wurden bereits sehr früh und Dosisreduktionen eher spät durchgeführt.
Bei knapp 46 % der Patient:innen wurde die Dosis gar nicht angepasst und bei 46 % der Patient:innen wurde insgesamt eine Dosisreduktion durchgeführt. Dies war zu 96 % eine Halbierung der Tagesdosis auf 3 g/d. Die gemessenen Wirkkonzentrationen unterschieden sich bei Patient:innen die 6 g/d und bei Patient:innen die 3 g/d Meropenem erhielten letztendlich nicht signifikant voneinander. Dies zeigt, dass die Dosisanpassungen genutzt wurden um andere Einflussfaktoren auf die Konzentration auszugleichen.
In einer multivarianten Regressionsanalyse zeigten die Nierenfunktion, die Körpergröße und das Körpergewicht einen signifikanten Einfluss auf die Antibiotikumkonzentration. Dennoch zeigte die Regressionsanalyse sich in den Extrembereichen ungenau, weshalb ein TDM sehr sinnvoll ist. Gerade bei einer veränderten Nierenfunktion oder bei Patient:innen mit RRT zeigte sich ein TDM als sehr hilfreich. Patient:innen mit ARC zeigten sich in der vorliegenden Arbeit signifikant häufiger unterdosiert und Patient:innen mit RRT wiesen eine höhere Variabilität der gemessenen Konzentrationen auf. Tools zur Anpassung der Dosierung anhand der Nierenfunktion wurden in Studien bisher überwiegend als unzureichend beschrieben. Bei Patient:innen mit RRT werden verschiedenste Dosierungsoptionen aktuell diskutiert. Insgesamt wurde bei knapp 5,8 % der Patient:innen eine Unterdosierung detektiert. Daraufhin wurde vom ärztlichen Personal inkonsequent reagiert. Einen Einfluss auf das klinische Outcome konnte durch das TDM oder durch die Unterdosierungen nicht ausgemacht werden. Lediglich die Schwere der Sepsisart zeigte einen signifikanten Einfluss auf die Mortalität.
Neurologische Auffälligkeiten, wie Krampfanfälle konnten nur selten detektiert werden. Patient:innen, bei denen diese auffielen, zeigten zwar signifikant höhere Meropenemkonzentrationen, allerdings ließen sich die Symptome nicht mit Sicherheit auf die Antibiotikatherapie zurückführen, da diese Patient:innen zusätzlich eine neurologische Grunderkrankung hatten. In gezielten Studien zu neurotoxischen Nebenwirkungen bei Betalaktamen wird der Zusammenhang mit supratherapeutischen Konzentrationen aber immer öfter beschrieben.
Zusammenfassend zeigt sich, dass das TDM einen maßgeblichen Einfluss auf die Therapieentscheidungen hatte. Unterdosierungen sind unter der gewählten Dosierungsform nur selten aufgetreten und Dosissteigerungen waren kaum nötig. Gerade bei Patient:innen mit RRT oder erhöhter Nierenfunktion zeigte sich das TDM als nützlich. Die Grenzen für Anpassungen variierten sehr stark und wurden eher konservativ gewählt. Ein genau definierter Zielbereich der angestrebten Meropenemkonzentration und festgelegte Optionen zur Dosisanpassung könnten den Nutzen des TDMs weiter erhöhen. Weitere prospektive Studien sind nötig, um eine Obergrenze zu definieren und Toxizität zu vermeiden.
Empfehlungen für die Praxis:
• Fortsetzung des TDMs bei kritisch kranken Patient:innen
• Etablierung einer SOP zur Dosisanpassung sowie Reduzierung der Startdosierung auf 3 g Meropenem/d mit Initialbolus von 0,5 g
• Hinweise bei Patientengruppen mit Gefahr für Unter- oder Überdosierungen.
Changes in the microcirculation of the skin are a frequently observed accompanying phenomenon of many diseases, far beyond the spectrum of dermatological diseases. Not all of these changes are pathological, many are transient and have no serious consequences. This is true for many inflammatory diseases such as psoriasis vulgaris or atopic eczema.
However, there are also diseases in which functionally and morphologically recognizable microangiopathies lead to severe disease consequences. One of the most important diseases in this context is systemic sclerosis, an autoimmune systemic disease with multiple organ manifestations. Investigations of the cutaneous microcirculation are of great importance for the initial diagnosis as well as for prognosis and assessment of disease progression.
In peripheral hemodynamic disorders such as peripheral arterial disease (PAD) and chronic venous insufficiency (CVI), understanding microcirculatory disturbances also plays an important role in therapy and in monitoring the success of therapeutic interventions.
In this article, we address the transition of the Kolbe electrolysis of valeric acid (VA) to n-octane as an exemplary electrosynthesis process from a batch reaction to a continuous, self-regulated process. Based on a systematic assessment of chemical boundary conditions and sustainability aspects, we propose a continuous electrosynthesis including a simple product separation and electrolyte recirculation, as well as an online-pH-controlled VA feeding. We demonstrate how essential performance parameters such as product selectivity (S) and coulombic efficiency (CE) are significantly improved by the transition from batch to a continuous process. Thus, the continuous and pH-controlled electrolysis of a 1 M valeric acid, starting pH 6.0, allowed a constantly high selectivity of around 47 % and an average Coulomb efficiency about 52 % throughout the entire experimental duration. Under otherwise identical conditions, the conventional batch operation suffered from lower and strongly decreasing performance values (Sn-octane, 60min=10.4 %, Sn-octane, 240min=1.3 %; CEn-octane, 60min=7.1 %, CEn-octane, 240min=0.5 %). At the same time, electrolyte recirculation significantly reduces wastes and limits the use of electrolyte components.
Aims
To investigate factors that influence the willingness of inactive nurses to return to nursing in a crisis situation and to identify aspects that need to be considered with regard to a possible deployment.
Design
A deductive and inductive qualitative content analysis of semi-structured focus group interviews.
Methods
Semi-structured focus group interviews with inactive or marginally employed nurses, nurses who have been inactive for some time and nursing home managers in October and November 2021. The participating inactive nurses had declared their willingness for a deployment during the COVID-19 pandemic or not. Data were analysed using qualitative content analysis.
Results
Communication was seen as essential by the participants for an informed decision for or against a temporary return to nursing and to potential or actual deployments. To make them feel safe, inactive nurses need to know what to expect and what is expected of them, for example, regarding required training and responsibilities. Considering their current employment status, some flexibility in terms of deployment conditions is needed.
A remaining attachment to care can trigger a sense of duty. Knowledge of (regular) working conditions in nursing can lead to both a desire to support former colleagues and a refusal to be exposed to these conditions again.
Conclusion
Past working experiences and the current employment situation play a major role in the willingness of inactive nurses to return to nursing in a crisis situation. Unbureaucratic arrangements must be provided for those who are willing to return.
Summary Statement
What already is known - In crisis situations, not every inactive nurse is willing or able to return to nursing and therefore, the ‘silent reserve’ may not be as large as suspected.
What this paper adds - Inactive nurses need to know what to expect and what is expected of them for their decision regarding a return to active patient care during a crisis situation.
Implications for practice/policy – Inactive nurses need to be informed and should be offered free training and refresher courses to ensure patient safety.
Impact
This research shows that the group of inactive nurses are not a silent workforce which can be activated anytime. Those who are able and willing to return to direct patient care in crisis situations need the best possible support – during and between crises.
Reporting Method
This study adhered to COREQ guidelines.
No Patient or Public Contribution
The involvement of patients or members of the public did not apply for the study, as the aim was to gain insight into the motivations and attitudes of the group of inactive nurses.
Enzymatic degradation and recycling can reduce the environmental impact of plastics. Despite decades of research, no enzymes for the efficient hydrolysis of polyurethanes have been reported. Whereas the hydrolysis of the ester bonds in polyester‐polyurethanes by cutinases is known, the urethane bonds in polyether‐polyurethanes have remained inaccessible to biocatalytic hydrolysis. Here we report the discovery of urethanases from a metagenome library constructed from soil that had been exposed to polyurethane waste for many years. We then demonstrate the use of a urethanase in a chemoenzymatic process for polyurethane foam recycling. The urethanase hydrolyses low molecular weight dicarbamates resulting from chemical glycolysis of polyether‐polyurethane foam, making this strategy broadly applicable to diverse polyether‐polyurethane wastes.
Aim
To determine the long-term effects of the use of powered tooth brush (PTB) in comparison to manual tooth brush (MTB) on periodontitis severity, coronal caries experience, and the number of missing teeth using in a population-based cohort study.
Materials and Methods
Using 7-year follow-up data of 2214 participants of the Study of Health in Pomerania (SHIP-TREND), comprehensively adjusted linear models using generalized least squares and ordinal regression models estimated the effects of PTB usage on dental outcomes in complete case and imputed data.
Results
At follow-up, PTB users had lower medians for mean probing depth (PD; 2.21 mm) and mean clinical attachment levels (1.73 mm) than MTB users (2.30 and 1.96 mm, respectively). Adjusted models revealed the beneficial effects of PTB usage on follow-up levels of plaque, bleeding on probing, mean PD, percentage of sites with PDs ≥4 mm, mean clinical attachment levels (all, interdental, and non-interdental sites, respectively), and the number of missing teeth. For the number of missing teeth, the effects were more pronounced in participants aged ≥50 years. No significant effects of PTB usage on the number of decayed or filled surfaces (all and interdental sites) were found.
Conclusions
A recommendation of PTB usage in dental practice could contribute to the long-term promotion of oral health.
Aim
The aim of this study was to evaluate whether extraction thresholds in persons with severe periodontitis have changed between 2000 and 2010 and whether potential shifts have contributed to the reported decrease in tooth extractions in German adults over the last decades.
Materials and Methods
Data from two German population-based cohort studies in Northeast Germany (Studies of Health in Pomerania; SHIP-START [baseline 1997–2001; 11-year follow-up] and SHIP-TREND [baseline 2008–2012; 7-year follow-up]) were used. In SHIP-START (SHIP-TREND), 522 (478) participants with severe periodontitis according to the CDC/AAP case definition were included. Patterns of maximum probing depth (PD) and maximum clinical attachment level (CAL) for retained and extracted teeth were compared between SHIP-START and SHIP-TREND participants.
Results
No major differences in patterns of baseline maximum CAL of retained or extracted teeth were detected between SHIP-START and SHIP-TREND. Extraction thresholds were identified at the baseline at maximum CAL ≥6 and ≥9 mm. Tooth-level incidence rates for extraction for baseline maximum CAL of 6 mm were comparable between SHIP-START and SHIP-TREND (17.1 vs. 15.9 events per 1000 person-years).
Conclusions
After a decade, teeth in persons with severe periodontitis were still undergoing extraction with minor or moderate attachment loss. A change in extraction pattern did not contribute to the higher tooth retention rate.
Poly(vinyl alcohol) (PVA) is a water‐soluble synthetic vinyl polymer with remarkable physical properties including thermostability and viscosity. Its biodegradability, however, is low even though a large amount of PVA is released into the environment. Established physical‐chemical degradation methods for PVA have several disadvantages such as high price, low efficiency, and secondary pollution. Biodegradation of PVA by microorganisms is slow and frequently involves pyrroloquinoline quinone (PQQ)‐dependent enzymes, making it expensive due to the costly cofactor and hence unattractive for industrial applications. In this study, we present a modified PVA film with improved properties as well as a PQQ‐independent novel enzymatic cascade for the degradation of modified and unmodified PVA. The cascade consists of four steps catalyzed by three enzymes with in situ cofactor recycling technology making this cascade suitable for industrial applications.
For the characterization of Kv7.2/3 channel activators, several analytical methods are available that vary in effort and cost. In addition to the technically elaborate patch-clamp method, which serves as a reference method, there exist several medium to high-throughput screening methods including a rubidium efflux flame-atomic absorption spectrometry (F-AAS) assay and a commercial thallium uptake fluorescence-based assay. In this study, the general suitability of a graphite furnace atomic absorption spectrometry (GF-AAS)-based rubidium efflux assay as a screening method for Kv7.2/3 channel activators was demonstrated. With flupirtine serving as a reference compound, 16 newly synthesizedcompounds and the known Kv7.2/3 activator retigabine were first classified as either active or inactive by using the GF-AAS-based rubidium (Rb) efflux assay. Then, the results were compared with a thallium (Tl) uptake fluorescence-based fluorometric imaging plate reader (FLIPR) potassium assay. Overall, 16 of 17 compounds were classified by the GF-AAS-based assay in agreement with their channel-activating properties determined by the more expensive Tl uptake, fluorescence-based assay. Thus, the performance of the GF-AAS-based Rb assay for primary drug screening of Kv7.2/3-activating compounds was clearly demonstrated, as documented by the calculated Z’-factor of the GF-AAS-based method. Moreover, method development included optimization of the coating of the microtiter plates and the washing procedure, which extended the range of this assay to poorly adherent cells such as the HEK293 cells used in this study.
In temperate regions, climate warming alters temperature and precipitation regimes. During winter, a decline in insulating snow cover changes the soil environment, where especially frost exposure can have severe implications for soil microorganisms and subsequently for soil nutrient dynamics. Here, we investigated winter climate change responses in European beech forests soil microbiome. Nine study sites with each three treatments (snow exclusion, insolation, and ambient) were investigated. Long-term adaptation to average climate was explored by comparing across sites. Triplicated treatment plots were used to evaluate short-term (one single winter) responses. Community profiles of bacteria, archaea and fungi were created using amplicon sequencing. Correlations between the microbiome, vegetation and soil physicochemical properties were found. We identify core members of the forest-microbiome and link them to key processes, for example, mycorrhizal symbiont and specialized beech wood degraders (fungi) and nitrogen cycling (bacteria, archaea). For bacteria, the shift of the microbiome composition due to short-term soil temperature manipulations in winter was similar to the community differences observed between long-term relatively cold to warm conditions. The results suggest a strong link between the changes in the microbiomes and changes in environmental processes, for example, nitrogen dynamics, driven by variations in winter climate.
Being a master of metaphors
(2023)
Combining solid acid catalysts with enzyme reactions in aqueous environments is challenging because either very acidic conditions inactivate the enzymes, or the solid acid catalyst is neutralized. In this study, Amberlyst-15 encapsulated in polydimethylsiloxane (Amb-15@PDMS) is used to deprotect the lignin depolymerization product G−C2 dioxolane phenol in a buffered system at pH 6.0. This reaction is directly coupled with the biocatalytic reduction of the released homovanillin to homovanillyl alcohol by recombinant horse liver alcohol dehydrogenase, which is subsequently acylated by the promiscuous acyltransferase/hydrolase PestE_I208A_L209F_N288A in a one-pot system. The deprotection catalyzed with Amb-15@PDMS attains up to 97 % conversion. Overall, this cascade enables conversions of up to 57 %.
Baeyer-Villiger monooxygenases (BVMOs) are important flavin-dependent enzymes which perform oxygen insertion reactions leading to valuable products. As reported in many studies, BVMOs are usually unstable during application, preventing a wider usage in biocatalysis. Here, we discovered a novel NADPH-dependent BVMO which originates from Halopolyspora algeriensis using sequence similarity networks (SSNs). The enzyme is stable at temperatures between 10 °C to 30 °C up to five days after the purification, and yields the normal ester product. In this study, the substrate scope was investigated for a broad range of aliphatic ketones and the enzyme was biochemically characterized to identify optimum reaction conditions. The best substrate (86 % conversion) was 2-dodecanone using purified enzyme. This novel BVMO could potentially be applied as part of an enzymatic cascade or in bioprocesses which utilize aliphatic alkanes as feedstock.
In mandibulate arthropods, the primary olfactory centers, termed olfactory lobes in crustaceans, are typically organized in distinct fields of dense synaptic neuropils called olfactory glomeruli. In addition to olfactory sensory neuron terminals and their postsynaptic efferents, the glomeruli are innervated by diverse neurochemically distinctive interneurons. The functional morphology of the olfactory glomeruli is understudied in crustaceans compared with insects and even less well understood and described in a particular crustacean subgroup, the Peracarida, which embrace, for example, Amphipoda and Isopoda. Using immunohistochemistry combined with confocal laser scanning microscopy, we analyzed the neurochemistry of the olfactory pathway in the amphipod Parhyale hawaiensis. We localized the biogenic amines serotonin and histamine as well as the neuropeptides RFamide, allatostatin, orcokinin, and SIFamide. As for other classical neurotransmitters, we stained for γ-aminobutyric acid and glutamate decarboxylase and used choline acetyltransferase as indicator for acetylcholine. Our study is another step in understanding principles of olfactory processing in crustaceans and can serve as a basis for understanding evolutionary transformations of crustacean olfactory systems.
Boronate esters formed by reaction of an oligonucleotide carrying a 5′-boronic acid moiety with the 3′-terminal cis-diol of another have been shown previously to assist assembly of fragmented DNAzymes. Here we demonstrate that boronate esters replacing the natural phosphodiester linkage at selected sites of two functional RNAs, the hairpin ribozyme and the Mango aptamer, allow assembly of functional structures. The hairpin ribozyme, a small naturally occurring RNA that supports the reversible cleavage of appropriate RNA substrates, is very sensitive to fragmentation. Splitting the ribozyme at four different sites led to a significant decrease or even loss of cleavage and ligation activity. Ribozymes assembled from fragments capable of boronate ester formation showed restoration of cleavage activity in some but not all cases, dependent on the split site. Ligation proved to be more challenging, no supportive effect of the boronate ester was observed. Split variants of the Mango aptamer also showed a dramatic loss of functionality, which however, was restored when 5′-boronic acid modified fragments were used for assembly. These studies show for the first time that boronate esters as internucleoside linkages can act as surrogates of natural phosphodiesters in functional RNA molecules.
Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. Machine learning provides a promising approach for protein engineering, but activity prediction models for ATAs remain elusive due to the difficulty of obtaining high-quality training data. Thus, we first created variants of the ATA from Ruegeria sp. (3FCR) with improved catalytic activity (up to 2000-fold) as well as reversed stereoselectivity by a structure-dependent rational design and collected a high-quality dataset in this process. Subsequently, we designed a modified one-hot code to describe steric and electronic effects of substrates and residues within ATAs. Finally, we built a gradient boosting regression tree predictor for catalytic activity and stereoselectivity, and applied this for the data-driven design of optimized variants which then showed improved activity (up to 3-fold compared to the best variants previously identified). We also demonstrated that the model can predict the catalytic activity for ATA variants of another origin by retraining with a small set of additional data.
In der Klinik wird eine inter- und intraindividuelle Variabilität in Wirkung und Nebenwirkung von Opioiden beobachtet [5,6]. Ursächlich hierfür könnte unter anderem eine individuelle Ausstattung mit Transportproteinen sein, welche pharmakologische Substanzen wie zum Beispiel Opioide über körpereigene Barrieren zu ihren Wirkorten transportieren. Mit dieser Arbeit sollte die Affinität der Opioide Fentanyl und Sufentanil zu ausgewählten organic anion transporting polypeptides (OATP) untersucht werden. Ein weiteres Ziel war die Generierung eines neuen OATP1A2-Transportmodells. Im Vergleich zum bisherig verwendeten Modell mit pQCXIN::OATP1A2 sollte eine Zelllinie mit definiert integriertem Transportprotein-Gen für eine reproduzierbarere OATP1A2-Überexpression generiert werden.
Eine Affinität von Fentanyl zu OATP1A2 konnte in Kompetitionsversuchen
(IC50 14,17 µM) belegt werden. Für die Kombination Fentanyl/ OATP1B1 war keine Inhibition des Transporters nachweisbar. Sufentanil inhibierte OATP1A2 geringfügig, konnte aber herstellerbedingt nicht in vergleichbaren Konzentrationen untersucht werden. Es zeigte sich kein Transport von Fentanyl durch OATP1A2.
Da Funktionskontrollen mit den vorhandenen HEK-pQCXIN::OATP-Zelllinien mit zunehmender Passagennummer fluktuierende oder abnehmende Aktivitäten zeigten, sollten stabile Zelllinien mit definierter vorzugsweise singulärer Integration des Zielgens in HEK-293-Zellen generiert werden. Mittels Flp-In™-System wurden über drei verschiedene Klonierungsstrategien Klone von T-REx™-pcDNA5/FRT::OATP1A2 hergestellt. Auf RNA- und DNA-Ebene konnte die korrekte Integration der OATP1A2-Sequenz nachgewiesen werden. In der Funktionskontrolle zeigte sich aber nur eine maximal 1,7 fache erhöhte Aktivität gegenüber Kontrollzellen. Mit keiner der drei gewählten Klonierungsstrategien konnten ausreichend funktionelle OATP1A2 überexprimierende Zellen generiert werden, trotz intakt integrierter OATP1A2-Sequenz sowie korrekter Übergänge, Startcodon und Kozak-Sequenz, bestätigt durch Sequenzierung des Genoms der T-REx™-pcDNA5/FRT::OATP1A2 (Variante 3). In stabil transfizierten Zellen ließ sich durch Immunfluoreszenz keine Expression, ordnungsgemäße Lokalisation und Überexpression von OATP1A2 darstellen. Ob dies an einer Proteinfehlfaltung oder einer zu niedrigen Proteinexpression liegt, konnte nicht zweifelsfrei bestimmt werden.
Insgesamt trägt diese Arbeit zur Beantwortung der Frage bei, inwiefern Fentanyl die Aufnahmetransporter der OATP-Familie beeinflusst und somit durch pharmakologische Hemmung die Wirkungen und Nebenwirkungen anderer Arzneimittel verändern kann. Obwohl die Generierung OATP1A2-überexprimierender T-REx™-pcDNA5/FRT::OATP mit dem Flp-In™-System im Rahmen dieser Arbeit nicht erfolgreich verlief, konnten weitere Erfahrungen zum Flp-In™-System gesammelt werden.
Chronic kidney disease is a major public health burden associated with a drastically reduced quality of living and life span that lacks suitable, individualized therapeutic strategies. Here we present a human induced pluripotent stem cell line (iPSC, UMGACBi001-A) reprogrammed from urine cells of an acute septic dialysis patient suffering from chronic kidney disease using non-integrating administration of RNAs. The generated iPSCs were positively characterized for typical morphology, pluripotency marker expression, directed differentiation potential, non-contamination, chromosomal consistency and donor identity. This iPSC-line can be a useful source for in vitro disease modelling and individualized therapeutic approaches.
Background and Aims
Hepatocellular ballooning is a common finding in chronic liver disease, mainly characterized by rarefied cytoplasm that often contains Mallory-Denk bodies (MDB). Ballooning has mostly been attributed to degeneration but its striking resemblance to glycogenotic/steatotic changes characterizing preneoplastic hepatocellular lesions in animal models and chronic human liver diseases prompts the question whether ballooned hepatocytes (BH) are damaged cells on the path to death or rather viable cells, possibly involved in neoplastic development.
Methods
Using specimens from 96 cirrhotic human livers, BH characteristics were assessed for their glycogen/lipid stores, enzyme activities, and proto-oncogenic signaling cascades by enzyme- and immunohistochemical approaches with serial paraffin and cryostat sections.
Results
BH were present in 43.8% of cirrhotic livers. Particularly pronounced excess glycogen storage of (glycogenosis) and/or lipids (steatosis) were characteristic, ground glass features and MDB were often observed. Decreased glucose-6-phosphatase, increased glucose-6-phosphate dehydrogenase activity and altered immunoreactivity of enzymes involved in glycolysis, lipid metabolism, and cholesterol biosynthesis were discovered. Furthermore, components of the insulin signaling cascade were upregulated along with insulin dependent glucose transporter glucose transporter 4 and the v-akt murine thymoma viral oncogene homolog/mammalian target of rapamycin signaling pathway associated with de novo lipogenesis.
Conclusions
BH are hallmarked by particularly pronounced glycogenosis with facultative steatosis, many of their features being reminiscent of metabolic aberrations documented in preneoplastic hepatocellular lesions in experimental animals and chronic human liver diseases. Hence, BH are not damaged entities facing death but rather viable cells featuring metabolic reprogramming, indicative of a preneoplastic nature.