Die Korrespondenz des Daniel von Cornides mit Tamás Róth von Királyfalva

Im Mittelpunkt dieser Arbeit steht das Leben und Wirken des Daniel Cornides, eines Gelehrten im ungarischen Königreich des 18. Jahrhunderts vor dem kulturpolitischen Hintergrund in Europa allgemein mit Erwähnung der wichtigsten Protagonisten der Aufklärung und Skizzierung der speziellen Lage in Ungarn nach den Befreiungskämpfen gegen die Türken und Niederwerfung des Rákóczi-Aufstandes, was natürlich eine Phasenverschiebung bezüglich Ausbreitung auklärerischen Gedankengutes bewirkte. Cornides besuchte die renommierteste Schule des Landes, das Evangelische Lyzeum in Preßburg, absolvierte das Studium auf der geisteswissenschaftlichen Fakultät in Erlangen, da zu dieser Zeit der Zutritt für evangelische Studenten an die Universitäten des Kaiser- und Königreichs noch verwehrt war. Cornides kehrte dann in die Heimat zurück. Da er im Gegensatz zu den meisten seiner gelehrten Freunde nicht Theologe war, musste er sich um eine entsprechende Anstellung umsehen. Nach den schweren Jahren als Erzieher bei der Familie Baron Wesselényi und als Deutschlehrer am reformierten Kollegium in Klausenburg folgte vielleicht die glücklichste Zeit in seinem Leben, als József Graf Teleki ihn als Privatsekretär anstellte. Teleki konnte ihm ein Umfeld bieten, in dem er genug Zeit fand, sich historischen Studien widmen zu können. Als Reisebegleiter des Grafen war es Cornides möglich verschiedene Bibliotheken und Familienarchive studieren zu können. Unter Josef II. erfolgte seine Ernennung zum Professor der Diplomaik und Heraldik und zum Kustos der Universitätsbibliothek an der Universität Pest, da diese nun auch den Protestanten offen stand. Ausgangspunkt für diese Dissertation war die umfangreiche Briefsammlung des Daniel Cornides, die zum großen Teil in der Ungarischen Akademie der Wissenschaften aufbewahrt wird. Aus diesem Konvulut wählte ich seine lateinische Korrespondenz mit Tamás Róth, dem Schwiegervater seines Mäzens, József Graf Teleki. Es wa meine Aufgabe diese Biefe zu übersetzen, den Briefstil Cornides´ zu analysieren und seine wissenschaftlichen Forschungsergebnisse mit dem heutigen Stand der Wissenschaft zu vergleichen. Dieser Briefwechsel spiegelt nicht nur den großen Respekt füreinander wider, sondern gibt auch preis, welche historischen Themen den Gelehrten gerade beschäftigten und seinen nicht minder belesenen Briefpartner interessierten. Als Privatsekretär bei Teleki konnte er einen intimen gelehrten Kreis aus den Familienmitgliedern um sich scharen, wie Teleki, Róth und Gedeon Graf Ráday, Telekis Onkel. In diesem Kreis konnte er seine neuesten Forschungsergebnisse vortragen. Die Briefe an Róth entspringen dem Umstand, dass dieser sich zumeist auf Schloss Szirák aufhielt, und auf diese Weise von Cornides über Themen, wie die Abstammungsgeschichte der Ungarn, die Taten der Hunnen, der Verbleib der Awaren, die Privilegien der Kumanen und Jassen, die ungarische Kerbschrift und ihr Ursprung, sowie die ungarische Sprache mit Etymologie besonderer Begriffe, unterrichtet wurde. Allein die Namen der Briefpartner verraten schon, dass Cornides einer der bekanntesten und umtriebigsten der Gelehrten seiner Zeit war. Die Länge der Literaturliste dieser Dissertation bezeugt die enorme Belesenheit Cornides´, der selbstverständlich die antiken Autoren, aber genauso auch die neuesten Erscheinungen auf dem Buchmarkt studierte. Umso größer ist die Verwunderung darüber, dass er in Ungarn in Vergessenheit geraten ist. Eine Erklärung dafür ist die lateinische Sprache, die den Zugang zu seinen Briefen und Manuskripten mit Sicherheit erschweren. Vielleicht dient diese Arbeit seiner Wiederentdeckung. Er selbst war aufgrund seines frühen Todes nicht in der Lage, seine umfangreiche Manuskripten- und Münzsammlung zu publizieren.The focus of this thesis lies on the life and work of Daniel Cornides, a scholar in the Hungarian Kingdom of the 18th century, and on the cultural and political background in Europe generally in the Age of Enleightenment and in Hungary specifically. There these ideas arrived later, because of the political situation after the defeat of the Turcs and the abolition of the Rákóczi-insurrection. Cornides attended the best school at that time, the Evangelical Lyceum in Preßburg (Pozsony, Bratislava), completed his studies at the University of Erlangen and finally returned home. Contrarily to most of his scholar friends he was not theologian, so he had to look for an appropriate job. After the difficult years spent as educator with the family of the Baronet Wesselényi and as German teacher at the Calvinist College in Klausenburg (Kolozsvár, Cluj) followed the maybe happiest period of his life when the Count József Teleki hired him as his private secretary. Teleki could offer him a milieu in which Cornides had enough time to devote to historical studies before he would become, under the reign of Joseph II, a professor at the University of Pest. The starting point of this thesis was formed by the extensive collection of letters of Daniel Cornides, largely kept in the Hungarian Academy of Sciences. Out of this collection I have chosen his correspondence in Latin with Tamás Róth de Királyfalva, the father in law of his patron, the Count József Teleki. It was my task to translate these letters, to study Cornides´s style of expression, to compare his conclusions to today´s scientific research. This exchange of letters reflects not only the great respect shown towards each other by the corresponding partners but also reveals the historical issues which occupied the scholar at that time and also interested his correspondent who was not less erudite. He was able, as private secretary at Teleki´s, to gather an intimate circle of scholars out of the family members around himself, like Teleki, Róth and Count Gedeon Ráday, Teleki´s uncle. In this circle, he could present the most recent results of his research. Róth spent most of his time at his castle of Szirák, this is why Cornides informed him of topics such as origin of the Hungarians, the deeds of the Huns, the fate of the Avars, the privileges of the Cumans and Iasses, the Hungarian runes and their origin or the Hungarian language and the etymology of some special expressions via letters. Even the names of his correspondents reveal that Cornides was one of the most famous and busiest scholars of his time. The length of the bibliography of this thesis testifies the enormous erudition of Cornides who knew – as matter of course – the ancient authors but studied the most recent publications on the bookmarket as well. The greater is the astonishment about the fact that he has sunk into oblivion in Hungary. One possible explanation could be the fact that he wrote in Latin, which surely makes access to his letters and manuscripts more difficult. Perhaps this work will serve his re-discovery. Due to his early death, Cornides was not able to publish the extensive collection of his manuscripts and coins

Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus

The absolute or relative lack of insulin is the key factor in the pathogenesis of diabetes mellitus. Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet. In this analysis, 787 patients with diabetes and 900 healthy people participated. Genotyping of the 7 WFS1 SNPs was carried out by TaqMan assays. Association study was performed by chi2-test in combination with correction for multiple testing. For functional analysis, the entire 3' UTR of the WFS1 gene was subcloned in a pMIR-Report plasmid and relative luciferase activities were determined. Linkage disequilibrium analysis showed a generally high LD within the investigated region, however the rs1046322 locus was not in LD with the other SNPs. The two miR-SNPs, rs1046322 and rs9457 showed significant association with T1DM and T2DM, respectively. Haplotype analysis also confirmed the association between the 3' UTR loci and both disease types. In vitro experiments showed that miR-185 reduces the amount of the resulting protein, and rs9457 miRSNP significantly influences the rate of reduction in a luciferase reporter assay. Genetic variants of the WFS1 gene might contribute to the genetic risk of T1DM and T2DM. Furthermore demonstrating the effect of rs9457 in binding of miR-185, we suggest that the optimal level of wolframin protein, potentially influenced by miR-regulation, is crucial in normal beta cell function

Evaluation of yarrow (<i>Achillea</i>) accessions by phytochemical and molecular genetic tools

Yarrow (Achillea) species are known and utilized worldwide. In the recent study our primarily goal was to get information about the intraspecific diversity of A. collina in the Carpathian Basin. Five cultivated genotypes and six populations of wild origin were compared involving seven other species as control. Essential oil (EO) and proazulene (PA) contents were determined and the DNA samples were evaluated by RAPD (11 primers) and ISSR (12 primers) methods. The EO content varied between 0.010 (A. distans) and 0.365 (A. collina) ml/100g DW, the PA content was found between 0.021 and 0.173% DW. The used RAPD markers provided 140 bands (97.14% polymorphic). They distinguished primarily among species and less characteristically among the A. collina populations. With ISSR primers we detected 188 bands (97.34% polymorphic). ISSR markers and combined RAPD and ISSR method enabled an informative intraspecific evaluation of A. collina accessions. The largest genetic distances were found between A. ptarmica and the members of sect. Achillea (genetic distances 0.52-0.72). Similarity is highest (genetic distance 0.27) among the populations of lower geographical distances. Nei’s genetic distances of cultivated populations are also relatively low (0.23- 0.36). Some wild accessions may represent valuable biological resources for breeding

Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control

The rapidly proliferating cells in plant meristems must be protected from genome damage. Here, we show that the regulatory role of the Arabidopsis RETINOBLASTOMA RELATED (RBR) in cell proliferation can be separated from a novel function in safeguarding genome integrity. Upon DNA damage, RBR and its binding partner E2FA are recruited to heterochromatic γH2AX-labelled DNA damage foci in an ATM- and ATR-dependent manner. These γH2AX-labelled DNA lesions are more dispersedly occupied by the conserved repair protein, AtBRCA1, which can also co-localise with RBR foci. RBR and AtBRCA1 physically interact in vitro and in planta. Genetic interaction between the RBR-silenced amiRBR and Atbrca1 mutants suggests that RBR and AtBRCA1 may function together in maintaining genome integrity. Together with E2FA, RBR is directly involved in the transcriptional DNA damage response as well as in the cell death pathway that is independent of SOG1, the plant functional analogue of p53. Thus, plant homologs and analogues of major mammalian tumour suppressor proteins form a regulatory network that coordinates cell proliferation with cell and genome integrity

T cell immune response predicts survival in severely ill COVID-19 patients requiring venovenous extracorporeal membrane oxygenation support

IntroductionThere is a critical gap in understanding which SARS-CoV-2 patients would benefit most from venovenous extracorporeal membrane oxygenation (VV-ECMO) support. The potential role of a dysregulated immune response is still unclear in this patient population.ObjectivesTo assess the potential predictive value of SARS-CoV-2 specific cellular and humoral immune responses for survival in critically ill COVID-19 patients requiring VV-ECMO.MethodsWe conducted a prospective single-center observational study of unvaccinated patients requiring VV-ECMO support treated at the intensive care unit of Semmelweis University Heart and Vascular Center between March and December 2021. Peripheral blood samples were collected to measure the humoral and cellular immune statuses of the patients at the VV-ECMO cannulation. Patients were followed until hospital discharge.ResultsOverall, 35 COVID-19 patients (63% men, median age 37 years) on VV-ECMO support were included in our study. The time from COVID-19 verification to ECMO support was a median (IQR) of 10 (7-14) days. Of the patients, 9 (26%) were discharged alive and 26 (74%) died during their hospital stay. Immune tests confirmed ongoing SARS-CoV-2 infection in all the patients, showing an increased humoral immune response. SARS-CoV-2-specific cellular immune response was significantly higher among survivors compared to the deceased patients. A higher probability of survival was observed in patients with markers indicating a higher T cell response detected by both QuantiFeron (QF) and flow cytometry (Flow) assays. (Flow S1 CD8+ ≥ 0.15%, Flow S1 CD4+ ≥ 0.02%, QF CD4 ≥ 0.07, QF whole genome ≥ 0.59). In univariate Cox proportional hazard regression analysis BMI, right ventricular (RV) failure, QF whole genome T cell level, and Flow S1 CD8+ T cell level were associated with mortality, and we found that an increased T cell response showed a significant negative association with mortality, independent of BMI and RV failure.ConclusionEvaluation of SARS-CoV-2 specific T cell response before the cannulation can aid the risk stratification and evaluation of seriously ill COVID-19 patients undergoing VV-ECMO support by predicting survival, potentially changing our clinical practice in the future

FLIP: A Targetable Mediator of Resistance to Radiation in Non-Small Cell Lung Cancer

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IRinduced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR

Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387Peer reviewedPublisher PD

Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors.

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage