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Susceptibility to and severity of tuberculosis infection in mice depends upon MHC-II-determined level of activation-inhibition balance in CD4 T-cells
Get PDFPreviously we have shown that H2-congenic recombinant mice of the B6.I-9.3 (H2-Ab1 j) strain are significantly more susceptible to tuberculosis (TB) infection compared to their C57BL/6 (B6, H2-A b) ancestors. Impaired TB control was characterized by decreased selection and maintenance of CD4+ T-cells, their profoundly narrower TCR repertoires, and a disproportionally enlarged neutrophil population. All phenotypes were expressed before TB infection, thus reflecting the steady state of the immune system and providing the basis of true genetic TB susceptibility. We anticipated that the differences in parameters of pre-infection immune homeostasis would seriously influence development of specific immune responses shortly after mycobacterial invasion and affect TB defense thereafter. In this study, we report on the dynamic phenotypes of CD4+ T-cells responding to infection which differ profoundly between mice bearing different MHC-II alleles. First, during post-challenge week 3, despite identical lung mycobacterial load, mice carrying the "resistant" H2-A b allele recruited significantly more mycobacteria-specific, IFN-γ-producing CD4+ T-cells to their lungs compared to H2-Ab1 j allele carriers. Second, during a few months post challenge, B6 mice were able to control both the size of the IFN-γ-producing CD4+ T-cell population and the total proportion of activated CD4+ T-cells at levels significantly lower than those in B6.I-9.3 mice. Finally, in TB-susceptible mice, a higher proportion of CD4+ T-cells expressed both activation-associated and immune inhibition (checkpoint) markers, accompanied by functional CD4+ T-cell exhaustion at late stages of infection. [...
Open-Access-Publizieren an der CAU
Get PDFDie Broschüre gibt einen informativen Überblick über die Services der Universitätsbibliothek Kiel für das Publizieren im Open Access (OA) an der Christian-Albrechts-Universität zu Kiel (CAU): Open-Access-Finanzierung, Universitätsverlag, OA-Publikationsservice MACAU. Beschrieben werden die verschiedenen Veröffentlichungsoptionen und Hilfestellungen für Wissenschaftlerinnen und Wissenschaftler der CAU. Zudem werden Themen angesprochen, die im Rahmen des Publikationsprozesses von Bedeutung sind: Rechte und Lizenzen, Metadaten, Forschungsdaten und die PDF-Erstellung.The brochure provides an informative overview of the services offered by Kiel University Library for publishing in Open Access (OA) at Kiel University (CAU): Open Access funding, Kiel University Publishing, and the OA publication service MACAU. It describes the various publication options and support available for CAU researchers. In addition, it addresses topics relevant to the publication process: rights and licenses, metadata, research data, and PDF creation
Kontinuierliche Erhebung von Gangparametern im nicht-standardisierten Umfeld mittels Bewegungssensoren zur Bestimmung des Grades der Behinderung bei Multipler Sklerose
No full textDie MS ist eine demyelinisierende entzündliche Erkrankung des ZNS. Sie tritt häufig im jungen Erwachsenenalter auf und führt zu motorischer und kognitiver Beeinträchtigung. Insbesondere die Gehfähigkeit ist betroffen. Für die Behandlung der MS ist die objektive Einschätzung der Behinderung essenziell. Der Goldstandard in der klinischen Beurteilung ist die Expanded Disability Status Scale (EDSS). In der Fachliteratur wird deren Güte kritisch gesehen, da sie untersucherabhängig sind und begrenzte Aussagen über die Behinderung im realen Alltag der Betroffenen zulassen. Hier könnte die kontinuierliche Messung von Gangparametern im nicht-standardisierten Umfeld mit Bewegungssensoren die klinische Diagnostik ergänzen. Bisher konnte noch kein Outcomeparameter etabliert werden. Ziel dieser Arbeit war es daher zu überprüfen, ob Gangparameter und Aktivität im nicht-standardisierten Umfeld mit den Ergebnissen etablierter klinischer Instrumente korrelieren. Außerdem sollte überprüft werden, ob sich Gangparameter und Aktivität im nicht-standardisierten Umfeld zwischen klinisch mild und moderat Betroffenen unterscheiden. Hierfür wurde eine Kohorte von Patient*innen (EDSS 1,0 bis 6,5 Punkte) rekrutiert. Die Teilnehmer*innen wurden mit den etablierten klinischen Gang- und Funktionstests untersucht. Mit Bewegungssensoren wurden alle Walking Bouts innerhalb von sieben Tagen mit einem validierten Algorithmus detektiert. Die quantitativen Gangparameter korrelieren mit EDSS und anderen klinischen Tests. Eine statistisch signifikante Unterscheidung der mild von den moderat Betroffenen war nur anhand der durchschnittlichen Schrittzahl pro Walking Bout möglich. Dieser Parameter unterschied sich deutlich und korrelierte mit der Lebensqualität. Die ergänzende Untersuchung alltäglicher WB sollte daher bei MS erfolgen
OKAY as a content word: Regulating language and constructing centres of norms in Finnish, Finland-Swedish, and Sweden-Swedish academic writing consultation meetings
Get PDFThe focus of this article is on OKAY as a resource for regulating language and constructing norm centres in authentic consultation meetings related to academic writing and recorded in Finland and Sweden. It gives an overview of all occurrences of OKAY in the interactional data in question, revealing that the word occurs frequently in academic writing consultations in Finnish, Finland Swedish, and Sweden Swedish. There are similarities in the frequency of its use and the distribution of occurrences between counsellor and student in the Finnish and the Finland-Swedish data, whereas the Sweden-Swedish counselling interactions follow a slightly different pattern. Through the lens of conversation analysis and systemic–functional linguistics, we further demonstrate how the counsellors and the students use the evaluative content word OKAY as a resource for regulating both academic writing and the counselling interaction, and thereby position themselves epistemically and orient towards different centres of norms
Isolation and Characterization of [MnFe(CO)10]+: The Missing Link in the 3 d Dimetal Decacarbonyl Series
Get PDFThe heterodinuclear dimetal decacarbonyl cation [MnFe(CO)10]+ has been synthesized by combining the metalloradical [Fe(CO)5]+⋅ with half an equivalent of Mn2(CO)10. The complex was subsequently isolated and characterized using single-crystal X-Ray Diffraction (scXRD), as well as IR, Raman, NMR and Mössbauer spectroscopy. Experimental results, complemented by DFT calculations of the relaxed force constants and an analysis of the electron density, reveal that the interaction between the two {M(CO)5} fragments in [MnFe(CO)10]+ is in between a covalent and a dative bond, representing a borderline case between the 2x17 VE and the 16+18 VE electron counting. Additionally, the known isoelectronic anion [CrMn(CO)10]- was prepared as its [PPN]+ salt and characterized for the first time by scXRD. These finding complete the series of structurally characterized isoelectronic dimetal decacarbonyls, spanning from [Cr2(CO)10]2- to [Fe2(CO)10]2+, the characteristics of all of which are compared based on experiment and theory
Regioisomeric branched trisaccharides: a combined synthetic, biological, and computational approach to understand details of FimH-mediated bacterial adhesion
Get PDFCarbohydrate-mediated interactions are crucial in many biological processes, including microbial adhesion and infections, where glycan recognition is often governed by the three-dimensional presentation of saccharide ligands. In this study, we systematically explored how regioisomeric structural variations of a Glc/Man pair, scaffolded on various monosaccharides, influence the mannose-specific adhesion of E. coli bacteria which is mediated by the bacterial lectin FimH. A targeted synthetic library of di- and trisaccharides featuring α-D-mannopyranoside/β-D-glucopyranoside (Man/Glc) and Man/Man motifs was synthesized, focusing on variations of regio- and stereochemistry. These glycans were functionalized with anomeric azido groups allowing for an eventual conjugation. Screening of all saccharides in bacterial adhesion-inhibition assays using GFP-tagged type 1 fimbriated live E. coli revealed pronounced differences in inhibitory potencies which could be correlated with the specific spatial arrangement of the saccharide units, underscoring the significance of glycan topology in lectin recognition. Complementary molecular modeling provided a structure-based rationale for the observed structure-function relationships. This work highlights the critical role of three-dimensional glycan architecture in heteromultivalent carbohydrate recognition events
CD19-ReTARGTPR: A Novel Fusion Protein for Physiological Engagement of Anti-CMV Cytotoxic T Cells Against CD19-Expressing Malignancies
Get PDF[...] In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARGTPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02/β2-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARGTPR makes them recognizable for pre-existing anti-CMVpp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARGTPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19/CD3 BiTE blinatumomab, CD19-ReTARGTPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARGTPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways
Anticipating how spatial fishing restrictions in EU waters perform to protect marine species, habitats, and dependent fisheries
Get PDFThis study investigates the implications of spatial management strategies on fish populations and fisheries across EU waters, particularly focusing on establishing potential areas for fishing closures to protect nurseries, benthic communities, and biodiversity hotspots in the Northeast Atlantic and Mediterranean Sea. The research addresses the effectiveness of prohibiting certain fishing practices in the context of the EU Common Fisheries Policy (CFP). We investigate spatial- and effort-based fisheries management strategies based on spatial ecosystem modelling, which provides insights into species interactions and distribution shifts, and bioeconomic fisheries models which incorporate finely defined fishing fleets and economic dynamics. Our findings emphasize that redistributing fishing effort without reducing overall effort and catches may negate intended decreases in mortality rates of sensitive marine species or restoration of vulnerable marine habitats to the status targeted by the European marine legislation (EU Marine Strategy Framework Directive MSFD). We highlight the complex interplay of social, economic, ecological, and institutional factors influencing fishers’ decision-making in effort displacement. As the proportion of closed regions increases, potential effects on marine ecosystems can even be damaging in the short term to some sensitive species (such as the endangered, threatened and protected species ETP) and vulnerable habitats (with currently high relative benthic status RBS). [...] . Where the prohibitions contribute to improved selectivity or productivity of the fish stocks, these losses may be regained in the long term. Finally, the long-term benefits for marine life that are expected through the spatial protection of vulnerable life stages and habitats will rely on the extent to which climate change affects ocean productivity and distribution of species and habitats
Novel oxygen optode sensor with fast response time: an in-depth characterization and assessment of the HydroFlash O2, applicable for several ocean observing platforms
Get PDFOptics-based sensors, called optodes, for oxygen are used for routine operations on autonomous instrumentation and profiling platforms with great success. Observations of oxygen gradients with high spatial and temporal resolution become increasingly important, while shortcomings still exist, namely, time constant problems, stability issues, or accuracy levels, that limit leveraging their full scientific and operational potential. Here, we demonstrate the utility of a novel, although currently not commercially available optode, the HydroFlash O2. It was manufactured by Kongsberg Maritime Contros GmbH between 2014 and 2019, and peer-reviewed studies illustrate its use until today. Our work comprises its first integrated characterization with data from 13 HydroFlash O2 optodes assessing oxygen, temperature, salinity and hydrostatic pressure dependence, long-term stability and drift, response time, and air-calibration compatibility. We multi-point calibrated this optode up to a root mean square error (RMSE) of <1 µmol L-1 (mean RMSE: 1.79 ± 0.50 µmol L-1), depending on the fit model type. Our laboratory setup yielded a temperature-dependent response time of τ63% = 3.31 ± 0.58 s, showing no significant difference between a weakly turbulent and turbulent flow, and was at least 50 % faster compared to the two most common optodes in oceanography, i.e., 4330 (Aanderaa) and SBE 63 (Sea-Bird Scientific). We assessed its pressure dependence between 0–5797 dbar, yielding an overall factor of 2.372 ± 0.409 % per 1,000 dbar based on three multi-point calibrated, drift-corrected optodes and five CTD (conductivity - temperature - depth) profiles. Ship-underway, mooring, and CTD-cast applications promise high-quality observations, including fast oxygen level changes.[...
In memoriam Prof. Dr. Manfred Willms (1934–2024)
Get PDFNachruf auf Manfred Willms, ehemaliger Professor für Wirtschaftspolitik und Direktor des Instituts für Wirtschaftspolitik sowie des Instituts für Regionalforschung an der Christian-Albrechts-Universität zu Kiel.Obituary for Manfred Willms, former professor of economic policy and director of the Institute for Economic Policy and the Institute for Regional Research at Kiel University