Publications by authors named "Peter Daniel"

114 Publications

IL36 is a critical upstream amplifier of neutrophilic lung inflammation in mice.

Commun Biol 2021 Feb 8;4(1):172. Epub 2021 Feb 8.

Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.
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http://dx.doi.org/10.1038/s42003-021-01703-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870940PMC
February 2021

Rising to the challenge: The emergency nursing response to COVID-19 in the Pacific.

Australas Emerg Care 2021 Mar 1;24(1):1-3. Epub 2020 Oct 1.

Emergency & Trauma Centre, Alfred Hospital, Melbourne, Australia; School of Public Health & Preventive Medicine, Melbourne, Australia.

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http://dx.doi.org/10.1016/j.auec.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528973PMC
March 2021

Conservative management of congenital upper eyelid eversion.

J AAPOS 2020 02 6;24(1):46-48. Epub 2019 Dec 6.

Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham.

We report 2 cases of congenital upper eyelid eversion and highlight nonsurgical treatment options, including a novel approach.
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http://dx.doi.org/10.1016/j.jaapos.2019.10.005DOI Listing
February 2020

Molecular basis for GIGYF-Me31B complex assembly in 4EHP-mediated translational repression.

Genes Dev 2019 10 22;33(19-20):1355-1360. Epub 2019 Aug 22.

Department of Biochemistry, Max Planck Institute for Developmental Biology, D-72076 Tübingen, Germany.

GIGYF (Grb10-interacting GYF [glycine-tyrosine-phenylalanine domain]) proteins coordinate with 4EHP (eIF4E [eukaryotic initiation factor 4E] homologous protein), the DEAD (Asp-Glu-Ala-Asp)-box helicase Me31B/DDX6, and mRNA-binding proteins to elicit transcript-specific repression. However, the underlying molecular mechanism remains unclear. Here, we report that GIGYF contains a motif necessary and sufficient for direct interaction with Me31B/DDX6. A 2.4 Å crystal structure of the GIGYF-Me31B complex reveals that this motif arranges into a coil connected to a β hairpin on binding to conserved hydrophobic patches on the Me31B RecA2 domain. Structure-guided mutants indicate that 4EHP-GIGYF-DDX6 complex assembly is required for tristetraprolin-mediated down-regulation of an AU-rich mRNA, thus revealing the molecular principles of translational repression.
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http://dx.doi.org/10.1101/gad.329219.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771390PMC
October 2019

Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression.

Nucleic Acids Res 2019 07;47(13):7035-7048

Department of Biochemistry, Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, D-72076 Tübingen, Germany.

The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5'-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4-NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP-GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.
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http://dx.doi.org/10.1093/nar/gkz429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648886PMC
July 2019

The use of dispatcher assistance in improving the quality of cardiopulmonary resuscitation: A randomised controlled trial.

Resuscitation 2019 05 12;138:153-159. Epub 2019 Mar 12.

Saw Swee Hock School of Public Health, National University of Singapore, 12 Science Drive 2, #10-01, 117549, Singapore. Electronic address:

Aims: The introduction of dispatcher assistance (DA) services has led to increased bystander cardiopulmonary resuscitation (CPR) participation rates. However, the extent to which DA improves CPR quality remains unclear. This study aimed to evaluate the efficacy of DA in improving CPR quality among healthcare professionals and laypersons within a multi-ethnic Southeast Asian population.

Methods: A parallel, randomised controlled, open label trial was performed. Four hundred and twelve participants were recruited via convenience sampling in a public location. In a simulated cardiac-arrest scenario, the participants were randomised to perform CPR with DA over the phone (DA+) or CPR without DA (DA-). The ratio of participant assignment to DA+ and DA- was 1:1. The primary outcomes were CPR compression depth, compression rate, no-flow time, complete release of pressure between compressions, and hand location. The assessment involved CPR manikins and human assessors.

Results: A larger proportion of participants in DA + achieved the correct compression rate (34.3% vs 18.1%, p < 0.001). There was no difference in the other primary outcomes. A subgroup analysis revealed that healthcare professionals in DA+ had a higher proportion of correct hand location compared to those in DA- (82.1% vs. 53.5%, p < 0.05). There was no significant difference in CPR quality among laypersons with valid CPR certification regardless of whether they received DA.

Conclusion: DA should be provided to laypersons without valid CPR certification, as well as healthcare professionals. The identification of gaps in the current DA protocol highlights areas where specific changes can be made to improve CPR quality.
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http://dx.doi.org/10.1016/j.resuscitation.2019.03.003DOI Listing
May 2019

Bicycle-Related Injuries in Paediatric Patients.

Ann Acad Med Singap 2018 Oct;47(10):424-428

University Orthopaedic, Hand and Reconstructive Microsurgery Cluster, National University Health System, Singapore.

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October 2018

Structural motifs in eIF4G and 4E-BPs modulate their binding to eIF4E to regulate translation initiation in yeast.

Nucleic Acids Res 2018 07;46(13):6893-6908

Department of Biochemistry, Max Planck Institute for Developmental Biology, Max-Planck-Ring 5, D-72076 Tübingen, Germany.

The interaction of the eukaryotic initiation factor 4G (eIF4G) with the cap-binding protein eIF4E initiates cap-dependent translation and is regulated by the 4E-binding proteins (4E-BPs), which compete with eIF4G to repress translation. Metazoan eIF4G and 4E-BPs interact with eIF4E via canonical and non-canonical motifs that bind to the dorsal and lateral surface of eIF4E in a bipartite recognition mode. However, previous studies pointed to mechanistic differences in how fungi and metazoans regulate protein synthesis. We present crystal structures of the yeast eIF4E bound to two yeast 4E-BPs, p20 and Eap1p, as well as crystal structures of a fungal eIF4E-eIF4G complex. We demonstrate that the core principles of molecular recognition of eIF4E are in fact highly conserved among translational activators and repressors in eukaryotes. Finally, we reveal that highly specialized structural motifs do exist and serve to modulate the affinity of protein-protein interactions that regulate cap-dependent translation initiation in fungi.
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http://dx.doi.org/10.1093/nar/gky542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061780PMC
July 2018

Interleukin-1α Mediates Ozone-Induced Myeloid Differentiation Factor-88-Dependent Epithelial Tissue Injury and Inflammation.

Front Immunol 2018 7;9:916. Epub 2018 May 7.

Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans, Orleans, France.

Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1α after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1α-dependent. IL-1α signaling IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1α in MyD88 mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1α. Therefore, a major part of inflammation is mediated by IL-1α signaling in epithelial cells. In conclusion, the alarmin IL-1α released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1α may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.
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http://dx.doi.org/10.3389/fimmu.2018.00916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950844PMC
June 2019

Development and psychometric pilot-testing of a questionnaire for the evaluation of satisfaction with continuing education in infection control nurses.

Nurse Educ Pract 2018 Jul 16;31:77-82. Epub 2018 May 16.

University of Freiburg, Faculty of Medicine, Institute of Nursing Science, Freiburg, Germany. Electronic address:

Satisfaction with continuing education can be defined as positive attitudes towards educational programs, which has potential to strengthen learning outcomes. A multi-dimensional construct may enhance continuing education program evaluation processes. The objective is to describe the development and psychometric testing of the 'affective - behavioral - cognitive - satisfaction questionnaire' (ABC-SAT) for assessing participants' satisfaction with a continuing education program for nurses in infection control. The multi-staged development of a satisfaction questionnaire comprised of three subscales. The pilot tool was administered to a nationwide sample of 126 infection control nurses to assess satisfaction after participating in a continuing education program. Satisfaction scores were calculated and psychometric testing was performed to determine reliability, using Cronbach's alpha, face validity, objectivity, and economy. A principle component analysis using varimax rotation and Kaiser normalization was performed. The analysis led to a three-factor solution of the questionnaire with 11 items, explaining 61.4% of the variance. Internal consistency of three scales using Cronbach's alpha was 0.83, 0.60, and 0.66, respectively. Selectivity coefficients varied between 0.39 and 0.70. Participants needed approximately three minutes to complete the questionnaire. Initial findings refer to a satisfying scale structure and internal consistency of the 3-dimensional ABC-SAT questionnaire. Further research is required to confirm the questionnaires' psychometric properties.
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http://dx.doi.org/10.1016/j.nepr.2018.05.003DOI Listing
July 2018

Delayed allogeneic skin graft rejection in CD26-deficient mice.

Cell Mol Immunol 2019 06 23;16(6):557-567. Epub 2018 Mar 23.

Institut für Laboratoriumsmedizin, Klinische Chemie und Pathobiochemie, CVK, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Organ transplantation is an effective therapeutic tool for treating many terminal diseases. However, one of the biggest challenges of transplantation is determining how to achieve the long-term survival of the allogeneic or xenogeneic transplant by, for example, preventing transplant rejection. In the current study, CD26 gene-knockout mice were used to investigate the potential role of CD26/dipeptidyl peptidase-4 (DPPIV) in allogeneic skin graft rejection by tail-skin transplantation. Compared with wild-type (CD26) counterparts, CD26 mice showed reduced necrosis of grafts and delayed graft rejection after skin transplantation. Concentrations of serum IgG, including its subclasses IgG1 and IgG2a, were significantly reduced in CD26 mice during graft rejection. Moreover, after allogeneic skin transplantation, the secretion levels of the cytokines IFN-γ, IL-2, IL-6, IL-4, and IL-13 were significantly reduced, whereas the level of the cytokine IL-10 was increased in the serum of CD26 mice compared with that in the serum of CD26 mice. Additionally, the concentration of IL-17 in serum and the percentage of cells secreting IL-17 in mouse peripheral blood lymphocytes (MPBLs) were both significantly lower, while the percentage of regulatory T cells (Tregs) was significantly higher in MPBLs of CD26 mice than in those of CD26 mice. Furthermore, a lower percentage of CD8 T cells in MPBLs and fewer infiltrated macrophages and T cells in graft tissues of CD26 mice were detected during graft rejection. These results indicate that CD26 is involved in allogeneic skin graft rejection and provides another hint that CD26 deficiency leads to less rejection due to lower activation and proliferation of host immune cells.
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http://dx.doi.org/10.1038/s41423-018-0009-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804736PMC
June 2019

Pan-class I  PI3-kinase inhibitor BKM120 induces MEK1/2-dependent mitotic catastrophe in non-Hodgkin lymphoma leading to apoptosis or polyploidy determined by Bax/Bak and p53.

Cell Death Dis 2018 03 7;9(3):384. Epub 2018 Mar 7.

Department of Hematology, Oncology and Tumor Immunology, Charité - University Medicine Berlin, Campus Berlin-Buch, Lindenberger Weg 80, Berlin, 13125, Germany.

Constitutive signaling of PI3K/Akt/mTOR plays a prominent role in malignant transformation and progression of B-cell non-Hodgkin lymphomas (B-NHL) underscoring the need for PI3K targeted therapies. The pan-class I PI3-kinase inhibitor BKM120 has shown preclinical activity in distinct malignancies and is currently tested in clinical trials. Intratumor heterogeneity is an intrinsic property of cancers that contributes to drug resistance and tumor recurrence. Here, we demonstrate that inhibition of PI3-kinases by BKM120 attenuates growth and survival of B-NHL cell lines by inducing mitotic arrest with subsequent induction of intrinsic apoptosis. BKM120-mediated downregulation of Cyclin A and activation of the CDK1/Cyclin B1 complex facilitates mitotic entry. In addition, concomitant BKM120-mediated upregulation of Cyclin B1 expression attenuates completion of mitosis, which results in mitotic catastrophe and apoptotic cell death. In Bax and Bak deficient B-NHL, which are resistant to BKM120-induced apoptosis, BKM120-induced mitotic catastrophe results in polyploidy. Upon re-expression of wt p53 in these p53 mutated cells, BKM120-induced polyploidy is strongly reduced demonstrating that the genetic status of the cells determines the outcome of a BKM120-mediated pathway inhibition. Mitotic catastrophe and unfavorable induction of polyploidy can be prevented in this setting by additional inhibition of MEK1/2 signaling. Combining MEK1/2 inhibitors with BKM120 enhances the anti-tumor effects of BKM120, prevents prognostic unfavorable polyploidy and might be a potential strategy for the treatment of B-NHL.
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http://dx.doi.org/10.1038/s41419-018-0413-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841308PMC
March 2018

Strategies to promote infection prevention and control in acute care hospitals with the help of infection control link nurses: A systematic literature review.

Am J Infect Control 2018 02;46(2):207-216

Klinken der Stadt Köln gGmbH, Institute of Hospital Hygiene, Köln-Merheim, Hospital of the Private University of Witten/Herdecke, Cologne, Germany.

Background: Infection control link nurses (ICLNs) are important backup personnel for the prevention and control of infections in hospitals. To identify facilitators and barriers for the implementation of and long-term collaboration with ICLNs.

Methods: We conducted a systematic literature review, following the preferred reporting items for systematic reviews and meta-analyses guidelines. Inclusion criteria were defined as description of de novo implementation of an ICLN system, strengthening of an existing ICLN system, or analysis of an ICLN system.

Results: In 10 publications, facilitators and barriers were identified for mode of selection of ICLN candidates, characteristics and responsibilities of ICLNs, composition of a training curriculum, educational strategies, and external influencing factors. Experienced nurses with an interest in infection control seemed appropriate candidates. The importance of psychological skills in addition to technical knowledge was emphasized. A clear definition of responsibilities was important. Viable tasks for ICLNs included surveillance and teaching activities and the implementation of prevention measures. Ongoing teaching was superior to a single course. Management support was pivotal for success.

Conclusion: Research on ICLNs is scarce. The potential to decrease health care-associated infections with the help of ICLNs has been demonstrated. The training in psychological skills in addition to technical knowledge deserves more attention.
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http://dx.doi.org/10.1016/j.ajic.2017.07.031DOI Listing
February 2018

GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression.

Genes Dev 2017 06 11;31(11):1147-1161. Epub 2017 Jul 11.

Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.

The eIF4E homologous protein (4EHP) is thought to repress translation by competing with eIF4E for binding to the 5' cap structure of specific mRNAs to which it is recruited through interactions with various proteins, including the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins 1 and 2 (GIGYF1/2). Despite its similarity to eIF4E, 4EHP does not interact with eIF4G and therefore fails to initiate translation. In contrast to eIF4G, GIGYF1/2 bind selectively to 4EHP but not eIF4E. Here, we present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP. Complementation assays in a GIGYF1/2-null cell line using structure-based mutants indicate that 4EHP requires interactions with GIGYF1/2 to down-regulate target mRNA expression. Our studies provide structural insights into the assembly of 4EHP-GIGYF1/2 repressor complexes and reveal that rather than merely facilitating 4EHP recruitment to transcripts, GIGYF1/2 proteins are required for repressive activity.
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http://dx.doi.org/10.1101/gad.299420.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538437PMC
June 2017

MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers.

Cancer Lett 2017 09 23;403:231-245. Epub 2017 Jun 23.

Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address:

MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target. MACC1 knockdown drastically reduced STAT1/3 activating phosphorylation, thereby regulating the expression of its apoptosis targets Mcl-1 and Fas. STAT signaling inhibition by the JAK1/2 inhibitor ruxolitinib mimicked MACC1 knockdown-mediated molecular signatures and apoptosis sensitization to Fas activation. Despite the increased Fas expression, the reduced Mcl-1 expression was instrumental in apoptosis sensitization. This reduced Mcl-1-mediated apoptosis sensitization was Bax and Bak dependent. MACC1 knockdown also increased TRAIL-induced apoptosis. MACC1 overexpression enhanced STAT1/3 phosphorylation and increased Mcl-1 expression, which was abrogated by ruxolitinib. The central role of Mcl-1 was strengthened by the resistance of Mcl-1 overexpressing cells to apoptosis induction. The clinical relevance of Mcl-1 regulation by MACC1 was supported by their positive expression correlation in patient-derived tumors. Altogether, we reveal a novel death receptor-mediated apoptosis regulatory mechanism by MACC1 in solid cancers through modulation of the STAT1/3-Mcl-1 axis.
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http://dx.doi.org/10.1016/j.canlet.2017.06.020DOI Listing
September 2017

Persistence of acetochlor, atrazine, and S-metolachlor in surface and subsurface horizons of 2 typic argiudolls under no-tillage.

Environ Toxicol Chem 2017 11 19;36(11):3065-3073. Epub 2017 Jul 19.

Facultad de Ciencias Agrarias, Universidad Nacional de Mar del Plata, Balcarce, Buenos Aires, Argentina.

Variations in soil properties with depth strongly influence the degradation and persistence of herbicides, underlining the importance of studying these processes in soil horizons with distinctively different properties. The persistence of the herbicides acetochlor, atrazine, and S-metolachlor was measured in samples of the A, B, and C horizons of 2 Typic Argiudolls from Argentina under no-till management. The soils studied differed in soil organic carbon (OC) content, pH, particle size distribution, and structure. Quantification of herbicides in soil was done through high-performance liquid chromatography with diode array detector. There were interactions of herbicide × horizon (p < 0.01) that resulted in degradation rates (k) of all herbicides decreasing, and their corresponding dissipation half-life (DT50) values increasing, with soil depth. Herbicide persistence across all soils and horizons ranged from 15 to 73 d for acetochlor, 13 to 29 d for atrazine, and 82 to 141 d for S-metolachlor, which had significantly (p < 0.01) greater persistence than atrazine and acetochlor. The DT50 values of herbicides were negatively correlated with the contents of OC (correlation coefficients ranging from -0.496 to -0.773), phosphorus (-0.427 to -0.564), and nitrogen-nitrate (-0.507 to -0.662), and with microbial activity (-0.454 to -0.687) and the adsorption coefficient (-0.530 to -0.595); DT50s were positively correlated with pH (0.366 to 0.648). Adsorption was likely the most influential process in determining persistence of these herbicides in surface and subsurface horizons. The present study can potentially improve the prediction of the fate of acetochlor, atrazine, and S-metolachlor in soils because it includes much needed information on the degradation of the herbicides in subsurface horizons. Environ Toxicol Chem 2017;36:3065-3073. © 2017 SETAC.
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http://dx.doi.org/10.1002/etc.3874DOI Listing
November 2017

Neutralization of both IL-1α/IL-1β plays a major role in suppressing combined cigarette smoke/virus-induced pulmonary inflammation in mice.

Pulm Pharmacol Ther 2017 06 15;44:96-105. Epub 2017 Mar 15.

Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, Biberach an der Riss, Germany. Electronic address:

Smoking is an important risk factor for the development of chronic obstructive pulmonary disease (COPD) and viral infections are believed to be major triggers of exacerbations, which periodically lead to a worsening of symptoms. The pro-inflammatory IL-1 family members IL-1α and IL-1β are increased in COPD patients and might contribute to disease pathology. We investigated whether individual or combined inhibition of these cytokines reduced lung inflammation in cigarette smoke (CS)-exposed and H1N1-infected BALB/c mice. Animals were treated with individual or combined antibodies (Abs) directed against IL-1α, IL-1β or IL-1R1. Cells in BAL fluid and cytokines/chemokines in lung homogenate were determined. The viral load was investigated. Blocking IL-1α had significant suppressive effects on total cells, neutrophils, and macrophages. Furthermore, it reduced KC levels significantly. Blocking of IL-1β did not provide significant activity. In primary human bronchial epithelial air-liquid-interface cell cultures infected with H1N1, IL-1α Abs but not IL-1β Abs reduced levels of TNF-α and IL-6. Concomitant usage of Abs against IL-1α/IL-1β revealed strong effects in vivo and reduced total cells, neutrophils and macrophages. Additionally, levels of KC, IL-6, TNF-α, MCP-1, MIP-1α and MIP-1β were significantly reduced and ICAM-1 and MUC5 A/C mRNA expression was attenuated. The viral load decreased significantly upon combined IL-1α/IL-1β Ab treatment. Blocking the IL-1R1 provided significant effects on total cells, neutrophils and macrophages but was inferior compared to inhibiting both its soluble ligands IL-1α/IL-1β. Our results suggest that combined inhibition of IL-1α/IL-1β might be beneficial to reduce CS/H1N1-induced airway inflammation. Moreover, combined targeting of both IL-1α/IL-1β might be more efficient compared to individual neutralization IL-1α or IL-1β or inhibition of the IL-1R1.
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http://dx.doi.org/10.1016/j.pupt.2017.03.008DOI Listing
June 2017

Bax/Bak-independent mitochondrial depolarization and reactive oxygen species induction by sorafenib overcome resistance to apoptosis in renal cell carcinoma.

J Biol Chem 2017 04 1;292(16):6478-6492. Epub 2017 Feb 1.

From the Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany,

Renal cell carcinoma (RCC) is polyresistant to chemo- and radiotherapy and biologicals, including TNF-related apoptosis-inducing ligand (TRAIL). Sorafenib, a multikinase inhibitor approved for the treatment of RCC, has been shown to sensitize cancer cells to TRAIL-induced apoptosis, in particular by down-regulation of the Bak-inhibitory Bcl-2 family protein Mcl-1. Here we demonstrate that sorafenib overcomes TRAIL resistance in RCC by a mechanism that does not rely on Mcl-1 down-regulation. Instead, sorafenib induces rapid dissipation of the mitochondrial membrane potential (ΔΨ) that is accompanied by the accumulation of reactive oxygen species (ROS). Loss of ΔΨ and ROS production induced by sorafenib are independent of caspase activities and do not depend on the presence of the proapoptotic Bcl-2 family proteins Bax or Bak, indicating that both events are functionally upstream of the mitochondrial apoptosis signaling cascade. More intriguingly, we find that it is sorafenib-induced ROS accumulation that enables TRAIL to activate caspase-8 in RCC. This leads to apoptosis that involves activation of an amplification loop via the mitochondrial apoptosis pathway. Thus, our mechanistic data indicate that sorafenib bypasses central resistance mechanisms through a direct induction of ΔΨ breakdown and ROS production. Activation of this pathway might represent a useful strategy to overcome the cell-inherent resistance to cancer therapeutics, including TRAIL, in multiresistant cancers such as RCC.
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http://dx.doi.org/10.1074/jbc.M116.754184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399102PMC
April 2017

Development of a curriculum for infection control nurses for the qualification of infection control link nurses – results of focus group interviews with ward managers and infection control nurses in acute care hospitals in Germany

Pflege 2017 5;30(2):65-75. Epub 2017 Jan 5.

1 Department für Pflegewissenschaft, Fakultät für Gesundheit, Universität Witten / Herdecke.

Background: In the guidelines issued by the Robert Koch Institute, the training and establishing of infection control link nurses (HYG-PFLEGs) as multipliers is stipulated in order to propagate the acceptance and implementation of recommended hygiene measures. To date, there is no standardized format for the further education of these nurses in Germany. Aim: To develop a modular curriculum for HYG-PFLEGs to be trained by infection control nurses. Method: Ward managers (n = 15) and infection control nurses (n = 14) from different hospitals in North Rhine-Westphalia were interviewed about the specific requirements for curricula for infection control link nurses. Four focus group interviews were carried out between October 2012 and January 2013. The tape recordings were transcribed and analysed according to Mayring’s content analysis. Results: HYG-PFLEGs were regarded as an indispensable entity for controlling the flow of information between the wards and hygiene teams in hospitals. A core curriculum adjustable for differing institutions should contain a high share of hygiene-related contents, pedagogical-didactical, and psychological competencies as well as practical forms of education. Conclusions: Within the context of the implementation of complex interventions these results provide a basis for the development and implementation of a modular curriculum for infection control link nurses.
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http://dx.doi.org/10.1024/1012-5302/a000520DOI Listing
July 2017

The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation.

Mol Cell 2016 11 20;64(3):467-479. Epub 2016 Oct 20.

Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address:

Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E. Here, we describe crystal structures of human and Drosophila melanogaster eIF4E-eIF4G complexes, which unexpectedly reveal that the eIF4G auxiliary sequences bind to the lateral surface of eIF4E, using a similar mode to that of 4E-BPs. Our studies provide a molecular model of the eIF4E-eIF4G complex, shed light on the competition mechanism of 4E-BPs, and enable the rational design of selective eIF4G inhibitors to dampen dysregulated translation in disease.
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http://dx.doi.org/10.1016/j.molcel.2016.09.020DOI Listing
November 2016

Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak.

J Cell Sci 2016 06 13;129(11):2213-23. Epub 2016 Apr 13.

Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard Karls University, Tübingen 72076, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

The pro-apoptotic multidomain Bcl-2 proteins Bax and Bak (also known as BAK1) are considered the gatekeepers of the intrinsic pathway of apoptosis by triggering the mitochondrial release of cytochrome c The role of the third Bax- and Bak-homologous multidomain protein Bok, however, is still unresolved. As cells doubly deficient for Bax and Bak are largely resistant to various apoptotic stimuli, it has been proposed that Bok is either dispensable for apoptosis or that its role is dependent on Bax and Bak. Here, we demonstrate, in several cell systems, that Bok efficiently induces cytochrome c release and apoptosis even in the complete absence of both Bak and Bax. Moreover, modulation of endogenous Bok levels affects the apoptosis response. By RNA interference and targeted deletion of the Bok gene, we demonstrate that Bok can significantly influence the apoptotic response to chemotherapeutic drugs in ovarian carcinoma cells. Hence, our results not only establish Bok as a Bak- and Bax-independent apoptosis inducer, but also suggest a potential impact of Bok expression in ovarian cancer therapy.
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http://dx.doi.org/10.1242/jcs.181727DOI Listing
June 2016

A Psychometric Evaluation of the Danish Version of the Theory of Mind Storybook for 8-14 Year-Old Children.

Front Psychol 2016 8;7:330. Epub 2016 Mar 8.

Child and Adolescent Mental Health Centre, Mental Health ServicesGlostrup, Denmark; Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia ResearchCopenhagen, Denmark; Center for Neuropsychiatric Schizophrenia Research, Psychiatric Centre GlostrupGlostrup, Denmark.

Background: Theory-of-Mind (ToM) keeps on developing in late childhood and early adolescence, and the study of ToM development later in childhood had to await the development of sufficiently sensitive tests challenging more mature children. The current study aimed to investigate the psychometric properties of the Danish version of the Theory-of-Mind Storybook Frederik (ToM-Frederik).

Methods: We assessed whether ToM-Frederik scores differed between a group of 41 typically developing (TD) children and a group of 33 children with High Functioning Autism Spectrum Disorder (HFASD). A lower mean ToM-Frederik score was expected in the HFASD group. To determine the convergent validity of ToM-Frederik, potential associations with Strange Stories and Animated Triangles (AT) were analyzed. Furthermore, potential associations between ToM-Frederik and the Social Responsiveness Scale (SRS) and between ToM-Frederik and the Social Emotional Evaluation (SEE) Total score were analyzed.

Results: A significantly higher ToM-Frederik score was observed in the TD group compared to the HFASD group. Furthermore, the convergent validity of ToM-Frederik as a measure of ToM was supported by significant and positive associations with the Strange Stories and the AT scores in the HFASD group, whereas ToM-Frederik was significantly correlated with Strange Stories, but not with AT in the TD group. ToM-Frederik was not significantly associated with SRS in neither the HFASD nor the TD group.

Conclusion: The findings are supportive of ToM-Frederik as a valid indicator of deficits at the group level in children with HFASD between 7 and 14 years of age. Furthermore, the convergent validity is supported.
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http://dx.doi.org/10.3389/fpsyg.2016.00330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4781859PMC
March 2016

2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib.

BMC Bioinformatics 2015 Sep 24;16:308. Epub 2015 Sep 24.

Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany.

Background: Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds.

Results: We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral "multi-targeted" small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action.

Conclusion: In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib.
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http://dx.doi.org/10.1186/s12859-015-0730-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582733PMC
September 2015

Mextli proteins use both canonical bipartite and novel tripartite binding modes to form eIF4E complexes that display differential sensitivity to 4E-BP regulation.

Genes Dev 2015 Sep 20;29(17):1835-49. Epub 2015 Aug 20.

Department of Biochemistry, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany.

The eIF4E-binding proteins (4E-BPs) are a diverse class of translation regulators that share a canonical eIF4E-binding motif (4E-BM) with eIF4G. Consequently, they compete with eIF4G for binding to eIF4E, thereby inhibiting translation initiation. Mextli (Mxt) is an unusual 4E-BP that promotes translation by also interacting with eIF3. Here we present the crystal structures of the eIF4E-binding regions of the Drosophila melanogaster (Dm) and Caenorhabditis elegans (Ce) Mxt proteins in complex with eIF4E in the cap-bound and cap-free states. The structures reveal unexpected evolutionary plasticity in the eIF4E-binding mode, with a classical bipartite interface for Ce Mxt and a novel tripartite interface for Dm Mxt. Both interfaces comprise a canonical helix and a noncanonical helix that engage the dorsal and lateral surfaces of eIF4E, respectively. Remarkably, Dm Mxt contains a C-terminal auxiliary helix that lies anti-parallel to the canonical helix on the eIF4E dorsal surface. In contrast to the eIF4G and Ce Mxt complexes, the Dm eIF4E-Mxt complexes are resistant to competition by bipartite 4E-BPs, suggesting that Dm Mxt can bind eIF4E when eIF4G binding is inhibited. Our results uncovered unexpected diversity in the binding modes of 4E-BPs, resulting in eIF4E complexes that display differential sensitivity to 4E-BP regulation.
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http://dx.doi.org/10.1101/gad.269068.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573856PMC
September 2015

Molecular architecture of 4E-BP translational inhibitors bound to eIF4E.

Mol Cell 2015 Mar 19;57(6):1074-1087. Epub 2015 Feb 19.

Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany. Electronic address:

The eIF4E-binding proteins (4E-BPs) represent a diverse class of translation inhibitors that are often deregulated in cancer cells. 4E-BPs inhibit translation by competing with eIF4G for binding to eIF4E through an interface that consists of canonical and non-canonical eIF4E-binding motifs connected by a linker. The lack of high-resolution structures including the linkers, which contain phosphorylation sites, limits our understanding of how phosphorylation inhibits complex formation. Furthermore, the binding mechanism of the non-canonical motifs is poorly understood. Here, we present structures of human eIF4E bound to 4E-BP1 and fly eIF4E bound to Thor, 4E-T, and eIF4G. These structures reveal architectural elements that are unique to 4E-BPs and provide insight into the consequences of phosphorylation. Guided by these structures, we designed and crystallized a 4E-BP mimic that shows increased repressive activity. Our studies pave the way for the rational design of 4E-BP mimics as therapeutic tools to decrease translation during oncogenic transformation.
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http://dx.doi.org/10.1016/j.molcel.2015.01.017DOI Listing
March 2015

Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma.

J Mol Med (Berl) 2015 May 30;93(5):559-72. Epub 2014 Dec 30.

Clinical and Molecular Oncology, University Medical Center Charité and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin-Buch, Germany.

Unlabelled: Resistance to cell death is the major cause of chemotherapy failure in most kinds of cancers, including Burkitt lymphoma (BL). When analyzing therapy resistance in Burkitt lymphoma (BL), we discovered a link between apoptosis resistance and ploidy control. We therefore studied systematically a panel of 15 BL lines for apoptosis induction upon treatment with microtubule inhibitors and compared three types of microtubule toxins, i.e., paclitaxel, nocodazole and vincristine. We found an inverse relationship between apoptosis sensitivity and ploidy control. Thus, cells resistant to paclitaxel- or nocodazole-induced apoptosis underwent mitotic catastrophe and developed polyploidy (>4N). Mechanistically, apoptosis resistance was linked to failure of caspase activation, which was most pronounced in cells lacking the pro-apoptotic multidomain Bcl-2 homologs Bax and Bak. Pharmacological caspase inhibition promoted polyploidy upon exposure to paclitaxel and nocodazole supporting the relationship between resistance to apoptosis and polyploidization. Of note, vincristine induced persistent mitotic arrest but no loss of ploidy control. Considering targets to facilitate Bax/Bak-independent cell death and to avoid drug-induced mitotic catastrophe and consecutive mitotic catastrophe should be of great importance to overcome therapy resistance and therapy-related events that result in ploidy changes and tumor progression.

Key Message: Inverse relation of apoptosis and polyploidy induction by paclitaxel or nocodazole in BL. Resistant cells undergo mitotic catastrophe and develop polyploidy. Lack of Bax/Bak confers resistance and leads to induction of polyploidy in BL. Intact apoptosis response protects from polyploidy as a result of mitotic catastrophe.
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http://dx.doi.org/10.1007/s00109-014-1242-2DOI Listing
May 2015

4E-BPs require non-canonical 4E-binding motifs and a lateral surface of eIF4E to repress translation.

Nat Commun 2014 Sep 2;5:4790. Epub 2014 Sep 2.

Department of Biochemistry, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen, Germany.

eIF4E-binding proteins (4E-BPs) are a widespread class of translational regulators that share a canonical (C) eIF4E-binding motif (4E-BM) with eIF4G. Consequently, 4E-BPs compete with eIF4G for binding to the dorsal surface on eIF4E to inhibit translation initiation. Some 4E-BPs contain non-canonical 4E-BMs (NC 4E-BMs), but the contribution of these motifs to the repressive mechanism--and whether these motifs are present in all 4E-BPs--remains unknown. Here, we show that the three annotated Drosophila melanogaster 4E-BPs contain NC 4E-BMs. These motifs bind to a lateral surface on eIF4E that is not used by eIF4G. This distinct molecular recognition mode is exploited by 4E-BPs to dock onto eIF4E-eIF4G complexes and effectively displace eIF4G from the dorsal surface of eIF4E. Our data reveal a hitherto unrecognized role for the NC4E-BMs and the lateral surface of eIF4E in 4E-BP-mediated translational repression, and suggest that bipartite 4E-BP mimics might represent efficient therapeutic tools to dampen translation during oncogenic transformation.
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http://dx.doi.org/10.1038/ncomms5790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164784PMC
September 2014

An asymmetric PAN3 dimer recruits a single PAN2 exonuclease to mediate mRNA deadenylation and decay.

Nat Struct Mol Biol 2014 Jul 1;21(7):599-608. Epub 2014 Jun 1.

Department of Biochemistry, Max Planck Institute for Developmental Biology, Tübingen, Germany.

The PAN2-PAN3 complex functions in general and microRNA-mediated mRNA deadenylation. However, mechanistic insight into PAN2 and its complex with the asymmetric PAN3 dimer is lacking. Here, we describe crystal structures that show that Neurospora crassa PAN2 comprises two independent structural units: a C-terminal catalytic unit and an N-terminal assembly unit that engages in a bipartite interaction with PAN3 dimers. The catalytic unit contains the exonuclease domain in an intimate complex with a potentially modulatory ubiquitin-protease-like domain. The assembly unit contains a WD40 propeller connected to an adaptable linker. The propeller contacts the PAN3 C-terminal domain, whereas the linker reinforces the asymmetry of the PAN3 dimer and prevents the recruitment of a second PAN2 molecule. Functional data indicate an essential role for PAN3 in coordinating PAN2-mediated deadenylation with subsequent steps in mRNA decay, which lead to complete mRNA degradation.
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http://dx.doi.org/10.1038/nsmb.2837DOI Listing
July 2014

Containment of a cheesecake-associated outbreak of salmonellosis in 3 different hospitals, detected by continuous microbiologic surveillance.

Am J Infect Control 2014 Jul 10;42(7):816-7. Epub 2014 May 10.

Institut für Hygiene, Klinken der Stadt Köln gGmbH, Krankenhaus Merheim, Köln, Germany.

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http://dx.doi.org/10.1016/j.ajic.2014.03.013DOI Listing
July 2014