Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk ...factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4
T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.
Omeprazole was shown to improve the anti-cancer effects of the nucleoside analogue 5-fluorouracil. Here, we combined omeprazole with the antiviral nucleoside analogues ribavirin and acyclovir. ...Omeprazole did not affect the antiviral effects of ribavirin in non-toxic concentrations up to 80 μg/mL but increased the acyclovir-mediated effects on herpes simplex virus 1 and 2 (HSV-1 and -2) replication in a dose-dependent manner. Omeprazole alone reduced HSV-1 and -2 titers but not HSV-induced formation of cytopathogenic effects (CPE) at concentrations ≥40 μg/mL. However, it exerted substantially stronger effects on acyclovir activity and also increased acyclovir activity at lower concentrations that did not directly interfere with HSV replication. Omeprazole 80 μg/mL caused a 10.8-fold (Vero cells) and 47.7-fold (HaCaT cells) decrease of the acyclovir concentrations that reduced HSV-1-induced CPE formation by 50% (IC
). In HSV-2-infected cells, omeprazole 80 μg/mL reduced the acyclovir IC
by 7.3- (Vero cells) and 12.9-fold (HaCaT cells). In HaCaT cells, omeprazole 80 μg/mL reduced the HSV-1 titer in the presence of acyclovir 1 μg/mL by 1.6 × 10
-fold and the HSV-2 titer in the presence of acyclovir 2 μg/mL by 9.2 × 10
-fold. The proton pump inhibitors pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole increased the antiviral effects of acyclovir in a similar fashion as omeprazole, indicating this to be a drug class effect. In conclusion, proton pump inhibitors increase the anti-HSV activity of acyclovir and are candidates for antiviral therapies in combination with acyclovir, in particular for topical preparations for the treatment of immunocompromised individuals who are more likely to suffer from severe complications.
West Nile virus (WNV) infection can cause severe meningitis and encephalitis in humans. Apoptosis was recently shown to contribute to the pathogenesis of WNV encephalitis. Here, we used WNV-infected ...glioma cells to study WNV-replication and WNV-induced apoptosis in human brain-derived cells.
T98G cells are highly permissive for lytic WNV-infection as demonstrated by the production of infectious virus titre and the development of a characteristic cytopathic effect. WNV replication decreased cell viability and induced apoptosis as indicated by the activation of the effector caspase-3, the initiator caspases-8 and -9, poly(ADP-ribose)polymerase (PARP) cleavage and the release of cytochrome c from the mitochondria. Truncation of BID indicated cross-talk between the extrinsic and intrinsic apoptotic pathways. Inhibition of the caspases-8 or -9 inhibited PARP cleavage, demonstrating that both caspases are involved in WNV-induced apoptosis. Pan-caspase inhibition prevented WNV-induced apoptosis without affecting virus replication.
We found that WNV infection induces cell death in the brain-derived tumour cell line T98G by apoptosis under involvement of constituents of the extrinsic as well as the intrinsic apoptotic pathways. Our results illuminate the molecular mechanism of WNV-induced neural cell death.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Display omitted
•Rothia spp. are rare but relevant pathogens in Infective Endocarditis.•Rothia spp. build destructive biofilms in the heart valve.•Use of biofilm-effective antibiotics in Rothia ...Endocarditis should be discussed.
Rothia sp. are Gram-positive bacteria in the class of Actinobacteria that are part of the physiological oral flora. In rare cases, Rothia aeria and Rothia dentocariosa can cause infective endocarditis (IE). The biofilm potential of Rothia in endocarditis is unknown.
Specimen from two cases of Rothia endocarditis were obtained during cardiac surgery. One of the patients suffered mitral valve IE from Rothia aeria. In the other case, IE of a prosthetic pulmonary valve was caused by Rothia dentocariosa. Fluorescence in situ hybridization (FISH) was used for visualization of microorganisms within heart valve tissues in combination with PCR and sequencing (FISHseq).
The two heart valve specimens featured mature biofilms of bacteria that were identified by FISHseq as Rothia aeria and Rothia dentocariosa, respectively. FISH showed in situ biofilms of both microorganisms that feature distinct phenotypes for the first time ex vivo. Both of our reported cases were treated successfully by heart valve surgery and antibiotic therapy using beta-lactam antibiotics.
The biofilm potential of Rothia sp. must be taken into account. The awareness of Rothia aeria and Rothia dentocariosa as rare but relevant pathogens for infective endocarditis must be raised. Use of biofilm-effective antibiotics in Rothia IE should be discussed.
The hypoxia‐inducible factor (HIF) is the master regulator for oxygen‐dependent gene expression. The HIF signal transduction pathway can be manipulated by inhibiting the activity of the ...HIFα‐regulating prolyl‐4‐hydroxylase domain (PHD) enzymes. The consequence of inhibiting the PHD activity for chemoresistance was studied. Inhibiting the PHD activity with the 2‐oxoglutarate analog dimethyloxaloylglycine (DMOG) results in increased chemoresistance towards etoposide but not carboplatin in HeLa cells. Evidence for an etoposide‐specific resistance, which develops as a consequence of inhibiting the PHD activity, was further supported in a tetracycline‐inducible PHD2 knockdown HeLa cell model. The etoposide‐resistance was mediated by HIF‐1α as shown in mouse embryonic fibroblast HIF‐1α+/+ and HIF‐1α−/− cells. Decreased cellular cytotoxicity after etoposide treatment inversely correlated with a dimethyloxaloylglycine (DMOG)‐inducible, HIF‐1α‐dependent enhanced MDR‐1 expression and efflux activity as determined by RT‐PCR, immunoblots, and with the fluorescent dye DiOC2. Taken together, our data indicate that PHD inhibitors might increase chemoresistance of tumor cells in a HIF‐1‐dependent manner. (Cancer Sci 2009; 101: xxx–xxx)
Nutrient starvation results in the interaction of Saccharomyces cerevisiae cells with each other and with surfaces. Adhesive growth requires the expression of the FLO11 gene regulated by the ...Ras/cAMP/cAMP-dependent protein kinase, the Kss1p/MAPK, and the Gcn4p/general amino acid control pathway, respectively. Proteomics two-dimensional DIGE experiments revealed post-transcriptionally regulated proteins in response to amino acid starvation including the ribosomal protein Cpc2p/Asc1p. This putative translational regulator is highly conserved throughout the eukaryotic kingdom and orthologous to mammalian RACK1. Deletion of CPC2/ASC1 abolished amino acid starvation-induced adhesive growth and impaired basal expression of FLO11 and its activation upon starvation in haploid cells. In addition, the diploid Flo11p-dependent pseudohyphal growth during nitrogen limitation was CPC2/ASC1-dependent. A more detailed analysis revealed that a CPC2/ASC1 deletion caused increased sensitivity to cell wall drugs suggesting that the gene is required for general cell wall integrity. Phosphoproteome and Western hybridization data indicate that Cpc2p/Asc1p affected the phosphorylation of the translational initiation factors eIF2α and eIF4A and the ribosome-associated complex RAC. A crucial role of Cpc2p/Asc1p at the ribosomal interface coordinating signal transduction, translation initiation, and transcription factor formation was corroborated.
The investigation is about which ideas ninth form students at grammar schools and secondary modern schools have about globalisation. It shall be investigated if the perception of and judgement on ...globalisation-connected contexts happens along social structure-specific patterns. At first, by way of a questionnaire, the field of ideas is supposed to be broadly recorded, a selection of interview partners based on the results of the questionnaire aims at a deeper analysis of the students´ ideas. Knowledge of these subjective preconditions for learning, as far as the topic of globalisation is concerned, is supposed to provide empirically-grounded hints for what curricula in the political-economic field of learning might look like. Apart from the education-political background, also the methodical outline of the investigation is described. This is followed by a presentation of the results of the analysis of the questionnaire.
The investigation is about which ideas ninth form students at grammar schools and secondary modern schools have about globalisation. It shall be investigated if the perception of and judgement on ...globalisation-connected contexts happens along social structure-specific patterns. At first, by way of a questionnaire, the field of ideas is supposed to be broadly recorded, a selection of interview partners based on the results of the questionnaire aims at a deeper analysis of the students' ideas. Knowledge of these subjective preconditions for learning, as far as the topic of globalisation is concerned, is supposed to provide empirically-grounded hints for what curricula in the political-economic field of learning might look like. Apart from the education-political background, also the methodical outline of the investigation is described. This is followed by a presentation of the results of the analysis of the questionnaire (Original übernommen).
In diesem Open-Access-Buch setzt sich Malte Kleinschmidt mit der Frage auseinander, wie politische Bildung zu einer Dekolonisierung beitragen kann. Nicht erst durch die Auseinandersetzungen um Black ...Lives Matter wird deutlich, dass Rassismus und Kolonialität nicht als Phänomene der Vergangenheit abgetan werden können. Anhand von der Analyse von 44 Interviews mit Schüler_innen von 9. Klassen an Hauptschulen und Gymnasien wird herausgearbeitet, wie diese Phänomene die Lebenswelt der Schüler_innen prägen. In den subjektiven Sinnbildungen der Lernenden werden zum einen koloniale Muster reproduziert, sie aber zum anderen auch massiv infrage gestellt. Diese Vorstellungen dienen als Ausgangspunkt, um dekoloniale Impulse für eine radikaldemokratisch verstandene politische Bildung zu entwickeln. Vor diesem Hintergrund diskutiert Malte Kleinschmidt dekoloniale didaktische Strategien in Bezug auf den erinnerungspolitischen Umgang mit dem historischen Kolonialismus, die koloniale Globalität der Gegenwart, die Verwerfungen des natio-ethno-kulturellen Zugehörigkeitsregimes sowie epistemische Ordnungen der Kolonialität.
PDF
