TY - JOUR A1 - Melfsen, Siebke A1 - Romanos, Marcel A1 - Jans, Thomas A1 - Walitza, Susanne T1 - Betrayed by the nervous system: a comparison group study to investigate the ‘unsafe world’ model of selective mutism JF - Journal of Neural Transmission N2 - The study presented in the following verifies some assumptions of the novel ‘unsafe world’ model of selective mutism (SM). According to this model, SM is a stress reaction to situations erroneously experienced via cognition without awareness as ‘unsafe’. It assumes a high sensitivity to unsafety, whereby the nervous system triggers dissociation or freeze mode at relatively low thresholds. We examine whether there is a correlation between SM, sensory-processing sensitivity and dissociation. We compared a sample of 28 children and adolescents with SM (mean age 12.66 years; 18 females) to 33 controls without SM (mean age 12.45 years; 21 females). Both groups were compared using a medical history sheet, the ‘Selective Mutism Questionnaire’ (SMQ), a ‘Checklist for Speaking Behaviour’ (CheckS), the ‘Highly Sensitive Person Scale’ (HSPS), the ‘Child Dissociative Checklist’ (CDC), the ‘Adolescent Dissociative Experience Scale’ (A-DES) and the ‘Social Phobia and Anxiety Inventory for Children’ (SPAIK). Appropriate parametric and non-parametric tests were conducted to examine differences between groups. The results indicate that sensory-processing sensitivity was significantly higher in the group of children and adolescents with SM [X2(1) = 7.224, p = 0.0007; d = 1.092]. Furthermore, dissociative symptoms were more common in children and adolescents with SM than in controls [F(1, 33) = 13.004, p = 0.001; d = 0.986]. The results indicate that sensory-processing sensitivity and dissociation are important factors of SM that may hold important implications for the treatment. KW - selective mutism KW - aetiology KW - high sensory-processing sensitivity KW - dissociation KW - anxiety KW - schoolchildren Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370681 VL - 128 ER - TY - JOUR T1 - Search for heavy long-lived multicharged particles in proton-proton collisions at √\(s\)=13 TeV using the ATLAS detector JF - Physical Review D N2 - A search for heavy long-lived multicharged particles is performed using the ATLAS detector at the LHC. Data with an integrated luminosity of 36.1 fb(-1) collected in 2015 and 2016 from proton-proton collisions at root s = 13 TeV are examined. Particles producing anomalously high ionization, consistent with long-lived massive particles with electric charges from vertical bar q vertical bar = 2e to vertical bar q vertical bar = 7e, are searched for. No events are observed, and 95% confidence level cross-section upper limits are interpreted as lower mass limits for a Drell-Yan production model. Multicharged particles with masses between 50 and 980-1220 GeV (depending on their electric charge) are excluded. KW - Symmetry KW - Matter KW - Extensions of fermion sector Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-314061 VL - 99 IS - 5 ER - TY - JOUR A1 - Mansour, Ahmed M. A1 - Soliman, Fatma A. A1 - Shehab, Ola R. A1 - Abdel-Ghani, Nour T. T1 - Photodegradation of sulfadiazine catalyzed by p-benzoquinones and picric acid: application to charge transfer complexes JF - RSC Advances N2 - As the treatment of effluents containing the antibiotic drug sulfadiazine (SZ) is one of the challenging problems in the field of environmental chemistry, it is essential to determine the concentration of SZ by a rapid and accurate method and then find a suitable method to degrade the assayed products into harmless chemicals. The color of the charge transfer (CT) complexes developed from the reaction of SZ with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), chloranilic acid (CHL) and picric acid (PA) was used to determine the concentration of SZ at 528, 510 and 410 nm, respectively. The Lambert–Beer's law is obeyed in the ranges of 6.80–68.06, 13.61–136.12 and 6.80–27.22 μg mL\(^{−1}\) for DDQ, CHL and PA complexes. The photolysis of SZ → DDQ in presence of sodium nitrite at 256 nm leads to faster degradation of SZ compared with the control experiments. This was simply spectrophotometrically followed by a decrease in the intensity of the CT band. The effect of some additives such as oxalic acid, and hematite nano particles was studied. For comparison, other π-acceptor reagents such as CHL and PA were used. About 80% of SZ is degraded in 45 min upon the illumination of SZ → DDQ at 256 nm, whereas 90 min is required in the case of CHL and PA to attain the same degradation limit. KW - antibiotic drug sulfadiazine (SZ) KW - environmental chemistry KW - effluents Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181507 VL - 7 IS - 63 ER - TY - JOUR A1 - Sharma, Piyush A1 - Khairnar, Vishal A1 - Madunic, Ivana Vrhovac A1 - Singh, Yogesh A1 - Pandyra, Aleksandra A1 - Salker, Madhuri S. A1 - Koepsell, Hermann A1 - Sabolic, Ivan A1 - Lang, Florian A1 - Lang, Pilipp A. A1 - Lang, Karl S. T1 - SGLT1 deficiency turns listeria infection into a lethal disease in mice JF - Cellular Physiology and Biochemistry N2 - Background: Cellular glucose uptake may involve either non-concentrative glucose carriers of the GLUT family or Na\(^+\)-coupled glucose-carrier SGLT1, which accumulates glucose against glucose gradients and may thus accomplish cellular glucose uptake even at dramatically decreased extracellular glucose oncentrations. SGLT1 is not only expressed in epithelia but as well in tumour cells and immune cells. Immune cell functions strongly depend on their metabolism, therefore we hypothesized that deficiency of SGLT1 modulates the defence against bacterial infection. To test this hypothesis, we infected wild type mice and gene targeted mice lacking functional SGLT1 with Listeria monocytogenes. Methods: SGLT1 deficient mice and wild type littermates were infected with 1x10\(^4\) CFU Listeria monocytogenes intravenously. Bacterial titers were determined by colony forming assay, SGLT1, TNF-α, IL-6 and IL-12a transcript levels were determined by qRT-PCR, as well as SGLT1 protein abundance and localization by immunohistochemistry. Results: Genetic knockout of SGLT1 (Slc5a1\(^{–/–}\) mice) significantly compromised bacterial clearance following Listeria monocytogenes infection with significantly enhanced bacterial load in liver, spleen, kidney and lung, and significantly augmented hepatic expression of TNF-α and IL-12a. While all wild type mice survived, all SGLT1 deficient mice died from the infection. Conclusions: SGLT1 is required for bacterial clearance and host survival following murine Listeria infection. KW - glucose uptake KW - Na+-coupled glucose transport KW - Listeria infection KW - TNF-α and IL-12a KW - survival KW - liver KW - spleen KW - kidney KW - lung KW - bacterial clearance Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181496 VL - 42 IS - 4 ER - TY - JOUR A1 - Ma, Jie A1 - Gulbins, Erich A1 - Edwards, Michael J. A1 - Caldwell, Charles C. A1 - Fraunholz, Martin A1 - Becker, Katrin Anne T1 - Staphylococcus aureus α-toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides JF - Cellular Physiology and Biochemistry N2 - Staphylococcus aureus (S. aureus) infections are a major clinical problem and range from mild skin and soft-tissue infections to severe and even lethal infections such as pneumonia, endocarditis, sepsis, osteomyelitis, and toxic shock syndrome. Toxins that are released from S. aureus mediate many of these effects. Here, we aimed to identify molecular mechanisms how α-toxin, a major S. aureus toxin, induces inflammation. Methods: Macrophages were isolated from the bone marrow of wildtype and acid sphingomyelinase-deficient mice, stimulated with S. aureus α-toxin and activation of the acid sphingomyelinase was quantified. The subcellular formation of ceramides was determined by confocal microscopy. Release of cathepsins from lysosomes, activation of inflammasome proteins and formation of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α) were analyzed by western blotting, confocal microscopy and ELISA. Results: We demonstrate that S. aureus α-toxin activates the acid sphingomyelinase in ex vivo macrophages and triggers a release of ceramides. Ceramides induced by S. aureus α-toxin localize to lysosomes and mediate a release of cathepsin B and D from lysosomes into the cytoplasm. Cytosolic cathepsin B forms a complex with Nlrc4. Treatment of macrophages with α-toxin induces the formation of IL-1β and TNF-α. These events are reduced or abrogated, respectively, in cells lacking the acid sphingomyelinase and upon treatment of macrophages with amitriptyline, a functional inhibitor of acid sphingomyelinase. Pharmacological inhibition of cathepsin B prevented activation of the inflammasome measured as release of IL-1β, while the formation of TNF-α was independent of cathepsin B. Conclusion: We demonstrate a novel mechanism how bacterial toxins activate the inflammasome and mediate the formation and release of cytokines: S. aureus α-toxin triggers an activation of the acid sphingomyelinase and a release of ceramides resulting in the release of lysosomal cathepsin B and formation of pro-inflammatory cytokines. KW - Staphylococcus aureus KW - sphingomyelinase KW - ceramide KW - toxins KW - macrophages KW - cytokines Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181481 VL - 43 IS - 6 ER - TY - JOUR A1 - Wang, Yiwen A1 - Zhang, Zhen A1 - Bai, Liying A1 - Lin, Chongde A1 - Osinsky, Roman A1 - Hewig, Johannes T1 - Ingroup/outgroup membership modulates fairness consideration: neural signatures from ERPs and EEG oscillations JF - Scientific Reports N2 - Previous studies have shown that ingroup/outgroup membership influences individual’s fairness considerations. However, it is not clear yet how group membership influences brain activity when a recipient evaluates the fairness of asset distribution. In this study, subjects participated as recipients in an Ultimatum Game with alleged members of both an experimentally induced ingroup and outgroup. They either received extremely unequal, moderately unequal, or equal offers from proposers while electroencephalogram was recorded. Behavioral results showed that the acceptance rates for unequal offers were higher when interacting with ingroup partners than with outgroup partners. Analyses of event related potentials revealed that proposers’ group membership modulated offer evaluation at earlier processing stages. Feedback-related negativity was more negative for extremely and moderately unequal offers compared to equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Analyses of event related oscillations revealed that the theta power (4–6 Hz) was larger for moderately unequal offers than equal offers in the ingroup interaction whereas it did not show differential responses to different offers in the outgroup interaction. Thus, early mechanisms of fairness evaluation are strongly modulated by the ingroup/outgroup membership of the interaction partner. KW - psychology KW - group membership KW - brain activity KW - asset distribution Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181461 VL - 7 ER - TY - JOUR A1 - Scheunert, Gunther A1 - Cohen, Sidney R. A1 - Kullock, René A1 - McCarron, Ryan A1 - Rechev, Katya A1 - Kaplan-Ashiri, Ifat A1 - Bitton, Ora A1 - Dawson, Paul A1 - Hecht, Bert A1 - Oron, Dan T1 - Grazing-incidence optical magnetic recording with super-resolution JF - Beilstein Journal of Nanotechnology N2 - Heat-assisted magnetic recording (HAMR) is often considered the next major step in the storage industry: it is predicted to increase the storage capacity, the read/write speed and the data lifetime of future hard disk drives. However, despite more than a decade of development work, the reliability is still a prime concern. Featuring an inherently fragile surface-plasmon resonator as a highly localized heat source, as part of a near-field transducer (NFT), the current industry concepts still fail to deliver drives with sufficient lifetime. This study presents a method to aid conventional NFT-designs by additional grazing-incidence laser illumination, which may open an alternative route to high-durability HAMR. Magnetic switching is demonstrated on consumer-grade CoCrPt perpendicular magnetic recording media using a green and a near-infrared diode laser. Sub-500 nm magnetic features are written in the absence of a NFT in a moderate bias field of only μ0H = 0.3 T with individual laser pulses of 40 mW power and 50 ns duration with a laser spot size of 3 μm (short axis) at the sample surface – six times larger than the magnetic features. Herein, the presence of a nanoscopic object, i.e., the tip of an atomic force microscope in the focus of the laser at the sample surface, has no impact on the recorded magnetic features – thus suggesting full compatibility with NFT-HAMR. KW - laser absorption KW - laser heating KW - thermally assisted magnetic recording Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181457 VL - 8 ER - TY - JOUR A1 - Szklarczyk, Damian A1 - Morris, John H. A1 - Cook, Helen A1 - Kuhn, Michael A1 - Wyder, Stefan A1 - Simonovic, Milan A1 - Santos, Aalberto A1 - Doncheva, Nadezhda T. A1 - Roth, Alexander A1 - Bork, Peer A1 - Jensen, Lars J. A1 - von Mering, Christian T1 - The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible JF - Nucleic Acids Research N2 - A system-wide understanding of cellular function requires knowledge of all functional interactions between the expressed proteins. The STRING database aims to collect and integrate this information, by consolidating known and predicted protein–protein association data for a large number of organisms. The associations in STRING include direct (physical) interactions, as well as indirect (functional) interactions, as long as both are specific and biologically meaningful. Apart from collecting and reassessing available experimental data on protein–protein interactions, and importing known pathways and protein complexes from curated databases, interaction predictions are derived from the following sources: (i) systematic co-expression analysis, (ii) detection of shared selective signals across genomes, (iii) automated text-mining of the scientific literature and (iv) computational transfer of interaction knowledge between organisms based on gene orthology. In the latest version 10.5 of STRING, the biggest changes are concerned with data dissemination: the web frontend has been completely redesigned to reduce dependency on outdated browser technologies, and the database can now also be queried from inside the popular Cytoscape software framework. Further improvements include automated background analysis of user inputs for functional enrichments, and streamlined download options. The STRING resource is available online, at http://string-db.org/. KW - string database KW - quality control KW - proteins KW - cellular function Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181445 VL - 45 IS - D1 ER - TY - JOUR A1 - Rhee, Jae-Sung A1 - Choi, Beom-Soon A1 - Kim, Jaebum A1 - Kim, Bo-Mi A1 - Lee, Young-Mi A1 - Kim, Il-Chan A1 - Kanamori, Akira A1 - Choi, Ik-Young A1 - Schartl, Manfred A1 - Lee, Jae-Seong T1 - Diversity, distribution, and significance of transposable elements in the genome of the only selfing hermaphroditic vertebrate Kryptolebias marmoratus JF - Scientific Reports N2 - The Kryptolebias marmoratus is unique because it is the only selffertilizing hermaphroditic vertebrate, known to date. It primarily reproduces by internal self-fertilization in a mixed ovary/testis gonad. Here, we report on a high-quality genome assembly for the K. marmoratus South Korea (SK) strain highlighting the diversity and distribution of transposable elements (TEs). We find that K. marmoratus genome maintains number and composition of TEs. This can be an important genomic attribute promoting genome recombination in this selfing fish, while, in addition to a mixed mating strategy, it may also represent a mechanism contributing to the evolutionary adaptation to ecological pressure of the species. Future work should help clarify this point further once genomic information is gathered for other taxa of the family Rivulidae that do not self-fertilize. We provide a valuable genome resource that highlights the potential impact of TEs on the genome evolution of a fish species with an uncommon life cycle. KW - ecological genetics KW - evolutionary genetics KW - ichthyology KW - Kryptolebias marmoratus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181329 VL - 7 ER - TY - THES A1 - Reichelt, Niklas T1 - Exploring the natural variation of heat-dependent metabolic rearrangements in \(Arabidopsis\) \(thaliana\) to identify genes involved in thermotolerance T1 - Untersuchung der natürlichen Variation des hitzeregulierten Metaboloms in \(Arabidopsis\) \(thaliana\), um Gene der pflanzlichen Thermotoleranz zu identifizieren N2 - Climate change and associated extreme weather events are a threat not only for agricultural yields but the plant kingdom in general. Therefore, there is a great necessity to better understand the plants' intrinsic mechanisms to combat heat stress. The plant heat stress response already has been investigated in many studies, including the role of HSFA1 transcription factors as the central regulators. Other aspects such as the initial perception of heat and the role of heat-induced changes in plant metabolism are rather unknown. In this thesis, the natural variation of 250 different accessions of Arabidopsis thaliana was investigated regarding the temperature-dependent accumulation of raffinose and triacylglycerols. A connection between these phenotypes and respective genotypes was established using genome-wide association studies. As a result, the candidate gene TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1), was identified. Enzymatic TPS1 is responsible for the synthesis of trehalose 6-phosphate (T6P), which serves as an indicator and regulator of sucrose homeostasis. Subsequent analyses using tps1 tilling mutants demonstrated a link between T6P metabolism and an increased accumulation of various soluble carbohydrates and starch, including raffinose both under control conditions and during heat exposure. Furthermore, the mutant lines displayed enhanced thermotolerance and survival rates following long-term heat stress. Transcriptome analyses, however, did not show any difference in the regulation of canonical heat stress-associated genes. Instead, genes related to photosynthesis were overrepresented among the differentially upregulated genes in tps1 tilling lines during heat exposure. In this work, a direct connection of T6P signaling, sucrose homeostasis, and thermotolerance is shown for the first time. In a second project, two Arabidopsis thaliana accessions (Oberursel-0, accession ID: 7276; Nieps-0, accession ID: 7268) showing distinct capacities to acquire short-term thermotolerance were compared to identify the putative causative regulators or mechanisms that lead to the different levels of thermotolerance. An examination of the transcriptomes of 7268 and 7276 showed that several hundreds of genes were already differentially regulated within 10 minutes of exposure to 32 °C or 34 °C. Among these, several genes associated with sulfur metabolism were more highly induced in the more thermotolerant accession 7268. However, experimental as well as genetic manipulation of sulfur availability and metabolism did not result in altered thermotolerance. In addition to sulfur-related genes, most of the canonical heat stress-associated genes were more highly expressed in 7268 than in 7276. While we could not identify a causative regulator or mechanism of differential thermotolerances, the data strongly suggests that 7268 either has a higher overall sensitivity, i.e., the heat stress response is initiated at lower temperatures, or stronger overall heat stress response when exposed to a certain elevated temperature. N2 - Der Klimawandel und die damit einhergehenden extremen Wetterereignisse stellen eine große Bedrohung für den Ertrag der Landwirtschaft aber auch das Reich der Pflanzen im Allgemeinen dar. Es ist daher von großer Notwendigkeit, die der Pflanzen intrinsischen Mechanismen zur Bekämpfung von Hitzestress besser zu verstehen. Die hierbei zugrundeliegende Hitzestressantwort der Pflanzen ist bereits durch viele Studien untersucht worden, unter anderem die Rolle von HSFA1 Transkriptionsfaktoren als zentrale Regulatoren. Andere Aspekte wie die initiale Wahrnehmung von Hitze sowie die Rolle von hitzeinduzierten Veränderungen des Pflanzenmetabolismus sind eher unbekannt. In dieser Thesis wurde die natürliche Variation von 250 Populationen von Arabidopsis thaliana hinsichtlich der temperatur-abhängigen Akkumulation von Raffinose und Triacylglycerolen untersucht. Ein statistischer Zusammenhang dieser Phänotypen sowie zugrundeliegender Genotypen wurde mittels Genomweiter Assoziationsstudien erstellt. Als Ergebnis konnte das Kandidatengen Trehalose-6-Phosphate Synthase 1 (TPS1) identifiziert werden. Das Enzym TPS1 ist verantwortlich für die Synthese von T6P, welches als Indikator sowie Regulator der Homöostase von Saccharose fungiert. Folgestudien an tps1 tilling lines konnten sowohl unter Kontrollbedingungen als auch bei Hitzestress einen Zusammenhang zwischen dem T6P Metabolismus und einer erhöhten Akkumulation von Raffinose, weiterer löslicher Zucker, sowie Stärke nachweisen. Des Weiteren zeigten die tps1 tilling lines eine erhöhte Thermotoleranz und Überlebensrate gegenüber Langzeit-Hitzestress. Eine Analyse der Transkriptome zeigte keinen Unterschied in der Regulation klassischer Hitzestress-assoziierter Gene. In beiden tps1 tilling lines war in Folge von Hitzestress eine Überrepräsentation von signifikant hochregulierten Genen vorzufinden, welche mit der Photosynthese der Pflanze assoziiert sind. In dieser Arbeit konnte erstmalig ein direkter Zusammenhang von T6P Signaling, Zucker-Homöostase und Thermotoleranz gezeigt werden. In einem zweiten Projekt wurden zwei Arabidopsis thaliana Populationen (Oberursel-0, Populations-ID: 7276; Nieps-0, Populations-ID: 7268) verglichen, welche deutliche Unterschiede in ihrer Fähigkeit der kurzzeitig akquirierten Thermotoleranz aufweisen. Ziel war hierbei die Identifikation etwaiger kausaler Regulatoren oder Mechanismen, welche zu den unterschiedlich ausgeprägten Thermotoleranzen führen. Eine Untersuchung der Transkriptome von 7268 und 7276 konnte zeigen, dass bereits nach 10 Minuten einer 32 °C oder auch 37 °C Hitzebehandlung hunderte von Genen differentiell reguliert sind. Hierbei waren in der hitzetoleranteren Population 7268 mehrere Gene, welche mit dem Schwefel-Metabolismus assoziiert sind, im Vergleich zu 7276 höher exprimiert. Jedoch hatten sowohl die experimentelle Schwefelverfügbarkeit als auch die genetische Manipulation des Schwefelmetabolismus keinen Effekt auf die Thermotoleranz. Neben den Schwefel-assoziierten Genen waren auch die meisten der klassischen Hitzestress-assoziierten Gene in 7268 höher exprimiert als in 7276. Zwar konnte kein kausaler Regulator oder Mechanismus für die unterschiedlichen Thermotoleranzen identifiziert werden, jedoch weisen die generierten Daten auf eine allgemein stärkere Hitzestressantwort oder aber eine höhere Hitzesensitivität von 7268 gegenüber 7276 hin. KW - Schmalwand KW - Hitzestress KW - Stärke KW - Raffinose KW - Genomweite-Assoziationsstudien KW - Genome-wide association studies KW - RNA-Seq KW - Natürliche Variation KW - Natural Variation KW - Trehalose-6-Phosphate Synthase 1 (TPS1) KW - Triacylglycerole Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371324 ER - TY - THES A1 - Schneider, Philipp T1 - Beeinflusst eine Pisotriquetralarthrose das mittel- und langfristige Ergebnis einer mediokarpalen Teilarthrodese des Handgelenks? T1 - Does pisotriquetral arthrosis influence the medium- and long-term outcome of a mediocarpal arthrodesis of the wrist? N2 - Ziel: Die mediokarpale Teilarthrodese (MKTA) des Handgelenks ist eine sehr häufig durchgeführte Rettungsoperation, wenn intolerable Schmerzen aufgrund eines KK ein operatives Vorgehen erforderlich machen. Zahlreiche Studien beschreiben eine deutliche Beschwerdelinderung durch die MKTA, aber keine vollständige Schmerzfreiheit. Die Ursachen hierfür sind vielfältig, unter anderem kommt eine Pisotriquetralarthrose in Be-tracht. Die Entstehung einer solchen wird durch die Handwurzelfehlstellung beim KK begünstigt [8]. In dieser Arbeit wurde der Einfluss einer PT-Arthrose auf das mittel- bis langfristige Ergebnis einer MKTA untersucht. Des Weiteren wurde untersucht, inwie-fern sich eine PT-Arthrose nach einer MKTA entwickeln kann, sofern diese nicht bereits zum Operationszeitpunkt bestand. Methode: Es wurden 48 Personen, die zwischen 2004 und 2016 eine MKTA erhielten und deren Status hinsichtlich einer PT-Arthrose zum OP-Zeitpunkt durch eine Schnitt-bilddiagnostik analysiert werden konnte, in die Studie eingeschlossen. Zum Zeitpunkt der MKTA hatten 25 Patienten eine ausgeprägte PT-Arthrose und 23 Patienten keine PT-Arthrose. Die Patienten wurden durchschnittlich 75 Monate postoperativ klinisch und radiologisch nachuntersucht. Es wurde der Krimmer-Score und der DASH-Score erfasst. Ferner wurden klinische Untersuchungsparameter erhoben sowie die Handkraft und Handgelenksbeweglichkeit gemessen. Arthrose-Zeichen im pisotriquetralen und radiolunären Gelenk wurden durch Röntgenaufnahmen des Handgelenks in zwei Ebe-nen und einer Pisiformen-Zielaufnahme beurteilt. Ergebnis: Es zeigte sich, dass eine PT-Arthrose keinen negativen Einfluss auf das Er-gebnis einer MKTA ausübt. Darüber hinaus entwickelten einige Patienten auch nach einer MKTA eine PT-Arthrose, sodass die veränderte Biomechanik durch die Operation keinen protektiven Faktor hierfür darstellt hat. Als klinischer Test erwies sich der Schmerz am Pisiforme bei passivem Überstrecken des Handgelenks als aussagekräftigs-ter Untersuchungsparameter hinsichtlich des Vorhandenseins einer PT-Arthrose. Diskussion: Selbst bei einer radiologisch nachgewiesenen PT-Arthrose kann ein KK ausschließlich mit einer MKTA behandelt werden. Halten nach einer MKTA ulnopalma-re Beschwerden am Handgelenk an oder treten neu auf, muss ätiologisch eine PT-Arthrose in Erwägung gezogen, abgeklärt und gegebenenfalls behandelt werden. N2 - Four-corner-fusion of the wrist is a very frequently performed rescue operation when intolerable pain due to carpal collapse necessitates a surgical procedure. Numerous studies describe a significant reduction in pain with Four-corner-fusion, but not complete freedom from pain. There are many causes for this, including pisotriquetral arthrosis. In this study, the influence of PT arthrosis on the medium- to long-term outcome of four-corner-fusion was investigated. Furthermore, the extent to which PT osteoarthritis can develop after four-corner-fusion was investigated, provided it did not already exist at the time of surgery. Methods: 48 people who underwent four-corner-fusion between 2004 and 2016 and whose status with regard to PT osteoarthritis at the time of surgery could be analyzed by cross-sectional imaging were included in the study. At the time of four-corner-fusion, 25 patients had severe PT osteoarthritis and 23 patients had no PT osteoarthritis. The patients were followed up clinically and radiologically at an average of 75 months postoperatively. The Krimmer score and the DASH score were recorded. Clinical examination parameters were also recorded and hand strength and wrist mobility were measured. Signs of osteoarthritis in the pisotriquetral and radiolunate joint were assessed by radiographs of the wrist in two planes and a target pisiform radiograph. Result: It was shown that PT osteoarthritis does not have a negative influence on the result of a four-corner-fusion. In addition, some patients also developed PT osteoarthritis after four-corner-fusion, meaning that the altered biomechanics caused by the operation were not a protective factor. As a clinical test, pain at the pisiform during passive hyperextension of the wrist proved to be the most meaningful examination parameter with regard to the presence of PT osteoarthritis. Discussion: Even in the case of radiologically proven PT arthrosis, a carpal collapse can only be treated with a four-corner-fusion. If ulnopalmar wrist symptoms persist or recur after an four-corner-fusion, a PT osteoarthritis must be considered, clarified and treated if necessary. KW - Mediokarpale Teilarthrodese KW - PT-Arthrose KW - karpaler Kollaps KW - Handgelenk KW - MKTA Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-372106 ER - TY - JOUR A1 - Megy, Karyn A1 - Downes, Kate A1 - Morel-Kopp, Marie-Christine A1 - Bastida, José M. A1 - Brooks, Shannon A1 - Bury, Loredana A1 - Leinoe, Eva A1 - Gomez, Keith A1 - Morgan, Neil V. A1 - Othman, Maha A1 - Ouwehand, Willem H. A1 - Perez Botero, Juliana A1 - Rivera, José A1 - Schulze, Harald A1 - Trégouët, David-Alexandre A1 - Freson, Kathleen T1 - GoldVariants, a resource for sharing rare genetic variants detected in bleeding, thrombotic, and platelet disorders: Communication from the ISTH SSC Subcommittee on Genomics in Thrombosis and Hemostasis JF - Journal of Thrombosis and Haemostasis N2 - The implementation of high‐throughput sequencing (HTS) technologies in research and diagnostic laboratories has linked many new genes to rare bleeding, thrombotic, and platelet disorders (BTPD), and revealed multiple genetic variants linked to those disorders, many of them being of uncertain pathogenicity when considering the accepted evidence (variant consequence, frequency in control datasets, number of reported patients, prediction models, and functional assays). The sequencing effort has also resulted in resources for gathering disease‐causing variants associated with specific genes, but for BTPD, such well‐curated databases exist only for a few genes. On the other hand, submissions by individuals or diagnostic laboratories to the variant database ClinVar are hampered by the lack of a submission process tailored to capture the specific features of hemostatic diseases. As we move toward the implementation of HTS in the diagnosis of BTPD, the Scientific and Standardization Committee for Genetics in Thrombosis and Haemostasis has developed and tested a REDCap‐based interface, aimed at the community, to submit curated genetic variants for diagnostic‐grade BTPD genes. Here, we describe the use of the interface and the initial submission of 821 variants from 30 different centers covering 14 countries. This open‐access variant resource will be shared with the community to improve variant classification and regular bulk data transfer to ClinVar. KW - blood KW - genes KW - hemorrhage KW - mutation KW - platelets KW - thrombosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370602 VL - 19 ER - TY - JOUR A1 - Maynard, Stephanie A A1 - Rostaing, Philippe A1 - Schaefer, Natascha A1 - Gemin, Olivier A1 - Candat, Adrien A1 - Dumoulin, Andréa A1 - Villmann, Carmen A1 - Triller, Antoine A1 - Specht, Christian G T1 - Identification of a stereotypic molecular arrangement of endogenous glycine receptors at spinal cord synapses JF - eLife N2 - Precise quantitative information about the molecular architecture of synapses is essential to understanding the functional specificity and downstream signaling processes at specific populations of synapses. Glycine receptors (GlyRs) are the primary fast inhibitory neurotransmitter receptors in the spinal cord and brainstem. These inhibitory glycinergic networks crucially regulate motor and sensory processes. Thus far, the nanoscale organization of GlyRs underlying the different network specificities has not been defined. Here, we have quantitatively characterized the molecular arrangement and ultra-structure of glycinergic synapses in spinal cord tissue using quantitative super-resolution correlative light and electron microscopy. We show that endogenous GlyRs exhibit equal receptor-scaffold occupancy and constant packing densities of about 2000 GlyRs µm-2 at synapses across the spinal cord and throughout adulthood, even though ventral horn synapses have twice the total copy numbers, larger postsynaptic domains, and more convoluted morphologies than dorsal horn synapses. We demonstrate that this stereotypic molecular arrangement is maintained at glycinergic synapses in the oscillator mouse model of the neuromotor disease hyperekplexia despite a decrease in synapse size, indicating that the molecular organization of GlyRs is preserved in this hypomorph. We thus conclude that the morphology and size of inhibitory postsynaptic specializations rather than differences in GlyR packing determine the postsynaptic strength of glycinergic neurotransmission in motor and sensory spinal cord networks. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370504 VL - 10 ER - TY - JOUR A1 - Maulana, Tengku Ibrahim A1 - Kromidas, Elena A1 - Wallstabe, Lars A1 - Cipriano, Madalena A1 - Alb, Miriam A1 - Zaupa, Cécile A1 - Hudecek, Michael A1 - Fogal, Birgit A1 - Loskill, Peter T1 - Immunocompetent cancer-on-chip models to assess immuno-oncology therapy JF - Advanced Drug Delivery Reviews N2 - The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines. KW - tumor-on-chip KW - microphysiological systems KW - immunotherapy KW - in vitro models KW - adoptive cell therapy KW - immune checkpoint inhibitor KW - cytokine therapy KW - oncolytic viruses KW - cancer vaccine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370493 VL - 173 ER - TY - JOUR A1 - Mateos, Maria-Victoria A1 - Dimopoulos, Meletios A. A1 - Cavo, Michele A1 - Suzuki, Kenshi A1 - Knop, Stefan A1 - Doyen, Chantal A1 - Lucio, Paulo A1 - Nagy, Zsolt A1 - Pour, Ludek A1 - Grosicki, Sebastian A1 - Crepaldi, Andre A1 - Liberati, Anna Marina A1 - Campbell, Philip A1 - Yoon, Sung-Soo A1 - Iosava, Genadi A1 - Fujisaki, Tomoaki A1 - Garg, Mamta A1 - Iida, Shinsuke A1 - Bladé, Joan A1 - Ukropec, Jon A1 - Pei, Huiling A1 - Van Rampelbergh, Rian A1 - Kudva, Anupa A1 - Qi, Ming A1 - San-Miguel, Jesus T1 - Daratumumab Plus Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Frailty Subgroup Analysis of ALCYONE JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Background In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status. Patients and Methods Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients. Results Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%). Conclusion Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status. KW - CD38 KW - clinical study KW - efficacy KW - frail KW - monoclonal antibody Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370456 VL - 21 ER - TY - JOUR A1 - Matarranz, Beatriz A1 - Ghosh, Goutam A1 - Kandanelli, Ramesh A1 - Sampedro, Angel A1 - Kartha, Kalathil K. A1 - Fernández, Gustavo T1 - Understanding the role of conjugation length on the self-assembly behaviour of oligophenyleneethynylenes JF - Chemical Communications N2 - Oligophenyleneethynylenes (OPEs) are prominent building blocks with exciting optical and supramolecular properties. However, their generally small spectroscopic changes upon aggregation make the analysis of their self-assembly challenging, especially in the absence of additional hydrogen bonds. Herein, by investigating a series of OPEs of increasing size, we have unravelled the role of the conjugation length on the self-assembly properties of OPEs. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370444 VL - 57 ER - TY - JOUR A1 - Masias, J. A1 - Cerna-Velazco, N. A1 - Jones-Pérez, J. A1 - Porod, W. T1 - Resolving a challenging supersymmetric low-scale seesaw scenario at the ILC JF - Physical Review D N2 - We investigate a scenario inspired by natural supersymmetry, where neutrino data is explained within a low-scale seesaw scenario. For this the minimal supersymmetric Standard Model is extended by adding light right-handed neutrinos and their superpartners, the R-sneutrinos. Moreover, we consider the lightest neutralinos to be Higgsino-like. We first update a previous analysis and assess to which extent does existing LHC data constrain the allowed slepton masses. Here we find scenarios where sleptons with masses as low as 175 GeV are consistent with existing data. However, we also show that the upcoming run will either discover or rule out sleptons with masses of 300 GeV, even for these challenging scenarios. We then take a scenario which is on the borderline of observability of the upcoming LHC run assuming a luminosity of 300 fb(-1). We demonstrate that a prospective international e(+)e(-) linear collider with a center of mass energy of 1 TeV will be able to discover sleptons in scenarios which are difficult for the LHC. Moreover, we also show that a measurement of the spectrum will be possible within 1-3 percent accuracy. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370328 VL - 103 ER - TY - JOUR A1 - Martinez, Simon A1 - Lenz, Jürgen A1 - Schindler, Hans A1 - Wendler, Willi A1 - Rues, Stefan A1 - Schweizerhof, Karl A1 - Terebesi, Sophia A1 - Giannakopoulos, Nikolaos Nikitas A1 - Schmitter, Marc T1 - Clinical Data-Driven Finite Element Analysis of the Kinetics of Chewing Cycles in Order to Optimize Occlusal Reconstructions JF - Computer Modeling in Engineering & Sciences N2 - The occlusal design plays a decisive role in the fabrication of dental restorations. Dentists and dental technicians depend on mechanical simulations of mandibular movement that are as accurate as possible, in particular, to produce interference-free yet chewing-efficient dental restorations. For this, kinetic data must be available, i.e., movements and deformations under the influence of forces and stresses. In the present study, so-called functional data were collected from healthy volunteers to provide consistent information for proper kinetics. For the latter purpose, biting and chewing forces, electrical muscle activity and jaw movements were registered synchronously, and individual magnetic resonance tomograms (MRI) were prepared. The acquired data were then added to a large complex finite element model of the complete masticatory system using the functional information obtained and individual anatomical geometries so that the kinetics of the chewing process and teeth grinding could be realistically simulated. This allows developing algorithms that optimize computer-aided manufacturing of dental prostheses close to occlusion. In this way, a failure-free function of the dental prosthesis can be guaranteed and its damage during usage can be reduced or prevented even including endosseous implants. KW - occlusal design KW - mechanical simulations of mandibular movement KW - finite element model of the complete masticatory system KW - simulation of chewing process and teeth grinding Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370318 VL - 129 ER - TY - JOUR A1 - Maron, Roman C. A1 - Haggenmüller, Sarah A1 - von Kalle, Christof A1 - Utikal, Jochen S. A1 - Meier, Friedegund A1 - Gellrich, Frank F. A1 - Hauschild, Axel A1 - French, Lars E. A1 - Schlaak, Max A1 - Ghoreschi, Kamran A1 - Kutzner, Heinz A1 - Heppt, Markus V. A1 - Haferkamp, Sebastian A1 - Sondermann, Wiebke A1 - Schadendorf, Dirk A1 - Schilling, Bastian A1 - Hekler, Achim A1 - Krieghoff-Henning, Eva A1 - Kather, Jakob N. A1 - Fröhling, Stefan A1 - Lipka, Daniel B. A1 - Brinker, Titus J. T1 - Robustness of convolutional neural networks in recognition of pigmented skin lesions JF - European Journal of Cancer N2 - Background A basic requirement for artificial intelligence (AI)–based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems. Objective To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)–mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing). Methods We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes (‘brittleness’) was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions. Results All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor. Conclusions Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic. KW - artificial intelligence KW - machine learning KW - deep learning KW - neural networks KW - dermatology KW - skin neoplasms KW - melanoma KW - nevus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370245 VL - 145 ER - TY - JOUR A1 - Marcu, Ana A1 - Schlosser, Andreas A1 - Keupp, Anne A1 - Trautwein, Nico A1 - Johann, Pascal A1 - Wölfl, Matthias A1 - Lager, Johanna A1 - Monoranu, Camelia Maria A1 - Walz, Juliane S A1 - Henkel, Lisa M A1 - Krauß, Jürgen A1 - Ebinger, Martin A1 - Schuhmann, Martin A1 - Thomale, Ulrich Wilhelm A1 - Pietsch, Torsten A1 - Klinker, Erdwine A1 - Schlegel, Paul G A1 - Oyen, Florian A1 - Reisner, Yair A1 - Rammensee, Hans-Georg A1 - Eyrich, Matthias T1 - Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors JF - Journal for ImmunoTherapy of Cancer N2 - Background Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS tumors of infancy and early childhood. Hallmark is the surprisingly simple genome with inactivating mutations or deletions in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T cells. However, it is unclear which epitopes T cells might recognize on AT/RT cells. Methods Here, we report a comprehensive mass spectrometry (MS)-based analysis of naturally presented human leukocyte antigen (HLA) class I and class II ligands on 23 AT/RTs. MS data were validated by matching with a human proteome dataset and exclusion of peptides that are part of the human benignome. Cryptic peptide ligands were identified using Peptide-PRISM. Results Comparative HLA ligandome analysis of the HLA ligandome revealed 55 class I and 139 class II tumor-exclusive peptides. No peptide originated from the SMARCB1 region. In addition, 61 HLA class I tumor-exclusive peptide sequences derived from non-canonically translated proteins. Combination of peptides from natural and cryptic class I and class II origin gave optimal representation of tumor cell compartments. Substantial overlap existed with the cryptic immunopeptidome of glioblastomas, but no concordance was found with extracranial tumors. More than 80% of AT/RT exclusive peptides were able to successfully prime CD8+ T cells, whereas naturally occurring memory responses in AT/RT patients could only be detected for class II epitopes. Interestingly, >50% of AT/RT exclusive class II ligands were also recognized by T cells from glioblastoma patients but not from healthy donors. Conclusions These findings highlight that AT/RTs, potentially paradigmatic for other pediatric tumors with a low mutational load, present a variety of highly immunogenic HLA class I and class II peptides from canonical as well as non-canonical protein sources. Inclusion of such cryptic peptides into therapeutic vaccines would enable an optimized mapping of the tumor cell surface, thereby reducing the likelihood of immune evasion. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370214 VL - 9 ER - TY - JOUR A1 - Marcu, Ana A1 - Bichmann, Leon A1 - Kuchenbecker, Leon A1 - Kowalewski, Daniel Johannes A1 - Freudenmann, Lena Katharina A1 - Backert, Linus A1 - Mühlenbruch, Lena A1 - Szolek, András A1 - Lübke, Maren A1 - Wagner, Philipp A1 - Engler, Tobias A1 - Matovina, Sabine A1 - Wang, Jian A1 - Hauri-Hohl, Mathias A1 - Martin, Roland A1 - Kapolou, Konstantina A1 - Walz, Juliane Sarah A1 - Velz, Julia A1 - Moch, Holger A1 - Regli, Luca A1 - Silginer, Manuela A1 - Weller, Michael A1 - Löffler, Markus W. A1 - Erhard, Florian A1 - Schlosser, Andreas A1 - Kohlbacher, Oliver A1 - Stevanović, Stefan A1 - Rammensee, Hans-Georg A1 - Neidert, Marian Christoph T1 - HLA Ligand Atlas: a benign reference of HLA-presented peptides to improve T-cell-based cancer immunotherapy JF - Journal for ImmunoTherapy of Cancer N2 - Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org . Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370160 VL - 9 ER - TY - JOUR A1 - Mannucci, Ilaria A1 - Dang, Nghi D. P. A1 - Huber, Hannes A1 - Murry, Jaclyn B. A1 - Abramson, Jeff A1 - Althoff, Thorsten A1 - Banka, Siddharth A1 - Baynam, Gareth A1 - Bearden, David A1 - Beleza-Meireles, Ana A1 - Benke, Paul J. A1 - Berland, Siren A1 - Bierhals, Tatjana A1 - Bilan, Frederic A1 - Bindoff, Laurence A. A1 - Braathen, Geir Julius A1 - Busk, Øyvind L. A1 - Chenbhanich, Jirat A1 - Denecke, Jonas A1 - Escobar, Luis F. A1 - Estes, Caroline A1 - Fleischer, Julie A1 - Groepper, Daniel A1 - Haaxma, Charlotte A. A1 - Hempel, Maja A1 - Holler-Managan, Yolanda A1 - Houge, Gunnar A1 - Jackson, Adam A1 - Kellogg, Laura A1 - Keren, Boris A1 - Kiraly-Borri, Catherine A1 - Kraus, Cornelia A1 - Kubisch, Christian A1 - Le Guyader, Gwenael A1 - Ljungblad, Ulf W. A1 - Brenman, Leslie Manace A1 - Martinez-Agosto, Julian A. A1 - Might, Matthew A1 - Miller, David T. A1 - Minks, Kelly Q. A1 - Moghaddam, Billur A1 - Nava, Caroline A1 - Nelson, Stanley F. A1 - Parant, John M. A1 - Prescott, Trine A1 - Rajabi, Farrah A1 - Randrianaivo, Hanitra A1 - Reiter, Simone F. A1 - Schuurs-Hoeijmakers, Janneke A1 - Shieh, Perry B. A1 - Slavotinek, Anne A1 - Smithson, Sarah A1 - Stegmann, Alexander P. A. A1 - Tomczak, Kinga A1 - Tveten, Kristian A1 - Wang, Jun A1 - Whitlock, Jordan H. A1 - Zweier, Christiane A1 - McWalter, Kirsty A1 - Juusola, Jane A1 - Quintero-Rivera, Fabiola A1 - Fischer, Utz A1 - Yeo, Nan Cher A1 - Kreienkamp, Hans-Jürgen A1 - Lessel, Davor T1 - Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders JF - Genome Medicine N2 - Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306477 VL - 13 ER - TY - JOUR A1 - Maksimova, Varvara A1 - Shalginskikh, Natalya A1 - Vlasova, Olga A1 - Usalka, Olga A1 - Beizer, Anastasia A1 - Bugaeva, Polina A1 - Fedorov, Dmitry A1 - Lizogub, Olga A1 - Lesovaya, Ekaterina A1 - Katz, Richard A1 - Belitsky, Gennady A1 - Kirsanov, Kirill A1 - Yakubovskaya, Marianna T1 - HeLa TI cell-based assay as a new approach to screen for chemicals able to reactivate the expression of epigenetically silenced genes JF - PLoS ONE N2 - Chemicals reactivating epigenetically silenced genes target diverse classes of enzymes, including DNMTs, HDACs, HMTs and BET protein family members. They can strongly influence the expression of genes and endogenous retroviral elements with concomitant dsRNA synthesis and massive transcription of LTRs. Chemicals reactivating gene expression may cause both beneficial effects in cancer cells and may be hazardous by promoting carcinogenesis. Among chemicals used in medicine and commerce, only a small fraction has been studied with respect to their influence on epigenetic silencing. Screening of chemicals reactivating silent genes requires adequate systems mimicking whole-genome processes. We used a HeLa TSA-inducible cell population (HeLa TI cells) obtained by retroviral infection of a GFP-containing vector followed by several rounds of cell sorting for screening purposes. Previously, the details of GFP epigenetic silencing in HeLa TI cells were thoroughly described. Herein, we show that the epigenetically repressed gene GFP is reactivated by 15 agents, including HDAC inhibitors–vorinostat, sodium butyrate, valproic acid, depsipeptide, pomiferin, and entinostat; DNMT inhibitors–decitabine, 5-azacytidine, RG108; HMT inhibitors–UNC0638, BIX01294, DZNep; a chromatin remodeler–curaxin CBL0137; and BET inhibitors–JQ-1 and JQ-35. We demonstrate that combinations of epigenetic modulators caused a significant increase in cell number with reactivated GFP compared to the individual effects of each agent. HeLa TI cells are competent to metabolize xenobiotics and possess constitutively expressed and inducible cytochrome P450 mono-oxygenases involved in xenobiotic biotransformation. Thus, HeLa TI cells may be used as an adequate test system for the extensive screening of chemicals, including those that must be metabolically activated. Studying the additional metabolic activation of xenobiotics, we surprisingly found that the rat liver S9 fraction, which has been widely used for xenobiotic activation in genotoxicity tests, reactivated epigenetically silenced genes. Applying the HeLa TI system, we show that N-nitrosodiphenylamine and N-nitrosodimethylamine reactivate epigenetically silenced genes, probably by affecting DNA methylation. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370152 VL - 16 ER - TY - JOUR A1 - Maistrenko, Oleksii A1 - Scharf, Benedikt A1 - Manske, Dirk A1 - Hankiewicz, Ewelina M. T1 - Planar Josephson Hall effect in topological Josephson junctions JF - Physical Review B N2 - Josephson junctions based on three-dimensional topological insulators offer intriguing possibilities to realize unconventional 𝑝-wave pairing and Majorana modes. Here, we provide a detailed study of the effect of a uniform magnetization in the normal region: We show how the interplay between the spin-momentum locking of the topological insulator and an in-plane magnetization parallel to the direction of phase bias leads to an asymmetry of the Andreev spectrum with respect to transverse momenta. If sufficiently large, this asymmetry induces a transition from a regime of gapless, counterpropagating Majorana modes to a regime with unprotected modes that are unidirectional at small transverse momenta. Intriguingly, the magnetization-induced asymmetry of the Andreev spectrum also gives rise to a Josephson Hall effect, that is, the appearance of a transverse Josephson current. The amplitude and current phase relation of the Josephson Hall current are studied in detail. In particular, we show how magnetic control and gating of the normal region can enable sizable Josephson Hall currents compared to the longitudinal Josephson current. Finally, we also propose in-plane magnetic fields as an alternative to the magnetization in the normal region and discuss how the planar Josephson Hall effect could be observed in experiments. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370139 VL - 103 ER - TY - JOUR A1 - Maina, Ezio A1 - Pelliccioli, Giovanni T1 - Polarized Z bosons from the decay of a Higgs boson produced in association with two jets at the LHC JF - The European Physical Journal C N2 - Investigating the polarization of weak bosons provides an important probe of the scalar and gauge sector of the Standard Model. This can be done in the Higgs decay to four leptons, whose Standard-Model leading-order amplitude enables to generate polarized observables from unpolarized ones via a fully-differential reweighting method. We study the Z-boson polarization from the decay of a Higgs boson produced in association with two jets, both in the gluon-fusion and in the vector-boson fusion channel. We also address the possibility of extending the results of this work to higher orders in perturbation theory. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370126 VL - 81 ER - TY - JOUR A1 - Maier, Gerrit S. A1 - Weissenberger, Manuel A1 - Rudert, Maximilian A1 - Roth, Klaus E. A1 - Horas, Konstantin T1 - The role of vitamin D and vitamin D deficiency in orthopaedics and traumatology—a narrative overview of the literature JF - Annals of Translational Medicine N2 - Vitamin D is considered to play an important role in musculoskeletal health. It’s classical function is the regulation of calcium and phosphate homeostasis, thus ensuring a balanced bone metabolism that is characterised by an equal amount of bone resorption and bone formation. In the past decades, a plethora of pre-clinical and clinical studies reporting on potential health-beneficial properties of vitamin D have emerged. Moreover, there is an abundance of reports highlighting vitamin D deficiency and insufficiency in patients with almost innumerable diseases. Further, it is estimated that more than one billion people globally are affected by insufficient vitamin D levels. As such, research on vitamin D has been particularly popular over the past years. In orthopaedics and traumatology, most studies describe favourable effects of vitamin D in general. However, the relative importance of vitamin D is oftentimes debated. In this narrative review of the literature, we consider first, the properties of vitamin D and how vitamin D, vitamin D deficiency and the vitamin D receptor (VDR) impact on musculoskeletal health. Secondly, we provide an overview of studies reporting the prevalence of vitamin D deficiency in traumatology and diverse orthopaedic diseases including bone oncology. Lastly, we emphasise recent findings and touch on future perspectives in vitamin D research. KW - vitamin D KW - vitamin D deficiency (VDR) KW - orthopaedics KW - orthopedics KW - traumatology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370110 VL - 9 ER - TY - JOUR A1 - Magunia, Harry A1 - Lederer, Simone A1 - Verbuecheln, Raphael A1 - Gilot, Bryant Joseph A1 - Koeppen, Michael A1 - Haeberle, Helene A. A1 - Mirakaj, Valbona A1 - Hofmann, Pascal A1 - Marx, Gernot A1 - Bickenbach, Johannes A1 - Nohe, Boris A1 - Lay, Michael A1 - Spies, Claudia A1 - Edel, Andreas A1 - Schiefenhövel, Fridtjof A1 - Rahmel, Tim A1 - Putensen, Christian A1 - Sellmann, Timur A1 - Koch, Thea A1 - Brandenburger, Timo A1 - Kindgen-Milles, Detlef A1 - Brenner, Thorsten A1 - Berger, Marc A1 - Zacharowski, Kai A1 - Adam, Elisabeth A1 - Posch, Matthias A1 - Moerer, Onnen A1 - Scheer, Christian S. A1 - Sedding, Daniel A1 - Weigand, Markus A. A1 - Fichtner, Falk A1 - Nau, Carla A1 - Prätsch, Florian A1 - Wiesmann, Thomas A1 - Koch, Christian A1 - Schneider, Gerhard A1 - Lahmer, Tobias A1 - Straub, Andreas A1 - Meiser, Andreas A1 - Weiss, Manfred A1 - Jungwirth, Bettina A1 - Wappler, Frank A1 - Meybohm, Patrick A1 - Herrmann, Johannes A1 - Malek, Nisar A1 - Kohlbacher, Oliver A1 - Biergans, Stephanie A1 - Rosenberger, Peter T1 - Machine learning identifies ICU outcome predictors in a multicenter COVID-19 cohort JF - Critical Care N2 - Background Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes. Methods A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results 1039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models. Trial registration “ClinicalTrials” (clinicaltrials.gov) under NCT04455451. KW - COVID-19 KW - critical care KW - ARDS KW - outcome KW - prognostic models Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306766 VL - 25 ER - TY - THES A1 - Weigel, Sandra Carina T1 - Zum besseren Verständnis von Evaluationen verschiedener Lehrformate: Wie Charisma der Dozierenden und studentische Technikaffinität die Wahrnehmung didaktischer Qualität beeinflussen T1 - For a better understanding of evaluations of different teaching formats: How teacher charisma and student digital affinity influence the perception of didactic quality N2 - Seit Beginn des neuen Jahrtausends haben Tablets in der medizinischen Lehre zunehmend an Bedeutung gewonnen. In dieser Studie wurden ein Tablet-basiertes und ein Dozierenden-zentriertes Lehrformat im Rahmen eines Radiologie-Seminars verglichen. Ziel war es, vergleichende Erkenntnisse über selbsteingeschätzten und objektiven Lernzuwachs und empfundene didaktische Qualität zu erlangen und mögliche Einflüsse des Charismas der Dozierenden sowie der studentischen Technikaffinität auf diese Variablen zu untersuchen. Von n=366 Studierenden wurden über drei Semester hinweg Daten zu studentischer Technikaffinität generell sowie didaktischer Qualität und Zufriedenheit mit den Seminaren abhängig vom Lehrformat erhoben. Im letzten Studiensemester nahmen die Studierenden zudem eine Selbsteinschätzung ihres Lernzuwachses vor und legten ein Wissens- und Bildinterpretationstestat sowie eine Einschätzung des Charismas der Dozierenden ab. Mittels Maximum-Likelihood Faktorenanalyse erfolgte eine Strukturaufklärung der didaktischen Qualität und des Charismas. Pearson-Korrelationskoeffizienten wurden zur Untersuchung möglicher Korrelationen zwischen den Variablen berechnet. Ein Strukturregressionsmodell des Charismas der Dozierenden, der studentischen Technikaffinität und der didaktischen Qualität wurde erstellt und daraus eine lineare Regressionsgleichung abgeleitet. Dem Tablet-basierten Lehrformat wurden signifikant höhere Werte in didaktischer Qualität und studentischer Zufriedenheit zugeschrieben. Das Dozierenden-zentrierte Format schnitt hingegen in selbsteingeschätztem und objektivem Lernzuwachs signifikant besser ab. Ausschließlich im Tablet-basierten Unterricht korrelierte das Charisma der Dozierenden mit dem selbsteingeschätzten Lernzuwachs. Die studentische Technikaffinität wirkte sich in diesem Format stärker auf die didaktische Qualität aus. Zudem wurden gute Organisation, eindeutige Lernziele und adäquate Lernformvariation als bedeutsame Faktoren identifiziert. Diese Studie hebt die Relevanz des dozentischen Charismas und der studentischen Technikaffinität für die Sicherstellung hoher didaktischer Qualität in Tablet-basiertem Unterricht hervor. Sie zeigt zudem die Wichtigkeit der Kongruenz von Lernzielen, Lehrkonzept und Prüfungsmethode dieses Lehrformats auf, um hohe Studienleistungen sicherzustellen. Die untersuchten Faktoren sollten bei Entwurf digitaler Lehrkonzepte über spezifische Messinstrumente objektiviert und bei Bedarf geschult oder angepasst werden, um eine erfolgreiche Integration digitaler Medien in die medizinische Lehre zu gewährleisten. N2 - Since the beginning of the new millennium, tablets have become increasingly important in medical teaching. In this study, a tablet-based and a teacher-centred teaching format were compared in the context of a radiology seminar. The aim was to gain comparative insights into estimated and objective learning gain and perceived didactic quality, and to investigate possible influences of teacher charisma and student digital affinity on these variables. Data on student digital affinity in general as well as didactic quality and satisfaction with the seminars depending on the teaching format were collected from n=366 students over three semesters. In the last semester, students also estimated their learning gain, completed a knowledge and image interpretation test and rated teacher charisma. Maximum likelihood factor analysis was used to provide a structural elucidation of didactic quality and charisma. Pearson correlation coefficients were calculated to investigate possible correlations between the variables. A structural regression model of teacher charisma, student digital affinity, and didactic quality was constructed and a linear regression equation was derived. The tablet-based teaching format was attributed significantly higher values in didactic quality and student satisfaction. The teacher-centred format, on the other hand, performed significantly better in estimated and objective learning gain. Only in tablet-based teaching did teacher charisma correlate with estimated learning gain. Student digital affinity had a stronger effect on didactic quality in this format. In addition, good organization, clear learning objectives, and adequate variation of learning activities were identified as important factors. This study highlights the relevance of teacher charisma and student digital affinity in ensuring high didactic quality in tablet-based teaching. It also shows the importance of congruence of learning objectives, teaching concept, and assessment method of this teaching format to ensure high academic performance. The factors examined should be objectified via specific measuring instruments when designing digital teaching concepts and trained or adapted as necessary to ensure successful integration of digital media in medical teaching. KW - Didaktik KW - Charisma KW - Tablet PC KW - Lehre KW - Technikaffinität KW - Tablet Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371565 ER - TY - THES A1 - Müller, Lisa T1 - Der Reformbedarf des Stammzellgesetzes : eine sowohl retrospektive als auch prospektive Untersuchung unter besonderer Berücksichtigung der Stichtagsregelung T1 - The need for reform of the Stem Cell Act: a retrospective and prospective investigation with particular attention to the cut-off date rule N2 - Die vorliegende Dissertation beleuchtet den bestehenden Reformbedarf des Stammzellgesetzes, wobei überdies eine Auseinandersetzung mit der bereits 2008 erfolgten Reform vorgenommen wird. N2 - This paper deals with the existing regulations of the current Stem Cell Act. It also examines the previous version of the Stem Cell Act, before the deadline was postponed, as well as the necessity of postponing the deadline again and the need for further amendments to the Stem Cell Act. KW - Reformbedarf KW - Stammzellgesetz Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371416 ER - TY - THES A1 - Seth, Celina Marcella T1 - Erfassung und Bewertung der Immunzell-Dynamik ausgehend vom Transkriptom der Milz T1 - Recording and evaluation of immune cell dynamics based on the spleen transcriptome N2 - Erfassung und Bewertung der Immunzell-Dynamik ausgehend vom Transkriptom der Milz, Dissertation zum Vergleich von DCQ-Vorhersagen einzelner Immunzellpopulationen während akuter und chronischer LCMV-Infektionen mit experimentellen Daten. N2 - The outcome of viral infections is determined by a complex interaction between the spreading virus and the host's immune response. In order to understand this interaction in detail, acute and chronic infections were generated in previous experiments in the mouse model with the lymphocytic choriomeningitis virus and the transcriptomes of the entire spleen were determined in chronological order. This experimental approach results in the loss of information about the cells that produce the identified transcripts. This cell information can be recovered using special analysis programmes such as DCQ. However, it must then be confirmed using experimental methods. The aim of my work was to experimentally validate the prediction of individual immune cell populations. To this end, spleens were removed from LCMV-infected mice, the spleen cells were isolated and characterised by means of specific surface proteins using flow cytometry. I was thus able to partially validate the DCQ predictions of different immune cells and immune cell subtypes such as CD8+ T cells, CD103+ DCs, neutrophils, regulatory CD4+/ FOXP3+ T cells, NK cells and monocytes. These results made it possible to correlate the dynamics of the different cell types with immunological processes. The results were included in a previously published paper (Pedragosa et al., 2019). KW - Infektion KW - Transkriptom KW - Milz KW - LCMV Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371294 ER - TY - THES A1 - Köhler, Jonas T1 - Predicting Future Snow Line Elevation Dynamics in the Alps - The Potential of Long Earth Observation Time Series T1 - Prognose zukünftiger Schneeliniendynamiken in den Alpen - Das Potential langer Zeitreihen aus Erdbeobachtungsdaten N2 - The seasonal snow cover in the European Alps plays a crucial role in the region's climate, ecology, and economy. It affects the local climate through its high albedo, protects permafrost, provides habitats, and acts as a water reservoir that feeds European rivers. However, these functions are threatened by climate change. Analyzing snow cover dynamics is essential to predict future developments and assess related ecological and economic impacts. This study explores the potential of long Earth Observation (EO) time series for modeling and predicting the snow line elevation (SLE) in the Alps. Based on approximately 15,000 Landsat satellite images, SLE time series were generated for the years 1985 to 2022. Various univariate forecasting models were evaluated, with the best results achieved by Random Forests, Telescope, and Seasonal ARIMA. A newly developed approach combines the best models into a robust ensemble, achieving an average Nash-Sutcliffe efficiency (NSE) of 0.8 in catchments with strong seasonal signals. Forecasts for 2030 indicate significant upward shifts in the SLE, particularly in the Western and Southern Alps. Given the variability in results, a multivariate modeling approach using climate variables is recommended to improve prediction accuracy. This study lays the groundwork for future models that could potentially project SLE dynamics through the end of the 21st century under various climate scenarios, which is highly relevant for climate policy in the Alpine region. N2 - Die saisonale Schneedecke in den europäischen Alpen spielt eine zentrale Rolle für das Klima, die Ökologie und die Wirtschaft der Region. Sie beeinflusst das lokale Klima durch ihre Albedo, beeinflusst den Permafrost, bildet Lebensräume und fungiert als Wasserspeicher, der große europäische Flüsse speist. Diese Funktionen sind jedoch durch den Klimawandel bedroht. Um zukünftige Entwicklungen der Schneedecke vorherzusagen und die damit verbundenen ökologischen und wirtschaftlichen Auswirkungen abzuschätzen, ist die Analyse vergangener und Prognose zukünftiger Schneedeckendynamiken essenziell. Diese Arbeit untersucht das Potenzial langer Zeitreihen aus der Satellitenfernerkundung (Earth Observation, EO) zur Modellierung und Vorhersage der Schneelinienhöhe (SLE) in den Alpen. Auf Basis von etwa 15.000 Landsat-Satellitenbildern wurden SLE-Zeitreihen für die Jahre 1985 bis 2022 erstellt. Verschiedene univariate Prognosemodelle wurden evaluiert, wobei die besten Ergebnisse mit Random Forests, Telescope und Seasonal ARIMA erzielt wurden. Ein neu entwickelter Ansatz kombiniert die besten Modelle zu einer Ensemble-Prognose und erreicht einen mittleren Nash-Sutcliffe-Effizienz-Wert (NSE) von 0,8 in Einzugsgebieten mit starkem saisonalem Signal. Die Prognosen bis 2030 zeigen signifikante Verschiebungen der SLE in höhere Lagen, besonders in den West- und Südalpen. Angesichts der Varianz in den Ergebnissen wird eine multivariate Modellierung mit Klimavariablen vorgeschlagen, um die Vorhersagegenauigkeit zu verbessern. Diese Ergebnisse legen den Grundstein für zukünftige Ansätze, die SLE-Dynamiken bis zum Ende des 21. Jahrhunderts unter verschiedenen Klimaszenarien auf Basis von EO-Daten projizieren können, was für die Klimapolitik im Alpenraum potenziell von hoher Relevanz ist. KW - Fernerkundung KW - Schnee KW - Prognose KW - Zeitreihe KW - Alps KW - remote sensing KW - snow KW - prediction KW - time series KW - Alpen Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371392 ER - TY - THES A1 - Scholl, Lena T1 - Die Rolle des Typ-I-Rezeptors ALK1 in BMP-vermittelter Signaltransduktion T1 - The role of the type I receptor ALK1 in BMP-mediated signal transduction N2 - Im experimentellen Ansatz sollte mithilfe der CRISPR-Cas9-Methode eine gerichtete ALK1-Rezeptor-Eliminierung in myoblastischen C2C12-Zellen durchgeführt werden. Nach erfolgreicher Klonierung der jeweiligen, für den Typ-I-Rezeptor ALK1-kodierenden, gRNA-Sequenzen in die Puro- und GFP-CRISPR-Plasmide gelang der mittels Lipofektion durchgeführte Transfer der vier klonierten Plasmide in die C2C12-Zellen. Parallel aufgetaut wurden C2C12*ALK2- sowie ALK3-Knockout-Zelllinien, welche zuvor durch die Masterandin L. Wiesmann, ebenfalls mithilfe der CRISPR-Cas9-Methode, induzierte Knockouts der jeweiligen Rezeptoren ALK2 sowie ALK3 enthielten. Anschließend erfolgte die Puromycin-Selektion der mit den Puro-Klonen transfizierten C2C12*ALK1-3, ALK1-4-, ALK2- sowie ALK3-KO-Zellpopulationen. Die Zellen der C2C12*ALK1-3-KO-Population überlebten die Selektion trotz erneuter Durchführung der Transfektion sowie Selektion nicht. Somit erfolgte die Kultivierung der verbliebenen Zellen der C2C12*ALK1 4-, C2C12*ALK2- sowie C2C12*ALK3-KO-Population. Anschließend galt es zu untersuchen, wie responsiv die einzelne KO-Zelle für verschiedene Liganden ist. Im Rahmen der Durchführung differenter, zellbasierter Versuche wie der qPCR, des Western Blots und des ALP-Assays wirkten verschiedene BMPs auf die KO-Populationen ein. Somit konnten die BMP-induzierten, nachfolgenden Ereignisse wie die mRNA-Expression, die SMAD-Phosphorylierung sowie die Induktion der ALP-Expression innerhalb der KO-Populationen genauer betrachtet werden. Es ist allgemein bekannt, dass ALK1 sowohl bei der Angiogenese als auch bei der kardio-vaskulären Homöostase eine wichtige Rolle übernimmt. ALK1 ist vermutlich für die Gefäßneubildung in manchen Tumoren verantwortlich und auch die vaskuläre Erkrankung „Hereditäre hämorrhagische Teleangiektasie (HHT)“ steht im Zusammenhang mit einer Mutation des ALK1-Rezeptorgens. BMP9 beeinflusst als ALK1-bindender Ligand neben der Tumorentwicklung und der Angiogenese auch die osteogene Differenzierung mesenchymaler Stammzellen. Im Hinblick auf zukünftige Versuche sind daher weitere, noch aussagekräftigere Ergebnisse erstrebenswert, allerdings unter der Verwendung von ausschließlich homozygoten KO-Zelllinien. Weitere Erkenntnisse über die Rolle des ALK1-Rezeptors in BMP-vermittelter Signaltransduktion könnten für therapeutische Ansätze bei der Behandlung von vaskulären Erkrankungen und Tumorprogression sowie bei der Förderung der Knochenregeneration und -heilung hilfreich sein. N2 - In the experimental approach, targeted ALK1 receptor elimination was to be performed in myoblastic C2C12 cells using the CRISPR-Cas9 method. After successful cloning of the respective gRNA sequences coding for the type I receptor ALK1 into the Puro and GFP-CRISPR plasmids, the four cloned plasmids were transferred into the C2C12 cells by lipofection. In parallel, C2C12*ALK2 and ALK3 knockout cell lines were thawed, which previously contained knockouts of the respective ALK2 and ALK3 receptors induced by the master student L. Wiesmann, also using the CRISPR-Cas9 method. Puromycin was then used to select the C2C12*ALK1-3, ALK1-4, ALK2 and ALK3-KO cell populations transfected with the Puro clones. The cells of the C2C12*ALK1-3-KO population did not survive the selection despite renewed transfection and selection. The remaining cells of the C2C12*ALK1-4, C2C12*ALK2 and C2C12*ALK3-KO populations were therefore cultivated. It was then necessary to investigate how responsive the individual KO cells are to different ligands. By performing different cell-based experiments such as qPCR, Western blot and ALP assay, different BMPs affected the KO populations. Thus, the BMP-induced downstream events such as mRNA expression, SMAD phosphorylation and induction of ALP expression within the KO populations could be analysed precisely. KW - Activin receptor-like kinase 1 (ALK1) KW - CRISPR/Cas-Methode KW - Genome Editing KW - Knochen-Morphogenese-Proteine KW - Bone morphogenetic proteins (BMP9) Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371945 ER - TY - THES A1 - Valta-Seufzer, David T1 - Prognostischer und prädiktiver Wert von CA 19-9 nach Induktionschemotherapie beim lokal fortgeschrittenem Pankreaskarzinom: Ergebnisse einer prospektiven, multizentrischen Phase-2-Studie (NEOLAP-AIO-PAK-0113) T1 - Prognostic and predictive value of CA 19-9 after induction chemotherapy for locally advanced pancreatic cancer: results of a prospective, multicenter phase 2 study (NEOLAP-AIO-PAK-0113) N2 - Zusammenfassend lässt sich sagen, dass diese prospektive Studie sowohl den prognostischen als auch den prädiktiven Nutzen eines Tumormarker-Abfalls von CA19- 9 auf eine Induktionschemotherapie bei Patienten mit LAPC bestätigt. Nicht die Ausgangswerte des Tumormarkers vor Therapie sollten zur Planung des weiteren Vorgehens herangezogen werden, sondern die Werte nach Abschluss der Induktionschemotherapie bzw. der Abfall unter der Induktionschemotherapie. Das biochemische Ansprechen von CA19-9 ist ein bedeutender Indikator für den Behandlungserfolg und verbessert die diagnostische Genauigkeit bei der Auswahl von Patienten für eine chirurgische Exploration. Sowohl die Betrachtung des biochemischen Ansprechens allein als auch in Kombination mit dem radiologischen Ansprechen verbessert Sensitivität und Spezifität hinsichtlich einer möglichen R0-Resektion. Kombiniert man bei Patienten mit einer SD in Woche 16 ein gutes biochemisches Ansprechen (Rückgang von CA19-9 > 55%), so wird eine Sensitivität von 100% hinsichtlich der möglichen R0-Resektion erreicht. Zur Abschätzung des Gesamtüberlebens von Patienten mit LAPC sollten dagegen eher die absoluten Werte von CA19-9 nach Induktionschemotherapie verwendet werden und nicht der relative Rückgang des Markers. So zeigen Patienten, welche in Woche 16 einen CA19-9 Wert < 50 U/ml aufweisen mit 27,8 Monaten das beste mediane Gesamtüberleben. N2 - In summary, this prospective study confirms both the prognostic and predictive benefit of a tumor marker decrease in CA19-9 on induction chemotherapy for patients with LAPC. It is not the initial values of the tumor marker before therapy that should be used to plan the next steps, but the values after completion of induction chemotherapy or the drop during induction chemotherapy. The biochemical response of CA19-9 is an important indicator of treatment success and improves diagnostic accuracy when selecting patients for surgical exploration. Both the consideration of biochemical response alone and in combination with radiologic response improves sensitivity and specificity with regard to a possible R0 resection. If a good biochemical response (decrease in CA19-9 > 55%) is combined in patients with SD at week 16, a sensitivity of 100% with regard to possible R0 resection is achieved. In contrast, the absolute values of CA19-9 after induction chemotherapy rather than the relative decline of the marker should be used to estimate the overall survival of patients with LAPC. Patients with a CA19-9 value < 50 U/ml at week 16 show the best median overall survival of 27.8 months. KW - Bauchspeicheldrüsenkrebs KW - Tumorantigen CA 19-9 KW - Pankreaskarzinom KW - Induktionstherapie KW - Induktionschemotherapie KW - neoadjuvante Therapie KW - CA19-9 Tumormarker Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371996 ER - TY - THES A1 - Weber, Paula Martika T1 - Spinstrukturen in Manganoberflächen auf bcc- und fcc-Einkristallen aus 5d-Elementen, untersucht mittels spinpolarisierter Rastertunnelmikroskopie: Mn-W(001) und MnO\(_x\)-Ir(001) T1 - Spin structures in manganese surfaces on bcc and fcc single-crystals of 5d elements studied by spinpolarised scanning tunneling microscopy: Mn-W(001) and MnO\(_x\)-Ir(001) N2 - Die Entstehung kollinearer und nicht-kollinearer Spinstrukturen wird auf verschiedene magnetische Wechselwirkungen zurückgeführt. Für Anwendungen in der Medizin und in der Datenspeicherung ist es notwendig zu verstehen, unter welchen Parametern Frustrationen auftreten, um diese entweder zu vermeiden oder zu nutzen. In dieser Arbeit werden kollineare und nicht-kollineare Spinstrukturen auf zwei verschiedenen Materialsystemen untersucht. Das erste Materialsystem besteht aus drei atomaren Lagen Mangan auf einer (001) Oberfläche eines Wolfram-Einkristalls und das zweite Materialsystem enthält Mangan, welches verbunden mit Sauerstoff kettenförmig auf einer (001) Oberfläche eines Iridium-Einkristalls vorliegt. Spinpolarisierte Rastertunnelmikroskopie (SP-RTM)-Messungen und -Simulationen der dreilagigen, pseudomorphen Manganoberfläche ergeben eine nicht-kollineare Spinstruktur. Dichtefunktionaltheorie (DFT)-Berechnungen legen eine kollineare ↑↓↓- Spinkonstellation nahe. Unter Berücksichtigung der chiralen biquadratischen Paarwechselwirkung befinden sich konische Spinspiralen mit kleinem Öffnungswinkel nah an dem energetisch niedrigsten Zustand. Spinaufgelöste DFT-Berechnungen sind abhängig von der genäherten, geometrischen Relaxation der atomaren Struktur. Kombinierte SP-RTM-Methoden weisen auf einem dreilagigen Materialsystem Spinspiralen nach und zufolge der DFT ist der kollineare bzw. nicht-kollineare Zustand des Systems durch den Abstand seiner Lagen bedingt. SP-RTM-Messungen auf den Manganoxidketten weisen je nach Präparation eine kollineare antiferromagnetische (AFM) oder eine nicht-kollineare Spinstruktur nach. Zudem wird präsentiert, dass sich diese Spinstrukturen durch zwei verschiedene Sauerstoffdrücke und die Zufuhr von Wärme während der Präparation ineinander umschalten lassen. Durch niederenergetische Elektronenbeugung mit variabler Spannung werden zwei atomare Strukturen bestimmt, welche sich durch ihren Oxidationsgrad unterscheiden. Die nicht-kollineare Spinstruktur ist bereits in der Fachliteratur als 120° chirale Spinspirale, verursacht durch die Dzyaloshinskii-Moriya-verstärkte Ruderman-Kittel-Kasuya-Yosida (RKKY)-Wechselwirkung, bekannt. Nach aktuellen, kollinearen DFT-Berechnungen ist die kollineare Spinstruktur als AFM entlang der Ketten und als ferromagnetische Kopplung zwischen den Ketten ermittelt. Aufgrund des Nachweises eines höheren Oxidationsgrades wird eine stärkere RKKY-Austauschwechselwirkung auf der Basis der Heisenberg-Austauschwechselwirkung vermutet. Hier korreliert die Entstehung kollinearer oder nicht-kollinearer Spinstrukturen mit dem Oxidationsgrad. N2 - The formation of collinear and non-collinear spin structures is attributed to various magnetic interactions. For applications in medicine and data storage, it is necessary to understand under which parameters frustrations form in order to either avoid or use them. In this work, collinear and non-collinear spin structures on two different material systems are investigated. The first material system is composed of three atomic layers of manganese on a (001) surface of a tungsten single crystal and the second material system contains manganese combined with oxygen in a chain on a (001) surface of an iridium single crystal. Spin polarised scanning tunnelling microscopy (SP-STM) measurements and simulations of the three-layer pseudomorphic surface of manganese reveal a non-collinear spin structure. Density functional theory (DFT) calculations suggest a collinear ↑↓↓ spin constellation. Considering the chiral biquadratic pair interaction, conical spin spirals with a small opening angle are close to the energetically lowest state. Spin-resolved DFT calculations show a dependence on the approximated geometric relaxation of the atomic structure. Combined SP-RTM methods identify spin spirals on a three-layer material system and, according to DFT, the collinear or non-collinear state of the system depends on the spacing of its layers. Depending on the preparation, a collinear antiferromagnetic (AFM) or a non-collinear spin structure is revealed on the manganese oxide chains using SP-STM. Furthermore, it is presented that these spin structures can be switched into each other during the preparation by two different oxygen pressures and the supply of heat. Using intensity-voltage dependent low energy electron diffraction, two atomic structures are determined, which differ in their degree of oxidation. The non-collinear spin structure is already known in the literature as a 120° chiral spin spiral caused by the Dzyaloshinskii-Moriya-enhanced Ruderman-Kittel-Kasuya-Yosida (RKKY) interaction. According to present collinear DFT calculations, the collinear spin structure is calculated as AFM along the chains and ferromagnetic coupling between the chains. Based on the evidence of a higher degree of oxidation, a stronger RKKY interaction based on the Heisenberg exchange interaction is suspected. In this case, the formation of collinear or non-collinear spin structures correlates with the degree of oxidation. KW - Frustration KW - Rastertunnelmikroskopie KW - Spin KW - Dünne Schicht KW - Nanomagnetismus KW - Spinstrukturen KW - Spinpolarisierte Rastertunnelmikroskopie KW - spin structures KW - spinpolarised scanning tunneling microscopy KW - Antiferromagnetism KW - Manganese KW - Spin-Struktur KW - nanomagnetism Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371631 ER - TY - THES A1 - Hesen, Nienke Aiyuan T1 - The importance of antibody isotype and idiotype in FcγR-dependent agonism induced by anti-CD40 antibodies T1 - Die Bedeutung des Antikörper-Isotyps und des Idiotyps beim FcγR-abhängigen Agonismus, der durch Anti-CD40-Antikörper induziert wird N2 - The TRAF-binding receptor CD40 belongs to the TNFR superfamily and is broadly expressed on healthy cells, mainly on antigen-presenting cells, but also on other immune cells and non-immune cells. CD40 is bound by its ligand CD40L, which is essential for a wide range of immunological responses by inducing or inhibiting different pathways that are essential for a variety of cellular processes, including immune activation and maturation. (1,2) Dysregulated CD40 signalling has been implicated in inflammatory diseases, such as hyper-IgM syndrome, psoriasis, and cancer. (3–6) Due to its broad expression across various tumour types, it can serve as a tumour-associated antigen and has therefore been proposed as a target for antibodies for cancer treatment. (2,7,8) Agonistic anti-CD40 antibodies have been demonstrated to induce anti-tumoural immune responses as well as therapeutic immunity. (2) Furthermore, prolonged stimulation of CD40 in tumour cells in vitro has been shown to decrease proliferation, increase expression of cytotoxic TNFSFLs and induce apoptosis. (9,10) Their effect on anti-tumoral responses has been well studied and anti-tumoral responses by DC maturation and suppression of malignant growth of B-cells have been confirmed and were found to induce cell death in tumours in vitro. (11–14) Many agonistic anti-CD40 antibodies specifically have been reported to require secondary crosslinking by binding to either activating or inhibitory FcγRs to be agonistic in vitro, while in vivo studies have indicated inhibitory FcƴR2B expression as critical factor. (15–17) However, FcƴR independent agonism has also been reported for anti-CD40 antibodies. (18,19) While agonistic anti-CD40 IgG1, IgG3 and IgG4 antibodies have been shown to display FcƴR dependent agonism, agonistic anti-CD40 IgG2 antibodies have shown to display FcƴR independent agonism. Conversion of anti-CD40 IgG1 antibodies into IgG2 has also been shown to convert the antibody’s agonism into FcƴR independent agonism. (20) To overcome FcƴR dependency, bispecific antibody fusion proteins containing a scFv as anchoring domain allowing for crosslink independent of FcƴR binding have been designed before. This approach has been found to display strong agonism for other antibody fusion proteins when bound to both targets, with response levels resembling that of FcƴR bound antibodies. (21,22) The relevance of antibody isotype and idiotype for FcƴR-dependent agonism as well as the relevance of valency and antibody oligomerization for FcƴR-independent agonism were investigated in this study on a panel of different anti-CD40 antibodies. Several clinically investigated anti-CD40 antibodies (ADC-1013(23), APX005M(24), ChiLob7.4(25) and CP-870,893(26)) and one preclinical antibody (G28.5(27,28)) were considered. Selected antibodies were then cloned onto an IgG1, IgG1(N297A), IgG2 and IgG4 backbone. The IgG1(N297A) isotype is an IgG1 antibody with a point mutation (N297A) that is known to strongly reduce binding to FcƴR1, while reducing the binding affinity to FcƴR2B to undetectable levels. (29,30) In this work it is demonstrated that the investigated anti-CD40 antibody variants across different isotypes activate both the classical and alternative NFκB pathway by stimulating U2OS cells in an FcƴR dependent manner. Stimulation in the presence of both human FcƴRs as well as murine FcƴRs resulted in CD40 stimulation. A difference in binding competition was observed for the various anti-CD40 IgG1 antibodies, but no indication of a CRD-dependent mechanism responsible for their agonistic activity was found. Moreover, this FcƴR dependency could be overcome by creation of tetravalent antibody fusion proteins. N2 - Zusammenfassung Der TRAF-bindende Rezeptor CD40 ist Teil der TNFR-Superfamilie. CD40 wird auf gesunden Zellen, vor allem auf Antigen-präsentierenden Zellen, aber auch auf anderen Immunzellen und Nicht-Immunzellen in großem Umfang exprimiert. Die Aktivierung von CD40 durch seinen Liganden CD40L ist für zahlreiche immunologische Reaktionen von entscheidender Bedeutung, da sie verschiedene Signalwege induziert oder hemmt, die für zahlreiche zelluläre Prozesse, einschließlich Immunaktivierung und -reifung, wichtig sind. (1,2) Defekte CD40-Signalwege werden mit Entzündungskrankheiten wie dem Hyper-IgM-Syndrom, Psoriasis und Krebs in Verbindung gebracht. (3–6) Da CD40 auf verschiedenen Tumorarten weit verbreitet ist, kann es als tumorassoziiertes Antigen verwendet werden, das dann von zytotoxischen Antikörpern angegriffen werden kann, und wurde als Ziel für Antikörper zur Krebsbehandlung vorgeschlagen. (2,7,8) Es hat sich gezeigt, dass agonistische Anti-CD40-Antikörper antitumorale Immunreaktionen und therapeutische Immunität auslösen können. (2) Es hat sich gezeigt, dass die kontinuierliche Stimulation von CD40 in Tumorzellen in vitro die Proliferation reduziert, die Expression zytotoxischer TNFSFLs hochreguliert und Apoptose induziert. (9,10) Ihre Wirkung auf antitumorale Reaktionen wurde gut untersucht, und antitumorale Reaktionen durch DCReifung und Unterdrückung des malignen Wachstums von B-Zellen wurden bestätigt und es wurde festgestellt, dass sie in vitro den Zelltod in Tumoren induzieren. (11–14) Viele agonistische Anti-CD40-Antikörper erfordern Berichten zufolge eine sekundäre Vernetzung durch Bindung an entweder aktivierende oder hemmende FcγRs, um in vitro agonistisch zu wirken, während In-vivo-Studien auf eine hemmende FcƴR2B-Expression als kritischen Faktor hinwiesen. (15–17) Allerdings wurde auch für Anti-CD40-Antikörper ein FcƴR-unabhängiger Agonismus festgestellt. (18,19) Während agonistische Anti-CD40-IgG1-, IgG3- und IgG4-Antikörper nachweislich einen FcƴR-abhängigen Agonismus aufweisen, haben agonistische Anti-CD40-IgG2-Antikörper einen FcƴR-unabhängigen Agonismus gezeigt. Die Umwandlung von Anti-CD40-IgG1-Antikörpern in IgG2-Antikörper hat ebenfalls gezeigt, dass der Agonismus des Antikörpers in einen FcƴR-unabhängigen Agonismus umgewandelt wird. (20) Um die FcƴR-Abhängigkeit zu überwinden, wurden bereits bispezifische AntikörperFusionsproteine entwickelt, die ein scFv als Verankerungsdomäne enthalten und eine von der FcƴR-Bindung unabhängige Vernetzung ermöglichen. Es hat sich gezeigt, dass dieser Ansatz einen starken Agonismus für andere Antikörper-Fusionsproteine aufweist, wenn sie an beide Zielmoleküle gebunden sind, wobei die Ansprechraten denen von FcƴRgebundenen Antikörpern ähneln. (21,22) Die Bedeutung des Antikörper-Isotyps und des Idiotyps für den FcƴR-abhängigen Agonismus sowie die Bedeutung der Valenz und der Antikörper-Oligomerisierung für den FcƴRunabhängigen Agonismus wurden in dieser Studie an einem Panel verschiedener Anti-CD40-Antikörper untersucht. Es wurden mehrere klinisch untersuchte Anti-CD40-Antikörper (ADC1013(23), APX005M(24), ChiLob7.4(25) und CP-870,893(26)) und ein präklinischer Antikörper (G28.5(27,28)) berücksichtigt. Die ausgewählten Antikörper wurden dann auf ein IgG1-, IgG1(N297A)-, IgG2- und IgG4-Backbone kloniert. Beim Isotyp gG1(N297A) handelt es sich um einen IgG1-Antikörper mit einer Punktmutation (N297A), von der bekannt ist, dass sie die Bindung an FcƴR1 stark reduziert, während sie die Bindungsaffinität zu FcƴR2B auf ein nicht nachweisbares Niveau verringert. (29,30)In dieser Arbeit wird gezeigt, dass die Anti-CD40-Antikörper-Varianten verschiedener Isotypen sowohl den klassischen als auch den alternativen NFκB-Signalweg aktivieren, indem sie U2OS-Zellen in einer FcƴR-abhängigen Weise stimulieren. Die Stimulierung in Anwesenheit sowohl von humanen FcƴRs als auch von murinen FcƴRs führte zu einer CD40-Stimulierung. Während für die verschiedenen Anti-CD40-IgG1-Antikörper ein Unterschied in der Bindungskonkurrenz beobachtet wurde, konnten die CRD-Bindungsprofile keine Erkenntnisse über die zugrunde liegenden Mechanismen liefern. Darüber hinaus konnte diese FcƴR-Abhängigkeit durch die Herstellung von tetravalenten AntikörperFusionsproteinen überwunden werden. KW - Antigen CD40 KW - FcƴR Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371872 ER - TY - THES A1 - Vialetto, Elena T1 - Outcomes of genome targeting with CRISPR-Cas systems in bacteria T1 - Folgen des Genom-Targeting mit CRISPR-Cas-Systemen in Bakterien N2 - CRISPR-Cas systems are a versatile tool in genetic engineering because they can be easily reprogrammed to cut a specific chromosomal region or RNA transcript. The choice of nuclease, gRNA design, and target region all influence targeting efficiency, so the appropriate CRISPR components should be chosen depending on the desired application. This thesis examines factors that influence targeting in both DNA- and RNA-targeting CRISPR systems. Chapter 1 discusses the importance of target RNA abundance in shaping the immunity of type VI CRISPR systems. In bacteria, the Cas13 nuclease is known to degrade RNA specifically and non-specifically, leading to cell growth arrest, also known as dormancy. In this chapter, the factors that determine dormancy are investigated by targeting genome- and plasmid-encoded transcripts in E. coli. The observations are extended to a gRNA library targeting the entire coding genome and gRNA design rules are extrapolated. Finally, the role of Cas13 in defense is investigated by testing how the system behaves during viral infection or plasmid transformation. Chapter 2 also looks at the factors that characterize targeting efficiency, but focuses on the Cas12a DNA-targeting system in K. pneumoniae. The ultimate goal is to develop CRISPR antimicrobials as alternatives to antibiotics to eliminate multidrug-resistant and hypervirulent bacteria. Several nucleases are tested for antimicrobial activity, the Cas12a nuclease is selected and the same gRNAs are used against different strains to understand the robustness of the method. Rules for gRNA design are also investigated by looking at secondary structure and testing a gRNA library across several genomic regions in two different strains. This information is used to develop a machine-learning algorithm to predict gRNA activity. In addition, the CRISPR-Cas systems are also packaged in a T7-like phage with engineered tail fibers and delivered to K. pneumoniae. While Chapter 2 uncovers various factors that improve targeting efficiency, Chapter 3 aims to reduce targeting by the Cas9 and Cas12a nucleases to favor homology-directed repair for genome editing in E. coli. Targeting is slowed down so that some copies of the chromosomes remain intact, allowing the bacterium to survive and integrate the desired edit. To reduce targeting, different gRNA formats or nuclease variations are used, gRNA expression is modulated, or gRNAs with attenuated targeting are designed. Attenuated gRNAs are tested to introduce point mutations as well as whole gene deletions and substitutions, and the method is extended to Klebsiella oxytoca and Klebsiella pneumoniae, where it is applied to block transcription of an antibiotic resistance gene in the genome, restoring sensitivity to ampicillin. Overall, this work discusses how changing the CRISPR components alters the outcome of targeting and highlights strategies to achieve efficient or attenuated targeting depending on the desired application. N2 - CRISPR-Cas-Systeme sind ein vielseitiges Werkzeug in der Gentechnik, da sie leicht umprogrammiert werden können, um eine bestimmte chromosomale Region oder ein RNA-Transkript zu schneiden. Die Wahl der Nuklease, das Design der gRNA und die Zielregion beeinflussen alle die Effizienz des Targetings, so dass die richtigen CRISPR-Komponenten je nach gewünschter Anwendung ausgewählt werden sollten. In dieser Arbeit werden die Faktoren untersucht, die das Targeting sowohl bei DNA-targeting als auch bei RNA-targeting CRISPR-Systemen beeinflussen. In Kapitel 1 wird erörtert, wie die Häufigkeit der Ziel-RNA die Immunität von Typ VI CRISPR-Systemen ausprägt. In Bakterien ist von der Cas13-Nuklease bekannt, dass sie RNA spezifisch und unspezifisch abbaut, was zu einem Stillstand des Zellwachstums führt, der auch als Dormanz bezeichnet wird. In diesem Kapitel werden die Faktoren untersucht, die Dormanz determinieren, indem genom- und plasmidkodierte Transkripte in E. coli ins Visier genommen werden. Die Beobachtungen werden auf eine gRNA-Bibliothek ausgeweitet, die auf das gesamte kodierende Genom abzielt, und es werden gRNA-Designregeln extrapoliert. Schließlich wird die Rolle von Cas13 bei der Verteidigung untersucht, indem getestet wird, wie sich das System während einer Virusinfektion oder Plasmidtransformation verhält. Kapitel 2 befasst sich ebenfalls mit den Faktoren, die die Targeteffizienz charakterisieren, konzentriert sich jedoch auf das Cas12a-DNA-Targeting-System in K. pneumoniae. Das Endziel ist die Entwicklung von CRISPR-Antimikroben als Alternative zu Antibiotika, um multiresistente und hypervirulente Bakterien zu eliminieren. Mehrere Nukleasen werden auf ihre antimikrobielle Aktivität getestet, die Cas12a-Nuklease wird ausgewählt und dieselben gRNAs werden gegen verschiedene Stämme eingesetzt, um die Robustheit der Methode zu verstehen. Außerdem werden die Regeln für das Design von gRNAs untersucht, indem die Sekundärstruktur betrachtet und eine gRNA-Bibliothek, die verschiedenen genomische Regionen in zwei verschiedenen Stämmen umfasst, getestet wird. Diese Informationen werden zur Entwicklung eines Algorithmus für maschinelles Lernen verwendet, um die gRNA-Aktivität vorherzusagen. Darüber hinaus werden die CRISPR-Cas-Systeme auch in einen T7-ähnlichen Phagen mit manipulierten Schwanzfasern verpackt und an K. pneumoniae übertragen. Während in Kapitel 2 verschiedene Faktoren aufgedeckt werden, die die Effizienz des Targetings verbessern, zielt Kapitel 3 darauf ab, das Targeting durch die Cas9- und Cas12a-Nukleasen zu reduzieren, um homology directed repair für Genom-Editierung in E. coli zu begünstigen. Das Targeting wird verlangsamt, so dass einige Kopien der Chromosomen intakt bleiben und das Bakterium überleben und die gewünschte Veränderung integrieren kann. Um das Targeting zu reduzieren, werden verschiedene gRNA-Formate oder Nuklease-Variationen verwendet, die gRNA-Expression wird moduliert, oder es werden gRNAs mit abgeschwächten Targeting entwickelt. Abgeschwächte gRNAs werden getestet, um Punktmutationen, Deletionen und Substitutionen ganzer Gene einzuführen, und die Methode wird auf Klebsiella oxytoca und Klebsiella pneumoniae ausgeweitet, wo sie zur Blockierung der Transkription eines Antibiotikaresistenzgens im Genom eingesetzt wird, um die Empfindlichkeit gegenüber Ampicillin wiederherzustellen. Insgesamt wird in dieser Arbeit erörtert, wie die Veränderung der CRISPR-Komponenten die Folgen des Targetings verändert und es werden Strategien hervorgehoben, um effizientes oder abgeschwächtes Targeting, je nach der gewünschten Anwendung, zu erreichen. KW - CRISPR/Cas-Methode KW - CRISPR KW - Genome editing KW - Antimicrobials KW - Cas13 KW - Cas12a Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371264 ER - TY - THES A1 - Hackenesch, Ulla T1 - Variabilität der Penetranz und klinischen Manifestation der autosomal dominanten Osteopetrose Typ II T1 - Variability of penetrance and clinical manifestation of autosomal dominant osteopetrosis type II N2 - Die autosomal dominante Osteopetrose Typ II ist eine seltene sklerosierende Skeletterkrankung, die durch heterozygote Varianten im CLCN7-Gen verursacht wird. Die klinische Manifestation umfasst ein breites Symptomspektrum. Charakteristisch sind die unvollständige Penetranz und eine hohe Variabilität der Phänotyp-Expression. Beide Phänomene führen wir am ehesten auf eine monoallelische Inaktivierung zurück. Diese Studie war eine retrospektive Datenauswertung, die 14 ADO II-Betroffene mit klinischer Manifestation der Erkrankung sowie 5 PatientInnen mit Carrier-Status eingeschlossen hat. Diese wurden im Rahmen einer ausführlichen Diagnostik untersucht, bei der Parameter im Hinblick auf den Zustand des Skelettsystems, körperliche Funktionen und Symptome sowie die gesundheitsbezogene Lebensqualität und der Leidensdruck erfasst wurden. Diese Variablen wurden zwischen der Betroffenen- und Carrier-Gruppe verglichen, wobei die Ergebnisse humangenetischer Untersuchungen berücksichtigt wurden, welche Gene umfassten, deren Produkte im Knochenstoffwechsel eine Rolle spielen. In 6 Stammbäumen und einem sporadischen Fall konnten 5 verschiedene heterozygote CLCN7-Varianten festgestellt werden. Zusätzlich wurden ALPL- und LRP5-Varianten entdeckt. Der Einfluss dieser zusätzlichen Varianten auf die Penetranz und die klinische Manifestation des ADO II-Phänotyps wurden diskutiert. Es konnte festgestellt werden, dass Betroffene in allen betrachteten Bereichen, d.h. klinisch, osteodensitometrisch und laborchemisch krankheitstypische Veränderungen zeigten, wohingegen Carrier keinerlei Auffälligkeiten aufwiesen. Die nach Alter stratifizierte Auswertung der Funktionstestung und Lebensqualität offenbarte mit zunehmendem Alter stärkere Einbußen in der Funktionsfähigkeit und der gesundheitsbezogenen Lebensqualität bei Betroffenen gegenüber den Carriern. Eine Zunahme der Krankheitssymptome und eine Verschlechterung des Gesundheitszustandes im Laufe des Lebens könnten demnach angenommen werden. N2 - Autosomal dominant osteopetrosis type II is a rare sclerosing skeletal disorder caused by heterozygous variants in the CLCN7 gene. The clinical manifestations include a wide range of symptoms. Incomplete penetrance and high variability in phenotype expression are characteristic. We attribute both phenomena most likely to monoallelic inactivation. This study was a retrospective data analysis that included 14 ADO II patients with clinical manifestations of the disease and 5 patients with carrier status. They were examined as part of a detailed diagnostic process in which parameters relating to the condition of the skeletal system, physical functions, and symptoms as well as health-related quality of life and burden of disease were recorded. These variables were compared between the affected and carrier groups, taking into account the results of human genetic tests, which included genes whose products play a role in bone metabolism. In 6 pedigrees and one sporadic case, 5 different heterozygous CLCN7 variants were identified. In addition, ALPL and LRP5 variants were discovered. The influence of these additional variants on the penetrance and clinical manifestation of the ADO II phenotype were discussed. It was concluded that affected individuals showed disease-typical changes in all areas considered, i.e. clinically, in osteodensitometry and the laboratory tests, whereas carriers showed no abnormalities. The evaluation of the functional testing and quality of life, stratified by age, revealed that those affected experienced greater declines in their functional ability and health-related quality of life with increasing age than carriers. An increase in disease symptoms and a deterioration in health status over the course of a lifetime could therefore be assumed. KW - ADO II KW - M. Albers-Schönberg KW - CLCN7 KW - Clc-7 KW - phenotype KW - autosomal dominant osteopetrosis type II KW - Albers-Schönberg disease KW - clinical and radiological manifestations KW - fracture analysis KW - high bone mass Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370842 ER - TY - THES A1 - Seal, Rishav T1 - Selective inhibition of the transcription factor NFAT in mitigating GvHD with small molecule inhibitors T1 - Selektive Hemmung des Transkriptionsfaktors NFAT bei der Milderung von GvHD durch kleine Molekül-Inhibitoren N2 - Hematopoietic stem cell transplantation (HSCT) is a promising therapy for various malignancies and immune deficiency diseases, but it is often associated with graft versus host disease (GvHD), a life-threatening complication arising from immunological incompatibility between donor T cells and host tissues. Current standard therapies for GvHD involve the use of calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus (FK506), which effectively suppress T cell activation and proliferation. However, these drugs also impair the graft versus leukemia (GvL) effect, which is the advantageous ability of donor T cells to eliminate malignant cells. Our previous studies demonstrated that the selective deletion of one or two members of the nuclear factor of activated T cells (NFAT) transcription factor family in donor T cells effectively prevented harmful GvHD without compromising GvL activity. This finding highlighted the potential of NFAT as a therapeutic target for GvHD. In this study, we developed and evaluated novel treatment strategies that specifically target NFAT during allogeneic HSCT. We focused on the development of small molecules that mimic the PxIxIT motif of NFAT, thereby competitively inhibiting its binding to CN (CN) without affecting CN phosphatase activity. We identified two promising candidates, C17 and MRD37, and evaluated their efficacy in inhibiting NFAT and suppressing pro-inflammatory cytokine production. Among these molecules, MRD37 demonstrated the highest potency in selectively inhibiting NFAT at a sub-IC50 concentration without compromising the functional capacity of regulatory T cells (Tregs) in vitro. Furthermore, we demonstrated that MRD37 could effectively protect mice from major mismatch GvHD in vivo. This protection was initially predicted to be due to the enhanced presence of Tregs and Tr1-type cells but when pretreated T cells devoid of Tregs were transplanted it unraveled an additional increase of Th2-like cytokine release. Finally, our in vitro studies on human T cells confirmed that MRD37 could specifically inhibit NFAT while preserving the Treg population, suggesting its potential as a novel therapeutic strategy for GvHD. Our findings provide compelling evidence for the development of MRD37 as promising alternative to CNIs in mitigating GvHD. N2 - Die hämatopoetische Stammzelltransplantation (HSCT) ist eine vielversprechende Therapie für verschiedene bösartige Erkrankungen und Immunschwächekrankheiten, wird jedoch häufig mit der Graft versus Host Disease (GvHD) in Verbindung gebracht, einer lebensbe drohlichen Komplikation, die durch immunologische Inkompatibilität zwischen Spender T Zellen und Wirtsgewebe entsteht. Die derzeitigen Standardtherapien für die GvHD umfassen den Einsatz von Calcineurin Inhibitoren (CNI) wie Cyclosporin A (CsA) und Tacroli mus (FK506), die die Aktivierung und Vermehrung von T Zellen wirksam unterdrücken. Diese Medikamente beeinträchtigen jedoch auch den Transplantat gegen Leukämie Effekt (GvL), d. h. die vorteilhafte Fähigkeit von Spender T Zellen, bösartige Zellen zu elimin ieren. Unsere früheren Studien haben gezeigt, dass die selektive Deletion von einem oder zwei Mitgliedern der Transkriptionsfaktor Familie Nuclear Factor of Activated T Cells (NFAT) in Spender T Zellen die schädliche GvHD wirksam verhindert, ohne die GvL Aktivitä t zu beeinträchtigen. Dieses Ergebnis unterstreicht das Potenzial von NFAT als therapeutisches Ziel für GvHD. In dieser Studie haben wir neuartige Behandlungsstrategien entwickelt und evaluiert, die spezifisch auf NFAT bei allogener HSCT abzielen. Wir konzentrierten uns auf die Entwicklung kleiner Moleküle, die das PxIxIT Motiv von NFAT nachahmen und dadurch seine Bindung an Calcineurin (CN) kompetitiv hemmen, ohne die Phosphataseaktivität von CN zu beeinträchtigen. Wir haben zwei vielversprechende Kandidaten, C17 und MRD37, identifiziert und ihre Wirksamkeit bei der Hemmung von NFAT und der Unterdrückung der Produ ktion entzündungsfördernder Zytokine untersucht. Von diesen Molekülen zeigte MRD37 die höchste Wirksamkeit bei der selektiven Hemmung von NFAT in einer Konzentration unterhalb von IC50, ohne die Funktionsfähigkeit der regulatorischen T Zellen (Tregs) zu be einträchtigen. Darüber hinaus konnten wir zeigen, dass MRD37 Mäuse in vivo wirksam vor Major Mismatch GvHD schützen kann. Ursprünglich wurde angenommen, dass dieser Schutz auf das verstärkte Vorhandensein von Tregs und Zellen vom Tr1 Typ zurückzuführen ist , doch als vorbehandelte T Zellen ohne Tregs transplantiert wurden, zeigte sich darüberhinaus eine erhöhte Freisetzung von Th2 ähnlichen Zytokinen. Schließlich bestätigten unsere In vitro Studien an menschlichen T Zellen, dass MRD37 spezifisch NFAT hemmen kann, während die Treg 9 Population erhalten bleibt, was auf sein Potenzial als neuartige therapeutische Strategie für Population erhalten bleibt, was auf sein Potenzial als neuartige therapeutische Strategie für GvHD hindeutet.GvHD hindeutet. Unsere Ergebnisse liefern überzeugende Beweise für die Entwicklung von MRD37 als Unsere Ergebnisse liefern überzeugende Beweise für die Entwicklung von MRD37 als vielversprechende Alternative zu CNIs bei der Behandlung von GvHD.vielversprechende Alternative zu CNIs bei der Behandlung von GvHD. KW - GVHD KW - Transplantat-Wirt-Reaktion KW - Stammzelltransplantation KW - Graft versus host disease KW - NFAT inhibitor KW - Stem cell transplantation KW - CsA KW - T cell Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370537 ER - TY - JOUR A1 - Magnea, Lorenzo A1 - Pelliccioli, Giovanni A1 - Signorile-Signorile, Chiara A1 - Torrielli, Paolo A1 - Uccirati, Sandro T1 - Analytic integration of soft and collinear radiation in factorised QCD cross sections at NNLO JF - Journal of High Energy Physics N2 - Within the framework of local analytic sector subtraction, we present the full analytic integration of double-real and real-virtual local infrared counterterms that enter NNLO QCD computations with any number of massless final-state partons. We show that a careful choice of phase-space mappings leads to simple analytic results, including non-singular terms, that can be obtained with conventional integration techniques. KW - QCD Phenomenology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370064 VL - 2021 ER - TY - JOUR A1 - MacLeod, Lucy A1 - Suruliraj, Banuchitra A1 - Gall, Dominik A1 - Bessenyei, Kitti A1 - Hamm, Sara A1 - Romkey, Isaac A1 - Bagnell, Alexa A1 - Mattheisen, Manuel A1 - Muthukumaraswamy, Viswanath A1 - Orji, Rita A1 - Meier, Sandra T1 - A Mobile Sensing App to Monitor Youth Mental Health: Observational Pilot Study JF - JMIR mHealth and uHealth N2 - Background: Internalizing disorders are the most common psychiatric problems observed among youth in Canada. Sadly, youth with internalizing disorders often avoid seeking clinical help and rarely receive adequate treatment. Current methods of assessing internalizing disorders usually rely on subjective symptom ratings, but internalizing symptoms are frequently underreported, which creates a barrier to the accurate assessment of these symptoms in youth. Therefore, novel assessment tools that use objective data need to be developed to meet the highest standards of reliability, feasibility, scalability, and affordability. Mobile sensing technologies, which unobtrusively record aspects of youth behaviors in their daily lives with the potential to make inferences about their mental health states, offer a possible method of addressing this assessment barrier. Objective: This study aims to explore whether passively collected smartphone sensor data can be used to predict internalizing symptoms among youth in Canada. Methods: In this study, the youth participants (N=122) completed self-report assessments of symptoms of anxiety, depression, and attention-deficit hyperactivity disorder. Next, the participants installed an app, which passively collected data about their mobility, screen time, sleep, and social interactions over 2 weeks. Then, we tested whether these passive sensor data could be used to predict internalizing symptoms among these youth participants. Results: More severe depressive symptoms correlated with more time spent stationary (r=0.293; P=.003), less mobility (r=0.271; P=.006), higher light intensity during the night (r=0.227; P=.02), and fewer outgoing calls (r=−0.244; P=.03). In contrast, more severe anxiety symptoms correlated with less time spent stationary (r=−0.249; P=.01) and greater mobility (r=0.234; P=.02). In addition, youths with higher anxiety scores spent more time on the screen (r=0.203; P=.049). Finally, adding passively collected smartphone sensor data to the prediction models of internalizing symptoms significantly improved their fit. Conclusions: Passively collected smartphone sensor data provide a useful way to monitor internalizing symptoms among youth. Although the results replicated findings from adult populations, to ensure clinical utility, they still need to be replicated in larger samples of youth. The work also highlights intervention opportunities via mobile technology to reduce the burden of internalizing symptoms early on. KW - mobile sensing KW - youth KW - psychiatry KW - feasibility KW - mobile phone Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370054 VL - 9 ER - TY - JOUR A1 - Macchiaroli, Natalia A1 - Preza, Matías A1 - Gastón Pérez, Matías A1 - Kamenetzky, Laura A1 - Cucher, Marcela A1 - Koziol, Uriel A1 - Castillo, Estela A1 - Berriman, Matthew A1 - Brehm, Klaus A1 - Rosenzvit, Mara Cecilia T1 - Expression profiling of Echinococcus multilocularis miRNAs throughout metacestode development in vitro JF - PLOS Neglected Tropical Diseases N2 - The neglected zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode stage of the tapeworm parasite Echinococcus multilocularis. MicroRNAs (miRNAs) are small non-coding RNAs with a major role in regulating gene expression in key biological processes. We analyzed the expression profile of E. multilocularis miRNAs throughout metacestode development in vitro, determined the spatial expression of miR-71 in metacestodes cultured in vitro and predicted miRNA targets. Small cDNA libraries from different samples of E. multilocularis were sequenced. We confirmed the expression of 37 miRNAs in E. multilocularis being some of them absent in the host, such as miR-71. We found a few miRNAs highly expressed in all life cycle stages and conditions analyzed, whereas most miRNAs showed very low expression. The most expressed miRNAs were miR-71, miR-9, let-7, miR-10, miR-4989 and miR-1. The high expression of these miRNAs was conserved in other tapeworms, suggesting essential roles in development, survival, or host-parasite interaction. We found highly regulated miRNAs during the different transitions or cultured conditions analyzed, which might suggest a role in the regulation of developmental timing, host-parasite interaction, and/or in maintaining the unique developmental features of each developmental stage or condition. We determined that miR-71 is expressed in germinative cells and in other cell types of the germinal layer in E. multilocularis metacestodes cultured in vitro. MiRNA target prediction of the most highly expressed miRNAs and in silico functional analysis suggested conserved and essential roles for these miRNAs in parasite biology. We found relevant targets potentially involved in development, cell growth and death, lifespan regulation, transcription, signal transduction and cell motility. The evolutionary conservation and expression analyses of E. multilocularis miRNAs throughout metacestode development along with the in silico functional analyses of their predicted targets might help to identify selective therapeutic targets for treatment and control of AE. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370046 VL - 15 ER - TY - JOUR A1 - Maas, Bea A1 - Brandl, Manuela A1 - Hussain, Raja Imran A1 - Frank, Thomas A1 - Zulka, Klaus Peter A1 - Rabl, Dominik A1 - Walcher, Ronnie A1 - Moser, Dietmar T1 - Functional traits driving pollinator and predator responses to newly established grassland strips in agricultural landscapes JF - Journal of Applied Ecology N2 - Agricultural biodiversity and associated ecosystem functions are declining at alarming rates due to widespread land use intensification. They can only be maintained through targeted landscape management that supports species with different habitat preferences, dispersal capacities and other functional traits that determine their survival. However, we need better understanding whether short-term measures can already improve functional diversity in European agroecosystems. We investigated spatio-temporal responses of bees (solitary bees, bumblebees and honey bees), hoverflies, carabid beetles and spiders to newly established grassland strips in Lower Austria over 3 years, and along a distance gradient to old grasslands. Specifically, we asked if new grasslands, compared to old grasslands and cereal fields, serve as temporal dispersal habitat or corridor, and how species-specific traits affect dispersal patterns. Using a trait-based functional diversity approach, we investigated year and distance effects for nine selected key traits per taxon (e.g. body size, feeding guild and habitat preferences). Our results show that the functional diversity of predators and pollinators (i.e. functional richness and evenness), as well as community-weighted means of selected key traits in new grasslands significantly differed from adjacent cereal fields, but only slowly adjusted to adjacent old grasslands. These effects significantly decreased with increasing distance to old grasslands for carabids and spiders, but not for mobile bees and hoverflies. Synthesis and applications. Over 3 years, newly established grassland strips supported larger sized and actively foraging/hunting species in the agricultural landscape. Adjacent crops likely benefit from such measures through enhanced functional diversity and related ecosystem services. However, our results also suggest that 3-year period is too short to enhance the occurrence of pollinators and epigeic predators in new grasslands. Agri-environment measures need to be complemented by the conservation of permanent habitats to effectively maintain species and functional diversity. Our findings should be acknowledged by European policy and agricultural decision makers for the design of more effective agri-environment schemes, taking into account trait-dependent species responses to land use change. KW - agri-environment schemes KW - Common Agricultural Policy KW - ecosystem services; KW - Europe KW - functional diversity analysis; KW - pollination KW - predation KW - trait-based management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369992 VL - 58 ER - TY - JOUR A1 - Lux, Michael P. A1 - Schneeweiss, Andreas A1 - Hartkopf, Andreas D. A1 - Müller, Volkmar A1 - Janni, Wolfgang A1 - Belleville, Erik A1 - Stickeler, Elmar A1 - Thill, Marc A1 - Fasching, Peter A. A1 - Kolberg, Hans-Christian A1 - Untch, Michael A1 - Harbeck, Nadia A1 - Wöckel, Achim A1 - Thomssen, Christoph A1 - Schulmeyer, Carla E. A1 - Welslau, Manfred A1 - Overkamp, Friedrich A1 - Schütz, Florian A1 - Lüftner, Diana A1 - Ditsch, Nina T1 - Update Breast Cancer 2020 Part 5 – Moving Therapies From Advanced to Early Breast Cancer Patients JF - Geburtshilfe und Frauenheilkunde N2 - In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2−/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020. KW - early breast cancer KW - therapy KW - prognosis KW - immune therapy KW - digital medicine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369989 VL - 81 ER - TY - JOUR A1 - Luu, Maik A1 - Riester, Zeno A1 - Baldrich, Adrian A1 - Reichardt, Nicole A1 - Yuille, Samantha A1 - Busetti, Alessandro A1 - Klein, Matthias A1 - Wempe, Anne A1 - Leister, Hanna A1 - Raifer, Hartmann A1 - Picard, Felix A1 - Muhammad, Khalid A1 - Ohl, Kim A1 - Romero, Rossana A1 - Fischer, Florence A1 - Bauer, Christian A. A1 - Huber, Magdalena A1 - Gress, Thomas M. A1 - Lauth, Matthias A1 - Danhof, Sophia A1 - Bopp, Tobias A1 - Nerreter, Thomas A1 - Mulder, Imke E. A1 - Steinhoff, Ulrich A1 - Hudecek, Michael A1 - Visekruna, Alexander T1 - Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer JF - Nature Communications N2 - Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy. KW - tumour immunology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-309332 VL - 12 ER - TY - JOUR A1 - Luo, Yueming A1 - Ling, Chuanren A1 - Liu, Yangchen A1 - Deng, Chong A1 - Waaga-Gasser, Ana Maria A1 - Chen, Minggui A1 - He, Zehui A1 - Chen, Erhui A1 - Wei, Lin A1 - Luo, Shimiao A1 - Gong, Xiaozhen A1 - Ye, Hong A1 - Zhu, Jing A1 - Song, Shan A1 - Wang, Qiuting A1 - Li, Shunmin A1 - Gasser, Martin A1 - Lin, Meizhen T1 - The Beneficial Role of Auricular Point Pressure in Insomnia and Anxiety in Isolated COVID-19 Patients JF - Evidence-Based Complementary and Alternative Medicine N2 - Background Coronavirus disease 2019 (COVID-19) causes psychological distress and can have a negative impact on the general mental health and rehabilitation in affected patients under currently implemented isolation guidelines. Auricular point pressure (APP) as well-established technique in traditional Chinese medicine may help to relieve sleep disturbance and anxiety in COVID-19 patients. Methods During the early phase of the epidemic/pandemic, patients were enrolled in this study (02/2020 until 03/2020 n = 84). They were strictly isolated on specific wards at the Hubei Provincial Hospital of Integrated Chinese and Western Medicine in Hubei. The retrospective cohort study design included two groups. Group A patients were treated with an auricular point pressure (APP) in addition to standard intensive care medicine while Group B participants (No-APP) received routine nursing measures alone. Treatment outcome was measured using the St. Mary’s Hospital Sleep Questionnaire (SMH) Score and the 7-Item Generalized Anxiety Disorder Scale (GAD-7). Both scores were measured in each patient at baseline and on the discharge day. Results The SMH score and sleep status changed in APP patients at the end of the treatment period when compared with No-APP patients (P < 0.01). APP-treated patients demonstrated lower GAD-7 scores than No-APP controls (P < 0.01). Further, no significant differences in safety or adverse events between the APP and No-APP groups were observed. Conclusion The results from our snapshot study during the early phase of the SARS-CoV-2 epidemic/pandemic suggest that auricular point pressure could be a simple and effective tool to relieve insomnia and situational anxiety in hospitalized patients suffering from COVID-19 and kept under disconcerting conditions of isolation. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369658 VL - 2021 ER - TY - JOUR A1 - Luijten, Linda W G A1 - Leonhard, Sonja E A1 - van der Eijk, Annemiek A A1 - Doets, Alex Y A1 - Appeltshauser, Luise A1 - Arends, Samuel A1 - Attarian, Shahram A1 - Benedetti, Luana A1 - Briani, Chiara A1 - Casasnovas, Carlos A1 - Castellani, Francesca A1 - Dardiotis, Efthimios A1 - Echaniz-Laguna, Andoni A1 - Garssen, Marcel P J A1 - Harbo, Thomas A1 - Huizinga, Ruth A1 - Humm, Andrea M A1 - Jellema, Korné A1 - van der Kooi, Anneke J A1 - Kuitwaard, Krista A1 - Kuntzer, Thierry A1 - Kusunoki, Susumu A1 - Lascano, Agustina M A1 - Martinez-Hernandez, Eugenia A1 - Rinaldi, Simon A1 - Samijn, Johnny P A A1 - Scheidegger, Olivier A1 - Tsouni, Pinelopi A1 - Vicino, Alex A1 - Visser, Leo H A1 - Walgaard, Christa A1 - Wang, Yuzhong A1 - Wirtz, Paul W A1 - Ripellino, Paolo A1 - Jacobs, Bart C T1 - Guillain-Barré syndrome after SARS-CoV-2 infection in an international prospective cohort study JF - Brain N2 - In the wake of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, an increasing number of patients with neurological disorders, including Guillain-Barré syndrome (GBS), have been reported following this infection. It remains unclear, however, if these cases are coincidental or not, as most publications were case reports or small regional retrospective cohort studies. The International GBS Outcome Study is an ongoing prospective observational cohort study enrolling patients with GBS within 2 weeks from onset of weakness. Data from patients included in this study, between 30 January 2020 and 30 May 2020, were used to investigate clinical and laboratory signs of a preceding or concurrent SARS-CoV-2 infection and to describe the associated clinical phenotype and disease course. Patients were classified according to the SARS-CoV-2 case definitions of the European Centre for Disease Prevention and Control and laboratory recommendations of the World Health Organization. Forty-nine patients with GBS were included, of whom eight (16%) had a confirmed and three (6%) a probable SARS-CoV-2 infection. Nine of these 11 patients had no serological evidence of other recent preceding infections associated with GBS, whereas two had serological evidence of a recent Campylobacter jejuni infection. Patients with a confirmed or probable SARS-CoV-2 infection frequently had a sensorimotor variant 8/11 (73%) and facial palsy 7/11 (64%). The eight patients who underwent electrophysiological examination all had a demyelinating subtype, which was more prevalent than the other patients included in the same time window [14/30 (47%), P = 0.012] as well as historical region and age-matched control subjects included in the International GBS Outcome Study before the pandemic [23/44 (52%), P = 0.016]. The median time from the onset of infection to neurological symptoms was 16 days (interquartile range 12–22). Patients with SARS-CoV-2 infection shared uniform neurological features, similar to those previously described in other post-viral GBS patients. The frequency (22%) of a preceding SARS-CoV-2 infection in our study population was higher than estimates of the contemporaneous background prevalence of SARS-CoV-2, which may be a result of recruitment bias during the pandemic, but could also indicate that GBS may rarely follow a recent SARS-CoV-2 infection. Consistent with previous studies, we found no increase in patient recruitment during the pandemic for our ongoing International GBS Outcome Study compared to previous years, making a strong relationship of GBS with SARS-CoV-2 unlikely. A case-control study is required to determine if there is a causative link or not. KW - Guillain-Barré syndrome KW - COVID-19 KW - SARS-CoV-2 KW - preceding infections KW - clinical phenotype Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371609 VL - 144 ER - TY - JOUR A1 - Lüders, Carolin A1 - Pukrop, Matthias A1 - Rozas, Elena A1 - Schneider, Christian A1 - Höfling, Sven A1 - Sperling, Jan A1 - Schumacher, Stefan A1 - Aßmann, Marc T1 - Quantifying Quantum Coherence in Polariton Condensates JF - PRX Quantum N2 - We theoretically and experimentally investigate quantum features of an interacting light-matter system from a multidisciplinary perspective, combining approaches from semiconductor physics, quantum optics, and quantum-information science. To this end, we quantify the amount of quantum coherence that results from the quantum superposition of Fock states, constituting a measure of the resourcefulness of the produced state for modern quantum protocols. This notion of quantum coherence from quantum-information theory is distinct from other quantifiers of nonclassicality that have previously been applied to condensed-matter systems. As an archetypal example of a hybrid light-matter interface, we study a polariton condensate and implement a numerical model to predict its properties. Our simulation is confirmed by our proof-of-concept experiment in which we measure and analyze the phase-space distributions of the emitted light. Specifically, we drive a polariton microcavity across the condensation threshold and observe the transition from an incoherent thermal state to a coherent state in the emission, thus confirming the buildup of quantum coherence in the condensate itself. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369644 VL - 2 ER - TY - JOUR A1 - Ludwig, Jonas A1 - Dignath, David A1 - Lukas, Sarah T1 - Positive and negative action-effects improve task-switching performance JF - Acta Psychologica N2 - Anticipation of one's own actions' effects drives goal-directed behavior. In multitasking environments, the learning of stable action-effect associations seems particularly important, because establishing reliable response-effect associations for multiple competing tasks may help to differentiate between these tasks and thereby improve task-switching performance. Action-effects not only have cognitive, but also motivational aspects and often the consequences of our actions are hedonically marked. Thus, the anticipated hedonic quality of action-effects may also become part of the task representation, and positive and negative affect may distinctly modulate task-switching performance. We report a pre-registered experiment (N = 120) designed to examine how positive, negative, and neutral valence of action-effects impact performance in a cued task-switching paradigm. Pictures from the IAPS database were used to manipulate the action-effects' valence. Affective valence determined reaction times: participants who learned positive or negative action-effects responded faster than participants in the control condition. In particular, task-switch trials were faster in both conditions than in the control condition, while task-repetition trials were comparable across valence conditions. Our results further suggest that performance improvements in the positive and negative valence conditions occurred for different reasons. Negative action-effects expedited responses specifically for the task that produced the unpleasant outcome, while positive affect more generally promoted performance of both tasks. These findings point toward distinct roles of positive and negative valence of action-effects in regulating multitasking performance. KW - action control KW - multitasking KW - task-switching KW - action-effects KW - affective valence Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369638 VL - 221 ER - TY - JOUR A1 - Lu, Yuan A1 - Bierbach, David A1 - Ormanns, Jenny A1 - Warren, Wesley C. A1 - Walter, Ronald B. A1 - Schartl, Manfred T1 - Fixation of allelic gene expression landscapes and expression bias pattern shape the transcriptome of the clonal Amazon molly JF - Genome Research N2 - The Amazon molly is a unique clonal fish species that originated from an interspecies hybrid between Poecilia species P. mexicana and P. latipinna. It reproduces by gynogenesis, which eliminates paternal genomic contribution to offspring. An earlier study showed that Amazon molly shows biallelic expression for a large portion of the genome, leading to two main questions: (1) Are the allelic expression patterns from the initial hybridization event stabilized or changed during establishment of the asexual species and its further evolution? (2) Is allelic expression biased toward one parental allele a stochastic or adaptive process? To answer these questions, the allelic expression of P. formosa siblings was assessed to investigate intra- and inter-cohort allelic expression variability. For comparison, interspecies hybrids between P. mexicana and P. latipinna were produced in the laboratory to represent the P. formosa ancestor. We have identified inter-cohort and intra-cohort variation in parental allelic expression. The existence of inter-cohort divergence suggests functional P. formosa allelic expression patterns do not simply reflect the atavistic situation of the first interspecies hybrid but potentially result from long-term selection of transcriptional fitness. In addition, clonal fish show a transcriptional trend representing minimal intra-clonal variability in allelic expression patterns compared to the corresponding hybrids. The intra-clonal similarity in gene expression translates to sophisticated genetic functional regulation at the individuum level. These findings suggest the parental alleles inherited by P. formosa form tightly regulated genetic networks that lead to a stable transcriptomic landscape within clonal individuals. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369578 VL - 31 ER - TY - JOUR A1 - Loza-Valdes, Angel A1 - Mayer, Alexander E A1 - Kassouf, Toufic A1 - Trujillo-Viera, Jonathan A1 - Schmitz, Werner A1 - Dziaczkowski, Filip A1 - Leitges, Michael A1 - Schlosser, Andreas A1 - Sumara, Grzegorz T1 - A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism JF - Life Science Alliance N2 - Members of the protein kinase D (PKD) family (PKD1, 2, and 3) integrate hormonal and nutritional inputs to regulate complex cellular metabolism. Despite the fact that a number of functions have been annotated to particular PKDs, their molecular targets are relatively poorly explored. PKD3 promotes insulin sensitivity and suppresses lipogenesis in the liver of animals fed a high-fat diet. However, its substrates are largely unknown. Here we applied proteomic approaches to determine PKD3 targets. We identified more than 300 putative targets of PKD3. Furthermore, biochemical analysis revealed that PKD3 regulates cAMP-dependent PKA activity, a master regulator of the hepatic response to glucagon and fasting. PKA regulates glucose, lipid, and amino acid metabolism in the liver, by targeting key enzymes in the respective processes. Among them the PKA targets phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine. Consistently, we showed that PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Therefore, our data indicate that PKD3 might play a role in the hepatic response to glucagon. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369560 VL - 4 ER - TY - JOUR A1 - Lotan, Yair A1 - Gakis, Georgios A1 - Manfredi, Matteo A1 - Morote, Juan A1 - Mostafid, Hugh A1 - Porpiglia, Francesco A1 - Poyet, Cedric A1 - Roupret, Morgan A1 - Schulman, Claude A1 - Shariat, Shahrokh F. A1 - Witjes, Johannes Alfred T1 - Alternating Cystoscopy with Bladder EpiCheck® in the Surveillance of Low-Grade Intermediate-Risk NMIBC: A Cost Comparison Model JF - Bladder Cancer N2 - Background: Bladder cancer surveillance is invasive, intensive and costly. Patients with low grade intermediate risk non-muscle invasive bladder cancer (NMIBC) are at high risk of recurrence. Objective: The objective of this model is to compare the cost of a strategy to alternate surveillance with cystoscopy and a urine marker, Bladder EpiCheck, to standard surveillance. Methods: A decision tree model was built using TreeAge Pro Healthcare to compare standard surveillance (Standard) with a modified surveillance incorporating Bladder EpiCheck. The model was based on 2 years of surveillance. Outcomes were obtained from literature. Costs were obtained from US and 9 European countries. Sensitivity analyses were performed. Results: The efficacy of the model was equivalent in terms of recurrence for each arm with median recurrence rate of 22%. When setting marker price at 200 local currency, the marker arm was less expensive in the USA, Netherlands, Switzerland, Belgium, Italy, Austria and UK by 154€ to 329£ per patient, for a 2-year period. Cost was higher in France, Spain, and Germany by 33–103€. Cost parity was achieved with marker price between 148€ and $421. Marker cost and specificity have the greatest impact on the overall model cost. Conclusions: A strategy alternating the urine marker Bladder EpiCheck with cystoscopy in the surveillance of patients with low grade intermediate risk bladder cancer is cost equivalent in the US and European countries when the marker is priced 148€ –$421, as a result of the marker’s high specificity (86%). Prospective studies will be necessary to validate these findings. KW - bladder cancer KW - urinary markers KW - NMIBC surveillance KW - cost model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369512 VL - 7 ER - TY - JOUR A1 - Loscher, Georg A1 - Löhlein, Lukas A1 - Lenz, Hansrudi T1 - Dual Roles and Blurred Identities: A Framing Contest between Professional Associations in a Local Strategic Action Field JF - European Accounting Review N2 - This paper examines professional associations’ local responses to global demands of accounting standardisation. Our longitudinal study from 1998 to 2018 analyses how professional associations of the German audit profession engaged in an intense framing contest over the adoption of external quality controls. Drawing on the concept of strategic action field and the literature on framing, we unpack how the gap between large audit firms and small audit firms increasingly undermined the capacity of the professional associations to fulfil their dual role of governance and representation. We unveil how their failed attempt to maintain the image of an unified profession ultimately led to the creation of a new professional association representing the ‘small auditor’ professional, which successfully, albeit temporarily, took control over the field of German auditing. Our findings suggest that the passivity of small audit firms in the process of translating global regulatory regimes should not be presumed. Rather, we provide insight into how small audit firms can rebuild their own identity by actively responding to waves of global regulation. Doing so, and contrary to prior research, our case highlights that governance units within strategic action fields are not necessarily aligned with the interests of the most powerful field actors. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369504 VL - 30 ER - TY - JOUR A1 - Löw, Johannes A1 - Ullmann, Tobias A1 - Conrad, Christopher T1 - The Impact of Phenological Developments on Interferometric and Polarimetric Crop Signatures Derived from Sentinel-1: Examples from the DEMMIN Study Site (Germany) JF - Remote Sensing N2 - This study explores the potential of Sentinel-1 Synthetic Aperture Radar (SAR) to identify phenological phases of wheat, sugar beet, and canola. Breakpoint and extreme value analyses were applied to a dense time series of interferometric (InSAR) and polarimetric (PolSAR) features recorded during the growing season of 2017 at the JECAM site DEMMIN (Germany). The analyses of breakpoints and extrema allowed for the distinction of vegetative and reproductive stages for wheat and canola. Certain phenological stages, measured in situ using the BBCH-scale, such as leaf development and rosette growth of sugar beet or stem elongation and ripening of wheat, were detectable by a combination of InSAR coherence, polarimetric Alpha and Entropy, and backscatter (VV/VH). Except for some fringe cases, the temporal difference between in situ observations and breakpoints or extrema ranged from zero to five days. Backscatter produced the signature that generated the most breakpoints and extrema. However, certain micro stadia, such as leaf development of BBCH 10 of sugar beet or flowering BBCH 69 of wheat, were only identifiable by the InSAR coherence and Alpha. Hence, it is concluded that combining PolSAR and InSAR features increases the number of detectable phenological events in the phenological cycles of crops. KW - PolSAR KW - InSAR KW - Kennaugh matrix KW - time series KW - Sentinel-1 KW - crop phenology KW - DEMMIN Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369452 VL - 13 ER - TY - JOUR A1 - Löblein, Jochen A1 - Lorson, Thomas A1 - Komma, Miriam A1 - Kielholz, Tobias A1 - Windbergs, Maike A1 - Dalton, Paul D. A1 - Luxenhofer, Robert T1 - An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone) JF - Beilstein Journal of Organic Chemistry N2 - Additive manufacturing or 3D printing as an umbrella term for various materials processing methods has distinct advantages over many other processing methods, including the ability to generate highly complex shapes and designs. However, the performance of any produced part not only depends on the material used and its shape, but is also critically dependent on its surface properties. Important features, such as wetting or fouling, critically depend mainly on the immediate surface energy. To gain control over the surface chemistry post-processing modifications are generally necessary, since it′s not a feature of additive manufacturing. Here, we report on the use of initiator and catalyst-free photografting and photopolymerization for the hydrophilic modification of microfiber scaffolds obtained from hydrophobic medical-grade poly(ε-caprolactone) via melt-electrowriting. Contact angle measurements and Raman spectroscopy confirms the formation of a more hydrophilic coating of poly(2-hydroxyethyl methacrylate). Apart from surface modification, we also observe bulk polymerization, which is expected for this method, and currently limits the controllability of this procedure. KW - additive manufacturing KW - light-induced polymerization KW - self-initiated photografting and photopolymerization KW - surface-initiated polymerization KW - surface modification Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369433 VL - 17 ER - TY - JOUR A1 - Lock, Johan F A1 - Reimer, Stanislaus A1 - Pietryga, Sebastian A1 - Jakubietz, Rafael A1 - Flemming, Sven A1 - Meining, Alexander A1 - Germer, Christoph-Thomas A1 - Seyfried, Florian T1 - Managing esophagocutaneous fistula after secondary gastric pull-up: A case report JF - World Journal of Gastroenterology N2 - Background Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure. Case summary A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events. Conclusion A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition. KW - esophageal fistula KW - gastric fistula KW - esophageal stenosis KW - esophageal perforation KW - endoscopic vacuum therapy KW - free-jejunal graft KW - autogenous jejunum transplantation KW - case report Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369417 VL - 27 ER - TY - JOUR A1 - Ljubojević-Holzer, Senka A1 - Kraler, Simon A1 - Djalinac, Nataša A1 - Abdellatif, Mahmoud A1 - Voglhuber, Julia A1 - Schipke, Julia A1 - Schmidt, Marlene A1 - Kling, Katharina-Maria A1 - Franke, Greta Therese A1 - Herbst, Viktoria A1 - Zirlik, Andreas A1 - von Lewinski, Dirk A1 - Scherr, Daniel A1 - Rainer, Peter P A1 - Kohlhaas, Michael A1 - Nickel, Alexander A1 - Mühlfeld, Christian A1 - Maack, Christoph A1 - Sedej, Simon T1 - Loss of autophagy protein ATG5 impairs cardiac capacity in mice and humans through diminishing mitochondrial abundance and disrupting Ca2+ cycling JF - Cardiovascular Research N2 - Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve. KW - cardiomyocytes KW - calcium KW - mitochondria KW - autophagy KW - beta-adrenergic signalling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369345 VL - 118 ER - TY - JOUR A1 - Linz, Christian A1 - Brands, Roman C. A1 - Kertels, Olivia A1 - Dierks, Alexander A1 - Brumberg, Joachim A1 - Gerhard-Hartmann, Elena A1 - Hartmann, Stefan A1 - Schirbel, Andreas A1 - Serfling, Sebastian A1 - Zhi, Yingjun A1 - Buck, Andreas K. A1 - Kübler, Alexander A1 - Hohm, Julian A1 - Lapa, Constantin A1 - Kircher, Malte T1 - Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity – initial experience and comparison to [18F]FDG PET/CT and MRI JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Purpose While [18F]-fluorodeoxyglucose ([18F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [18F]FDG and [68Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUVmax) and peak (SUVpeak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [18F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([18F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [18F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted. KW - molecular imaging KW - fibroblast activation protein KW - head and neck cancer KW - PET Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369331 VL - 48 ER - TY - JOUR A1 - Linz, Christian A1 - Brands, Roman C. A1 - Herterich, Theresia A1 - Hartmann, Stefan A1 - Müller-Richter, Urs A1 - Kübler, Alexander C. A1 - Haug, Lukas A1 - Kertels, Olivia A1 - Bley, Thorsten A. A1 - Dierks, Alexander A1 - Buck, Andreas K. A1 - Lapa, Constantin A1 - Brumberg, Joachim T1 - Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity JF - JAMA Network Open N2 - Importance Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis. Objective To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases. Design, Setting, and Participants This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients’ tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled. Exposures All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection. Main Outcomes and Measures The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference. Results Of the 150 patients enrolled, 135 patients (74 [54.8%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3% sensitivity (95% CI, 71.2%-95.5%) and 84.8% specificity (95% CI, 77.8%-91.9%) and had a negative predictive value of 93.3% (95% CI, 88.2%-98.5%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0%; 95% CI, 57.4%-76.7%; P < .01) and cervical magnetic resonance imaging (62.6%; 95% CI, 52.7%-72.6%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6% sensitivity (95% CI, 63.4%-93.8%) and 83.1% specificity (95% CI, 75.1%-91.2%), and contralateral metastatic involvement was detected with 66.7% sensitivity (95% CI, 28.9%-100.0%) and 98.6% specificity (95% CI, 95.9%-100.0%). No distant metastases were observed. Conclusions and Relevance In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369313 VL - 4 ER - TY - JOUR A1 - Linz, Benedikt A1 - Hohl, Mathias A1 - Lang, Lisa A1 - Wong, Dickson W. L. A1 - Nickel, Alexander G. A1 - De La Torre, Carolina A1 - Sticht, Carsten A1 - Wirth, Klaus A1 - Boor, Peter A1 - Maack, Christoph A1 - Speer, Thimoteus A1 - Jespersen, Thomas A1 - Schotten, Ulrich A1 - Sanders, Prashanthan A1 - Böhm, Michael A1 - Linz, Dominik T1 - Repeated exposure to transient obstructive sleep apnea–related conditions causes an atrial fibrillation substrate in a chronic rat model JF - Heart Rhythm N2 - Background High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways. Objective We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate. Methods INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS). Results INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033). Conclusion Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development. KW - atrial fibrillation KW - night-to-night variability KW - obstructive sleep apnea KW - rats KW - substrate Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369298 VL - 18 ER - TY - JOUR A1 - Linhoff, Lena A1 - Sandrock, Alexander A1 - Kadler, Matthias A1 - Elsässer, Dominik A1 - Rhode, Wolfgang T1 - Excluding possible sites of high-energy emission in 3C 84 JF - Monthly Notices of the Royal Astronomical Society N2 - The FR-I galaxy 3C 84, that is identified with the misaligned blazar NGC 1275, is well known as one of the very few radio galaxies emitting gamma-rays in the TeV range. Yet, the gamma-ray emission region cannot be pinpointed and the responsible mechanisms are still unclear. We calculate the optical absorption depth of high-energy photons in the broad-line region of 3C 84 depending on their energy and distance to the central black hole. Based on these calculations, a lower limit on the distance of the emission region from the central black hole can be derived. These lower limits are estimated for two broad-line region geometries (shell and ring) and two states of the source, the low state in 2016 October–December and a flare state in 2017 January. For the shell geometry, we can place the emission region outside the Ly α radius. For the ring geometry and the low flux activity, the minimal distance between the black hole, and the gamma-ray emission region is close to the Ly α radius. In the case of the flaring state (ring geometry), the results are not conclusive. Our results exclude the region near the central black hole as the origin of the gamma-rays detected by Fermi–LAT and Major Atmospheric Gamma-Ray Imaging Cherenkov. With these findings, we can constrain the theoretical models of acceleration mechanisms and compare the possible emission region to the source’s morphology resolved by radio images from the Very Long Baseline Array. KW - acceleration of particles KW - astroparticle physics KW - galaxies: individual: NGC 1275 KW - galaxies: jets KW - gamma-rays: galaxies KW - radio continuum: galaxies Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369287 VL - 500 ER - TY - JOUR A1 - Liebers, Nora A1 - Duell, Johannes A1 - Fitzgerald, Donnacha A1 - Kerkhoff, Andrea A1 - Noerenberg, Daniel A1 - Kaebisch, Eva A1 - Acker, Fabian A1 - Fuhrmann, Stephan A1 - Leng, Corinna A1 - Welslau, Manfred A1 - Chemnitz, Jens A1 - Middeke, Jan-Moritz A1 - Weber, Thomas A1 - Holtick, Udo A1 - Trappe, Ralf A1 - Pfannes, Roald A1 - Liersch, Ruediger A1 - Spoer, Christian A1 - Fuxius, Stefan A1 - Gebauer, Niklas A1 - Caillé, Léandra A1 - Geer, Thomas A1 - Koenecke, Christian A1 - Keller, Ulrich A1 - Claus, Rainer A1 - Mougiakakos, Dimitrios A1 - Mayer, Stephanie A1 - Huettmann, Andreas A1 - Pott, Christiane A1 - Trummer, Arne A1 - Wulf, Gerald A1 - Brunnberg, Uta A1 - Bullinger, Lars A1 - Hess, Georg A1 - Mueller-Tidow, Carsten A1 - Glass, Bertram A1 - Lenz, Georg A1 - Dreger, Peter A1 - Dietrich, Sascha T1 - Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas JF - Blood Advances N2 - The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369173 VL - 5 ER - TY - JOUR A1 - Liang, Huan-Chang A1 - Costanza, Mariantonia A1 - Prutsch, Nicole A1 - Zimmerman, Mark W. A1 - Gurnhofer, Elisabeth A1 - Montes-Mojarro, Ivonne A. A1 - Abraham, Brian J. A1 - Prokoph, Nina A1 - Stoiber, Stefan A1 - Tangermann, Simone A1 - Lobello, Cosimo A1 - Oppelt, Jan A1 - Anagnostopoulos, Ioannis A1 - Hielscher, Thomas A1 - Pervez, Shahid A1 - Klapper, Wolfram A1 - Zammarchi, Francesca A1 - Silva, Daniel-Adriano A1 - Garcia, K. Christopher A1 - Baker, David A1 - Janz, Martin A1 - Schleussner, Nikolai A1 - Fend, Falko A1 - Pospíšilová, Šárka A1 - Janiková, Andrea A1 - Wallwitz, Jacqueline A1 - Stoiber, Dagmar A1 - Simonitsch-Klupp, Ingrid A1 - Cerroni, Lorenzo A1 - Pileri, Stefano A1 - de Leval, Laurence A1 - Sibon, David A1 - Fataccioli, Virginie A1 - Gaulard, Philippe A1 - Assaf, Chalid A1 - Knörr, Fabian A1 - Damm-Welk, Christine A1 - Woessmann, Wilhelm A1 - Turner, Suzanne D. A1 - Look, A. Thomas A1 - Mathas, Stephan A1 - Kenner, Lukas A1 - Merkel, Olaf T1 - Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma JF - Nature Communications N2 - Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL. KW - CRISPR-Cas9 genome editing KW - high-throughput screening KW - mechanisms of disease KW - T-cell lymphoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371581 VL - 12 ER - TY - JOUR A1 - Li, Yuanyue A1 - Kuhn, Michael A1 - Zukowska-Kasprzyk, Joanna A1 - Hennrich, Marco L. A1 - Kastritis, Panagiotis L. A1 - O'Reilly, Francis J. A1 - Phapale, Prasad A1 - Beck, Martin A1 - Gavin, Anne-Claude A1 - Bork, Peer T1 - Coupling proteomics and metabolomics for the unsupervised identification of protein–metabolite interactions in Chaetomium thermophilum JF - PLOS ONE N2 - Protein–metabolite interactions play an important role in the cell’s metabolism and many methods have been developed to screen them in vitro. However, few methods can be applied at a large scale and not alter biological state. Here we describe a proteometabolomic approach, using chromatography to generate cell fractions which are then analyzed with mass spectrometry for both protein and metabolite identification. Integrating the proteomic and metabolomic analyses makes it possible to identify protein-bound metabolites. Applying the concept to the thermophilic fungus Chaetomium thermophilum, we predict 461 likely protein-metabolite interactions, most of them novel. As a proof of principle, we experimentally validate a predicted interaction between the ribosome and isopentenyl adenine. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364299 VL - 16 ER - TY - JOUR A1 - Li, Wenhong A1 - Sancho, Ana A1 - Chung, Wen-Lu A1 - Vinik, Yaron A1 - Groll, Jürgen A1 - Zick, Yehiel A1 - Medalia, Ohad A1 - Bershadsky, Alexander D. A1 - Benjamin, Geiger T1 - Differential cellular responses to adhesive interactions with galectin-8- and fibronectin-coated substrates JF - Journal of Cell Science N2 - The mechanisms underlying the cellular response to extracellular matrices (ECMs) that consist of multiple adhesive ligands are still poorly understood. Here, we address this topic by monitoring specific cellular responses to two different extracellular adhesion molecules – the main integrin ligand fibronectin and galectin-8, a lectin that binds β-galactoside residues − as well as to mixtures of the two proteins. Compared with cell spreading on fibronectin, cell spreading on galectin-8-coated substrates resulted in increased projected cell area, more-pronounced extension of filopodia and, yet, the inability to form focal adhesions and stress fibers. These differences can be partially reversed by experimental manipulations of small G-proteins of the Rho family and their downstream targets, such as formins, the Arp2/3 complex and Rho kinase. We also show that the physical adhesion of cells to galectin-8 was stronger than adhesion to fibronectin. Notably, galectin-8 and fibronectin differently regulate cell spreading and focal adhesion formation, yet act synergistically to upregulate the number and length of filopodia. The physiological significance of the coherent cellular response to a molecularly complex matrix is discussed. This article has an associated First Person interview with the first author of the paper. KW - extracellular matrix KW - focal adhesions KW - filopodia KW - lamellipodia KW - myosin-II KW - Rho GTPases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364286 VL - 134 ER - TY - JOUR A1 - Li, Shushan A1 - Stöckl, Sabine A1 - Lukas, Christoph A1 - Herrmann, Marietta A1 - Brochhausen, Christoph A1 - König, Matthias A. A1 - Johnstone, Brian A1 - Grässel, Susanne T1 - Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1β-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p JF - Stem Cell Research & Therapy N2 - Background Curcumin has anti-inflammatory effects and qualifies as a potential candidate for the treatment of osteoarthritis (OA). However, curcumin has limited bioavailability. Extracellular vesicles (EVs) are released by multiple cell types and act as molecule carrier during intercellular communication. We assume that EVs can maintain bioavailability and stability of curcumin after encapsulation. Here, we evaluated modulatory effects of curcumin-primed human (h)BMSC-derived EVs (Cur-EVs) on IL-1β stimulated human osteoarthritic chondrocytes (OA-CH). Methods CellTiter-Blue Viability- (CTB), Caspase 3/7-, and live/dead assays were used to determine range of cytotoxic curcumin concentrations for hBMSC and OA-CH. Cur-EVs and control EVs were harvested from cell culture supernatants of hBMSC by ultracentrifugation. Western blotting (WB), transmission electron microscopy, and nanoparticle tracking analysis were performed to characterize the EVs. The intracellular incorporation of EVs derived from PHK26 labeled and curcumin-primed or control hBMSC was tested by adding the labeled EVs to OA-CH cultures. OA-CH were pre-stimulated with IL-1β, followed by Cur-EV and control EV treatment for 24 h and subsequent analysis of viability, apoptosis, and migration (scratch assay). Relative expression of selected anabolic and catabolic genes was assessed with qRT-PCR. Furthermore, WB was performed to evaluate phosphorylation of Erk1/2, PI3K/Akt, and p38MAPK in OA-CH. The effect of hsa-miR-126-3p expression on IL-1β-induced OA-CH was determined using CTB-, Caspase 3/7-, live/dead assays, and WB. Results Cur-EVs promoted viability and reduced apoptosis of IL-1β-stimulated OA-CH and attenuated IL-1β-induced inhibition of migration. Furthermore, Cur-EVs increased gene expression of BCL2, ACAN, SOX9, and COL2A1 and decreased gene expression of IL1B, IL6, MMP13, and COL10A1 in IL-1β-stimulated OA-CH. In addition, phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK, induced by IL-1β, is prevented by Cur-EVs. Cur-EVs increased IL-1β-reduced expression of hsa-miR-126-3p and hsa-miR-126-3p mimic reversed the effects of IL-1β. Conclusion Cur-EVs alleviated IL-1β-induced catabolic effects on OA-CH by promoting viability and migration, reducing apoptosis and phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK thereby modulating pro-inflammatory signaling pathways. Treatment of OA-CH with Cur-EVs is followed by upregulation of expression of hsa-miR-126-3p which is involved in modulation of anabolic response of OA-CH. EVs may be considered as promising drug delivery vehicles of curcumin helping to alleviate OA. KW - BMSC KW - curcumin KW - extracellular vesicles KW - IL-1β KW - osteoarthritis KW - pro-inflammatory signaling pathways KW - chondrocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364237 VL - 12 ER - TY - JOUR A1 - Li, Ming A1 - Zhang, Rui A1 - Fan, Guangyi A1 - Xu, Wenteng A1 - Zhou, Qian A1 - Wang, Lei A1 - Li, Wensheng A1 - Pang, Zunfang A1 - Yu, Mengjun A1 - Liu, Qun A1 - Liu, Xin A1 - Schartl, Manfred A1 - Chen, Songlin T1 - Reconstruction of the Origin of a Neo-Y Sex Chromosome and Its Evolution in the Spotted Knifejaw, Oplegnathus punctatus JF - Molecular Biology and Evolution N2 - Sex chromosomes are a peculiar constituent of the genome because the evolutionary forces that fix the primary sex-determining gene cause genic degeneration and accumulation of junk DNA in the heterogametic partner. One of the most spectacular phenomena in sex chromosome evolution is the occurrence of neo-Y chromosomes, which lead to X1X2Y sex-determining systems. Such neo-sex chromosomes are critical for understanding the processes of sex chromosome evolution because they rejuvenate their total gene content. We assembled the male and female genomes at the chromosome level of the spotted knifejaw (Oplegnathus punctatus), which has a cytogenetically recognized neo-Y chromosome. The full assembly and annotation of all three sex chromosomes allowed us to reconstruct their evolutionary history. Contrary to other neo-Y chromosomes, the fusion to X2 is quite ancient, estimated at 48 Ma. Despite its old age and being even older in the X1 homologous region which carries a huge inversion that occurred as early as 55–48 Ma, genetic degeneration of the neo-Y appears to be only moderate. Transcriptomic analysis showed that sex chromosomes harbor 87 genes, which may serve important functions in the testis. The accumulation of such male-beneficial genes, a large inversion on the X1 homologous region and fusion to X2 appear to be the main drivers of neo-Y evolution in the spotted knifejaw. The availability of high-quality assemblies of the neo-Y and both X chromosomes make this fish an ideal model for a better understanding of the variability of sex determination mechanisms and of sex chromosome evolution. KW - neo-Y KW - evolution; KW - spotted knifejaw KW - genome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-364215 VL - 38 ER - TY - JOUR A1 - Li, Jinlin A1 - Nagy, Noemi A1 - Liu, Jiangnan A1 - Gupta, Soham A1 - Frisan, Teresa A1 - Hennig, Thomas A1 - Cameron, Donald P. A1 - Baranello, Laura A1 - Masucci, Maria G. T1 - The Epstein-Barr virus deubiquitinating enzyme BPLF1 regulates the activity of topoisomerase II during productive infection JF - PLOS Pathogens N2 - Topoisomerases are essential for the replication of herpesviruses but the mechanisms by which the viruses hijack the cellular enzymes are largely unknown. We found that topoisomerase-II (TOP2) is a substrate of the Epstein-Barr virus (EBV) ubiquitin deconjugase BPLF1. BPLF1 co-immunoprecipitated and deubiquitinated TOP2, and stabilized SUMOy-lated TOP2 trapped in cleavage complexes (TOP2ccs), which halted the DNA damage response to TOP2-induced double strand DNA breaks and promoted cell survival. Induction of the productive virus cycle in epithelial and lymphoid cell lines carrying recombinant EBV encoding the active enzyme was accompanied by TOP2 deubiquitination, accumulation of TOP2ccs and resistance to Etoposide toxicity. The protective effect of BPLF1 was dependent on the expression of tyrosyl-DNA phosphodiesterase 2 (TDP2) that releases DNA-trapped TOP2 and promotes error-free DNA repair. These findings highlight a previously unrecognized function of BPLF1 in supporting a non-proteolytic pathway for TOP2ccs debulking that favors cell survival and virus production. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363841 VL - 17 ER - TY - JOUR A1 - Li, Donghai A1 - Trovatello, Chiara A1 - Dal Conte, Stefano A1 - Nuß, Matthias A1 - Soavi, Giancarlo A1 - Wang, Gang A1 - Ferrari, Andrea C. A1 - Cerullo, Giulio A1 - Brixner, Tobias T1 - Exciton–phonon coupling strength in single-layer MoSe2 at room temperature JF - Nature Communications N2 - Single-layer transition metal dichalcogenides are at the center of an ever increasing research effort both in terms of fundamental physics and applications. Exciton–phonon coupling plays a key role in determining the (opto)electronic properties of these materials. However, the exciton–phonon coupling strength has not been measured at room temperature. Here, we use two-dimensional micro-spectroscopy to determine exciton–phonon coupling of single-layer MoSe2. We detect beating signals as a function of waiting time induced by the coupling between A excitons and A′1 optical phonons. Analysis of beating maps combined with simulations provides the exciton–phonon coupling. We get a Huang–Rhys factor ~1, larger than in most other inorganic semiconductor nanostructures. Our technique offers a unique tool to measure exciton–phonon coupling also in other heterogeneous semiconducting systems, with a spatial resolution ~260 nm, and provides design-relevant parameters for the development of optoelectronic devices. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363837 VL - 12 ER - TY - JOUR A1 - Lewis, Richard A1 - Habringer, Stefan A1 - Kircher, Malte A1 - Hefter, Maike A1 - Peuker, Caroline Anna A1 - Werner, Rudolf A1 - Ademaj-Kospiri, Valëza A1 - Gäble, Alexander A1 - Weber, Wolfgang A1 - Wester, Hans-Jürgen A1 - Buck, Andreas A1 - Herhaus, Peter A1 - Lapa, Constantin A1 - Keller, Ulrich T1 - Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients JF - EJNMMI Research N2 - Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities. KW - solid tumors KW - clinical studies KW - retrospective studies KW - molecular imaging KW - PET KW - CXCR4 KW - Pentixafor KW - spleen KW - uptake Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363820 VL - 11 ER - TY - JOUR A1 - Levitis, Elizabeth A1 - Gould van Praag, Cassandra D A1 - Gau, Rémi A1 - Heunis, Stephan A1 - DuPre, Elizabeth A1 - Kiar, Gregory A1 - Bottenhorn, Katherine L A1 - Glatard, Tristan A1 - Nikolaidis, Aki A1 - Whitaker, Kirstie Jane A1 - Mancini, Matteo A1 - Niso, Guiomar A1 - Afyouni, Soroosh A1 - Alonso-Ortiz, Eva A1 - Appelhoff, Stefan A1 - Arnatkeviciute, Aurina A1 - Atay, Selim Melvin A1 - Auer, Tibor A1 - Baracchini, Giulia A1 - Bayer, Johanna M M A1 - Beauvais, Michael J S A1 - Bijsterbosch, Janine D A1 - Bilgin, Isil P A1 - Bollmann, Saskia A1 - Bollmann, Steffen A1 - Botvinik-Nezer, Rotem A1 - Bright, Molly G A1 - Calhoun, Vince D A1 - Chen, Xiao A1 - Chopra, Sidhant A1 - Chuan-Peng, Hu A1 - Close, Thomas G A1 - Cookson, Savannah L A1 - Craddock, R Cameron A1 - De La Vega, Alejandro A1 - De Leener, Benjamin A1 - Demeter, Damion V A1 - Di Maio, Paola A1 - Dickie, Erin W A1 - Eickhoff, Simon B A1 - Esteban, Oscar A1 - Finc, Karolina A1 - Frigo, Matteo A1 - Ganesan, Saampras A1 - Ganz, Melanie A1 - Garner, Kelly G A1 - Garza-Villarreal, Eduardo A A1 - Gonzalez-Escamilla, Gabriel A1 - Goswami, Rohit A1 - Griffiths, John D A1 - Grootswagers, Tijl A1 - Guay, Samuel A1 - Guest, Olivia A1 - Handwerker, Daniel A A1 - Herholz, Peer A1 - Heuer, Katja A1 - Huijser, Dorien C A1 - Iacovella, Vittorio A1 - Joseph, Michael J E A1 - Karakuzu, Agah A1 - Keator, David B A1 - Kobeleva, Xenia A1 - Kumar, Manoj A1 - Laird, Angela R A1 - Larson-Prior, Linda J A1 - Lautarescu, Alexandra A1 - Lazari, Alberto A1 - Legarreta, Jon Haitz A1 - Li, Xue-Ying A1 - Lv, Jinglei A1 - Mansour L., Sina A1 - Meunier, David A1 - Moraczewski, Dustin A1 - Nandi, Tulika A1 - Nastase, Samuel A A1 - Nau, Matthias A1 - Noble, Stephanie A1 - Norgaard, Martin A1 - Obungoloch, Johnes A1 - Oostenveld, Robert A1 - Orchard, Edwina R A1 - Pinho, Ana Luísa A1 - Poldrack, Russell A A1 - Qiu, Anqi A1 - Raamana, Pradeep Reddy A1 - Rokem, Ariel A1 - Rutherford, Saige A1 - Sharan, Malvika A1 - Shaw, Thomas B A1 - Syeda, Warda T A1 - Testerman, Meghan M A1 - Toro, Roberto A1 - Valk, Sofie L A1 - Van Den Bossche, Sofie A1 - Varoquaux, Gaël A1 - Váša, František A1 - Veldsman, Michele A1 - Vohryzek, Jakub A1 - Wagner, Adina S A1 - Walsh, Reubs J A1 - White, Tonya A1 - Wong, Fu-Te A1 - Xie, Xihe A1 - Yan, Chao-Gan A1 - Yang, Yu-Fang A1 - Yee, Yohan A1 - Zanitti, Gaston E A1 - Van Gulick, Ana E A1 - Duff, Eugene A1 - Maumet, Camille T1 - Centering inclusivity in the design of online conferences—An OHBM–Open Science perspective JF - GigaScience N2 - As the global health crisis unfolded, many academic conferences moved online in 2020. This move has been hailed as a positive step towards inclusivity in its attenuation of economic, physical, and legal barriers and effectively enabled many individuals from groups that have traditionally been underrepresented to join and participate. A number of studies have outlined how moving online made it possible to gather a more global community and has increased opportunities for individuals with various constraints, e.g., caregiving responsibilities. Yet, the mere existence of online conferences is no guarantee that everyone can attend and participate meaningfully. In fact, many elements of an online conference are still significant barriers to truly diverse participation: the tools used can be inaccessible for some individuals; the scheduling choices can favour some geographical locations; the set-up of the conference can provide more visibility to well-established researchers and reduce opportunities for early-career researchers. While acknowledging the benefits of an online setting, especially for individuals who have traditionally been underrepresented or excluded, we recognize that fostering social justice requires inclusivity to actively be centered in every aspect of online conference design. Here, we draw from the literature and from our own experiences to identify practices that purposefully encourage a diverse community to attend, participate in, and lead online conferences. Reflecting on how to design more inclusive online events is especially important as multiple scientific organizations have announced that they will continue offering an online version of their event when in-person conferences can resume. KW - online conferences KW - diversity KW - inclusivity KW - open science KW - collaborative events Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371574 VL - 10 ER - TY - JOUR A1 - Letunic, Ivica A1 - Bork, Peer T1 - Interactive Tree Of Life (iTOL) v5: an online tool for phylogenetic tree display and annotation JF - Nucleic Acids Research N2 - The Interactive Tree Of Life (https://itol.embl.de) is an online tool for the display, manipulation and annotation of phylogenetic and other trees. It is freely available and open to everyone. iTOL version 5 introduces a completely new tree display engine, together with numerous new features. For example, a new dataset type has been added (MEME motifs), while annotation options have been expanded for several existing ones. Node metadata display options have been extended and now also support non-numerical categorical values, as well as multiple values per node. Direct manual annotation is now available, providing a set of basic drawing and labeling tools, allowing users to draw shapes, labels and other features by hand directly onto the trees. Support for tree and dataset scales has been extended, providing fine control over line and label styles. Unrooted tree displays can now use the equal-daylight algorithm, proving a much greater display clarity. The user account system has been streamlined and expanded with new navigation options and currently handles >1 million trees from >70 000 individual users. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363803 VL - 49 ER - TY - JOUR A1 - Leich, Ellen A1 - Schreder, Martin A1 - Pischimarov, Jordan A1 - Stühmer, Thorsten A1 - Steinbrunn, Torsten A1 - Rudelius, Martina A1 - Brünnert, Daniela A1 - Chatterjee, Manik A1 - Langer, Christian A1 - Keppler, Sarah A1 - Heredia-Guerrero, Sofia Catalina A1 - Einsele, Hermann A1 - Knop, Stefan A1 - Bargou, Ralf Christian A1 - Rosenwald, Andreas T1 - Novel molecular subgroups within the context of receptor tyrosine kinase and adhesion signalling in multiple myeloma JF - Blood Cancer Journal N2 - No abstract available. KW - cancer genetics KW - cancer genomics KW - cancer therapy KW - myeloma KW - translational research Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363410 VL - 11 ER - TY - JOUR A1 - Leich, Ellen A1 - Maier, Claudia A1 - Bomben, Riccardo A1 - Vit, Filippo A1 - Bosi, Alessandro A1 - Horn, Heike A1 - Gattei, Valter A1 - Ott, German A1 - Rosenwald, Andreas A1 - Zamò, Alberto T1 - Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage JF - Blood Advances N2 - We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment-naive and relapsed tumors. The clonotype was determined by using a next-generation sequencing approach in a series of 68 FL with fresh frozen material [36 t(14;18) positive and 32 t(14;18) negative]. The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL stage III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL stage I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment-naive FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared with t(14;18)-positive treatment-naive cases with NANGS; IGHV4-34 usage was never recorded in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of B-cell receptor stimulation compared with the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363378 VL - 5 ER - TY - JOUR A1 - Lehnert, Teresa A1 - Prauße, Maria T. E. A1 - Hünniger, Kerstin A1 - Praetorius, Jan-Philipp A1 - Kurzai, Oliver A1 - Figge, Marc Thilo T1 - Comparative assessment of immune evasion mechanisms in human whole-blood infection assays by a systems biology approach JF - PLOS ONE N2 - Computer simulations of mathematical models open up the possibility of assessing hypotheses generated by experiments on pathogen immune evasion in human whole-blood infection assays. We apply an interdisciplinary systems biology approach in which virtual infection models implemented for the dissection of specific immune mechanisms are combined with experimental studies to validate or falsify the respective hypotheses. Focusing on the assessment of mechanisms that enable pathogens to evade the immune response in the early time course of a whole-blood infection, the least-square error (LSE) as a measure for the quantitative agreement between the theoretical and experimental kinetics is combined with the Akaike information criterion (AIC) as a measure for the model quality depending on its complexity. In particular, we compare mathematical models with three different types of pathogen immune evasion as well as all their combinations: (i) spontaneous immune evasion, (ii) evasion mediated by immune cells, and (iii) pre-existence of an immune-evasive pathogen subpopulation. For example, by testing theoretical predictions in subsequent imaging experiments, we demonstrate that the simple hypothesis of having a subpopulation of pre-existing immune-evasive pathogens can be ruled out. Furthermore, in this study we extend our previous whole-blood infection assays for the two fungal pathogens Candida albicans and C. glabrata by the bacterial pathogen Staphylococcus aureus and calibrated the model predictions to the time-resolved experimental data for each pathogen. Our quantitative assessment generally reveals that models with a lower number of parameters are not only scored with better AIC values, but also exhibit lower values for the LSE. Furthermore, we describe in detail model-specific and pathogen-specific patterns in the kinetics of cell populations that may be measured in future experiments to distinguish and pinpoint the underlying immune mechanisms. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363343 VL - 16 ER - TY - JOUR A1 - Lehnert, Teresa A1 - Leonhardt, Ines A1 - Timme, Sandra A1 - Thomas-Rüddel, Daniel A1 - Bloos, Frank A1 - Sponholz, Christoph A1 - Kurzai, Oliver A1 - Figge, Marc Thilo A1 - Hünniger, Kerstin T1 - Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions JF - Scientific Reports N2 - The assessment of a patient’s immune function is critical in many clinical situations. In complex clinical immune dysfunction like sepsis, which results from a loss of immune homeostasis due to microbial infection, a plethora of pro- and anti-inflammatory stimuli may occur consecutively or simultaneously. Thus, any immunomodulatory therapy would require in-depth knowledge of an individual patient’s immune status at a given time. Whereas lab-based immune profiling often relies solely on quantification of cell numbers, we used an ex vivo whole-blood infection model in combination with biomathematical modeling to quantify functional parameters of innate immune cells in blood from patients undergoing cardiac surgery. These patients experience a well-characterized inflammatory insult, which results in mitigation of the pathogen-specific response patterns towards Staphylococcus aureus and Candida albicans that are characteristic of healthy people and our patients at baseline. This not only interferes with the elimination of these pathogens from blood, but also selectively augments the escape of C. albicans from phagocytosis. In summary, our model could serve as a valuable functional immune assay for recording and evaluating innate responses to infection. KW - computational biology and bioinformatics KW - computational models KW - immunology KW - infection KW - inflammation KW - innate immunity Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363337 VL - 11 ER - TY - JOUR A1 - Lehmann, Julian A1 - Jørgensen, Morten E. A1 - Fratz, Stefanie A1 - Müller, Heike M. A1 - Kusch, Jana A1 - Scherzer, Sönke A1 - Navarro-Retamal, Carlos A1 - Mayer, Dominik A1 - Böhm, Jennifer A1 - Konrad, Kai R. A1 - Terpitz, Ulrich A1 - Dreyer, Ingo A1 - Mueller, Thomas D. A1 - Sauer, Markus A1 - Hedrich, Rainer A1 - Geiger, Dietmar A1 - Maierhofer, Tobias T1 - Acidosis-induced activation of anion channel SLAH3 in the flooding-related stress response of Arabidopsis JF - Current Biology N2 - Plants, as sessile organisms, gained the ability to sense and respond to biotic and abiotic stressors to survive severe changes in their environments. The change in our climate comes with extreme dry periods but also episodes of flooding. The latter stress condition causes anaerobiosis-triggered cytosolic acidosis and impairs plant function. The molecular mechanism that enables plant cells to sense acidity and convey this signal via membrane depolarization was previously unknown. Here, we show that acidosis-induced anion efflux from Arabidopsis (Arabidopsis thaliana) roots is dependent on the S-type anion channel AtSLAH3. Heterologous expression of SLAH3 in Xenopus oocytes revealed that the anion channel is directly activated by a small, physiological drop in cytosolic pH. Acidosis-triggered activation of SLAH3 is mediated by protonation of histidine 330 and 454. Super-resolution microscopy analysis showed that the increase in cellular proton concentration switches SLAH3 from an electrically silent channel dimer into its active monomeric form. Our results show that, upon acidification, protons directly switch SLAH3 to its open configuration, bypassing kinase-dependent activation. Moreover, under flooding conditions, the stress response of Arabidopsis wild-type (WT) plants was significantly higher compared to SLAH3 loss-of-function mutants. Our genetic evidence of SLAH3 pH sensor function may guide the development of crop varieties with improved stress tolerance. KW - SLAH3 KW - S-type anion channel KW - hypoxia KW - pH KW - cytosolic acidification KW - flooding KW - PALM KW - stoichiometry Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363320 VL - 31 ER - TY - JOUR A1 - Lee, Duk Hyun A1 - Choi, Sang-Jun A1 - Kim, Hakseong A1 - Kim, Yong-Sung A1 - Jung, Suyong T1 - Direct probing of phonon mode specific electron–phonon scatterings in two-dimensional semiconductor transition metal dichalcogenides JF - Nature Communications N2 - Electron–phonon scatterings in solid-state systems are pivotal processes in determining many key physical quantities such as charge carrier mobilities and thermal conductivities. Here, we report direct probing of phonon mode specific electron–phonon scatterings in layered semiconducting transition metal dichalcogenides WSe2, MoSe2, WS2, and MoS2 through inelastic electron tunneling spectroscopy measurements, quantum transport simulations, and density functional calculation. We experimentally and theoretically characterize momentum-conserving single- and two-phonon electron–phonon scatterings involving up to as many as eight individual phonon modes in mono- and bilayer films, among which transverse, longitudinal acoustic and optical, and flexural optical phonons play significant roles in quantum charge flows. Moreover, the layer-number sensitive higher-order inelastic electron–phonon scatterings, which are confirmed to be generic in all four semiconducting layers, can be attributed to differing electronic structures, symmetry, and quantum interference effects during the scattering processes in the ultrathin semiconducting films. KW - electronic properties and materials KW - two-dimensional materials Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363261 VL - 12 ER - TY - JOUR A1 - Lebedev, N. A1 - Stehno, M. A1 - Rana, A. A1 - Reith, P. A1 - Gauquelin, N. A1 - Verbeeck, J. A1 - Hilgenkamp, H. A1 - Brinkman, A. A1 - Aarts, J. T1 - Gate-tuned anomalous Hall effect driven by Rashba splitting in intermixed LaAlO3/GdTiO3/SrTiO3 JF - Scientific Reports N2 - The Anomalous Hall Effect (AHE) is an important quantity in determining the properties and understanding the behaviour of the two-dimensional electron system forming at the interface of SrTiO3-based oxide heterostructures. The occurrence of AHE is often interpreted as a signature of ferromagnetism, but it is becoming more and more clear that also paramagnets may contribute to AHE. We studied the influence of magnetic ions by measuring intermixed LaAlO3/GdTiO3/SrTiO3 at temperatures below 10 K. We find that, as function of gate voltage, the system undergoes a Lifshitz transition while at the same time an onset of AHE is observed. However, we do not observe clear signs of ferromagnetism. We argue the AHE to be due to the change in Rashba spin-orbit coupling at the Lifshitz transition and conclude that also paramagnetic moments which are easily polarizable at low temperatures and high magnetic fields lead to the presence of AHE, which needs to be taken into account when extracting carrier densities and mobilities. KW - materials science KW - surfaces, interfaces and thin films Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363244 VL - 11 ER - TY - JOUR A1 - Jotz Lean, Madeleine A1 - Mackenzie, Kirill C. H. T1 - Transitive double Lie algebroids via core diagrams JF - Journal of Geometric Mechanics N2 - The core diagram of a double Lie algebroid consists of the core of the double Lie algebroid, together with the two core-anchor maps to the sides of the double Lie algebroid. If these two core-anchors are surjective, then the double Lie algebroid and its core diagram are called transitive. This paper establishes an equivalence between transitive double Lie algebroids, and transitive core diagrams over a fixed base manifold. In other words, it proves that a transitive double Lie algebroid is completely determined by its core diagram. The comma double Lie algebroid associated to a morphism of Lie algebroids is defined. If the latter morphism is one of the core-anchors of a transitive core diagram, then the comma double algebroid can be quotiented out by the second core-anchor, yielding a transitive double Lie algebroid, which is the one that is equivalent to the transitive core diagram. Brown's and Mackenzie's equivalence of transitive core diagrams (of Lie groupoids) with transitive double Lie groupoids is then used in order to show that a transitive double Lie algebroid with integrable sides and core is automatically integrable to a transitive double Lie groupoid. KW - double Lie algebroids KW - double Lie groupoids KW - comma category KW - representations up to homotopy KW - matched pairs KW - Lie bialgebroids KW - infinitesimal ideal systems KW - integration Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363224 VL - 13 ER - TY - JOUR A1 - Le Provost, Gaëtane A1 - Thiele, Jan A1 - Westphal, Catrin A1 - Penone, Caterina A1 - Allan, Eric A1 - Neyret, Margot A1 - van der Plas, Fons A1 - Ayasse, Manfred A1 - Bardgett, Richard D. A1 - Birkhofer, Klaus A1 - Boch, Steffen A1 - Bonkowski, Michael A1 - Buscot, Francois A1 - Feldhaar, Heike A1 - Gaulton, Rachel A1 - Goldmann, Kezia A1 - Gossner, Martin M. A1 - Klaus, Valentin H. A1 - Kleinebecker, Till A1 - Krauss, Jochen A1 - Renner, Swen A1 - Scherreiks, Pascal A1 - Sikorski, Johannes A1 - Baulechner, Dennis A1 - Blüthgen, Nico A1 - Bolliger, Ralph A1 - Börschig, Carmen A1 - Busch, Verena A1 - Chisté, Melanie A1 - Fiore-Donno, Anna Maria A1 - Fischer, Markus A1 - Arndt, Hartmut A1 - Hoelzel, Norbert A1 - John, Katharina A1 - Jung, Kirsten A1 - Lange, Markus A1 - Marzini, Carlo A1 - Overmann, Jörg A1 - Paŝalić, Esther A1 - Perović, David J. A1 - Prati, Daniel A1 - Schäfer, Deborah A1 - Schöning, Ingo A1 - Schrumpf, Marion A1 - Sonnemann, Ilja A1 - Steffan-Dewenter, Ingolf A1 - Tschapka, Marco A1 - Türke, Manfred A1 - Vogt, Juliane A1 - Wehner, Katja A1 - Weiner, Christiane A1 - Weisser, Wolfgang A1 - Wells, Konstans A1 - Werner, Michael A1 - Wolters, Volkmar A1 - Wubet, Tesfaye A1 - Wurst, Susanne A1 - Zaitsev, Andrey S. A1 - Manning, Peter T1 - Contrasting responses of above- and belowground diversity to multiple components of land-use intensity JF - Nature Communications N2 - Land-use intensification is a major driver of biodiversity loss. However, understanding how different components of land use drive biodiversity loss requires the investigation of multiple trophic levels across spatial scales. Using data from 150 agricultural grasslands in central Europe, we assess the influence of multiple components of local- and landscape-level land use on more than 4,000 above- and belowground taxa, spanning 20 trophic groups. Plot-level land-use intensity is strongly and negatively associated with aboveground trophic groups, but positively or not associated with belowground trophic groups. Meanwhile, both above- and belowground trophic groups respond to landscape-level land use, but to different drivers: aboveground diversity of grasslands is promoted by diverse surrounding land-cover, while belowground diversity is positively related to a high permanent forest cover in the surrounding landscape. These results highlight a role of landscape-level land use in shaping belowground communities, and suggest that revised agroecosystem management strategies are needed to conserve whole-ecosystem biodiversity. KW - biodiversity KW - community ecology KW - grassland ecology Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371552 VL - 12 ER - TY - JOUR A1 - Lauruschkat, Chris D. A1 - Page, Lukas A1 - Etter, Sonja A1 - Weis, Philipp A1 - Gamon, Florian A1 - Kraus, Sabrina A1 - Einsele, Hermann A1 - Wurster, Sebastian A1 - Loeffler, Juergen T1 - T-Cell Immune Surveillance in Allogenic Stem Cell Transplant Recipients: Are Whole Blood–Based Assays Ready to Challenge ELISPOT? JF - Open Forum Infectious Diseases N2 - We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology. KW - immunoassay KW - biomarker KW - aspergillosis KW - cytomegalovirus KW - T cells KW - cytokines KW - flow cytometry KW - ELISPOT Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363164 VL - 8 ER - TY - JOUR A1 - Larrieu, Laurent A1 - Cabanettes, Alain A1 - Courbaud, Benoit A1 - Goulard, Michel A1 - Heintz, Wilfried A1 - Kozák, Daniel A1 - Kraus, Daniel A1 - Lachat, Thibault A1 - Ladet, Sylvie A1 - Müller, Jörg A1 - Paillet, Yoan A1 - Schuck, Andreas A1 - Stillhard, Jonas A1 - Svoboda, Miroslav T1 - Co-occurrence patterns of tree-related microhabitats: A method to simplify routine monitoring JF - Ecological Indicators N2 - A Tree-related Microhabitat (TreM) is a distinct, well-delineated morphological singularity occurring on living or standing dead trees, which constitutes a crucial substrate or life site for various species. TreMs are widely recognized as key features for biodiversity. Current TreM typology identifies 47 TreM types according to their morphology and their associated taxa. In order to provide a range of resolutions and make the typology more user-friendly, these 47 TreM types have been pooled into 15 groups and seven forms. Depending on the accuracy required and the time available, a user can now choose to describe TreMs at resolution levels corresponding to type, group or form. Another way to more easily record TreMs during routine management work would be to use co-occurrence patterns to reduce the number of observed TreMs required. Based on a large international TreM database (2052 plots; 70,958 individual trees; 78 tree species), we evaluated both the significance and the magnitude of TreM co-occurrence on living trees for 11 TreM groups. We highlighted 33 significant co-occurrences for broadleaves and nine for conifers. Bark loss, rot hole, crack and polypore had the highest number of positive co-occurrences (N = 8) with other TreMs on broadleaves; bark loss (N = 4) had the highest number for conifers. We found mutually exclusive occurrences only for conifers: Exposed Heartwood excluded both dendrotelm and sap run. Among the four variables we tested for their positive contribution to significant co-occurrences, tree diameter at breast height was the most consistent. Based on our results and practical considerations, we selected three TreM groups for broadleaves, and nine for conifers, and formed useful short lists to reduce the number of TreM groups to assess during routine forest management work in the field. In addition, detecting potential similarities or associations between TreMs has potential theoretical value, e.g. it may help researchers identify common factors favouring TreM formation or help managers select trees with multiple TreMs as candidates for retention. KW - TreM monitoring KW - biodiversity-friendly forest management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363158 VL - 127 ER - TY - JOUR A1 - Landing, Ed A1 - Geyer, Gerd A1 - Schmitz, Mark D. A1 - Wotte, Thomas A1 - Kouchinsky, Artem T1 - (Re)proposal of three Cambrian Subsystems and their Geochronology JF - Episodes N2 - The Cambrian is anomalous among geological systems as many reports divide it into three divisions of indeterminate rank. This use of “lower”, “middle”, and “upper” has been a convenient way to subdivide the Cambrian despite agreement it consists of four global series. Traditional divisions of the system into regional series (Lower, Middle, Upper) reflected local biotic developments not interprovincially correlatable with any precision. However, use of “lower”, “middle”, and “upper” is unsatisfactory. These adjectives lack standard definition, evoke the regional series, and are misused. Notably, there is an almost 50 year use of three Cambrian subsystems and a 1997 proposal to divide the Avalonian and global Cambrian into four series and three subsystems. The global series allow proposal of three formal subsystems: a ca. 32.6 Ma Lower Cambrian Subsystem (Terreneuvian and Series 2/proposed Lenaldanian Series), a ca. 9.8 Ma Middle, and a ca. 10 Ma Upper Cambrian Subsystem (=Furongian Series). Designations as “Lower Cambrian Subsystem” or “global Lower Cambrian” distinguish the new units from such earlier units as “Lower Cambrian Series” and substitute for the de facto subsystem terms “lower”, “middle”, and “upper”. Cambrian subsystems are comparable to the Carboniferous’ Lower (Mississippian) and Upper (Pennsylvanian) Subsystems. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363144 VL - 44 ER - TY - JOUR A1 - Lackner, L. A1 - Dusel, M. A1 - Egorov, O. A. A1 - Han, B. A1 - Knopf, H. A1 - Eilenberger, F. A1 - Schröder, S. A1 - Watanabe, K. A1 - Taniguchi, T. A1 - Tongay, S. A1 - Anton-Solanas, C. A1 - Höfling, S. A1 - Schneider, C. T1 - Tunable exciton-polaritons emerging from WS2 monolayer excitons in a photonic lattice at room temperature JF - Nature Communications N2 - Engineering non-linear hybrid light-matter states in tailored lattices is a central research strategy for the simulation of complex Hamiltonians. Excitons in atomically thin crystals are an ideal active medium for such purposes, since they couple strongly with light and bear the potential to harness giant non-linearities and interactions while presenting a simple sample-processing and room temperature operability. We demonstrate lattice polaritons, based on an open, high-quality optical cavity, with an imprinted photonic lattice strongly coupled to excitons in a WS2 monolayer. We experimentally observe the emergence of the canonical band-structure of particles in a one-dimensional lattice at room temperature, and demonstrate frequency reconfigurability over a spectral window exceeding 85 meV, as well as the systematic variation of the nearest-neighbour coupling, reflected by a tunability in the bandwidth of the p-band polaritons by 7 meV. The technology presented in this work is a critical demonstration towards reconfigurable photonic emulators operated with non-linear photonic fluids, offering a simple experimental implementation and working at ambient conditions. KW - Bose–Einstein condensates KW - nonlinear optics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363080 VL - 12 ER - TY - JOUR A1 - Kuhl, Heiner A1 - Guiguen, Yann A1 - Höhne, Christin A1 - Kreuz, Eva A1 - Du, Kang A1 - Klopp, Christophe A1 - Lopez-Roques,, Céline A1 - Yebra-Pimentel, Elena Santidrian A1 - Ciorpac, Mitica A1 - Gessner, Jörn A1 - Holostenco, Daniela A1 - Kleiner, Wibke A1 - Kohlmann, Klaus A1 - Lamatsch, Dunja K. A1 - Prokopov, Dmitry A1 - Bestin, Anastasia A1 - Bonpunt, Emmanuel A1 - Debeuf, Bastien A1 - Haffray, Pierrick A1 - Morvezen, Romain A1 - Patrice, Pierre A1 - Suciu, Radu A1 - Dirks, Ron A1 - Wuertz, Sven A1 - Kloas, Werner A1 - Schartl, Manfred A1 - Stöck, Matthias T1 - A 180 Myr-old female-specific genome region in sturgeon reveals the oldest known vertebrate sex determining system with undifferentiated sex chromosomes JF - Philosophical Transactions of the Royal Society B N2 - Several hypotheses explain the prevalence of undifferentiated sex chromosomes in poikilothermic vertebrates. Turnovers change the master sex determination gene, the sex chromosome or the sex determination system (e.g. XY to WZ). Jumping master genes stay main triggers but translocate to other chromosomes. Occasional recombination (e.g. in sex-reversed females) prevents sex chromosome degeneration. Recent research has uncovered conserved heteromorphic or even homomorphic sex chromosomes in several clades of non-avian and non-mammalian vertebrates. Sex determination in sturgeons (Acipenseridae) has been a long-standing basic biological question, linked to economical demands by the caviar-producing aquaculture. Here, we report the discovery of a sex-specific sequence from sterlet (Acipenser ruthenus). Using chromosome-scale assemblies and pool-sequencing, we first identified an approximately 16 kb female-specific region. We developed a PCR-genotyping test, yielding female-specific products in six species, spanning the entire phylogeny with the most divergent extant lineages (A. sturio, A. oxyrinchus versus A. ruthenus, Huso huso), stemming from an ancient tetraploidization. Similar results were obtained in two octoploid species (A. gueldenstaedtii, A. baerii). Conservation of a female-specific sequence for a long period, representing 180 Myr of sturgeon evolution, and across at least one polyploidization event, raises many interesting biological questions. We discuss a conserved undifferentiated sex chromosome system with a ZZ/ZW-mode of sex determination and potential alternatives. This article is part of the theme issue ‘Challenging the paradigm in sex chromosome evolution: empirical and theoretical insights with a focus on vertebrates (Part I)’. KW - acipenseridae KW - sturgeon KW - sex chromosomes KW - female-specific KW - polyploidy KW - evolution Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363050 VL - 376 ER - TY - JOUR A1 - Lobbezoo, Frank A1 - Aarab, Ghizlane A1 - Ahlers, M. Oliver A1 - Baad-Hansen, Lene A1 - Bernhardt, Olaf A1 - Castrillon, Eduardo E. A1 - Giannakopoulos, Nikolaos Nikitas A1 - Grønbeck, Anders A1 - Hauschild, Justus A1 - Holst-Knudsen, Marianne A1 - Skovlund, Naja A1 - Thymi, Magdalini A1 - Svensson, Peter T1 - Consensus-based clinical guidelines for ambulatory electromyography and contingent electrical stimulation in sleep bruxism JF - Journal of Oral Rehabilitation N2 - As yet, there are still no evidence-based clinical diagnostic and management guidelines for ambulatory single-channel EMG devices, like the BUTLER® GrindCare® (GrindCare), that are used in patients with sleep bruxism. Therefore, a consensus meeting was organised with GrindCare developers, researchers, and academic and non-academic clinicians experienced with the use of ambulatory EMG devices. The aim of the meeting was to discuss and develop recommendations for clinical guidelines for GrindCare usage, based on the existing clinical and research experience of the consensus meeting's participants. As an important outcome of the consensus meeting, clinical guidelines were proposed in which an initial 2-week baseline phase with the device in its inactive (non-stimulus) mode for habituation and assessment of the number of jaw-muscle activities is followed by a 4-week active phase with contingent electrical stimuli suppressing the jaw-muscle activities. As to avoid the commonly reported reduction in sensitivity to the stimuli, a 2-week inactive phase is subsequently installed, followed by a repetition of active and inactive phases until a lasting reduction in the number of jaw-muscle activities and/or associated complaints has been achieved. This proposal has the characteristics of a single-patient clinical trial. From a research point of view, adoption of this approach by large numbers of GrindCare users creates a great opportunity to recruit relatively large numbers of study participants that follow the same protocol. KW - assessment KW - clinical guideline KW - contingent electrical stimulation KW - electromyography KW - management KW - sleep bruxism Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237032 VL - 47 ER - TY - JOUR A1 - Banas, Bernhard A1 - Steubl, Dominik A1 - Renders, Lutz A1 - Chittka, Dominik A1 - Banas, Miriam C. A1 - Wekerle, Thomas A1 - Koch, Martina A1 - Witzke, Oliver A1 - Mühlfeld, Anja A1 - Sommerer, Claudia A1 - Habicht, Antje A1 - Hugo, Christian A1 - Hünig, Thomas A1 - Lindemann, Monika A1 - Schmidt, Traudel A1 - Rascle, Anne A1 - Barabas, Sascha A1 - Deml, Ludwig A1 - Wagner, Ralf A1 - Krämer, Bernhard K. A1 - Krüger, Bernd T1 - Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study JF - Transplant International N2 - Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88–92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042). KW - CMV-specific cell-mediated immunity KW - cytomegalovirus KW - IFN‐γ ELISpot KW - immunomonitoring KW - in vitro diagnostic KW - kidney or renal transplantation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221468 VL - 31 ER - TY - JOUR A1 - Andreatta, Marta A1 - Pauli, Paul T1 - Generalization of appetitive conditioned responses JF - Psychophysiology N2 - A stimulus (conditioned stimulus, CS) associated with an appetitive unconditioned stimulus (US) acquires positive properties and elicits appetitive conditioned responses (CR). Such associative learning has been examined extensively in animals with food as the US, and results are used to explain psychopathologies (e.g., substance-related disorders or obesity). Human studies on appetitive conditioning exist, too, but we still know little about generalization processes. Understanding these processes may explain why stimuli not associated with a drug, for instance, can elicit craving. Forty-seven hungry participants underwent an appetitive conditioning protocol during which one of two circles with different diameters (CS+) became associated with an appetitive US (chocolate or salty pretzel, according to participants’ preference) but never the other circle (CS−). During generalization, US were delivered twice and the two CS were presented again plus four circles (generalization stimuli, GS) with gradually increasing diameters from CS− to CS+. We found successful appetitive conditioning as reflected in appetitive subjective ratings (positive valence, higher contingency) and physiological responses (startle attenuation and larger skin conductance responses) to CS+ versus CS−, and, importantly, both measures confirmed generalization as indicated by generalization gradients. Small changes in CS-US contingency during generalization may have weakened generalization processes on the physiological level. Considering that appetitive conditioned responses can be generalized to non-US-associated stimuli, a next important step would be to investigate risk factors that mediate overgeneralization. KW - appetitive conditioning; ; KW - generalization KW - primary reinforcer KW - startle reflex Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221132 VL - 56 ER - TY - JOUR A1 - Chevalier‐Roignant, Benoît A1 - Flath, Christoph M. A1 - Trigeorgis, Lenos T1 - Disruptive Innovation, Market Entry and Production Flexibility in Heterogeneous Oligopoly JF - Production and Operations Management N2 - We develop a model of oligopoly competition involving innovation effort, market entry and production flexibility under demand uncertainty. Several heterogeneous firms make efforts to develop new prototypes; if they succeed, they hold a shared option to enter a new market under stochastic demand. We derive analytic results for the Markov perfect equilibrium accounting for development effort, market entry and production decisions and complement these by numerical analyses. Firm value—which embeds real options—is not convex increasing in demand but exhibits “competitive waves” due to market entries by rivals. A firm with a development advantage (“innovator”) exerts greater innovation effort if the market is a niche, whereas another benefiting from economies of scale (“incumbent”) invests more if the market is larger. Positive externalities benefit the incumbent in the development stage, whereas the innovator is better off in counteracting negative externalities. Demand volatility raises firm incentives to innovate as it enhances the value of firm market‐entry and production flexibility. KW - disruptive innovation KW - market entry KW - production flexibility KW - oligopoly Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-356226 VL - 28 ER - TY - JOUR A1 - Huang, Shouguang A1 - Waadt, Rainer A1 - Nuhkat, Maris A1 - Kollist, Hannes A1 - Hedrich, Rainer A1 - Roelfsema, M. Rob G. T1 - Calcium signals in guard cells enhance the efficiency by which abscisic acid triggers stomatal closure JF - New Phytologist N2 - During drought, abscisic acid (ABA) induces closure of stomata via a signaling pathway that involves the calcium (Ca2+)-independent protein kinase OST1, as well as Ca2+-dependent protein kinases. However, the interconnection between OST1 and Ca2+ signaling in ABA-induced stomatal closure has not been fully resolved. ABA-induced Ca2+ signals were monitored in intact Arabidopsis leaves, which express the ratiometric Ca2+ reporter R-GECO1-mTurquoise and the Ca2+-dependent activation of S-type anion channels was recorded with intracellular double-barreled microelectrodes. ABA triggered Ca2+ signals that occurred during the initiation period, as well as in the acceleration phase of stomatal closure. However, a subset of stomata closed in the absence of Ca2+ signals. On average, stomata closed faster if Ca2+ signals were elicited during the ABA response. Loss of OST1 prevented ABA-induced stomatal closure and repressed Ca2+ signals, whereas elevation of the cytosolic Ca2+ concentration caused a rapid activation of SLAC1 and SLAH3 anion channels. Our data show that the majority of Ca2+ signals are evoked during the acceleration phase of stomatal closure, which is initiated by OST1. These Ca2+ signals are likely to activate Ca2+-dependent protein kinases, which enhance the activity of S-type anion channels and boost stomatal closure. KW - abscisic acid (ABA) KW - Ca2+- indicator KW - cytosolic Ca2+ signals KW - OST1 protein kinase KW - R-GECO1-mTurquoise KW - SLAC1 and SLAH3 anion channels KW - stomata Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322716 VL - 224 ER - TY - JOUR A1 - Wan, Wei-Lin A1 - Zhang, Lisha A1 - Pruitt, Rory A1 - Zaidem, Maricris A1 - Brugman, Rik A1 - Ma, Xiyu A1 - Krol, Elzbieta A1 - Perraki, Artemis A1 - Kilian, Joachim A1 - Grossmann, Guido A1 - Stahl, Mark A1 - Shan, Libo A1 - Zipfel, Cyril A1 - van Kan, Jan A. L. A1 - Hedrich, Rainer A1 - Weigel, Detlef A1 - Gust, Andrea A. A1 - Nürnberger, Thorsten T1 - Comparing Arabidopsis receptor kinase and receptor protein-mediated immune signaling reveals BIK1-dependent differences JF - New Phytologist N2 - Pattern recognition receptors (PRRs) sense microbial patterns and activate innate immunity against attempted microbial invasions. The leucine-rich repeat receptor kinases (LRR-RK) FLS2 and EFR, and the LRR receptor protein (LRR-RP) receptors RLP23 and RLP42, respectively, represent prototypical members of these two prominent and closely related PRR families. We conducted a survey of Arabidopsis thaliana immune signaling mediated by these receptors to address the question of commonalities and differences between LRR-RK and LRR-RP signaling. Quantitative differences in timing and amplitude were observed for several early immune responses, with RP-mediated responses typically being slower and more prolonged than those mediated by RKs. Activation of RLP23, but not FLS2, induced the production of camalexin. Transcriptomic analysis revealed that RLP23-regulated genes represent only a fraction of those genes differentially expressed upon FLS2 activation. Several positive and negative regulators of FLS2-signaling play similar roles in RLP23 signaling. Intriguingly, the cytoplasmic receptor kinase BIK1, a positive regulator of RK signaling, acts as a negative regulator of RP-type immune receptors in a manner dependent on BIK1 kinase activity. Our study unveiled unexpected differences in two closely related receptor systems and reports a new negative role of BIK1 in plant immunity. KW - Arabidopsis KW - immune receptor KW - immune signaling comparison KW - plant immunity KW - receptor kinase KW - receptor protein Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233385 VL - 221 ER - TY - JOUR A1 - Graus, Dorothea A1 - Konrad, Kai R. A1 - Bemm, Felix A1 - Nebioglu, Meliha Görkem Patir A1 - Lorey, Christian A1 - Duscha, Kerstin A1 - Güthoff, Tilman A1 - Herrmann, Johannes A1 - Ferjani, Ali A1 - Cuin, Tracey Ann A1 - Roelfsema, M. Rob G. A1 - Schumacher, Karin A1 - Neuhaus, H. Ekkehard A1 - Marten, Irene A1 - Hedrich, Rainer T1 - High V-PPase activity is beneficial under high salt loads, but detrimental without salinity JF - New Phytologist N2 - The membrane-bound proton-pumping pyrophosphatase (V-PPase), together with the V-type H+-ATPase, generates the proton motive force that drives vacuolar membrane solute transport. Transgenic plants constitutively overexpressing V-PPases were shown to have improved salinity tolerance, but the relative impact of increasing PPi hydrolysis and proton-pumping functions has yet to be dissected. For a better understanding of the molecular processes underlying V-PPase-dependent salt tolerance, we transiently overexpressed the pyrophosphate-driven proton pump (NbVHP) in Nicotiana benthamiana leaves and studied its functional properties in relation to salt treatment by primarily using patch-clamp, impalement electrodes and pH imaging. NbVHP overexpression led to higher vacuolar proton currents and vacuolar acidification. After 3 d in salt-untreated conditions, V-PPase-overexpressing leaves showed a drop in photosynthetic capacity, plasma membrane depolarization and eventual leaf necrosis. Salt, however, rescued NbVHP-hyperactive cells from cell death. Furthermore, a salt-induced rise in V-PPase but not of V-ATPase pump currents was detected in nontransformed plants. The results indicate that under normal growth conditions, plants need to regulate the V-PPase pump activity to avoid hyperactivity and its negative feedback on cell viability. Nonetheless, V-PPase proton pump function becomes increasingly important under salt stress for generating the pH gradient necessary for vacuolar proton-coupled Na+ sequestration. KW - cell death KW - plasma membrane voltage KW - proton pump currents KW - salt KW - vacuolar pH KW - vacuolar proton-ATPase (V-ATPase) KW - vacuolar proton-pyrophosphatase (V-PPase) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227553 VL - 219 ER - TY - JOUR A1 - Voss, Lena J. A1 - McAdam, Scott A. M. A1 - Knoblauch, Michael A1 - Rathje, Jan M. A1 - Brodribb, Tim A1 - Hedrich, Rainer A1 - Roelfsema, M. Rob G. T1 - Guard cells in fern stomata are connected by plasmodesmata, but control cytosolic Ca2+ levels autonomously JF - New Phytologist N2 - Recent studies have revealed that some responses of fern stomata to environmental signals differ from those of their relatives in seed plants. However, it is unknown whether the biophysical properties of guard cells differ fundamentally between species of both clades. Intracellular micro-electrodes and the fluorescent Ca2+ reporter FURA2 were used to study voltage-dependent cation channels and Ca2+ signals in guard cells of the ferns Polypodium vulgare and Asplenium scolopendrium. Voltage clamp experiments with fern guard cells revealed similar properties of voltage-dependent K+ channels as found in seed plants. However, fluorescent dyes moved within the fern stomata, from one guard cell to the other, which does not occur in most seed plants. Despite the presence of plasmodesmata, which interconnect fern guard cells, Ca2+ signals could be elicited in each of the cells individually. Based on the common properties of voltage-dependent channels in ferns and seed plants, it is likely that these key transport proteins are conserved in vascular plants. However, the symplastic connections between fern guard cells in mature stomata indicate that the biophysical mechanisms that control stomatal movements differ between ferns and seed plants. KW - calcium signals KW - ferns KW - guard cell KW - plasmodesmata KW - potassium channels KW - seed plants KW - stomata Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233247 VL - 219 ER - TY - JOUR A1 - Shih, Po-Yuan A1 - Chou, Shu-Jen A1 - Müller, Caroline A1 - Halkier, Barbara Ann A1 - Deeken, Rosalia A1 - Lai, Erh-Min T1 - Differential roles of glucosinolates and camalexin at different stages of Agrobacterium-mediated transformation JF - Molecular Plant Pathology N2 - Agrobacterium tumefaciens is the causal agent of crown gall disease in a wide range of plants via a unique interkingdom DNA transfer from bacterial cells into the plant genome. Agrobacterium tumefaciens is capable of transferring its T-DNA into different plant parts at different developmental stages for transient and stable transformation. However, the plant genes and mechanisms involved in these transformation processes are not well understood. We used Arabidopsis thaliana Col-0 seedlings to reveal the gene expression profiles at early time points during Agrobacterium infection. Common and differentially expressed genes were found in shoots and roots. A gene ontology analysis showed that the glucosinolate (GS) biosynthesis pathway was an enriched common response. Strikingly, several genes involved in indole glucosinolate (iGS) modification and the camalexin biosynthesis pathway were up-regulated, whereas genes in aliphatic glucosinolate (aGS) biosynthesis were generally down-regulated, on Agrobacterium infection. Thus, we evaluated the impacts of GSs and camalexin during different stages of Agrobacterium-mediated transformation combining Arabidopsis mutant studies, metabolite profiling and exogenous applications of various GS hydrolysis products or camalexin. The results suggest that the iGS hydrolysis pathway plays an inhibitory role on transformation efficiency in Arabidopsis seedlings at the early infection stage. Later in the Agrobacterium infection process, the accumulation of camalexin is a key factor inhibiting tumour development on Arabidopsis inflorescence stalks. In conclusion, this study reveals the differential roles of GSs and camalexin at different stages of Agrobacterium-mediated transformation and provides new insights into crown gall disease control and improvement of plant transformation. KW - Agrobacterium-mediated transformation KW - Agrobac-terium tumefaciens KW - camalexin KW - crown gall KW - glucosinolates KW - plant defence KW - transcriptome Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237883 VL - 19 ER - TY - JOUR A1 - Dittberner, Hannes A1 - Korte, Arthur A1 - Mettler-Altmann, Tabea A1 - Weber, Andreas P. M. A1 - Monroe, Grey A1 - de Meaux, Juliette T1 - Natural variation in stomata size contributes to the local adaptation of water-use efficiency in Arabidopsis thaliana JF - Molecular Ecology N2 - Stomata control gas exchanges between the plant and the atmosphere. How natural variation in stomata size and density contributes to resolve trade-offs between carbon uptake and water loss in response to local climatic variation is not yet understood. We developed an automated confocal microscopy approach to characterize natural genetic variation in stomatal patterning in 330 fully sequenced Arabidopsis thaliana accessions collected throughout the European range of the species. We compared this to variation in water-use efficiency, measured as carbon isotope discrimination (δ13C). We detect substantial genetic variation for stomata size and density segregating within Arabidopsis thaliana. A positive correlation between stomata size and δ13C further suggests that this variation has consequences on water-use efficiency. Genome wide association analyses indicate a complex genetic architecture underlying not only variation in stomatal patterning but also to its covariation with carbon uptake parameters. Yet, we report two novel QTL affecting δ13C independently of stomatal patterning. This suggests that, in A. thaliana, both morphological and physiological variants contribute to genetic variance in water-use efficiency. Patterns of regional differentiation and covariation with climatic parameters indicate that natural selection has contributed to shape some of this variation, especially in Southern Sweden, where water availability is more limited in spring relative to summer. These conditions are expected to favour the evolution of drought avoidance mechanisms over drought escape strategies. KW - Arabidopsis thaliana KW - genomewide association study KW - local adaptation to climate KW - QST-FST analysis KW - stomata KW - water-use efficiency Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225371 VL - 27 ER - TY - JOUR A1 - Merkies, Ingemar S.J. A1 - van Schaik, Ivo N. A1 - Léger, Jean-Marc A1 - Bril, Vera A1 - van Geloven, Nan A1 - Hartung, Hans-Peter A1 - Lewis, Richard A. A1 - Sobue, Gen A1 - Lawo, John-Philip A1 - Durn, Billie L. A1 - Cornblath, David R. A1 - De Bleecker, Jan L. A1 - Sommer, Claudia A1 - Robberecht, Wim A1 - Saarela, Mika A1 - Kamienowski, Jerzy A1 - Stelmasiak, Zbigniew A1 - Tackenberg, Björn A1 - Mielke, Orell T1 - Efficacy and safety of IVIG in CIDP: Combined data of the PRIMA and PATH studies JF - Journal of the Peripheral Nervous System N2 - Intravenous immunoglobulin (IVIG) is a potential therapy for chronic inflammatory demyelinating polyneuropathy (CIDP). To investigate the efficacy and safety of the IVIG IgPro10 (Privigen) for treatment of CIDP, results from Privigen Impact on Mobility and Autonomy (PRIMA), a prospective, open-label, single-arm study of IVIG in immunoglobulin (Ig)-naïve or IVIG pre-treated subjects (NCT01184846, n = 28) and Polyneuropathy And Treatment with Hizentra (PATH), a double-blind, randomized study including an open-label, single-arm IVIG phase in IVIG pre-treated subjects (NCT01545076, IVIG restabilization phase n = 207) were analyzed separately and together (n = 235). Efficacy assessments included change in adjusted inflammatory neuropathy cause and treatment (INCAT) score, grip strength and Medical Research Council (MRC) sum score. Adverse drug reactions (ADRs) and ADRs/infusion were recorded. Adjusted INCAT response rate was 60.7% in all PRIMA subjects at Week 25 (76.9% in IVIG pre-treated subjects) and 72.9% in PATH. In the pooled cohort (n = 235), INCAT response rate was 71.5%; median time to INCAT improvement was 4.3 weeks. No clear demographic differences were noticed between early (responding before Week 7, n = 148) and late responders (n = 21). In the pooled cohort, median change from baseline to last observation was −1.0 (interquartile range −2.0; 0.0) point for INCAT score; +8.0 (0.0; 20.0) kPa for maximum grip strength; +3.0 (1.0; 7.0) points for MRC sum score. In the pooled cohort, 271 ADRs were reported in 105 subjects (44.7%), a rate of 0.144 ADRs per infusion. This analysis confirms the efficacy and safety of IgPro10, a recently FDA-approved IVIG for CIDP, in a population of mainly pre-treated subjects with CIDP [Correction added on 14 March 2019 after first online publication: the INCAT response rate has been corrected.]. KW - CIDP KW - efficacy KW - IVIG KW - PATH KW - PRIMA Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224013 VL - 24 ER - TY - JOUR A1 - Kadowaki, Takashi A1 - Nangaku, Masaomi A1 - Hantel, Stefan A1 - Okamura, Tomoo A1 - von Eynatten, Maximilian A1 - Wanner, Christoph A1 - Koitka-Weber, Audrey T1 - Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME® trial JF - Journal of Diabetes Investigation N2 - Aims/Introduction In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. Materials and Methods Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. Results Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49–0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49–0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25–0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. Conclusions In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings. KW - diabetic kidney disease KW - empagliflozin KW - type 2 diabetes mellitus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325246 VL - 10 ER - TY - JOUR A1 - Eickholz, Peter A1 - Koch, Raphael A1 - Kocher, Thomas A1 - Hoffmann, Thomas A1 - Kim, Ti-Sun A1 - Meyle, Joerg A1 - Kaner, Doğan A1 - Schlagenhauf, Ulrich A1 - Harmsen, Dag A1 - Harks, Inga A1 - Ehmke, Benjamin T1 - Clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age: An exploratory sub-analysis of the ABPARO trial JF - Journal of Clinical Periodontology N2 - Aim The aim was to identify benefit thresholds for clinical variables. We hypothesize, if variables fall below or exceed these threshold levels, systemic amoxicillin/metronidazole may contribute to reducing progression of periodontitis. Material & Methods This is an explorative per-protocol collective analysis (n = 345) conducted on the placebo-controlled, multi-centre ABPARO trial (ClinicalTrials.gov NCT00707369). Patients received debridement with systemic amoxicillin 500 mg/metronidazole 400 mg (3×/day, 7 days, n = 170) or placebo (n = 175) and maintenance therapy every three months. To identify thresholds, each of the following baseline characteristics was classified into two groups (≥threshold value/ 5 mm (5.2%) at baseline compared to the placebo (9.0%, 11.6%, and 12.5%, respectively; p < 0.005). Conclusions The clinical benefits of systemic amoxicillin/metronidazole may depend on periodontitis severity and patients' age. KW - amoxicillin/metronidazole KW - attachment loss KW - clinical threshold KW - periodontitis KW - systemic antimicrobials Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226579 VL - 46 ER - TY - JOUR A1 - Kunzmann, Steffen A1 - Krempl, Christine A1 - Seidenspinner, Silvia A1 - Glaser, Kirsten A1 - Speer, Christian P. A1 - Fehrholz, Markus T1 - Increase in CTGF mRNA expression by respiratory syncytial virus infection is abrogated by caffeine in lung epithelial cells JF - Influenza and Other Respiratory Viruses N2 - Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infection in early childhood. Underlying pathomechanisms of elevated pulmonary morbidity in later infancy are largely unknown. We found that RSV-infected H441 cells showed increased mRNA expression of connective tissue growth factor (CTGF), a key factor in airway remodeling. Additional dexamethasone treatment led to further elevated mRNA levels, indicating additive effects. Caffeine treatment prevented RSV-mediated increase in CTGF mRNA. RSV may be involved in airway remodeling processes by increasing CTGF mRNA expression. Caffeine might abrogate these negative effects and thereby help to restore lung homeostasis. KW - caffeine KW - CCN2 KW - dexamethasone KW - lung remodeling KW - poly(I:C) Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230909 VL - 12 ER - TY - JOUR A1 - Lämmermann, Tim A1 - Kastenmüller, Wolfgang T1 - Concepts of GPCR-controlled navigation in the immune system JF - Immunological Reviews N2 - G-protein–coupled receptor (GPCR) signaling is essential for the spatiotemporal control of leukocyte dynamics during immune responses. For efficient navigation through mammalian tissues, most leukocyte types express more than one GPCR on their surface and sense a wide range of chemokines and chemoattractants, leading to basic forms of leukocyte movement (chemokinesis, haptokinesis, chemotaxis, haptotaxis, and chemorepulsion). How leukocytes integrate multiple GPCR signals and make directional decisions in lymphoid and inflamed tissues is still subject of intense research. Many of our concepts on GPCR-controlled leukocyte navigation in the presence of multiple GPCR signals derive from in vitro chemotaxis studies and lower vertebrates. In this review, we refer to these concepts and critically contemplate their relevance for the directional movement of several leukocyte subsets (neutrophils, T cells, and dendritic cells) in the complexity of mouse tissues. We discuss how leukocyte navigation can be regulated at the level of only a single GPCR (surface expression, competitive antagonism, oligomerization, homologous desensitization, and receptor internalization) or multiple GPCRs (synergy, hierarchical and non-hierarchical competition, sequential signaling, heterologous desensitization, and agonist scavenging). In particular, we will highlight recent advances in understanding GPCR-controlled leukocyte navigation by intravital microscopy of immune cells in mice. KW - chemokines KW - dendritic cells KW - invivo imaging KW - neutrophils KW - T cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236357 VL - 289 ER -