TY - JOUR A1 - Zimniak, Melissa A1 - Kirschner, Luisa A1 - Hilpert, Helen A1 - Geiger, Nina A1 - Danov, Olga A1 - Oberwinkler, Heike A1 - Steinke, Maria A1 - Sewald, Katherina A1 - Seibel, Jürgen A1 - Bodem, Jochen T1 - The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 in human lung tissue JF - Scientific Reports N2 - To circumvent time-consuming clinical trials, testing whether existing drugs are effective inhibitors of SARS-CoV-2, has led to the discovery of Remdesivir. We decided to follow this path and screened approved medications "off-label" against SARS-CoV-2. Fluoxetine inhibited SARS-CoV-2 at a concentration of 0.8 mu g/ml significantly in these screenings, and the EC50 was determined with 387 ng/ml. Furthermore, Fluoxetine reduced viral infectivity in precision-cut human lung slices showing its activity in relevant human tissue targeted in severe infections. Fluoxetine treatment resulted in a decrease in viral protein expression. Fluoxetine is a racemate consisting of both stereoisomers, while the S-form is the dominant serotonin reuptake inhibitor. We found that both isomers show similar activity on the virus, indicating that the R-form might specifically be used for SARS-CoV-2 treatment. Fluoxetine inhibited neither Rabies virus, human respiratory syncytial virus replication nor the Human Herpesvirus 8 or Herpes simplex virus type 1 gene expression, indicating that it acts virus-specific. Moreover, since it is known that Fluoxetine inhibits cytokine release, we see the role of Fluoxetine in the treatment of SARS-CoV-2 infected patients of risk groups. KW - SARS-CoV-2 KW - viral epidemiology KW - viral infection Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259820 VL - 11 ER - TY - JOUR A1 - Zahran, Eman Maher A1 - Albohy, Amgad A1 - Khalil, Amira A1 - Ibrahim, Alyaa Hatem A1 - Ahmed, Heba Ali A1 - El-Hossary, Ebaa M. A1 - Bringmann, Gerhard A1 - Abdelmohsen, Usama Ramadan T1 - Bioactivity Potential of Marine Natural Products from Scleractinia-Associated Microbes and In Silico Anti-SARS-COV-2 Evaluation JF - Marine Drugs N2 - Marine organisms and their associated microbes are rich in diverse chemical leads. With the development of marine biotechnology, a considerable number of research activities are focused on marine bacteria and fungi-derived bioactive compounds. Marine bacteria and fungi are ranked on the top of the hierarchy of all organisms, as they are responsible for producing a wide range of bioactive secondary metabolites with possible pharmaceutical applications. Thus, they have the potential to provide future drugs against challenging diseases, such as cancer, a range of viral diseases, malaria, and inflammation. This review aims at describing the literature on secondary metabolites that have been obtained from Scleractinian-associated organisms including bacteria, fungi, and zooxanthellae, with full coverage of the period from 1982 to 2020, as well as illustrating their biological activities and structure activity relationship (SAR). Moreover, all these compounds were filtered based on ADME analysis to determine their physicochemical properties, and 15 compounds were selected. The selected compounds were virtually investigated for potential inhibition for SARS-CoV-2 targets using molecular docking studies. Promising potential results against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and methyltransferase (nsp16) are presented. KW - Scleractinia KW - marine bacteria KW - marine fungi KW - zooxanthellae KW - marine natural products KW - ADME analysis KW - SARS-CoV-2 KW - molecular docking KW - RNA-dependent RNA polymerase KW - methyltransferase Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220041 SN - 1660-3397 VL - 18 IS - 12 ER - TY - JOUR A1 - Wurmb, Thomas A1 - Scholtes, Katja A1 - Kolibay, Felix A1 - Schorscher, Nora A1 - Ertl, Georg A1 - Ernestus, Ralf-Ingo A1 - Vogel, Ulrich A1 - Franke, Axel A1 - Kowalzik, Barbara T1 - Hospital preparedness for mass critical care during SARS-CoV-2 pandemic JF - Critical Care N2 - Mass critical care caused by the severe acute respiratory syndrome corona virus 2 pandemic poses an extreme challenge to hospitals. The primary goal of hospital disaster preparedness and response is to maintain conventional or contingency care for as long as possible. Crisis care must be delayed as long as possible by appropriate measures. Increasing the intensive care unit (ICU) capacities is essential. In order to adjust surge capacity, the reduction of planned, elective patient care is an adequate response. However, this involves numerous problems that must be solved with a sense of proportion. This paper summarises preparedness and response measures recommended to acute care hospitals. KW - Mass critical care KW - Disaster response KW - SARS-CoV-2 KW - Hospital emergency plan Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230201 VL - 24 ER - TY - JOUR A1 - Tischer, Christina A1 - Stupp, Carolin A1 - Janson, Patrick A1 - Willeke, Kristina A1 - Hung, Chu-Wei A1 - Flöter, Jessica A1 - Kirchner, Anna A1 - Zink, Katharina A1 - Eder, Lisa A1 - Hackl, Christina A1 - Mühle, Ursula A1 - Weidmann, Manfred A1 - Nennstiel, Uta A1 - Kuhn, Joseph A1 - Weidner, Christian A1 - Liebl, Bernhard A1 - Wildner, Manfred A1 - Keil, Thomas T1 - Evaluation of screening tests in Bavarian healthcare facilities during the second wave of the SARS-CoV-2 pandemic JF - International Journal of Environmental Research and Public Health N2 - Due to the lack of data on asymptomatic SARS-CoV-2-positive persons in healthcare institutions, they represent an inestimable risk. Therefore, the aim of the current study was to evaluate the first 1,000,000 reported screening tests of asymptomatic staff, patients, residents, and visitors in hospitals and long-term care (LTC) facilities in the State of Bavaria over a period of seven months. Data were used from the online database BayCoRei (Bavarian Corona Screening Tests), established in July 2020. Descriptive analyses were performed, describing the temporal pattern of persons that tested positive for SARS-CoV-2 by real-time polymerase chain reaction (RT-PCR) or antigen tests, stratified by facility. Until 15 March 2021, this database had collected 1,038,146 test results of asymptomatic subjects in healthcare facilities (382,240 by RT-PCR, and 655,906 by antigen tests). Of the RT-PCR tests, 2.2% (n = 8380) were positive: 3.0% in LTC facilities, 2.2% in hospitals, and 1.2% in rehabilitation institutions. Of the antigen tests, 0.4% (n = 2327) were positive: 0.5% in LTC facilities, and 0.3% in both hospitals and rehabilitation institutions, respectively. In LTC facilities and hospitals, infection surveillance using RT-PCR tests, or the less expensive but less sensitive, faster antigen tests, could facilitate the long-term management of the healthcare workforce, patients, and residents. KW - SARS-CoV-2 KW - asymptomatic screening KW - RT-PCR KW - antigen testing KW - infection surveillance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242637 SN - 1660-4601 VL - 18 IS - 14 ER - TY - THES A1 - Stiller, Carina T1 - Synthesis and applications of modified nucleosides and RNA nucleotides T1 - Synthese und Anwendungen von modifizierten Nukleosiden und RNA-Nukleotiden N2 - As central components of life, DNA and RNA encode the genetic information. However, RNA performs several functions that exceed the competences stated in the ‘central dogma of life‘. RNAs undergo extensive post-transcriptional processing like chemical modifications. Among all classes of RNA, tRNAs are the most extensively modified. Their modifications are chemically diverse and vary from simple methylations (e.g. m3C, m6A) to more complex residues, like isopentenyl group (e.g. i6A, hypermodifications: e.g. ms2i6A) or even amino acids (e.g. t6A). Depending on their location within the overall structure, modifications can have an impact on tRNA stability and structure, as well as affinity for the ribosome and translation efficiency and fidelity. Given the importance of tRNA modifications new tools are needed for their detection and to study their recognition by proteins and enzymatic transformations. The chemical synthesis of these naturally occurring tRNA modifications as phosphoramidite building blocks is a prerequisite to incorporate the desired modification via solid-phase synthesis into oligonucleotides. With the help of the m3C, (ms2)i6A, and t6A oligonucleotides, the importance and impact of tRNA modifications was investigated in this thesis. To this end, the role of METTL8 as the methyltransferase responsible for the installation of the methyl group at C32 for mt-tRNAThr and mt-tRNASer(UCN) was resolved. Thereby, the respective adenosine modification on position 37 is essential for the effectiveness of the enzyme. Besides, by means of NMR analysis, CD spectroscopy, thermal denaturation experiments, and native page separation, the impact of m3C32 on the structure of the tRNA ASLs was shown. The modification appeared to fine-tune the tRNA structure to optimize mitochondrial translation. To investigate the regulation of the dynamic modification pathway of m3C, demethylation assays were performed with the modified tRNA-ASLs and the (α-KG)- and Fe(II)-dependent dioxygenase ALKBH1 and ALKHB3. A demethylation activity of ALKBH3 on the mt-tRNAs was observed, even though it has so far only been described as a cytoplasmic enzyme. Whether this is physiologically relevant and ALKBH3 present a mitochondrial localization needs further validation. In addition, ALKBH1 was confirmed to not be able to demethylate m3C on mt-tRNAs, but indications for a deprenylation and exonuclease activity were found. Furthermore, the aforementioned naturally occurring modifications were utilized to find analytical tools that can determine the modification levels by DNAzymes, which cleave RNA in the presence of a specific modification. Selective DNA enzymes for i6A, as well as the three cytidine isomers m3C, m4C, and m5C have been identified and characterized. Besides the naturally occurring tRNA modifications, the investigation on artificially modified nucleosides is also part of this thesis. Nucleosides with specific properties for desired applications can be created by modifying the scaffold of native nucleosides. During the pandemic, the potential of antiviral nucleoside analogues was highlighted for the treatment of the SARS-CoV-2 infection. For examinations of the potential drug-candidate Molnupiravir, the N4-hydroxycytidine phosphoramidite building block was synthesized and incorporated into several RNA oligonucleotides. A two-step model for the NHC-induced mutagenesis of SARS-CoV-2 was proposed based on RNA elongation, thermal denaturation, and cryo-EM experiments using the modified RNA strands with the recombinant SARS-CoV-2 RNA-dependent RNA polymerase. Two tautomeric forms of NHC enable base pairing with guanosine in the amino and with adenosine in the imino form, leading to error catastrophe after the incorporation into viral RNA. These findings were further corroborated by thermal melting curve analysis and NMR spectroscopy of the NHC-containing Dickerson Drew sequence. In conclusion, the anti-amino form in the NHC-G base pair was assigned by NMR analysis using a 15N-labeld NHC building block incorporated into the Dickerson Drew sequence. This thesis also addressed the synthesis of a 7-deazaguanosine crosslinker with a masked aldehyde as a diol linker for investigations of DNA-protein interactions. The diol functional group can be unmasked to release the reactive aldehyde, which can specifically form a covalent bond with amino acids Lys or Arg within the protein complex condensin. The incorporation of the synthesized phosphoramidite and triphosphate building blocks were shown and the functionality of the PCR product containing the crosslinker was demonstrated by oxidation and the formation of a covalent bond with a fluorescein label. The development of assays that detect changes in this methylation pattern of m6A could provide new insights into important biological processes. In the last project of this thesis, the influence of RNA methylation states on the structural properties of RNA was analyzed and a fluorescent nucleoside analog (8-vinyladenosine) as molecular tools for such assays was developed. Initial experiments with the fluorescent nucleoside analog N6-methyl-8-vinyladenosine (m6v8A) were performed and revealed a strong fluorescence enhancement of the free m6v8A nucleoside by the installation of the vinyl moiety at position 8. Overall, this thesis contributes to various research topics regarding the application of naturally occurring and artificial nucleoside analogues. Starting with the chemical synthesis of RNA and DNA modifications, this thesis has unveiled several open questions regarding the dynamic (de-)methylation pathway of m3C and the mechanism of action of molnupiravir through in-depth analysis and provided the basis for further investigations of the protein complex condensin, and a new fluorescent nucleoside analog m6v8A. N2 - Als zentrale Bestandteile des Lebens kodieren DNA und RNA die genetische Information. Die RNA erfüllt jedoch noch mehr Funktionen, die über die im 'zentralen Dogma des Lebens' ge-nannten Kompetenzen hinausreichen. RNA Stränge werden posttranskriptionell verändert, wie zum Beispiel durch chemische Modifikationen. tRNAs sind unter allen RNA-Klassen am umfangreichsten und chemisch vielfältigsten modifiziert. Ihre Modifikationen reichen von ein-fachen Methylierungen (z. B. m3C oder m6A) bis hin zu komplexeren Resten, wie einer Iso-pentenyl-Gruppe (i6A, Hypermodifikation: z. B. ms2i6A) oder sogar Aminosäuren (t6A). Ab-hängig von ihrer Position innerhalb der tRNA können Modifikationen Einfluss auf die tRNA Stabilität und Struktur, sowie die Affinität zu den Ribosomen und die Translationseffizienz und Genauigkeit, haben. Angesichts dieser Bedeutung von tRNA-Modifikationen werden zum einen Nachweisemethoden zur Detektion von Modifikationen, als auch Werkzeuge zur Unter-suchung der Erkennungsmechanismen spezifischer Proteine und deren enzymatischer Funk-tionalisierung benötigt. Dabei ist die chemische Synthese dieser natürlichen Modifikationen als Phosphoramidit-Bausteine die Voraussetzung, um die gewünschte Modifikation überhaupt erst über Festpha-sensynthese in Oligonukleotide einbauen zu können. Mit Hilfe der m3C-, (ms2)i6A- und t6A-modifizierten Oligonukleotide wurde die Bedeutung dieser tRNA-Modifikationen für die Struk-tur und Funktionalität des jeweiligen tRNA Anticodon-Loops (ACL) untersucht. Ein Kapitel dieser Arbeit klärte die tatsächliche Rolle von METTL8 auf. Als Methyltransferase ist das Protein für den Einbau der Methylgruppe an C32 in den mitochondrialen tRNAThr und tRNASer(UCN) verantwortlich, kann dies aber nur bewerkstelligen, wenn zuvor bereits eine ent-sprechende Adenosin-Modifikation an A37 installiert wurde. Außerdem wurde mittels NMR-Analyse, CD-Spektroskopie, Schmelzkurvenanalysen und Gelelektrophorese der Einfluss von m3C32 auf die Struktur der tRNA Anticodon-Stem-Loops (ASLs) gezeigt. Die Modifikation scheint die tRNA-Struktur anzupassen, um die mitochondriale Translation zu optimieren. Um herauszufinden, wie die dynamischen Modifikationswege von m3C reguliert werden, wurden mit den modifizierten tRNA-ASLs und den (α-KG)- und Fe(II)-abhängigen Dio-xygenasen ALKBH1 und ALKHB3 Demethylierungsassays durchgeführt. Obwohl ALKBH3 bisher nur als cytoplasmatisches Enzym bekannt war, konnte es mt-tRNAs demethylieren. Inwiefern diese Aktivität physiologisch relevant ist und ob ALKBH3 vielleicht zusätzlich auch eine mitochond-riale Lokalisierung aufweist, muss noch weiter untersucht werden. Zudem wurde gezeigt, dass ALKBH1 m3C32-modifizierte mt-tRNAs nicht demethylieren kann, es jedoch Hinweise darauf gibt, dass ALKBH1 zusätzlich zu der bereits beschriebenen Aktivität der Oxidation von m5C zu f5C in mitochondrialer tRNAMet eine noch näher zu untersuchende Deprenylierungs- und Exonuklease-Aktivität besitzt. Außerdem wurden die zuvor erwähnten natürlichen Modifikationen verwendet, um DNA-Enzyme als analytische Werkzeuge zur Bestimmung des Modifikationsgrades zu finden. Die Enzyme katalysieren die Spaltung von RNA, falls eine spezielle Modifikation vorhanden ist. Es wurden selektive DNA-Enzyme für i6A sowie die drei Cytidin-Isomere m3C, m4C und m5C identifiziert und charakterisiert. Neben den posttranskriptionalen Modifikationen war auch die Untersuchung künstlich modifi-zierter Nukleoside ein Teil dieser Arbeit. Das Gerüst nativer Nukleoside kann so modifiziert werden, dass die Nukleoside spezifischen Eigenschaften für die gewünschte Anwendung erhalten. Während der Pandemie wurde antiviralen Nukleosidanaloga zur Behandlung der SARS-CoV-2-Infektion eine große Bedeutung zugeschrieben. Um den potenziellen Arzneimittelkandidaten Molnupiravir zu untersuchen, wurde N4-Hydroxycytidin als Phosphoramidit-Baustein syntheti-siert und in mehrere RNA-Oligonukleotide mittels Festphasensynthese eingebaut. Basierend auf den Ergebnissen von RNA-Elongations-, thermischen Denaturierungs- und Cryo-EM-Experimenten, bei denen die modifizierten RNA-Stränge und die rekombinante SARS-CoV-2-RNA-abhängige RNA-Polymerase verwendet wurde, wurde ein zweistufiges Modell für die NHC-induzierte Mutagenese von SARS-CoV-2 postuliert. Dieser Mechanismus wird durch die zwei tautomeren Formen von NHC ermöglicht, wobei die Amino-Form ein Basenpaar mit Guanosin bildet und die Imino-Form mit Adenosin basenpaaren kann. Nach dem Einbau in die virale RNA kommt es zu Mutationen und zur sogenannten Fehlerkatastrophe. Diese Er-kenntnisse wurden durch thermische Schmelzkurvenanalyse und NMR-Spektroskopie der NHC-haltigen Dickerson Drew Sequenz ergänzt. Mit Hilfe eines 15N-markierten NHC-Bausteins, der in die Dickerson Drew Sequenz eingebaut wurde, konnte schließlich die Anti-Amino Form in dem NHC-G Basenpaar durch NMR-Analyse eindeutig nachgewiesen wer-den. Ein weiteres Forschungsprojekt dieser Arbeit befasste sich mit der Synthese eines 7-Deazaguanosin-Crosslinkers, welcher einen geschützten Aldehyd als Diol-Linker enthielt. Die-ser Crosslinker sollte zur Untersuchung von DNA-Protein-Interaktionen dienen. Der Einbau der synthetisierten Phosphoramidit- und Triphosphat-Bausteine konnte erfolgreich durchge-führt werden und die Funktionalität des PCR-Produktes, welches den Crosslinker enthielt, wurde durch Oxidation und die Bildung einer kovalenten Bindung mit einem Fluorescein-Label demonstriert. Der letzte Teil dieser Arbeit beschäftigte sich mit der der Entwicklung eines Assays, um Ver-änderungen im Methylierungslevel von m6A nachweisen zu können. Dies könnte neue Einbli-cke in wichtige biologische Prozesse liefern. Daher wurde im letzten Projekt der Einfluss von RNA-Methylierungszuständen auf die strukturellen Eigenschaften von RNA untersucht und dafür ein fluoreszierendes Nukleosidanalog (8-Vinyladenosin) als molekulares Werkzeug ent-wickelt. Die ersten Experimente mit dem Nukleosidanalog N6-Methyl-8-Vinyladenosin (m6v8A) zeigten einen deutlichen Fluoreszenzanstieg durch den Einbau der Vinyleinheit an Position 8 im Vergleich zu dem nicht fluoreszierenden m6A. Insgesamt trägt diese Arbeit zu verschiedenen Forschungsthemen bezüglich der Anwendung von natürlich vorkommenden und künstlichen Nukleosidanaloga bei. Ausgehend von der chemischen Synthese von RNA- und DNA-Modifikationen hat diese Arbeit durch eingehende Analysen mehrere offene Fragestellungen zum dynamischen (De-)Methylierungsweg von m3C und zum Wirkmechanismus von Molnupiravir aufgedeckt und die Grundlage für weitere Untersuchungen des Proteinkomplexes Condensin und eines neuen fluoreszierenden Nukle-osidanalogons m6v8A geschaffen. KW - Nucleinsäuren KW - Chemische Synthese KW - SARS-CoV-2 KW - Oligonucleotide KW - Festphasensynthese KW - Crosslinker KW - Phosphoramidite KW - Methyltransferase Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311350 ER - TY - JOUR A1 - Solimando, Antonio G. A1 - Bittrich, Max A1 - Shahini, Endrit A1 - Albanese, Federica A1 - Fritz, Georg A1 - Krebs, Markus T1 - Determinants of COVID-19 disease severity – lessons from primary and secondary immune disorders including cancer JF - International Journal of Molecular Sciences N2 - At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients’ risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients. KW - COVID-19 KW - SARS-CoV-2 KW - disorder of immunity KW - cancer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319412 SN - 1422-0067 VL - 24 IS - 10 ER - TY - JOUR A1 - Sitter, Magdalena A1 - Pecks, Ulrich A1 - Rüdiger, Mario A1 - Friedrich, Sabine A1 - Fill Malfertheiner, Sara A1 - Hein, Alexander A1 - Königbauer, Josefine T. A1 - Becke-Jakob, Karin A1 - Zöllkau, Janine A1 - Ramsauer, Babett A1 - Rathberger, Katharina A1 - Pontones, Constanza A. A1 - Kraft, Katrina A1 - Meybohm, Patrick A1 - Härtel, Christoph A1 - Kranke, Peter T1 - Pregnant and postpartum women requiring intensive care treatment for COVID-19 — first data from the CRONOS-registry JF - Journal of Clinical Medicine N2 - (1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. Median maternal age was 33 (IQR, 30–36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28–35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome. KW - maternal critical care KW - COVID-19 KW - ARDS KW - SARS-CoV-2 KW - pregnancy KW - obstetrics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255257 SN - 2077-0383 VL - 11 IS - 3 ER - TY - THES A1 - Seitz, Florian T1 - Synthesis, enzymatic recognition and antiviral properties of modified purine nucleosides T1 - Synthese, enzymatische Erkennung und antivirale Eigenschaften modifizierter Purin-Nukleoside N2 - Beyond the four canonical nucleosides as primary building blocks of RNA, posttranscriptional modifications give rise to the epitranscriptome as a second layer of genetic information. In eukaryotic mRNA, the most abundant posttranscriptional modification is N6-methyladenosine (m6A), which is involved in the regulation of cellular processes. Throughout this thesis, the concept of atomic mutagenesis was employed to gain novel mechanistic insights into the substrate recognition by human m6A reader proteins as well as in the oxidative m6A demethylation by human demethylase enzymes. Non-natural m6A atomic mutants featuring distinct steric and electronic properties were synthesized and incorporated into RNA oligonucleotides. Fluorescence anisotropy measurements using these modified oligonucleotides revealed the impact of the atomic mutagenesis on the molecular recognition by the human m6A readers YTHDF2, YTHDC1 and YTHDC2 and allowed to draw conclusions about structural prerequisites for substrate recognition. Furthermore, substrate recognition and demethylation mechanism of the human m6A demethylase enzymes FTO and ALKBH5 were analyzed by HPLC-MS and PAGE-based assays using the modified oligonucleotides synthesized in this work. Modified nucleosides not only expand the genetic alphabet, but are also extensively researched as drug candidates. In this thesis, the antiviral mechanism of the anti-SARS-CoV-2 drug remdesivir was investigated, which causes delayed stalling of the viral RNA-dependent RNA polymerase (RdRp). Novel remdesivir phosphoramidite building blocks were synthesized and used to construct defined RNA-RdRp complexes for subsequent studies by cryogenic electron microscopy (cryo-EM). It was found that the 1'-cyano substituent causes Rem to act as a steric barrier of RdRp translocation. Since this translocation barrier can eventually be overcome by the polymerase, novel derivatives of Rem with potentially improved antiviral properties were designed. N2 - Über die vier kanonischen Nukleoside als primäre RNA-Bausteine hinausgehend bauen posttranskriptionelle Modifikationen eine zweite Informationsebene, das Epitranskriptom, auf. Die häufigste posttranskriptionelle Modifikation in eukaryotischer mRNA ist N6-Methyladenosin (m6A), welches in die Regulierung zellulärer Prozesse involviert ist. In dieser Arbeit wurde das Konzept der atomaren Mutagenese genutzt, um neue Einblicke in die Erkennung von m6A durch menschliche m6A-bindende Proteine sowie in die oxidative Demethylierung von m6A durch menschliche Demethylase-Enzyme zu gewinnen. Es wurden nicht natürlich vorkommende m6A Atommutanten mit unterschiedlichen elektronischen und sterischen Eigenschaften synthetisiert und in RNA-Oligonukleotide eingebaut. Durch Fluoreszenzanisotropie-Messungen mit diesen Oligonukleotiden wurde der Einfluss der Atommutagenese auf die molekulare Erkennung durch die menschlichen m6A-bindenden Proteine YTHDF2, YTHDC1 und YTHDC2 untersucht. Die erhaltenen Ergebnisse ließen Rückschlüsse auf die strukturellen Voraussetzungen für die Erkennung eines Substrates zu. Weiterhin wurden die in dieser Arbeit synthetisierten modifizierten Oligonukleotide zur Untersuchung von Substraterkennung und Demethylierungs-Mechanismus der menschlichen m6A-Demethylasen FTO und ALKBH5 mittels HPLC-MS- und PAGE-basierter Analysen verwendet. Modifizierte Nukleoside dienen nicht nur zur Erweiterung des genetischen Alphabets, sondern werden auch als potentielle Wirkstoff-Kandidaten erforscht. In dieser Arbeit wurde der antivirale Wirkmechanismus des Anti-SARS-CoV-2-Wirkstoffes Remdesivir untersucht, der eine verzögerte Blockade der viralen RNA-abhängigen RNA-Polymerase (RdRp) bewirkt. Neuartige Remdesivir Phosphoramidit-Bausteine wurden synthetisiert und genutzt, um RNA-RdRp-Komplexe mit definierter Struktur zu konstruieren, welche anschließend mittels Cryoelektronenmikroskopie (Cryo-EM) untersucht wurden. Es wurde herausgefunden, dass der 1'-Cyano-Substituent dazu führt, dass Rem als sterische Blockade der RdRp-Translokation agiert. Da diese Tranlokationsbarriere von der Polymerase überwunden werden kann, wurden neuartige Rem-Derivate mit potentiell verbesserten antiviralen Eigenschaften entworfen. KW - Nucleinsäuren KW - Nucleoside KW - Demethylierung KW - COVID-19 KW - SARS-CoV-2 KW - Demethylase KW - Epitranskriptom Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313238 ER - TY - JOUR A1 - Schön, Michael P. A1 - Berking, Carola A1 - Biedermann, Tilo A1 - Buhl, Timo A1 - Erpenbeck, Luise A1 - Eyerich, Kilian A1 - Eyerich, Stefanie A1 - Ghoreschi, Kamran A1 - Goebeler, Matthias A1 - Ludwig, Ralf J. A1 - Schäkel, Knut A1 - Schilling, Bastian A1 - Schlapbach, Christoph A1 - Stary, Georg A1 - von Stebut, Esther A1 - Steinbrink, Kerstin T1 - COVID‐19 and immunological regulations – from basic and translational aspects to clinical implications JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - The COVID‐19 pandemic caused by SARS‐CoV‐2 has far‐reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS‐CoV‐2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS‐CoV‐2/COVID‐19 with mediators of the acute phase of inflammation (TNF, IL‐1, IL‐6), type 1 and type 17 immune responses (IL‐12, IL‐23, IL‐17, IL‐36), type 2 immune reactions (IL‐4, IL‐13, IL‐5, IL‐31, IgE), B‐cell immunity, checkpoint regulators (PD‐1, PD‐L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non‐specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte‐mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS‐CoV‐2/COVID‐19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID‐19 pandemic; some even appear to alleviate COVID‐19. KW - COVID-19 KW - SARS-CoV-2 KW - immunology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218205 VL - 18 IS - 8 SP - 795 EP - 807 ER - TY - JOUR A1 - Schneider-Schaulies, Sibylle A1 - Schumacher, Fabian A1 - Wigger, Dominik A1 - Schöl, Marie A1 - Waghmare, Trushnal A1 - Schlegel, Jan A1 - Seibel, Jürgen A1 - Kleuser, Burkhard T1 - Sphingolipids: effectors and Achilles heals in viral infections? JF - Cells N2 - As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention. KW - glycosphingolipids KW - ceramides KW - sphingosine 1-phosphate KW - sphingomyelinase KW - HIV KW - SARS-CoV-2 KW - measles Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245151 SN - 2073-4409 VL - 10 IS - 9 ER - TY - JOUR A1 - Schapovalova, Olesia A1 - Gorlova, Anna A1 - de Munter, Johannes A1 - Sheveleva, Elisaveta A1 - Eropkin, Mikhail A1 - Gorbunov, Nikita A1 - Sicker, Michail A1 - Umriukhin, Aleksei A1 - Lyubchyk, Sergiy A1 - Lesch, Klaus-Peter A1 - Strekalova, Tatyana A1 - Schroeter, Careen A. T1 - Immunomodulatory effects of new phytotherapy on human macrophages and TLR4- and TLR7/8-mediated viral-like inflammation in mice JF - Frontiers in Medicine N2 - Background While all efforts have been undertaken to propagate the vaccination and develop remedies against SARS-CoV-2, no satisfactory management of this infection is available yet. Moreover, poor availability of any preventive and treatment measures of SARS-CoV-2 in economically disadvantageous communities aggravates the course of the pandemic. Here, we studied a new immunomodulatory phytotherapy (IP), an extract of blackberry, chamomile, garlic, cloves, and elderberry as a potential low-cost solution for these problems given the reported efficacy of herbal medicine during the previous SARS virus outbreak. Methods The key feature of SARS-CoV-2 infection, excessive inflammation, was studied in in vitro and in vivo assays under the application of the IP. First, changes in tumor-necrosis factor (TNF) and lnteurleukin-1 beta (IL-1β) concentrations were measured in a culture of human macrophages following the lipopolysaccharide (LPS) challenge and treatment with IP or prednisolone. Second, chronically IP-pre-treated CD-1 mice received an agonist of Toll-like receptors (TLR)-7/8 resiquimod and were examined for lung and spleen expression of pro-inflammatory cytokines and blood formula. Finally, chronically IP-pre-treated mice challenged with LPS injection were studied for “sickness” behavior. Additionally, the IP was analyzed using high-potency-liquid chromatography (HPLC)-high-resolution-mass-spectrometry (HRMS). Results LPS-induced in vitro release of TNF and IL-1β was reduced by both treatments. The IP-treated mice displayed blunted over-expression of SAA-2, ACE-2, CXCL1, and CXCL10 and decreased changes in blood formula in response to an injection with resiquimod. The IP-treated mice injected with LPS showed normalized locomotion, anxiety, and exploration behaviors but not abnormal forced swimming. Isoquercitrin, choline, leucine, chlorogenic acid, and other constituents were identified by HPLC-HRMS and likely underlie the IP immunomodulatory effects. Conclusions Herbal IP-therapy decreases inflammation and, partly, “sickness behavior,” suggesting its potency to combat SARS-CoV-2 infection first of all via its preventive effects. KW - toll-like receptors KW - SARS-CoV-2 KW - inflammation KW - pro-inflammatory cytokines KW - mice Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286301 SN - 2296-858X VL - 9 ER - TY - JOUR A1 - Riederer, P. A1 - Monoranu, C. A1 - Strobel, S. A1 - Iordache, T. A1 - Sian-Hülsmann, J. T1 - Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease JF - Journal of Neural Transmission N2 - About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications. KW - SARS-CoV-2 KW - iron in parkinsonism KW - parkinson’s disease KW - iiron transporter KW - neuromelanin KW - iron pathology KW - neuroinflammation KW - iron model KW - ferroptosis KW - ɑ-Synuclein and iron KW - virus–iron interaction KW - COVID-19 KW - hepcidin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268539 SN - 1435-1463 VL - 128 IS - 10 ER - TY - JOUR A1 - Prada, Juan Pablo A1 - Maag, Luca Estelle A1 - Siegmund, Laura A1 - Bencurova, Elena A1 - Liang, Chunguang A1 - Koutsilieri, Eleni A1 - Dandekar, Thomas A1 - Scheller, Carsten T1 - Estimation of R0 for the spread of SARS-CoV-2 in Germany from excess mortality JF - Scientific Reports N2 - For SARS-CoV-2, R0 calculations in the range of 2–3 dominate the literature, but much higher estimates have also been published. Because capacity for RT-PCR testing increased greatly in the early phase of the Covid-19 pandemic, R0 determinations based on these incidence values are subject to strong bias. We propose to use Covid-19-induced excess mortality to determine R0 regardless of RT-PCR testing capacity. We used data from the Robert Koch Institute (RKI) on the incidence of Covid cases, Covid-related deaths, number of RT-PCR tests performed, and excess mortality calculated from data from the Federal Statistical Office in Germany. We determined R0 using exponential growth estimates with a serial interval of 4.7 days. We used only datasets that were not yet under the influence of policy measures (e.g., lockdowns or school closures). The uncorrected R0 value for the spread of SARS-CoV-2 based on RT-PCR incidence data was 2.56 (95% CI 2.52–2.60) for Covid-19 cases and 2.03 (95% CI 1.96–2.10) for Covid-19-related deaths. However, because the number of RT-PCR tests increased by a growth factor of 1.381 during the same period, these R0 values must be corrected accordingly (R0corrected = R0uncorrected/1.381), yielding 1.86 for Covid-19 cases and 1.47 for Covid-19 deaths. The R0 value based on excess deaths was calculated to be 1.34 (95% CI 1.32–1.37). A sine-function-based adjustment for seasonal effects of 40% corresponds to a maximum value of R0January = 1.68 and a minimum value of R0July = 1.01. Our calculations show an R0 that is much lower than previously thought. This relatively low range of R0 fits very well with the observed seasonal pattern of infection across Europe in 2020 and 2021, including the emergence of more contagious escape variants such as delta or omicron. In general, our study shows that excess mortality can be used as a reliable surrogate to determine the R0 in pandemic situations. KW - SARS-CoV-2 KW - R0 KW - mortality Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301415 VL - 12 IS - 1 ER - TY - JOUR A1 - Pilgram, Lisa A1 - Eberwein, Lukas A1 - Wille, Kai A1 - Koehler, Felix C. A1 - Stecher, Melanie A1 - Rieg, Siegbert A1 - Kielstein, Jan T. A1 - Jakob, Carolin E. M. A1 - Rüthrich, Maria A1 - Burst, Volker A1 - Prasser, Fabian A1 - Borgmann, Stefan A1 - Müller, Roman-Ulrich A1 - Lanznaster, Julia A1 - Isberner, Nora A1 - Tometten, Lukas A1 - Dolff, Sebastian T1 - Clinical course and predictive risk factors for fatal outcome of SARS-CoV-2 infection in patients with chronic kidney disease JF - Infection N2 - Purpose The ongoing pandemic caused by the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) has stressed health systems worldwide. Patients with chronic kidney disease (CKD) seem to be more prone to a severe course of coronavirus disease (COVID-19) due to comorbidities and an altered immune system. The study’s aim was to identify factors predicting mortality among SARS-CoV-2-infected patients with CKD. Methods We analyzed 2817 SARS-CoV-2-infected patients enrolled in the Lean European Open Survey on SARS-CoV-2-infected patients and identified 426 patients with pre-existing CKD. Group comparisons were performed via Chi-squared test. Using univariate and multivariable logistic regression, predictive factors for mortality were identified. Results Comparative analyses to patients without CKD revealed a higher mortality (140/426, 32.9% versus 354/2391, 14.8%). Higher age could be confirmed as a demographic predictor for mortality in CKD patients (> 85 years compared to 15–65 years, adjusted odds ratio (aOR) 6.49, 95% CI 1.27–33.20, p = 0.025). We further identified markedly elevated lactate dehydrogenase (> 2 × upper limit of normal, aOR 23.21, 95% CI 3.66–147.11, p < 0.001), thrombocytopenia (< 120,000/µl, aOR 11.66, 95% CI 2.49–54.70, p = 0.002), anemia (Hb < 10 g/dl, aOR 3.21, 95% CI 1.17–8.82, p = 0.024), and C-reactive protein (≥ 30 mg/l, aOR 3.44, 95% CI 1.13–10.45, p = 0.029) as predictors, while renal replacement therapy was not related to mortality (aOR 1.15, 95% CI 0.68–1.93, p = 0.611). Conclusion The identified predictors include routinely measured and universally available parameters. Their assessment might facilitate risk stratification in this highly vulnerable cohort as early as at initial medical evaluation for SARS-CoV-2. KW - chronic kidney disease KW - COVID-19 KW - LEOSS KW - predictive factor KW - SARS-CoV-2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308957 SN - 0300-8126 SN - 1439-0973 VL - 49 IS - 4 ER - TY - JOUR A1 - Osmanoglu, Özge A1 - Gupta, Shishir K. A1 - Almasi, Anna A1 - Yagci, Seray A1 - Srivastava, Mugdha A1 - Araujo, Gabriel H. M. A1 - Nagy, Zoltan A1 - Balkenhol, Johannes A1 - Dandekar, Thomas T1 - Signaling network analysis reveals fostamatinib as a potential drug to control platelet hyperactivation during SARS-CoV-2 infection JF - Frontiers in Immunology N2 - Introduction Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear. Methods We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved. Results Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients. Discussion Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/. KW - signaling network KW - controllability KW - platelet KW - SARS-CoV-2 KW - fostamatinib KW - drug repurposing KW - COVID-19 Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-354158 VL - 14 ER - TY - JOUR A1 - Nyawale, Helmut A. A1 - Moremi, Nyambura A1 - Mohamed, Mohamed A1 - Njwalila, Johnson A1 - Silago, Vitus A1 - Krone, Manuel A1 - Konje, Eveline T. A1 - Mirambo, Mariam M. A1 - Mshana, Stephen E. T1 - High seroprevalence of SARS-CoV-2 in Mwanza, northwestern Tanzania: a population-based survey JF - International Journal of Environmental Research and Public Health N2 - The transmission of the SARS-CoV-2 virus, which causes COVID-19, has been documented worldwide. However, the evidence of the extent to which transmission has occurred in different countries is still to be established. Understanding the magnitude and distribution of SARS-CoV-2 through seroprevalence studies is important in designing control and preventive strategies in communities. This study investigated the seropositivity of the SARS-CoV-2 virus antibodies in the communities of three different districts in the Mwanza region, Tanzania. A household cross-sectional survey was conducted in September 2021 using the modified African Centre for Disease and Prevention (ACDC) survey protocol. A blood sample was obtained from one member of each of the selected households who consented to take part in the survey. Immunochromatographic rapid test kits were used to detect IgM and IgG SARS-CoV-2 antibodies, followed by descriptive data analysis. Overall, 805 participants were enrolled in the study with a median age of 35 (interquartile range (IQR):27–47) years. The overall SARS-CoV-2 seropositivity was 50.4% (95%CI: 46.9–53.8%). The IgG and IgM seropositivity of the SARS-CoV-2 antibodies was 49.3% and 7.2%, respectively, with 6.1% being both IgG and IgM seropositive. A history of runny nose (aOR: 1.84, 95%CI: 1.03–3.5, p = 0.036), loss of taste (aOR: 1.84, 95%CI: 1.12–4.48, p = 0.023), and living in Ukerewe (aOR: 3.55, 95%CI: 1.68–7.47, p = 0.001) and Magu (aOR: 2.89, 95%CI: 1.34–6.25, p= 0.007) were all independently associated with SARS-CoV-2 IgM seropositivity. Out of the studied factors, living in the Ukerewe district was independently associated with IgG seropositivity (aOR 1.29, CI 1.08–1.54, p = 0.004). Twenty months after the first case of COVID-19 in Tanzania, about half of the studied population in Mwanza was seropositive for SARS-CoV-2. KW - SARS-CoV-2 KW - COVID-19 KW - seroprevalence KW - antibodies KW - Mwanza KW - Tanzania Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288134 SN - 1660-4601 VL - 19 IS - 18 ER - TY - JOUR A1 - Meintrup, David A1 - Borgmann, Stefan A1 - Seidl, Karlheinz A1 - Stecher, Melanie A1 - Jakob, Carolin E. M. A1 - Pilgram, Lisa A1 - Spinner, Christoph D. A1 - Rieg, Siegbert A1 - Isberner, Nora A1 - Hower, Martin A1 - Vehreschild, Maria A1 - Göpel, Siri A1 - Hanses, Frank A1 - Nowak-Machen, Martina T1 - Specific risk factors for fatal outcome in critically ill COVID-19 patients: results from a European multicenter study JF - Journal of Clinical Medicine N2 - (1) Background: The aim of our study was to identify specific risk factors for fatal outcome in critically ill COVID-19 patients. (2) Methods: Our data set consisted of 840 patients enclosed in the LEOSS registry. Using lasso regression for variable selection, a multifactorial logistic regression model was fitted to the response variable survival. Specific risk factors and their odds ratios were derived. A nomogram was developed as a graphical representation of the model. (3) Results: 14 variables were identified as independent factors contributing to the risk of death for critically ill COVID-19 patients: age (OR 1.08, CI 1.06–1.10), cardiovascular disease (OR 1.64, CI 1.06–2.55), pulmonary disease (OR 1.87, CI 1.16–3.03), baseline Statin treatment (0.54, CI 0.33–0.87), oxygen saturation (unit = 1%, OR 0.94, CI 0.92–0.96), leukocytes (unit 1000/μL, OR 1.04, CI 1.01–1.07), lymphocytes (unit 100/μL, OR 0.96, CI 0.94–0.99), platelets (unit 100,000/μL, OR 0.70, CI 0.62–0.80), procalcitonin (unit ng/mL, OR 1.11, CI 1.05–1.18), kidney failure (OR 1.68, CI 1.05–2.70), congestive heart failure (OR 2.62, CI 1.11–6.21), severe liver failure (OR 4.93, CI 1.94–12.52), and a quick SOFA score of 3 (OR 1.78, CI 1.14–2.78). The nomogram graphically displays the importance of these 14 factors for mortality. (4) Conclusions: There are risk factors that are specific to the subpopulation of critically ill COVID-19 patients. KW - COVID-19 KW - SARS-CoV-2 KW - risk factors KW - critically ill patients KW - comorbidities KW - lasso regression KW - nomogram Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245191 SN - 2077-0383 VL - 10 IS - 17 ER - TY - JOUR A1 - Liu, Fengming A1 - Han, Kun A1 - Blair, Robert A1 - Kenst, Kornelia A1 - Qin, Zhongnan A1 - Upcin, Berin A1 - Wörsdörfer, Philipp A1 - Midkiff, Cecily C. A1 - Mudd, Joseph A1 - Belyaeva, Elizaveta A1 - Milligan, Nicholas S. A1 - Rorison, Tyler D. A1 - Wagner, Nicole A1 - Bodem, Jochen A1 - Dölken, Lars A1 - Aktas, Bertal H. A1 - Vander Heide, Richard S. A1 - Yin, Xiao-Ming A1 - Kolls, Jay K. A1 - Roy, Chad J. A1 - Rappaport, Jay A1 - Ergün, Süleyman A1 - Qin, Xuebin T1 - SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro JF - Frontiers in Cellular and Infection Microbiology N2 - SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure. KW - endothelial cell infection KW - animal models KW - SARS-CoV-2 KW - aorta ring KW - hACE2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241948 SN - 2235-2988 VL - 11 ER - TY - JOUR A1 - Liang, Chunguang A1 - Bencurova, Elena A1 - Psota, Eric A1 - Neurgaonkar, Priya A1 - Prelog, Martina A1 - Scheller, Carsten A1 - Dandekar, Thomas T1 - Population-predicted MHC class II epitope presentation of SARS-CoV-2 structural proteins correlates to the case fatality rates of COVID-19 in different countries JF - International Journal of Molecular Sciences N2 - We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions. KW - COVID-19 KW - population coverage KW - MHC II KW - MHC I KW - B-cell KW - T-cell KW - epitope mapping KW - lethality rate KW - infection spread KW - SARS-CoV-2 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258936 SN - 1422-0067 VL - 22 IS - 5 ER - TY - JOUR A1 - Lambertini, Alessandro A1 - Hartrampf, Philipp E. A1 - Higuchi, Takahiro A1 - Serfling, Sebastian E. A1 - Meybohm, Patrick A1 - Schirbel, Andreas A1 - Buck, Andreas K. A1 - Werner, Rudolf A. T1 - CXCR4-targeted molecular imaging after severe SARS-Cov-2 infection JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - No abstract available. KW - CXCR4-targeting KW - SARS-CoV-2 KW - COVID-19 KW - molecular imaging Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324619 VL - 50 IS - 1 ER -