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  • 1
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    Data_Sheet_1.pdf
    Frontiers Media SA ; 2021
    In:  Frontiers in Neuroscience Vol. 15 ( 2021-7-13)
    Details
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 15 ( 2021-7-13)
    Abstract: Reducing α-synuclein pathology constitutes a plausible strategy against Parkinson’s disease. As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein, interferes with fibril nucleation, and reduces α-synuclein aggregation in vitro and in a fruit fly model of α-synuclein toxicity. The aim of this study was to investigate whether AS69 also reduces α-synuclein pathology in mammalian neurons. To induce α-synuclein pathology, primary mouse neurons were exposed to pre-formed fibrils (PFF) of human α-synuclein. PFF were also injected into the striatum of A30P-α-synuclein transgenic mice. The extent of α-synuclein pathology was determined by phospho-α-synuclein staining and by Triton X-100 solubility. The degeneration of neuronal somata, dendrites, and axon terminals was determined by immunohistochemistry. AS69 and PFF were taken up by primary neurons. AS69 did not alter PFF uptake, but AS69 did reduce PFF-induced α-synuclein pathology. PFF injection into mouse striatum led to α-synuclein pathology and dystrophic neurites. Co-injection of AS69 abrogated PFF-induced pathology. AS69 also reduced the PFF-induced degeneration of dopaminergic axon terminals in the striatum and the degeneration of dopaminergic dendrites in the substantia nigra pars reticulata. AS69 reduced the activation of astroglia but not microglia in response to PFF injection. Collectively, AS69 reduced PFF-induced α-synuclein pathology and the associated neurodegeneration in primary neurons and in mouse brain. Our data therefore suggest that small proteins binding the N-terminus of α-synuclein monomers are promising strategies to modify disease progression in Parkinson’s disease.
    Type of Medium: Online Resource
    ISSN: 1662-453X
    URL: Article
    URL: Article
    DOI: 10.3389/fnins.2021.696440
    DOI: 10.3389/fnins.2021.696440.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2411902-7
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  • 2
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    A Randomized Phase II Trial Comparing the Efficacy and Safety of Pioglitazone, Clarithromycin and Metronomic Low-Dose Chemotherapy with Single-Agent Nivolumab Therapy in Patients with Advanced Non-small Cell Lung Cancer Treated in Second or Further Line (ModuLung)
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 12 ( 2021-3-16)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-3-16)
    Abstract: Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous ( n = 11) and non-squamous non-small cell ( n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation ( N = 20) vs. nivolumab ( N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2–2.0) months vs. 1.6 (1.4–6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3–5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0–33.0) months vs. nivolumab 6.9 (4.6–24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    DOI: 10.3389/fphar.2021.599598
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
    SSG: 15,3
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  • 3
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    Data_Sheet_1.PDF
    Frontiers Media SA ; 2022
    In:  Frontiers in Psychology Vol. 12 ( 2022-2-2)
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    In: Frontiers in Psychology, Frontiers Media SA, Vol. 12 ( 2022-2-2)
    Abstract: Understanding risk factors for relationship dissolution and poor relationship adjustment among couples has been an active area of research in relationship science. One risk factor, non-marital cohabitation, has shown to predict higher rates of relationship dissolution and relationship instability in some samples, but the associations among German parents with children over time are less clear. In this study, we examined the links between non-marital cohabitation and 10-year outcomes (relationship dissolution, relationship adjustment over time, and child internalizing and externalizing symptoms) in 220 German families with preschool-aged children at the initial assessment followed into adolescence. Families were assessed 7 times over the 10 years and retention at the 10-year follow-up was over 92%. After accounting for multiple testing, only mother’s report of better initial interparental communication predicted whether parents were likely to stay together over the course of the 10 years. Adolescents of parents who cohabited were at higher risk for externalizing symptoms 10 years later compared to children of married parents. In addition, although there were no differences between cohabiting couples and married couples at the initial assessment in relationship adjustment, cohabiting mothers who stayed with their partner over the 10 years showed significantly greater declines in relationship adjustment over the 10 years compared to married mothers. Findings indicate the need for further research that explores family structure and dynamics over time to inform refinement of prevention programs targeting relationships and children’s mental health.
    Type of Medium: Online Resource
    ISSN: 1664-1078
    URL: Article
    URL: Article
    DOI: 10.3389/fpsyg.2021.746306
    DOI: 10.3389/fpsyg.2021.746306.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2563826-9
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  • 4
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    DataSheet_1.pdf
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-12-16)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-12-16)
    Abstract: We have previously shown that the microRNA (miRNA) processor complex consisting of the RNAse Drosha and the DiGeorge Critical Region (DGCR) 8 protein is essential for B cell maturation. To determine whether miRNA processing is required to initiate T cell-mediated antibody responses, we deleted DGCR8 in maturing B2 cells by crossing a mouse with loxP-flanked DGCR8 alleles with a CD23-Cre mouse. As expected, non-immunized mice showed reduced numbers of mature B2 cells and IgG-secreting cells and diminished serum IgG titers. In accordance, germinal centers and antigen-specific IgG-secreting cells were absent in mice immunized with T-dependent antigens. Therefore, DGCR8 is required to mount an efficient T-dependent antibody response. However, DGCR8 deletion in B1 cells was incomplete, resulting in unaltered B1 cell numbers and normal IgM and IgA titers in DGCR8-knock-out mice. Therefore, this mouse model could be used to analyze B1 responses in the absence of functional B2 cells.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.991347
    DOI: 10.3389/fimmu.2022.991347.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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  • 5
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    Table_1.xlsx
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-2-9)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-2-9)
    Abstract: Type I Interferons (IFN-I) are important inducers of the antiviral immune response and immune modulators. IFN-β is the most highly expressed IFN-I in the central nervous system (CNS). The infection of SJL mice with the BeAn or the DA strain of Theiler’s murine encephalomyelitis virus (TMEV) results in a progressive demyelinating disease. C57BL/6 mice are usually resistant to TMEV-induced demyelination and eliminate these strains from the CNS within several weeks. Using C57BL/6 IFN-β knockout (IFN-β -/- ) mice infected with TMEV, we evaluated the role of IFN-β in neuroinfection. Despite the resistance of C57BL/6 wild type (WT) mice to TMEV infection, DA-infected IFN-β -/- mice had to be killed at 7 to 8 days post infection (dpi) due to severe clinical disease. In contrast, BeAn-infected IFN-β -/- mice survived until 98 dpi. Nevertheless at 14 dpi, BeAn-infected IFN-β -/- mice showed a stronger encephalitis and astrogliosis, higher viral load as well as higher mRNA levels of Isg15 , Eif2ak2 (PKR), Tnfa , Il1b , Il10 , Il12 and Ifng in the cerebrum than BeAn-infected WT mice. Moreover, the majority of IFN-β -/- mice did not clear the virus from the CNS and developed mild demyelination in the spinal cord at 98 dpi, whereas virus and lesions were absent in the spinal cord of WT mice. Persistently infected IFN-β -/- mice also had higher Isg15 , Eif2ak1 , Tnfa , Il1a , Il1b and Ifng mRNA levels in the spinal cord at 98 dpi than their virus-negative counterparts indicating an activation of IFN-I signaling and ongoing inflammation. Most importantly, BeAn-infected NesCre +/- IFN-β fl/fl mice, which do not express IFN-β in neurons, astrocytes and oligodendrocytes, only developed mild brain lesions similar to WT mice. Consequently, IFN-β produced by neuroectodermal cells does not seem to play a critical role in the resistance of C57BL/6 mice against fatal and demyelinating disease induced by TMEV strains.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.786940
    DOI: 10.3389/fimmu.2022.786940.s001
    DOI: 10.3389/fimmu.2022.786940.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
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  • 6
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    Effects of active musical engagement during physical exercise on anxiety, pain and motivation in patients with chronic pain
    Frontiers Media SA ; 2022
    In:  Frontiers in Pain Research Vol. 3 ( 2022-11-22)
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    In: Frontiers in Pain Research, Frontiers Media SA, Vol. 3 ( 2022-11-22)
    Abstract: The experience of anxiety is central to the development of chronic pain. Music listening has been previously shown to exert analgesic effects. Here we tested if an active engagement in music making is more beneficial than music listening in terms of anxiety and pain levels during physical activity that is often avoided in patients with chronic pain. We applied a music feedback paradigm that combines music making and sports exercise, and which has been previously shown to enhance mood. We explored this method as an intervention to potentially reduce anxiety in a group of patients with chronic pain ( N  = 24, 20 female and 4 men; age range 34–64, M =  51.67, SD  = 6.84) and with various anxiety levels. All participants performed two conditions: one condition, Jymmin , where exercise equipment was modified with music feedback so that it could be played like musical instruments by groups of three. Second, a conventional workout condition where groups of three performed exercise on the same devices but where they listened to the same type of music passively. Participants' levels of anxiety, mood, pain and self-efficacy were assessed with standardized psychological questionnaires before the experiment and after each condition. Results demonstrate that exercise with musical feedback reduced anxiety values in patients with chronic pain significantly as compared to conventional workout with passive music listening. There were no significant overall changes in pain, but patients with greater anxiety levels compared to those with moderate anxiety levels were observed to potentially benefit more from the music feedback intervention in terms of alleviation of pain. Furthermore, it was observed that patients during Jymmin more strongly perceived motivation through others. The observed diminishing effects of Jymmin on anxiety have a high clinical relevance, and in a longer term the therapeutic application could help to break the Anxiety Loop of Pain, reducing chronic pain. The intervention method, however, also has immediate benefits to chronic pain rehabilitation, increasing the motivation to work out, and facilitating social bonding.
    Type of Medium: Online Resource
    ISSN: 2673-561X
    URL: Article
    DOI: 10.3389/fpain.2022.944181
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 3035397-X
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  • 7
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    Presentation1.pdf
    Frontiers Media SA ; 2022
    In:  Frontiers in Bioengineering and Biotechnology Vol. 10 ( 2022-11-18)
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    In: Frontiers in Bioengineering and Biotechnology, Frontiers Media SA, Vol. 10 ( 2022-11-18)
    Abstract: Tacrolimus (FK506) is a macrolide widely used as immunosuppressant to prevent transplant rejection. Synthetic production of FK506 is not efficient and costly, whereas the biosynthesis of FK506 is complex and the level produced by the wild type strain, Streptomyces tsukubaensis , is very low. We therefore engineered FK506 biosynthesis and the supply of the precursor L-lysine to generate strains with improved FK506 yield. To increase FK506 production, first the intracellular supply of the essential precursor lysine was improved in the native host S. tsukubaensis NRRL 18488 by engineering the lysine biosynthetic pathway. Therefore, a feedback deregulated aspartate kinase AskSt* of S. tsukubaensis was generated by site directed mutagenesis. Whereas overexpression of AskSt* resulted only in a 17% increase in FK506 yield, heterologous overexpression of a feedback deregulated AskCg* from Corynebacterium glutamicum was proven to be more efficient. Combined overexpression of AskCg* and DapASt, showed a strong enhancement of the intracellular lysine pool following increase in the yield by approximately 73% compared to the wild type. Lysine is coverted into the FK506 building block pipecolate by the lysine cyclodeaminase FkbL. Construction of a ∆fkbL mutant led to a complete abolishment of the FK506 production, confirming the indispensability of this enzyme for FK506 production. Chemical complementation of the ∆fkbL mutant by feeding pipecolic acid and genetic complementation with fkbL as well as with other lysine cyclodeaminase genes ( pipAf, pipASt , originating from Actinoplanes friuliensis and Streptomyces pristinaespiralis , respectively) completely restored FK506 production. Subsequently, FK506 production was enchanced by heterologous overexpression of PipAf and PipASp in S. tsukubaensis . This resulted in a yield increase by 65% compared to the WT in the presence of PipAf from A. friuliensis . For further rational yield improvement, the crystal structure of PipAf from A. friuliensis was determined at 1.3 Å resolution with the cofactor NADH bound and at 1.4 Å with its substrate lysine. Based on the structure the Ile91 residue was replaced by Val91 in PipAf, which resulted in an overall increase of FK506 production by approx. 100% compared to the WT.
    Type of Medium: Online Resource
    ISSN: 2296-4185
    URL: Article
    URL: Article
    DOI: 10.3389/fbioe.2022.1067467
    DOI: 10.3389/fbioe.2022.1067467.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2719493-0
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  • 8
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    DataSheet_1.pdf
    Frontiers Media SA ; 2023
    In:  Frontiers in Immunology Vol. 14 ( 2023-12-15)
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    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-12-15)
    Abstract: Neutrophil extracellular traps (NETs) are net-like structures released by activated neutrophils upon infection [e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] as part of the innate immune response that have protective effects by pathogen entrapment and immobilization or result in detrimental consequences for the host due to the massive release of NETs and their impaired degradation by nucleases like DNase-1. Higher amounts of NETs are associated with coronavirus disease 2019 (COVID-19) severity and are a risk factor for severe disease outcome. The objective of our study was to investigate NET formation in young versus aged ferrets to evaluate their value as translational model for SARS-CoV-2-infection and to correlate different NET markers and virological parameters. In each of the two groups (young and aged), nine female ferrets were intratracheally infected with 1 mL of 10 6 TCID 50 /mL SARS-CoV-2 (BavPat1/2020) and euthanized at 4, 7, or 21 days post-infection. Three animals per group served as negative controls. Significantly more infectious virus and viral RNA was found in the upper respiratory tract of aged ferrets. Interestingly, cell-free DNA and DNase-1 activity was generally higher in bronchoalveolar lavage fluid (BALF) but significantly lower in serum of aged compared to young ferrets. In accordance with these data, immunofluorescence microscopy revealed significantly more NETs in lungs of aged compared to young infected ferrets. The association of SARS-CoV-2-antigen in the respiratory mucosa and NET markers in the nasal conchae, but the absence of virus antigen in the lungs, confirms the nasal epithelium as the major location for virus replication as described for young ferrets. Furthermore, a strong positive correlation was found between virus shedding and cell-free DNA or the level of DNAse-1 activity in aged ferrets. Despite the increased NET formation in infected lungs of aged ferrets, the animals did not show a strong NET phenotype and correlation among tested NET markers. Therefore, ferrets are of limited use to study SARS-CoV-2 pathogenesis associated with NET formation. Nevertheless, the mild to moderate clinical signs, virus shedding pattern, and the lung pathology of aged ferrets confirm those animals as a relevant model to study age-dependent COVID-19 pathogenesis.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2023.1283595
    DOI: 10.3389/fimmu.2023.1283595.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 9
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    Patient Reported Outcomes in Chronic Inflammatory Diseases: Current State, Limitations and Perspectives
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-3-18)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-3-18)
    Abstract: Chronic inflammatory diseases (CID) are emerging disorders which do not only affect specific organs with respective clinical symptoms but can also affect various aspects of life, such as emotional distress, anxiety, fatigue and quality of life. These facets of chronic disease are often not recognized in the therapy of CID patients. Furthermore, the symptoms and patient-reported outcomes often do not correlate well with the actual inflammatory burden. The discrepancy between patient-reported symptoms and objectively assessed disease activity can indeed be instructive for the treating physician to draw an integrative picture of an individual’s disease course. This poses a challenge for the design of novel, more comprehensive disease assessments. In this mini-review, we report on the currently available patient-reported outcomes, the unmet needs in the field of chronic inflammatory diseases and the challenges of addressing these.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.614653
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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