Posttranslationale Modifikation des Proteins der Promyelozytenleukämie (PML) nach unterschiedlicher Stressinduktion

Posttranslational modifications such as sumoylation, ubiquitination or phosphorylation regulate multiple functions of the promyelocytic leukemia protein (PML) also the morphology of PML nuclear bodies. In this study, the influence of different stress factors as arsenic trioxide (ATO) and sorbitol on endogenous and overexpressed PML has been analysed to investigate the STUbL (sumo-targeted ubiquitin ligase) - signalling pathway of RNF4 (RING finger protein 4). Sumoylation of PML is a key regulator of PML stability in response to extracellular or intracellular stimuli. This study shows PML degradation via polysumoylation induced by ATO, a therapeutic agent for treatment of acute promyelocytic leukemia (APL). Sumoylated PML is targeted for ubiquitination by the E3 ligase RNF4 prior to the proteasome-mediated degradation. Furthermore, I was able to demonstrate that RNF4 interacts with PML as substrate in vivo using its two essential SIMs, SIM2 and SIM4. In contrast to ATO sorbitol treatment leads to increased PML-nuclear bodies (PML-NBs) in number and size and to a stabilization of PML, which is not affected by the inhibition of the 26S proteasome. Due to the discrepancy between the effects of ATO and sorbitol on PML and PML-NBs, the activity of cellular signalling cascades has been analysed upon those stress factors. After quantitative analysis of kinases, there is evidence that osmotic stress leads to the activation of the SAPK/JNK (Stress-activated Protein Kinase/Jun Nterminal Kinase) - and ERK (Extracellular-signal Regulated Kinase ) - signalling pathways. In conclusion, ATO leads to the proteolytic degradation of PML due to its sumodependant ubiquitination mediated by RNF4. So I assume, that in contrast to ATO, after osmotic stress PML is stabelized through its own phosphorylation via the SAPK/JNK- and the ERK-signalling cascade

Timeliness of Surveillance during Outbreak of Shiga Toxin–producing Escherichia coli Infection, Germany, 2011

In the context of a large outbreak of Shiga toxin–producing Escherichia coli O104:H4 in Germany, we quantified the timeliness of the German surveillance system for hemolytic uremic syndrome and Shiga toxin–producing E. coli notifiable diseases during 2003–2011. Although reporting occurred faster than required by law, potential for improvement exists at all levels of the information chain

LAUDATIO-Repository: Accessing a heterogeneous field of linguistic corpora with the help of an open access repository

International audienceAn open access to digital historical research data for historical linguistics enables a fruitful exchange of research sources and research methods. To achieve this goal the LAUDATIO-Repository provides a long-term open access to historical corpus linguistic data. By developing the LAUDATIO-Repository we also want to explore how to build repositories that are useful for a set of well defined communities but are also flexible enough to be used and extended to serve other communities not considered beforehand. Considering the user community's needs requires a clear understanding of the community's user scenarios and research

Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro

AimsWe explored the use of highly purified murine and human pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) to generate functional bioartificial cardiac tissue (BCT) and investigated the role of fibroblasts, ascorbic acid (AA), and mechanical stimuli on tissue formation, maturation, and functionality.Methods and resultsMurine and human embryonic/induced PSC-derived CMs were genetically enriched to generate three-dimensional CM aggregates, termed cardiac bodies (CBs). Addressing the critical limitation of major CM loss after single-cell dissociation, non-dissociated CBs were used for BCT generation, which resulted in a structurally and functionally homogenous syncytium. Continuous in situ characterization of BCTs, for 21 days, revealed that three critical factors cooperatively improve BCT formation and function: both (i) addition of fibroblasts and (ii) ascorbic acid supplementation support extracellular matrix remodelling and CB fusion, and (iii) increasing static stretch supports sarcomere alignment and CM coupling. All factors together considerably enhanced the contractility of murine and human BCTs, leading to a so far unparalleled active tension of 4.4 mN/mm2 in human BCTs using optimized conditions. Finally, advanced protocols were implemented for the generation of human PSC-derived cardiac tissue using a defined animal-free matrix composition.ConclusionBCT with contractile forces comparable with native myocardium can be generated from enriched, PSC-derived CMs, based on a novel concept of tissue formation from non-dissociated cardiac cell aggregates. In combination with the successful generation of tissue using a defined animal-free matrix, this represents a major step towards clinical applicability of stem cell-based heart tissue for myocardial repair. © 2013 The Author

Green Lifestyles Alternative Models and Up-scaling Regional Sustainability (GLAMURS). Work Package 4. Deliverable 4.3: Report on Future Lifestyle Scenarios and Backcasting Vision Workshops

[Abstract] A participatory backcasting methodology has been developed for the GLAMURS project, entitled participatory backcasting for sustainable lifestyles and a green economy. It consists of two stakeholder workshops; a first workshop for problem exploration and development of visions for sustainable lifestyle and a green economy followed by a second workshop focussing on pathways and implementation.In six regions studied in the GLAMURS project vision workshops have been successfully executed. Thirteen visions have been generated. Visions have been compared on several dimensions including (1) sufficiency versus green growth, (2) individual versus community orientation, (3) governance by government or market, and (4) urban versus rural focus.The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement Nº 61342

Impact of work arrangements during the COVID-19 pandemic on mental health in France

• Symptoms of anxiety/depression were found in 28.8% of the participants at least once. • Unemployment and financial difficulties were associated with anxiety/depression. • Targeted mental health support could lessen mental health impact

Register: Language Users’ Knowledge of Situational-Functional Variation

The Collaborative Research Center 1412 “Register: Language Users’ Knowledge of Situational-Functional Variation” (CRC 1412) investigates the role of register in language, focusing in particular on what constitutes a language user’s register knowledge and which situational-functional factors determine a user’s choices. The following paper is an extract from the frame text of the proposal for the CRC 1412, which was submitted to the Deutsche Forschungsgemeinschaft in 2019, followed by a successful onsite evaluation that took place in 2019. The CRC 1412 then started its work on January 1, 2020. The theoretical part of the frame text gives an extensive overview of the theoretical and empirical perspectives on register knowledge from the viewpoint of 2019. Due to the high collaborative effort of all PIs involved, the frame text is unique in its scope on register research, encompassing register-relevant aspects from variationist approaches, psycholinguistics, grammatical theory, acquisition theory, historical linguistics, phonology, phonetics, typology, corpus linguistics, and computational linguistics, as well as qualitative and quantitative modeling. Although our positions and hypotheses since its submission have developed further, the frame text is still a vital resource as a compilation of state-of-the-art register research and a documentation of the start of the CRC 1412. The theoretical part without administrative components therefore presents an ideal starter publication to kick off the CRC’s publication series REALIS. For an overview of the projects and more information on the CRC, see https://sfb1412.hu-berlin.de/

Linsitinib, an IGF-1R inhibitor, attenuates disease development and progression in a model of thyroid eye disease

IntroductionGraves’ disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED.MethodsLinsitinib was administered orally for four weeks with therapy initiating in either the early (“active”) or the late (“chronic”) phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify in vivo tissue remodeling inside the orbit.ResultsLinsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue.ConclusionHere, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves’ disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease

HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo

Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRα2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-ζ chain & ZAP70, and inhibition of IFN-γ and FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRα2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway